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diff --git a/.gitattributes b/.gitattributes new file mode 100644 index 0000000..d7b82bc --- /dev/null +++ b/.gitattributes @@ -0,0 +1,4 @@ +*.txt text eol=lf +*.htm text eol=lf +*.html text eol=lf +*.md text eol=lf diff --git a/LICENSE.txt b/LICENSE.txt new file mode 100644 index 0000000..6312041 --- /dev/null +++ b/LICENSE.txt @@ -0,0 +1,11 @@ +This eBook, including all associated images, markup, improvements, +metadata, and any other content or labor, has been confirmed to be +in the PUBLIC DOMAIN IN THE UNITED STATES. + +Procedures for determining public domain status are described in +the "Copyright How-To" at https://www.gutenberg.org. + +No investigation has been made concerning possible copyrights in +jurisdictions other than the United States. Anyone seeking to utilize +this eBook outside of the United States should confirm copyright +status under the laws that apply to them. diff --git a/README.md b/README.md new file mode 100644 index 0000000..a00beae --- /dev/null +++ b/README.md @@ -0,0 +1,2 @@ +Project Gutenberg (https://www.gutenberg.org) public repository for +eBook #66767 (https://www.gutenberg.org/ebooks/66767) diff --git a/old/66767-0.txt b/old/66767-0.txt deleted file mode 100644 index 3afc2f4..0000000 --- a/old/66767-0.txt +++ /dev/null @@ -1,9605 +0,0 @@ -The Project Gutenberg eBook of Irritability, by Max Verworn - -This eBook is for the use of anyone anywhere in the United States and -most other parts of the world at no cost and with almost no restrictions -whatsoever. You may copy it, give it away or re-use it under the terms -of the Project Gutenberg License included with this eBook or online at -www.gutenberg.org. If you are not located in the United States, you -will have to check the laws of the country where you are located before -using this eBook. - -Title: Irritability - A Physiological Analysis of the General Effect of Stimuli in - Living Substance - -Author: Max Verworn - -Release Date: November 19, 2021 [eBook #66767] - -Language: English - -Produced by: Thiers Halliwell, Tim Lindell, Bryan Ness and the Online - Distributed Proofreading Team at https://www.pgdp.net (This - file was produced from images generously made available by - The Internet Archive/American Libraries.) - -*** START OF THE PROJECT GUTENBERG EBOOK IRRITABILITY *** - -Transcriber’s notes: - -In this plain text transcription, italic text is denoted by -_underscores_ and subscripted characters are surrounded by curly -brackets preceded by an underscore, e.g. H_{12} - -The text of the book has largely been preserved in its original -form. However, some spelling errors have been corrected and some -missing punctuation items inserted (hyphen, space, parenthesis, -quotation mark). Inconsistent spellings have not been changed. A list -of spelling errors and inconsistencies has been appended at the end -of the book. Missing footnote markers on pages 96 and 136 have been -inserted at what seemed to be likely locations. - -The cover image of the book was created by the transcriber and is -placed in the public domain. - - -YALE UNIVERSITY - -MRS. HEPSA ELY SILLIMAN MEMORIAL LECTURES - - -IRRITABILITY - - - - -SILLIMAN MEMORIAL LECTURES - -PUBLISHED BY YALE UNIVERSITY PRESS - - -ELECTRICITY AND MATTER. _By_ JOSEPH JOHN THOMSON, D.SC., LL.D., PH.D., -F.R.S., _Fellow of Trinity College, Cambridge, Cavendish Professor of -Experimental Physics, Cambridge_. - -_Price $1.25 net; postage 10 cents extra._ - - -THE INTEGRATIVE ACTION OF THE NERVOUS SYSTEM. _By_ CHARLES S. -SHERRINGTON, D.SC., M.D., HON. LL.D., TOR., F.R.S., _Holt Professor of -Physiology in the University of Liverpool_. - -_Price $3.50 net; postage 25 cents extra._ - - -RADIOACTIVE TRANSFORMATIONS. _By_ ERNEST RUTHERFORD, D.SC., LL.D., -F.R.S., _Macdonald Professor of Physics, McGill University_. - -_Price $3.50 net; postage 22 cents._ - - -EXPERIMENTAL AND THEORETICAL APPLICATION OF THERMODYNAMICS TO -CHEMISTRY. _By_ WALTHER NERNST, _Professor and Director of the -Institute of Physical Chemistry in the University of Berlin_. - -_Price $1.25 net; postage 10 cents extra._ - - -PROBLEMS OF GENETICS. _By_ WILLIAM BATESON, M.A., F.R.S., _Director of -the John Innes Horticultural Institution, Merton Park, Surrey, England_. - -_Price $4.00 net; postage 25 cents extra._ - - -STELLAR MOTIONS, WITH SPECIAL REFERENCE TO MOTIONS DETERMINED BY MEANS -OF THE SPECTROGRAPH. _By_ WILLIAM WALLACE CAMPBELL, SC.D., LL.D., -_Director of the Lick Observatory, University of California_. - -_Price $4.00 net; postage 25 cents extra._ - - -THEORIES OF SOLUTION. _By_ SVANTE AUGUST ARRHENIUS, PH.D., SC.D., M.D., -_Director of the Physico-Chemical Department of the Nobel Institute, -Stockholm, Sweden_. - -_Price $2.25 net; postage 14 cents extra._ - - -IRRITABILITY, A PHYSIOLOGICAL ANALYSIS OF THE GENERAL EFFECT OF STIMULI -IN LIVING SUBSTANCE. _By_ MAX VERWORN, M.D., PH.D., _Professor at Bonn -Physiological Institute_. - -_Price $3.50 net; postage 20 cents extra._ - - - - - IRRITABILITY - - A PHYSIOLOGICAL ANALYSIS OF THE GENERAL - EFFECT OF STIMULI IN LIVING SUBSTANCE - - BY - - MAX VERWORN, M.D., PH.D. - - _Professor at Bonn Physiological Institute_ - - WITH DIAGRAMS AND ILLUSTRATIONS - - [Illustration] - - NEW HAVEN: YALE UNIVERSITY PRESS - LONDON: HENRY FROWDE - OXFORD UNIVERSITY PRESS - MCMXIII - - - - - COPYRIGHT, 1913 - BY YALE UNIVERSITY PRESS - - First Printed May, 1913, 600 Copies - - - - -THE SILLIMAN FOUNDATION. - - -In the year 1883 a legacy of eighty thousand dollars was left to the -President and Fellows of Yale College in the city of New Haven, to be -held in trust, as a gift from her children, in memory of their beloved -and honored mother, Mrs. Hepsa Ely Silliman. - -On this foundation Yale College was requested and directed to establish -an annual course of lectures designed to illustrate the presence and -providence, the wisdom and goodness of God, as manifested in the -natural and moral world. These were to be designated as the Mrs. Hepsa -Ely Silliman Lectures. It is the belief of the testator that any -orderly presentation of the facts of nature or history contributed -to the end of this foundation more effectively than any attempt to -emphasize the elements of doctrine or creed; and he therefore provided -that lectures on dogmatic or polemical theology should be excluded from -the scope of this foundation, and that the subjects should be selected -rather from the domains of natural science and history, giving special -prominence to astronomy, chemistry, geology, and anatomy. - -It was further directed that each annual course should be made the -basis of a volume to form part of a series constituting a memorial -to Mrs. Silliman. The memorial fund came into the possession of the -corporation of Yale University in the year 1901; and the present volume -constitutes the ninth of the series of memorial lectures. - - - - -PREFACE - - -The lectures on irritability here published were held at the University -of Yale in October, 1911. When the authorities of that University -honored me by an invitation to give a course of Silliman memorial -lectures, I accepted with the more pleasure as it furnished me with -the opportunity of summarizing the results of numerous experimental -researches carried out with the assistance of my co-workers during -the course of more than two decades in the physiological laboratories -of Jena, Göttingen and Bonn, to unite therewith the results obtained -by other investigators and thus present a uniform exposition of the -general effects and laws of stimulation in the living substance. I have -long entertained this plan and this for the following reason: - -The physiologist, the zoölogist, the botanist, the psychologist, -the pathologist, have to deal, day in, day out, with the effects of -stimulation on the living substance. No living substance exists without -stimulation. In the vital manifestations of all organisms the interplay -of the most varied stimuli produces an enormous and manifold variety of -effects. Experimental biological science employs artificial stimulation -as the most important aid in the methodic production of certain effects -of stimulation. The number of researches in which special effects -of stimulation are treated is endless. Nevertheless the systematic -investigation of the effects of stimulation have, curiously enough, -been strangely neglected. Although countless results of individual -effects of stimulation have been studied, the attempt has never been -made to establish a general physiology of the laws of stimulation -and consider it as an independent problem. This circumstance induced -me to systematically investigate the general laws of the effect of -stimulation. In the fifth and sixth chapters of my book on general -physiology the results of these studies are recorded for the first -time. Since then, especially during our own researches on the general -physiology of the nervous system, a great number of new facts of -importance for the general physiology of the effects of stimulation -have been obtained. All these results I have endeavored to combine and -elucidate in the following lectures. - -The text of the lectures in its present form was written in German in -1911. The English translation was made by my wife, with the help of -our friend, Dr. Lodholz of the University of Pennsylvania, who also -undertook the reading of the proofs. We wish here to thank him once -again and express our deep appreciation of the great sacrifice of -time and labor involved in this task. I am likewise much indebted to -Dr. Julius Vészi for his assistance unstintingly given, especially in -obtaining a number of curves. Finally, I wish to take this opportunity -to render warmest thanks to the authorities of Yale University, and -especially to President Hadley and Professor Chittenden, as well as -to my special colleagues, for the hospitality and cordial reception -extended to me in New Haven and for the pleasant hours I was privileged -to spend in their midst. - - MAX VERWORN. - - Bonn. - - Physiological Laboratory of the University. - - - - -CONTENTS - - - I - - _Contents_: Introductory. Earliest period. _Francis Glisson_ as - founder of the doctrine of irritability. _Albrecht von Haller._ The - vitalists. _Bordeu_ and _Barthez_. _John Brown’s_ system. _Johannes - Müller_ and the specific energy of living substance. _Rudolf - Virchow’s_ doctrine of the irritability of the cell. Discovery of - the inhibitory effects of stimulation. _Weber_, _Schiff_, _Goltz_, - _Setschenow_, _Sherrington_. _Claude Bernard_ studies on narcosis. - Tropisms. _Ehrenberg_, _Engelmann_, _Pfeffer_, _Strassburger_, - _Stahl_. _Semon’s_ speculations on mneme. 1 - - - II - - _Contents_: Principles of scientific knowledge and research. Origin - and meaning of the conception of cause. Cause and condition. - Criticism of the conception of cause. The conditional point of view. - Conception of cause. The conditional point of view applied to the - investigation of life. Conception of vital conditions. Definition of - the conception of stimulation. 18 - - - III - - _Contents_: The quality of the stimulus. Positive and negative - alterations of the factors which act as vital conditions. Extent of - the alteration in vital conditions or intensity of the stimulus. - Threshold stimuli, sub-threshold, submaximal, maximal and - supermaximal intensities of stimulus. Relations between the intensity - of stimulus and the amount of response. The _Weber_ and _Fechner_ - law. All or none law. Time relations of the course of the stimulus. - Form of individual stimulus. Absolute and relative rapidity in the - course of the stimulus. Duration of the stimulus after reaching its - highest point. Adaptation to persistent stimuli. Series of individual - stimuli. Rhythmical stimuli. The _Nernst_ law. 39 - - - IV - - _Contents_: Various examples of the effects of stimulation. - Metabolism of rest and metabolism of stimulation. Metabolic - equilibrium, Disturbances of equilibrium by stimuli. Quantitative and - qualitative alterations of the metabolism of rest under the influence - of stimuli. Excitation and depression. Specific energy of living - substance. Qualitative alterations of the specific metabolism and - their relations to pathology. Functional and cytoplastic stimuli. - Relations of the cytoplastic effects of stimuli to the functional. - Hypertrophy of activity and atrophy of inactivity. Metabolic - alterations during growth of the cell. Primary and secondary effects - of stimulation. Scheme of effects of stimulation. 65 - - - V - - _Contents_: Indicators for the investigation of the process of - excitation. Latent period. The question of the existence of - assimilatory excitations. Dissimilatory excitations. Excitations of - the partial components of functional metabolism. Production of energy - in the chemical splitting up processes. Oxydative and anoxydative - disintegration. Theory of oxydative disintegration. Dependence - of irritability on oxygen. Experiments on unicellular organisms, - nerve centers and nerve fibers. Restitution after disintegration by - metabolic self-regulation. Organic reserve supplies of the cell. - The question of a reserve supply of oxygen of the cell. Metabolic - self-regulation as a form of the law of mass effect, and metabolic - equilibrium as a condition of chemical equilibrium. Functional - hypertrophy. 87 - - - VI - - _Contents_: Only processes of excitation are conducted, not - processes of depression. Conduction of excitation in its two extreme - instances. Conduction in undifferentiated pseudopod protoplasm of - rhizopoda. Conduction of excitation with decrement of intensity - and rapidity. Conduction of excitation in the nerve. Rapidity of - conduction. Conduction of excitation without decrement. Relation - between irritability and conductivity. Conduction of excitation with - decrement of the nerve after artificial depression of irritability by - narcosis. Theory of the decrementless conduction of the normal nerve. - Proof of the validity of the “all or none law” in the medullated - nerve. Theory of the process of the conductivity of excitation. - Theory of core model (Kernleiter). Electrochemical theory of - conduction based on the properties of semi-permeable surfaces. 118 - - - VII - - _Contents_: Conception of specific irritability. Alteration of - specific irritability during and after excitation. Refractory - period in various forms of living substance. Absolute and relative - refractory period. Curve of irritability during refractory period. - Dependence of the duration of the refractory period on the rapidity - of the course of the metabolic processes in the living substance. - Dependence on temperature. Dependence on supply of oxygen. Theory of - refractory period. Refractory period as basis of fatigue. Fatigue as - a form of asphyxiation. Alterations of irritability and the course - of excitation in fatigue. Recovery from fatigue. The rôle played by - oxygen in recovery. Fatigue as an expression of the prolongation of - the refractory period conditioned by the relative want of oxygen. - Fatigue of the nerve. 154 - - - VIII - - _Contents_: Examples of effects of interference of stimuli in - unicellular organisms. Interference of galvanic and thermic - stimuli in Paramecia. Interference of galvanic and thermic stimuli - and narcotics. Interference of galvanic and mechanical stimuli. - Interference of galvanotaxis and thigmotaxis in Paramecia and hypotin - infusoria. Real or homotop interference, apparent or heterotop - interference. The two effects of homotop interference of excitations: - Summation and inhibition of excitations. Theory of the processes of - inhibition. _Hering-Gaskell_ Theory. Inhibition as an expression - of the refractory period. Individual possibilities of interference - of two stimuli. Interference of an excitating and a depressing - stimulus. Interference of two depressing stimuli. Interference of two - excitating stimuli. Analysis of the interference of two excitations. - Interference of two single stimuli. Conditions upon which the - result of interference is dependent. Heterobole and isobole living - systems. Intensity of the two stimuli. Interval between the stimuli. - Specific irritability and rapidity of reaction of the living system. - Latent period. Interference of single stimuli in a series. General - scheme of the development of the effect of interference. Summation - and inhibition. Apparent increase of irritability. Conditions of - summation. Tonic excitations. Conditions of inhibitions. Various - types of inhibition. Interference of two series of stimuli. Relations - in the nervous system. Peculiarities of the nerve fibers. Conversion - of the nerve by relative fatigue from an isobolic into a heterobolic - system. 189 - - - IX - - _Contents_: Necessity of cellular physiological analysis of toxic - depressions by pharmacology. Apparent variety of processes of - depression. Depression of oxydative disintegration as the most - extended principle in the processes of depression. Asphyxiation, - fatigue, heat depression, as a consequence of restriction of - oxydative disintegration. Narcosis. Theories of narcosis. The - alteration of specific irritability and conductivity in narcosis. - Depression of oxydative processes in narcosis. Asphyxiation of - living substance when oxygen is present during narcosis. Persistence - of anoxydative disintegration in narcosis. Increase of the same by - stimuli. Depression by narcosis as a form of acute asphyxiation. - Hypothesis on the mechanism of depression of oxygen exchange by - narcotics. Possibility of combining the facts with the observations - of _Meyer_ and _Overton_. 235 - - - - -IRRITABILITY - - - - -CHAPTER I - -THE HISTORY OF THE SUBJECT - - _Contents_: Introductory. Earliest period. _Francis Glisson_ as - founder of the doctrine of irritability. _Albrecht von Haller._ The - vitalists. _Bordeu_ and _Barthez_. _John Brown’s_ system. _Johannes - Müller_ and the specific energy of living substance. _Rudolf - Virchow’s_ doctrine of the irritability of the cell. Discovery of - the inhibitory effects of stimulation. _Weber_, _Schiff_, _Goltz_, - _Setschenow_, _Sherrington_. _Claude Bernard_ studies on narcosis. - Tropisms. _Ehrenberg_, _Engelmann_, _Pfeffer_, _Strassburger_, - _Stahl_. _Semon’s_ speculations on mneme. - - -Irritability is a _general_ property of living substance but not -exclusively so. Irritable systems also exist in inanimate nature. What -characterizes living substances is not irritability as _such_, but -an irritability of a specific type. The irritability of the living -system can, therefore, not be studied alone, but as the properties of -a living system are dependent upon each other, so this property must -be considered with the others possessed by a living substance. In this -sense irritability presents a problem of fundamental physiological -importance. For if we could analyze the irritability of living -substance to its essence, then the nature of life itself would be -fathomed. The analysis of irritability of living substance offers us, -therefore, a path to the investigation of life and herein lies the -importance of the study of irritability. - -I wish to follow this path toward the knowledge of the vital processes -and to endeavor to show in these lectures what information the analysis -of irritability and that of the effect of stimuli can give us of the -mechanism of the processes in living substance. Before doing so, -however, I wish to consider somewhat more in detail the question as to -how we have arrived at the conception of the nature of irritability. - -To the thinkers both in the field of physiology and medicine of -ancient and mediæval times the conception of irritability was quite -foreign. Even a comprehension of the nature of stimuli had not yet -begun to crystallize from vague impressions of the various influences -of different agents on the human being. Nevertheless they knew of -such influences of the most varying kinds upon the human body. The -ancients already possessed a materia medica, founded on the real or -supposed influence of various mineral, vegetable and animal substances -upon the organism. It was also known that heat and cold, light and -darkness had an effect upon disease. They likewise believed in the -influence of certain factors upon the health of man, which in reality -have no effect whatsoever, as the stars and the magnet. But neither -in ancient nor in mediæval times was the state of knowledge reached -wherein generalizations were made from these agents, which had a real -or supposed action upon the organism, and to combine these to a general -conception of stimulation. - -The conception of stimulation and irritability cannot however be -separated. - -The founder of the doctrine of the irritability of living substance -is _Francis Glisson_ (1597–1677), member of the _Collegium Medicum_ -in London and at the same time Professor in Cambridge. It is a fact -also not altogether without interest, that _Glisson_ at the same time -was in a certain sense a forerunner of those who interpreted nature -from a physical standpoint. _Glisson_ as an anatomist and physiologist -was an excellent observer and experimenter, but the most prominent -trait of his character was his inclination to philosophic observation -and analysis of nature. His “_Tractatus de natura substantiæ -energetica_”[1] must, therefore, be considered as the chief work of -his life. In this voluminous book _Glisson_ develops an entire system -of natural philosophy, which in accord with the character of the -philosophy of that time is unfortunately of an absolutely speculative -nature and which had hardly emancipated itself from the scholasticism -of the preceding period of thought. When the ideas of _Glisson_ are -isolated from the wilderness of scholastic phraseology, the system -is somewhat as follows. The basis of all existence, “_substance_,” -has according to him two general properties, its “_fundamental -subsistence_,” that is, the essence of its being, and its “_energetic -subsistence_,” that is, the essence of its activity. To these are added -the properties possessed in specific cases, that is, its “_additional -subsistence_.” The energetic subsistence forms the basis of all life. -Life is therefore present not only in organic nature, but in all -nature which is characterized by the union of the general energetic -subsistence with the special additional subsistence of an animal and -vegetable nature. In other forms of life in nature the energetic -subsistence is combined with other special forms of the additional -subsistence. The universal essence of all life, that is the energetic -subsistence, has only three fundamental faculties: the “_appetitiva_,” -the “_perceptiva_” and the “_motiva_.” The _modus_ is the result -of a “_perceptio_,” but the “_perceptio_” is not thinkable unless -the object has the “_appetitus_” to receive the external influence. -_Glisson’s_ doctrine of irritability is based on this conception, which -he develops in a second work already begun before the “_Tractatus de -natura substantiæ_,” but not finished until later and only published -after his death. In this “_Tractatus de ventriculo et intestinis_,”[2] -_Glisson_ dwells in detail on the physiological properties of -animal structures and develops for the first time his conception -of irritability in the chapter “_De irritabilitate fibrarum_.” The -“irritability” manifests itself in the appearance of the alteration of -movement, which is brought about by external influences on the animal -structure, for: “_Motiva fibrarum facultas nisi irritabilis foret, -vel, perpetuo quiesceret, vel perpetuo idem ageret._” The fundamental -factor of this irritability _Glisson_ attributes to the “_perceptio_,” -which he distinguishes as a “_perceptio naturalis_, _sensitiva_ and -_animalis_.” The want of clearness produced here by _Glisson’s_ -artificial distinctions and mode of expression is in part removed -if we endeavor to transfer his meaning into our present methods of -thought. This distinction would then simply point out the different -means by which the stimuli can reach the irritable structures. The -“_Perceptio naturalis_” is that which today we should call “direct -response” to stimulation, that is, the excitation of the fiber by -artificial stimuli applied directly to the tissue. _Glisson_ shows -here, that the intestines and muscles in the body immediately after -death and even when removed from the body can be stimulated to movement -by means of corrosive fluids or cold. The “_Perceptio sensitiva_” -is, according to _Glisson_, the excitation of the fibers by external -stimuli which act on the intact body as a whole by way of the sensory -nerves. The “_Perceptio ab appetitu animali regulata_” finally is the -excitation by inner stimuli proceeding from the brain. The _Perceptio -naturalis_ is possessed by all parts of the body, even the fluids, -the bones and the fat. All of them are irritable. But a “vitale” and -a special “animal” irritability they do not possess to a perceptible -degree. These forms of irritability belong only to the special parts -of the body. Here, however, the distinctions made by _Glisson_, are -quite vague and contradictory. In his “_Tractatus de ventriculo et -intestinis_” _Glisson_ sharply distinguishes the “_sensatio_” from the -“_perceptio_.” The perceptio in itself is not a sensation, for although -individual organs of the body are irritable, as they all possess a -“perceptio,” they are not in themselves sensitive. The “_sensatio_,” -the sensation, only arises when the external “_perceptio_” of the -individual organs combine through the nerves with the internal -“perceptio” of the brain. “_Nisi enim percepto externa ab interna simul -percipiatur, non est cognitio sensitiva completa._” Sensitivity is, -therefore, a special faculty, that is only based upon irritability. - - [1] _Franciscus Glissonius_: “Tractatus de natura substantiæ - energetica seu de vita natura ejusque tribus primis facultatibus - perceptiva, appetitiva, motiva,” etc. Londini M D C L XXII. - - [2] _Franciscus Glissonius_: “Tractatus de ventriculo et intestinis - cui præmittitur alius de partibus continentibus in genere et in - specie de iis abdominis.” Amstelodami M D C L XXVII. - -I have treated the views of _Glisson_ somewhat in detail for on the one -hand this seemed to me to be only due to the founder of the doctrine -of irritability, and on the other we have here for the first time, -although in somewhat vague and little worked out form, the discovery -of a general property of all living substance, and its fundamental -importance for the life of the organisms. One might, therefore, in -a _certain_ sense, date from _Glisson_ the beginning of general -physiology, and all the more so, because _Glisson_ from the very -first connected the irritability of the living substance through its -possessing universal energy with the phenomena in nature generally, -just as we do today two hundred years after, on the basis of the modern -teachings of energy. - -It might appear strange that a teaching of such fundamental importance -as that of _Glisson’s_ theory of irritability was not at once accepted -on all sides and further developed. There were two reasons, however, -which prevented this. Firstly, _Glisson_ did not devote himself to his -post of teacher at the University of Cambridge with any particular -zeal and so consequently did not establish a school of his own, to -further work out and develop his ideas. Secondly, his doctrines were -so speculative and difficult to understand, his differentiations and -definitions so artificial and labored, that it required the greatest -effort to penetrate to his fundamental conceptions and so it happened -that _Glisson’s_ theory of irritability received attention only at a -comparatively late date. Even then, of his speculative theories hardly -more than the name “doctrine of irritability” was adopted. Since the -middle of the eighteenth century this name, however, was destined to -lead to excited controversies. - -The first attempt to give _Glisson’s_ expression “irritability” a more -concrete meaning was made by _Haller_ (1708–1777)[3]. Unfortunately, -though, he confined this conception solely to muscles, in that he -understood by the term irritability “the capability of the muscles to -contract, when stimulated, as the result of vital force (_vi viva_).” -He, therefore, applied the term “irritability” to that which we today -refer to as “contractility.” On the other hand he applied the term -contractility solely to a property possessed by other living and -dead animal as well as vegetable matter, elasticity, that is, the -capability to resume its original form after distortion. He makes a -sharp distinction between “irritability,” which manifests itself by a -contraction of the muscles after stimulation by its own vital force -(_vi viva_), and the “sensitivity,” which is possessed only by the -nervous system. “_Sola fibra muscularis contrahitur vi viva; sentit -solus nervus et quæ nervos acciperunt animales partes._” By confining -the conception of irritability to a single living substance, the -muscle, _Haller’s_ theory represents a great regression in comparison -to the correct fundamental thoughts of _Glisson_. This unfortunate -use of the term of “irritability,” “contractility” and “sensitivity” -has opened wide the gates to confusion and misunderstanding. This -confusion was still further augmented by the fact that the vitalistic -school of Montpelier confused the idea of vital force with that -of irritability. In the works of _Bordeu_ (1722–1776) these views -are comparatively clear, if one bears in mind that he substitutes -_Glisson’s_ term of “_irritability_” with that of “_sensitivity_.” He -assumes a “_sensibilité générale_” or a common property of all living -structures, both solid and fluid. Besides this, each different part -has according to him its “_sensibilité propre_.” Here in place of the -clear conception of irritability we find one of more or less mythical -nature possessing traces of _Stahl’s_ “anima.” Nevertheless we observe -here the idea that all living organisms possess in common a capability -to respond to stimuli. Even though _Bordeu’s_ differentiation of the -“sensibilité propre” and the “sensibilité générale” is too artificial -and the coexistence of both not justifiable, his discussion of the -“sensibilité propre” shows that he is already on the track of the -characteristics of the effect of stimuli which only later under the -name of “specific energy” was clearly recognized as a fundamental -property of all living substance. On the other hand the celebrated -pupil of _Bordeu_, _Barthez_ (1734–1806), accepted the existence of -a meaningless vital principle, the “_principe vitale_,” governing -all vital manifestations. The two forms of vital force of all living -substances, the “_forces sensitives_” and the “_forces motrices_,” -were according to his views manifestations of this vital principle. -He differentiates the “_force sensitive_” into a “_sensibilité avec -perception_” and “_sensibilité sans perception_,” using the term -sensibility in the sense adopted by _Bordeu_ and which today we, with -_Glisson_, call irritability. - - [3] _Albrecht v. Haller_: “Elementa Physiologiæ corporis humani.” - Tomus IV. Lausannæ M D C L XVI. - -In this way serious thinkers of that time trifled with the words -irritability, sensitivity, contractility, perception. This led to -futile conceptions, which equalled the phantasies of the worst period -of speculative philosophy and which in no way led to progress. Hence it -is easy to understand that numerous attempts were made in those days -to reconcile in some way these different conceptions. An explanation, -which was the beginning of further development, came from England in -the works of _John Brown_ (1735–1788),[4] a man who was as talented -as he was dissolute. _Brown_ was an independent thinker, not without -genius, whose knowledge in practice and theory, however, was limited. -This combination in his mentality enabled him to observe the problems -somewhat differently than through the glasses of the usual conceptions -of that time. In direct opposition to his teacher _Cullen_ (1712–1790), -one of the leading minds in the medical school of Edinburgh, who -considered irritability only as an effect of sensibility and pronounced -the latter a specific property of the nervous system, _Brown_ took the -standpoint that all living substance, vegetable as well as animal, in -contrast to lifeless matter, possessed a fundamental property which he -designated as excitability, that is to say, the capability of being -stimulated to specific vital manifestations through external factors -or “stimuli,” in which sensitivity and indeed all mental processes -as well as movement are interpreted as specific effects, which the -“stimuli” produce on the irritable organs. This was an important -advance and from a wilderness of trifling conceptions his observations -led to a clearer knowledge of this subject. But _Brown_ went even -further. In his so-called “theory of irritation,” he has presented -a whole system of responsivity to stimulation, which in the first -chapters of his chief work he expounds with wonderful clearness. The -fundamental principles here established must be accepted even today. -The essential basis of this “theory of irritability” which he worked -out especially for his doctrine of disease, and which has also played -an important part in pathology, is the following: Every living, that -is, excitable system, is continually influenced by stimuli. The stimuli -consist of either external factors, such as heat, food, foreign matter, -poisons, etc., or inner factors which result from the influence of -the activity of one organ upon another. Only as a result of the -continual action of stimuli is life maintained, in that the stimuli -produce continual “excitement” in the irritable substance. The degree -of irritability differs in various plants, animals, in different -structures of the body, and even in the same individual at different -times under different circumstances. The strength of the “excitement” -depends on the one hand upon the degree of irritability, and on the -other upon the strength of the stimulus. The irritability itself is -influenced and changed by the action of the stimuli. If the stimuli are -too strong and are of prolonged duration, the irritability diminishes -as a result of exhaustion; if weak stimuli act during a prolonged -time, the irritability increases. The healthy organism has a mean -degree of irritability. Disease occurs when this state is altered by -_strong_ stimuli or by an _absence_ of stimulation. Disease and health, -therefore, differ not qualitatively but only quantitatively. It is here -seen that we have the first attempt at a systematic interpretation -of the effects of stimulation, and it is astonishing how sharply and -successfully _Brown_ has pointed out the foundations of this important -field. He has in this way not only amply compensated for the great -setback in the history of the teaching of irritability produced by -the confusions of conceptions created by _Haller_ and the vitalists, -but also placed the whole of the physiology of stimulation on a firm -foundation upon which it is possible to build further. Though it is -true that many of his special theories, in particular those on nature -and the origin of disease, are quite erroneous, still a just critic -must judge work in relation to the period in which it was written, and -I question if at the present day the science of medicine does _not_ -contain teachings which in a hundred years will also prove untenable. - - [4] _John Brown_: “Elementa medicinæ.” 1778. English translation. - London 1778. - -_Johannes Müller_ (1801–1858) then added an important stone to the -building up of our knowledge of irritability. This was the clear -recognition of the _specific energy_ of living substances. We have -already found the germ in _Bordeu’s_ term “_sensibilité propre_” or -“_sensibilité particulière_.” _Brown_ was also of the opinion that -different living objects possessed different types of irritability and -that excitation of their special functions was not dependent upon -the _kind_ of stimulus acting upon them. _Johannes Müller_, grasping -the idea hidden in this presentation, transformed it into a clear -and fundamental conception. Already in the work written in his early -years treating of optical illusions he says:[5] “It is immaterial by -which means the muscle is stimulated, whether by galvanism, chemical -agents, mechanical irritation, inner organic stimuli or sympathetic -response from quite different organs; to every means by which it is -stimulated and an effect produced, it responds by movement. Movement -is, therefore, the _effect_ and the _energy_ of the muscle at the same -time.” “Thus it is throughout with all reactions in the organisms.” -“The sensory nerve, responding to any stimulus of whatever kind, has -its specific energy; pressure, friction, galvanism and inner organic -stimuli produce in nerves of sight that which is peculiar to them, -light sensation; in the nerves of hearing, that which is peculiar to -them, sound sensation; and in the nerves of touch, touch sensations. -On the other hand, everything which affects a secretory organ produces -change of the secretion; that which affects the muscle, movement. -Galvanism is not superior to any other methods, of whatever kind, -which can bring about stimulation.” And in his handbook of physiology -_Johannes Müller_[6] formulates the law of specific energy for the -sensory structures briefly in the following words: “The same external -factor produces different sensations in the different senses according -to the nature of each sense, namely, the sensation of the particular -sensory nerves; and the reverse: the characteristic sensations peculiar -to every sensory nerve can be produced by several internal and external -influences.” This doctrine of the specific energy of the sense -substance possesses an importance which extends far beyond the domain -of the physiology of stimulation, for it forms the basis on which the -whole theory of human knowledge must be built up, no matter how it may -be constructed in detail. - - [5] _Johannes Müller_: “Über die phantastischen - Gesichtserscheinungen. Eine physiologische Untersuchung mit - einer physiologischen Urkunde des Aristotles über den Traum, den - Physiologen und den Arzten gewidmet.” Coblenz 1826. - - [6] _Johannes Müller_: “Handbuch der Physiologie des Menschen für - Vorlesungen.” Coblenz 1837. - -As _Johannes Müller_ already clearly emphasizes, it is here not -the question of a law confined to the sense substance, but one that -applies to all living substances. Every living substance has its -“specific energy,” that is, its characteristic vital phenomena and -this is produced by stimuli of the most varied kind. This doctrine -received an extension of inestimable value for its future development -by the great discovery of _Schleiden_, that the cell is the elementary -building stone of the plant organism. Subsequently _Schwann_ at the -instigation of _Schleiden_ made further investigations and found that -this discovery applied also to the animal organism. Irritability -having been recognized as a general property of living substance, -it followed that, after the foundation of the cell doctrine, every -cell must possess irritability and have its own specific energy. It -now became necessary to study the manifestations of irritability of -the cells in their specific form. Strange to say, this was done at -an earlier date in pathology than in physiology. Indeed, since the -time of _Brown_ the study of irritability was furthered far more by -pathology than by physiology. The chief reason for this is probably the -great practical interest that the investigation of disease possesses, -_Brown_ having already quite correctly ascribed the existence of -disease to the relations of the organism or its parts to stimuli. -_Rudolph Virchow_ then, after the establishment of the cell doctrine, -arrived at the momentous conclusion, that disease must be considered as -reactions of the body cells to stimuli. In his epoch-making “Cellular -pathologie,”[7] he has carried out this idea in a classical manner. -By irritability _Virchow_ understands “a property of the cells, by -virtue of which they are set into activity, when affected by external -influences.” There are, however, _various_ kinds of actions which -can be brought about by external influences. But essentially there -are three kinds. The effects produced are functional, nutritive, -formative. The result of excitation, or if one will, of stimulation of -a living part, can, therefore, according to circumstances, be either -merely a functional process, or there can be a more or less intense -nutritive activity produced without the function being necessarily at -the same time activated, or finally, it is possible that a process of -formative change may occur which produces new elements in greater or -less numbers. _Virchow_ touches here for the first time upon a question -of extraordinary moment, the important bearings of which have only -now begun to be recognized and seriously considered. We now know, for -example, that the functional excitation can be separated to a certain -degree from the cytoplastic excitation of the muscle. If the muscle is -acted upon by functional stimuli, the excitation takes place mainly in -the form of functional metabolism, nitrogen-free substances are broken -down in increased quantities, whereas cytoplastic metabolism, which -produces more profound alteration in the living substance, and which -goes so far as to bring about a breaking down and building up of the -nitrogen containing atom groups, is hardly at all increased. It would -be an error, however, to look upon these different kinds of metabolism -as quite independent. Considering the close correlation which all the -phases of metabolism bear to each other, this idea cannot well be -entertained. If, however, we question in what manner, for instance, -the functional and the cytoplastic metabolism are linked together, we -have a problem before us which does not belong to the past, but to the -present and future. Indeed, _Virchow_ seems already to have felt that -a sharp division between the different phases and parts of functional -metabolism in the cell does not exist, for he says: “It is true -that it cannot be denied that, especially between the nutritive and -formative processes and likewise between the functional and nutritive, -intermediate gradations occur.” Still they differ essentially in -their characteristic action and in the internal alterations which -the stimulated part undergoes, depending on whether it functionates, -nourishes itself, or is the seat of special growth. Disease consists of -the influence of stimuli upon these physiological processes. The law -of the specific energy of living substance is as clearly expressed in -functional disease as it is in the physiological effects of stimuli. -The pathological disturbance of function is purely quantitative, -“nowhere is there a qualitative divergence.” The function exists or -it does _not_ exist. If it is present, it is either strengthened or -weakened. This gives the three fundamental forms of disturbance: -absence, weakening and strengthening of the function. No function -other than the physiological, even under the greatest pathological -alterations, exists in any _structure_ of the body. “The muscle does -_not_ perceive, the nerve moves no bone, the cartilage does not think.” -In this way _Virchow_ rediscovered in the domain of pathology the -law that his great teacher, _Johannes Müller_, had already clearly -established in the field of physiology. But this law can no longer be -applied to all pathological disturbances of the nutritive and formative -activities of the cell. Here processes occur which do not consist of -a quantitative change of the normal phenomena, but in the appearance -of wholly foreign states, as in the case of amyloid degeneration or -heteroplastic tumors. The question today and for the future arises, -therefore, as to where the limits of the validity of the law of the -specific energy of living substances are to be placed, a question -closely connected with the other before mentioned, of the relations -between functional and cytoplastic metabolism. - - [7] _Rudolph Virchow_: Die Zellularpathologie in ihrer Begründung auf - physiologische und pathologische Gewebelehre. 1 Aufl. Berlin 1858–4 - Aufl. 1871. - -By means of cell pathology _Virchow_ has laid the foundations upon -which our modern medical attitude is built and which must remain -essentially forever the basis of all future medical thought. Certain -critics, lacking in appreciation of the interrelations between things -and ignoring the safer and established knowledge, have considered, -in view of the unfoldings of the researches on immunity and of serum -therapy, that the time of cell-pathology was _passed_ and must be -replaced by the humoral-pathological teaching. These ultramodern -critics, however, have here completely ignored the fact that, on the -one hand, the life of our body is built up from the life of all of the -contained cells, for life in our body exists only in the cells; and on -the other, a fact not considered by them is that the components of the -body fluids originate from vital activity of the cells either directly -or indirectly. No result, indeed, of present serology can alter in the -least degree the fact that every disease represents only a disturbance -of the physiological processes of cell life of the organism and the -harmony in their combined workings. Indeed the more recent observations -of serology and chemotherapy are so little opposed to cell-pathology -that they are in fact only possible when based on the latter. They are -only comprehensible then from the unfoldings of cellular pathology. - -Until quite recently all those effects of external factors on the -living substance which consist in excitation, that is, in an increase -of their specific vital processes, have always stood in the foreground -of all researches and observations on irritability. It was gradually, -however, more and more recognized that the depressing influence of -stimuli played a great rôle in the vital process of the organism. -_Brown_ was acquainted with exhaustion produced by stimuli, and the -discussion of “asthenic” diseases, in which the irritability was -reduced, occupied an important place in his pathology. That, however, -in the normal activities of the organism such depression or lessening -of vital manifestation could result from the influence of stimulation, -first became clear after the brothers _Weber_[8] in 1846 discovered the -inhibitory effects of the galvanic stimulation of the vagus upon the -heart. - - [8] _Eduard Weber_: “Muskelbewegung.” Article in Wagner’s - Handwörterbuch der Physiologie, Bd. 3. Braunschweig 1846. - -Since then the inhibitory processes in nerves have been frequently -investigated by _Schiff_ (1823–1896), _Goltz_ (1834–1901) and others, -who gave us a theory concerning the same. Only a small number of -inhibitory processes were known at that time, as for instance the -inhibition of the croak reflex of the frog, or the inhibition of -the grasp reflex during copulation of these animals through skin -stimuli, and a few other cases. They regarded the inhibitory nervous -processes as a special state, of which the inhibition of the heart -through the vagus was the best illustration. Further, the Russian -physiologist _Setschenow_ succeeded by directly stimulating certain -parts of the central nervous system, especially the optic lobes of -the frog, in producing inhibition. It was, therefore, frequently -assumed, as _Setschenow_ did, that in the brain there exist special -inhibitory centers, just as there are motor centers. This view was -later shown to be untenable. It is only quite recently, and especially -since _Sherrington_ has shown that inhibition plays a part in all -antagonistic muscle movements, that we have obtained a broad and more -thorough understanding of the inhibitory processes in the life of the -organism, and a physiological explanation of this important group of -activities of the central nervous system. This inhibitory effect of -stimulation, brought about by the involvement of the central nervous -system in the normal organism, was studied side by side with the -depressing effects of stimulation. _Claude Bernard_ (1813–1878)[9] -first discovered that the excitation of all living substance could -be depressed or totally suspended through the influence of certain -anæsthetics, such as ether or chloroform. By a series of experiments, -as simple as they were convincing, the French scientist showed that -irritability could be depressed in mimosa leaves, the growth of -germinating plant seeds and the ferment action of yeast cells stopped, -likewise the disintegration of the carbon dioxide in the cells of the -green leaf, as well as the development of the egg cells, and also the -movements of the animal organism and the sensations of man. By this -means he recognized that not only does all living protoplasm possess -irritability, but that it can also by means of certain substances -be put into the condition of “anæsthesia,” a state dependent upon -a change of the protoplasm, which he termed “semi-coagulation.” -Finally, besides the more apparent processes of excitation and those -less so, belonging to the group of inhibition and depression, in -the last century the knowledge of the subject was greatly increased -by the addition of another group, which recently in consequence of -various reasons has met with particular interest. These being effects -of stimuli on the direction of movements of motile organisms, it -became more and more recognized that these curious manifestations of -irritability, which appeared to have such a surprising likeness to -the mysterious attraction and repulsion in the sphere of electricity -and magnetism, occur universally in the vegetable as well as in -the animal world. These movements are of the greatest biological -importance for the obtaining of food, propagation, protection against -disease, etc. Botanists have long known of the geotaxis of the roots -and stems of plants, the heliotaxis of their leaves and flowers -and of the thigmotaxis of their tendrils. Likewise the phototaxis -of freely moving protistæ had been often observed, especially by -_Ehrenberg_[10] of Berlin, well known for his researches on infusoria. -Then _Engelmann_, _Pfeffer_, _Strassburger_, _Stahl_, and many others -discovered and studied more carefully the facts concerning chemotaxis, -thigmotaxis, rheotaxis, geotaxis, phototaxis, etc., of bacteria, motile -spores, rhizopoda, and so on. The question arose if one should regard -this singular behavior of the unicellular organisms as an expression -of conscious sensations, discrimination or will. This view was as -determinedly denied on the one hand as it was accepted on the other. -Whilst even today certain scientists still consider the reactions of -the unicellular organisms as a manifestation of conscious sensation, -discrimination or will, others look upon them as unconscious reflex -reactions of cell organism, taking place as purely mechanically as -the spinal cord reflexes of vertebrates. This divergence of opinion -would have practically no value for the development of our knowledge -of irritability had not here, as in the case of the relations between -the mental and physical processes in man, the view been entertained -with more or less fervor, that at some stage or other in the chain -of the purely physiological processes of responsivity, an intangible -factor had been introduced which was considered as the essential -“cause” of the peculiar reactions to stimuli. It is not here the -place to enter into the question if, and in what degree, animal -psychology may be a field of scientific research. Even if one looks -upon conscious processes as effects of stimulation, in both lower -animals and in man, in no case should one assume them to be factors -of an essentially different nature, interrupting the chain of the -mechanical reactions; neither should one consider the particular -characteristic responses observed in unicellular organisms as effects -of non-mechanical “causes.” As a result, a mysticism, in reality quite -foreign to it, would be introduced into physiology. As a matter of fact -the physiological investigations for the tropic reactions of stimuli, -which have been carried out in great number since the end of the -eighties, have shown more and more clearly that this peculiar behavior -of unicellular organisms towards unilateral stimuli is produced by a -comparatively simple mechanism. The analysis of this shows a difference -in the intensity of the exciting or depressing effect produced by the -stimulus. The stimulus exerts its influence unequally upon the specific -activity of the motor elements of different parts of the surface of the -cell body. This difference in response causes the axis of the freely -moving organism to assume a different direction in which to move. It -is _compelled_ to move in a definite direction and so, in this field, -the apparently mysterious attraction and repulsion of living organisms -toward stimuli has, by means of the most simple analysis, been robbed -of its mystical character. - - [9] _Claude Bernard_: “Lecons sur les phénomènes de la vie communs - aux animaux et aux végétaux.” Paris 1878. - - [10] _Ehrenberg_: “Die Infusionstiere als vollkommene Organismen.” - Leipzig 1838. - -Finally, I should like to touch briefly upon a view of the irritability -of living substance which has recently been brought forward by -_Semon_.[11] It assumes the proportions of a whole system and is -proclaimed as a basis for the comprehension of organic phenomena. It -originated with an idea which _Hering_[12] developed many years ago -and which later was accepted by _Haeckel_,[13] namely that heredity -is a species of memory of the living substance. _Semon_ attributes to -living substance, in contrast to non-living, a “_Mneme_.” By “_Mneme_” -he understands the capability of living substance to assume, through -the influence of a stimulus, a permanently altered condition. The -latent alteration resulting from the stimulus he terms “_Engramm_.” -These “_Engramms_” can later, however, not only be activated by the -reapplication of the original stimulus, but also by other stimuli, -so that the state of excitation once brought about by the original -stimulus reappears. _Semon_ calls the reproduction of the state of -primary excitation by a later stimulus “_Ekphorie_.” A great number of -other new word formations, such as “_chronogene Engramme_,” “_phasogene -Ekphorie_,” “_mnemische Homophonie_,” “_mnemisches Protomer_” and -countless others are supposed to serve for the better understanding -of a series of special facts, chiefly in the domain of the processes -of heredity. That which is termed “_Mneme_” and “_Engramm_” is not -further analyzed. _Semon_ expressly declines to discuss the kind of -alterations in which the physical or chemical nature of an “_Engramm_” -consists. Hence physiological analysis has not been advanced in any way -by _Semon’s_ new formation of words applied to long-known facts. With -a series of new expressions the originator of the “_Mneme doctrine_” -deceives himself, as well as a number of his readers not endowed with -the critical faculty, into supposing that he has achieved a serious -analysis. Of such, however, there is not a trace. As can be conceived, -this way of treating the manifestations of life has met with no further -attention from the physiological side. For indeed, what physiologist -would consider that the fact of muscle responding by a contraction -to an induction shock, or to any other stimulus, is sufficiently -analyzed by the explanation that we have the “_Ekphorie_” of a state of -excitation that was once previously produced by an original stimulus -of some unknown kind, and of which the living substance of the muscle, -in consequence of its “_Mneme_,” has retained a latent “_Engramm_”? -Here the deep gulf is apparent which exists between the demands of -a physiological analysis and the futile explanation of the mneme -doctrine. Physiological investigation must reject such a manner of -treating its problems. - - [11] _Semon_: “Die Mneme als erhaltendes Princip im Wechsel des - organischen Geschehens.” Zweite verbesserte Auflage, Leipzig. - - [12] _Ewald Hering_: “Uber das Gedächtniss als allgemeine Function - der organischen Materie.” Wein 1876. - - [13] _Ernst Haeckel_: “Die Perigenesis der Plastidule oder die - Wellenzeugung der Lebenstheilchen.” Berlin 1876. - -With this the history of the doctrine of irritability enters into its -present phase of development. To future research remains then the -problem of further analyzing irritability, this common property of -living substance, and finally rendering it into its simplest chemical -and physical components. This last goal can only be approached very -gradually, step by step. With the analysis of irritability we shall -investigate life itself. In the following lectures it will be my -endeavor to show how far, with our present knowledge, we can penetrate -by this path into the great secret. - - - - -CHAPTER II - -THE NATURE OF STIMULATION - - _Contents_: Principles of scientific knowledge and research. Origin - and meaning of the conception of cause. Cause and condition. Criticism - of the conception of cause. The conditional point of view. Conception - of cause. The conditional point of view applied to the investigation - of life. Conception of vital conditions. Definition of the conception - of stimulation. - - -The common problem of all scientific research is the investigation -and formulation of natural laws. The assumption of a unity in the -happenings and of existence in the world, in accordance with definite -laws, forms the indispensable foundation of all scientific study and -is fully justified by experience. Experience has taught us, as a -result of innumerable individual observations, the existence of such -an accordance, whereas in not a single instance has it been shown -that this is not the case. We are thus justified in assuming without -further discussion that every scientific research, every new problem -which we approach, is likewise founded on this unity of occurrences in -accordance with natural laws. Only on the firm basis of this assumption -has scientific investigation a purpose, and every success is a new -proof of this. There is an unanimity of opinion concerning this among -scientific investigators in all fields. - -Not such complete agreement, however, exists in regard to the question -by what symbols of human thought and speech these laws can be described -in part as well as _in toto_, so that existing laws can not only be -_fully_ and conclusively defined, but at the same time without the -use of _superfluous_ terms. According to _Ernst Mach_, thought is an -adaptation to facts. Our speech is simply a method of expression of -our thoughts and indeed the most satisfactory form we have. We must, -therefore, use those symbols which are most closely adapted to facts -as the most precise expression of these existing laws. What forms of -expression have we? - -It might appear that a discussion of this fundamental question -has not a close connection with our special subject of physiology -of stimulation. This, however, is not the case. Indeed, it is an -irremissibly previous requirement not only for the elucidation, but -also for the understanding itself in this particular field. We _could -not_ come to a clear understanding in this field without such analysis. -The interpretation of the unity of being and happenings in accordance -with natural laws, which today is widely accepted in the scientific -world as the only exact one, implies the assumption of a “_causation_” -according to which things are explained by the law of “_cause_” -and “_effect_.” I[14] have already on various occasions taken the -opportunity to criticise this view and to show the error and confusion -to which it leads. I should like here to enter somewhat more in detail -into the reason for this criticism. It is particularly directed against -the scientific use of the term “_cause_” on the basis of our best-known -theoretical principles. It is clear that all scientific observations -and explanations are founded on experience. Can it be said that the -conception of “cause” originates from experience? - - [14] Compare with this _Max Verworn_: “Die Entwickelung des - menschlichen Geistes.” Jena, Gustav Fischer, 1910. - - _Max Verworn_: “Die Erforschung des Lebens.” II Auflage. Jena, - _Gustav Fischer_, 1911. - - The same: “Die Fragen nach den Grenzen der Erkenntniss.” Jena, - _Gustav Fischer_, 1908. - - The same: “Allgemeine Physiologie.” V Auflage. _Gustav Fischer_, 1909. - -We can say with absolute certainty that the conception of cause dates -from prehistoric times. Its beginning reaches back to the stone age, -at least to neolithic, possibly to palæolithic culture. This is -demonstrated by the careful reconstruction of these prehistoric races -based on a critical comparison of the remains of their culture with -that of primitive races living today. The ideas of these primitive -races show an inclination to an extraordinary degree to explain -all happenings in the world anthropomorphously. All happenings in -surrounding nature are given the same origin as the activities of man -himself. To man, on this plane of phantastic religious speculation, all -events in nature appear as acts of the will of invisible powers, which, -having originally proceeded from the souls of dead human beings, think, -feel and act exactly as _he does_. This anthropomorphic conception of -the occurrences in the surrounding world is one of the many conclusions -which ensue from the supposition of an invisible soul, which can be -separated from the body. It was this conception which gave the impetus -for the transition of human thought from the era of the naïvely -practical to the era of the theoretical spirit in that far removed -age. In this anthropomorphic transference of personal subjective -impulses of will to the objectively observed events of the surrounding -world, lies the origin of causal conception, which since then has been -generally used as the explanation of the happenings in the world. One -cannot assert that the formation of the conception of cause is purely -a product of _experience_, but rather a result of _naïve speculation_. -Even if a later evolution of human thought shows a continued endeavor -to dismantle the conception of cause of its primitive trappings and -to modernize, as it were, its outer appearance, we still find today -many inner components clinging to it, which do not agree with the -strict demands of critical scientific exactness, demands which must -particularly be made concerning a conception which has been given such -fundamental importance in theoretical knowledge. - -I wish to observe here, however, that the conception of cause, even -though more or less unconsciously so, is still the remains of a part of -the old anthropomorphic mysticism carried over into our own times. This -shows itself especially in the conception of _force_, which is nothing -more than a form of the conception of cause. Force is the cause of -movement. One has here in anthropomorphic manner transferred the action -of the _will_ of man, which produces movement of the muscles, into -lifeless nature. The force of the sun attracts the earth, that of the -magnet attracts iron, etc. In short, one has introduced a mysterious -unknown factor instead of being content with the simple description of -facts, such as _Kirchhoff_[15] has advanced in the field of mechanics. -Although of late natural science has also dispensed more and more with -conception of force as a means of explanation, it is still today not -wholly done away with. That which applies to the conception of force is -likewise true of the conception of cause. - - [15] _Gustav Kirchhoff_: “Vorlesungen über mathematische Physik. - Mechanik.” Leipzig 1876. - -Another point concerning the application of the conception of cause -seems to me, however, to be of much more importance, namely that a -single cause is held responsible for the taking place of a process. One -endeavors to explain a process in general by seeking for its “cause.” -The cause being found, the process is considered as fully accounted -for. This idea is not only widely spread in everyday life, but is even -found frequently in natural science, especially in biology, although -here, it should be known, the processes are decidedly more complicated. -The search for the “cause” of development, for the “cause” of heredity, -for the “cause” of death, for the “cause” of the respiration, for the -“cause” of the heart beat, for the “cause” of sleep, for the “cause” -of disease, etc., was for a long time and frequently even today a -characteristic of biological investigation. As if such a complicated -process as development, death or disease could be explained by a single -factor! In reality, one has obtained very little as a result of the -analysis of a process by discovering its cause; and in addition the -false impression arises that through the finding of this one factor the -process has been definitely explained. It has been generally recognized -in the natural sciences in recent times that no process in the world is -dependent upon one single factor and attempts have been made to give -this fact more consideration. - -It is the custom at the present time to hold the view that every -process or state is brought about by its _cause_, but that a series -of _conditions_ are also necessary to the production of the process. -Such a view, however, which considers that two different factors -existing at the same time are necessary to the accomplishment of every -happening or state, namely, the cause and the conditions, leads to new -difficulties, for then, upon a more exact analysis arises the question: -Which is the cause and what are the conditions? It is very soon found, -however, that this does not permit of any strict differentiation, as -the two conceptions can not be sharply separated. This difficulty -was brought to my notice with particular force during an animated -discussion with a friend and colleague about twenty years ago, which I -have always remembered. I had observed at that time the dependence of -pseudopod formation of amœboid cells on the oxygen of the medium, and -had found that the expansion phase of protoplasmic movement, that is, -the extension of pseudopods, the centrifugal flowing of the protoplasm -into the surrounding medium and with this the enlargement of the -surface of the cell body, only takes place when oxygen is contained -in the surrounding medium and never occurs in its absence. Being at -that time wholly under the influence of the conception of cause, I -believed that oxygen was the cause of the formation of the pseudopods. -To this my friend made the objection: “Yes, I quite acknowledge the -fact of the dependence of the formation of pseudopods on oxygen, but -what informs me that the oxygen is really the _cause_? It might be -simply a necessary _condition_.” This objection led to a long debate, -which ended, however, without our being able to agree. We were not in -a position to distinguish between the conception of cause and that -of condition, and at that time the idea _did not occur_ to us to -emancipate ourselves from the conception of cause deeply implanted in -us as a result of our training. In fact, one is greatly embarrassed if -one attempts to sharply distinguish by a definition the conception of -cause and that of condition. A condition is a factor on which a state -or a process is dependent for its existence or its taking place. To the -conception of condition belongs, besides the factor of _relation_, that -of _necessity_. Every condition is necessary to the existence or taking -place of this state or process. Without the condition in question the -state or process does not occur. The same must be demanded for the -conception of cause. No state exists, no process takes place, without -its cause. The cause then has itself the specific character of a -condition, it is itself a condition. Has it perhaps then some specific -peculiarity in contrast to the other conditions, which would give it a -prominent place? Experience teaches us that nothing, that is to say, -no state or process in the world, is dependent upon a single factor -alone. There are always numerous factors which bring about the state or -process. Would it be possible to distinguish which of these particular -conditions is of the greatest importance? - -First of all, it must here be taken into consideration that the -importance of a condition is not one which is capable of increase -or decrease, for the simple reason that necessity, which forms an -essential component of the conception of cause cannot be varied. A -factor cannot be _more_ than necessary for the existence of a state or -the taking place of a process. If, however, it is less than necessary, -then it is not necessary at all, and the state or process exists also -without it, that is to say, the factor is not a condition. In other -words: _all conditions for a state or process are of equal value for -its existence, as they are all necessary_. - -If one attempts to prove by means of concrete examples this statement -obtained by purely logical deduction--a control which, considering the -experimental nature of modern thought, never should be neglected even -in the simplest of reasoning--it might appear that an objection could -still be made against its general validity. From various instances it -might be concluded that there are conditions, which as such are not -absolutely necessary for a state or process, but can be replaced by -other factors. An example may serve to make this clear. I pour diluted -hydrochloric acid on powdered carbonate of sodium, and carbon dioxide -is set free. The addition of hydrochloric acid is here a condition -for the liberation of the carbon dioxide. Without the presence of -the hydrochloric acid the process does not occur. Nevertheless I can -substitute diluted sulphuric acid for the hydrochloric acid. Here it -would appear that one condition can be replaced by another. But one -must not be deceived. A closer observation soon shows that the process -has not been sufficiently analyzed if we look upon the addition of -hydrochloric acid as a condition for the liberation of carbon dioxide. -It is not the presence of hydrochloric acid or sulphuric acid, as such, -which is a condition for the process, but rather the separation of the -sodium atoms from their combinations with the oxygen in the molecule of -the carbonate. This reaction can occur as a partial component in very -different complexes of processes. Or to quote another example, taken -from the subject with which we are especially here concerned. I allow -an induction shock to act on the nerve of a nerve muscle preparation of -the frog. The muscle contracts. The electric stimulus is the condition -for the muscle contraction. But I can substitute for the induction -shock a mechanical stimulus by sudden pressure of the nerve. The -muscle again contracts. The analysis again shows that the induction -shock as such was not the condition for the muscle contraction, but -the excitation of the nerve which it produced and which is conducted -as a specific impulse to the muscle. This excitation of the nerve can, -however, be induced by very different kinds of processes, namely, -by all processes which possess in common the condition that they -suddenly increase certain disintegration processes in the living -nerve substance. Indeed, the further analysis of the whole process -shows in addition that the nerve impulse as such likewise does not -form a condition for the contraction of the muscle, but it first of -all produces the necessary condition for the muscle contraction by -suddenly greatly increasing certain chemical processes, which take -place in the living substance of the resting muscle. The nerve impulse -can, therefore, also be replaced by other processes, if only these -contain the condition for an increase of disintegration of the muscle -substance, as in the case of the direct stimulation of the curarized -muscle, where the influence of nervous impulses is totally eliminated. -In a further analysis of this process we should penetrate even more -deeply into the differentiation of the individual constituent processes -and the isolating of the special conditions on which each link in the -chain is dependent. - -Such an analysis then shows us the following: Every thing, every state -or process, is a complex of numerous components, of which _one_ always -conditions the other in the manner that the individual conditioning -components are themselves in their turn contained as constituents of -other complexes and are conditioned here again by other factors. These -factors in themselves as such are not directly necessary to the taking -place or existing of the special component and can, therefore, be -replaced by others. Closer observation shows that there is a constant -interdependence between all things in the world. _Every_ thing in the -world is _indirectly_ dependent upon _every other_, although often so -remotely that we are not able to trace the connection. Absolute things, -completely isolated and independent of others, _do not_ exist in the -world. In observing and studying complexes individually, we must not -forget that we only _think_ of them as isolated from the great eternal -coherence, from which they are in reality not separated. The conception -of condition, however, only then has meaning, if we refer to it in -connection with the direct dependence of one factor upon another. -Nevertheless if we understand by conditions those which are connected -by multitudinous intermediate components, then we would render the -conception of conditions useless. For if every thing in the world were -the condition for every other, the conception of relation would lose -its value in special states or processes. Should the conception of -condition have a meaning in regard to a _certain_ state or process, -then we should only look upon _that_ part of a complex upon which the -other is _directly_ dependent as a condition. When, however, we meet -with a factor for a process or state, which can apparently be replaced -by another factor, we have not carried the analysis far enough. Upon -deeper penetration into the subject, it is found that the essential -condition for the process, which exists, is a component common to both -factors, one of which in consequence can replace the other. - -It is the task of all scientific research to penetrate deeper and -deeper into these relations, these connections and the order of -succession of states and processes and to separate them into their -individual components, and in this way gain a more thorough knowledge -of the constancy of existence and happenings in the world. - -This analytical process, it is true, only advances very gradually, and -we must accept for the present, especially in the complex biological -processes, that a whole complexity of members appear conditioned, -and that a complex aggregate is a condition of the whole process. -We are not yet in the position to define the special components of -the constituent processes. It is only step by step that we are able -to differentiate the necessary from the accessory parts in these -complexes. However, we are here only concerned for the present with -a purely theoretical question and we may be permitted to say: If we -maintain that the conception of condition has as an integral part the -element of necessity and of relation to a special thing, then there -are no substituting conditions. For then every condition for a state -or process is of equal value. There is no justification to give more -prominence to one condition and place it in the position of being the -“_cause_.” - -If the cause is elevated, then it is done from some superficial motive. -This is confirmed by a glance at the practical use of the term cause. -The cases in which the cause is always at once clearly recognized and -named without doubt or hesitation are those where a new factor is -added to an already existing system of conditions, which bring about -a process. When such a process is produced, the last added condition -is considered as “cause.” A shock acts on an explosive body, the body -explodes: the shock is considered the cause. An induction shock acts -on a muscle, the muscle contracts; the induction shock is looked upon -as the cause of the muscle contraction. To regard only the last added -condition as being of especial importance to the taking place and the -explanation for a process is, however, a standpoint which could satisfy -only the most superficial of observers. - -In a scientific investigation such methods should play no rôle. For to -every careful observer it must appear quite clear from the beginning, -that the previously existing conditions have as great a value for the -taking place of the process and its explanation as that last added. - -The induction shock would not have produced the characteristic effect -had not the other conditions been already previously combined, had not -certain special atoms in the molecule of the explosive combination -in consequence of former processes assumed quite a peculiar labile -position, had not in the evolution of the muscle in the growth and -metabolism certain combinations been formed, and certain chemical -processes taken place. - -Therefore if I do not analyze these previously existing processes and -the conditions brought about by them in the system of the explosive -substances or the muscle, and simply know the condition added last, -then I have learned nothing of the process itself, have _explained_ -nothing. The time of application of a new condition does not justify -in any degree the assignment of a dominant position to a factor. But -more: in many cases there is not a question at all of the _addition_ -of a process to an existing state, but rather of the _simultaneous_ -interference of two or more processes. Several conditions can appear -at the _same_ time. In other cases the sequence of the combination can -be reversed. Which then is the cause? Has the process several causes, -or has it no cause? Here one sees plainly to what absurd results it -leads if time alone is used as a basis of the conception of cause. -To illustrate this I return to the case of the liberation of carbon -dioxide from carbonate of sodium. I place anhydrous carbonate of sodium -in a beaker and add hydrochloric acid. The carbon dioxide escapes. Here -the addition of hydrochloric acid would be assumed to be the cause of -the freeing of the gas. Then I put hydrochloric acid in a beaker and -add carbonate of sodium. The same process takes place, but now the -addition of _carbonate of sodium_ would be considered the cause for the -formation of gas. Now I put both simultaneously into a beaker. Again -the same process. Which was now the cause? Has the process now _two_ or -has it _no_ cause at all? Finally I put anhydrous carbonate of sodium -and hydrochloric acid in ether solution into the beaker. The formation -of gas does not take place, and _yet_ both causes for this formation -of gas are present, the carbonate of sodium and the hydrochloric acid. -Only when I add water to the mixture does the formation of carbon -dioxide take place. Here water would be considered the cause. Hence -every condition would be in succession the cause for one and the same -process. Under some circumstances the same process would have _several_ -and in others _no_ cause at all. It is scarcely necessary for further -comments upon the value of the conception of cause for the scientific -explanation of a state or process. If we do not seek to introduce -into exact science the antiquated symbols which have become useless -and belong to a primitive phase of development of human thought, -there cannot be a moment’s doubt that a strict scientific analysis in -whatever field of investigation it may be carried on can consist only -in the study of all the conditions concerned in a state or process. If -this is done, then the work of exact research is accomplished. Further -problems do not exist. The use of superfluous terms or symbols for -the definition of things would be in opposition to the fundamental -principle, already brought forward by _Kirchhoff_, especially for -mechanics, namely, that of formulating comprehensively and in the -simplest manner the processes which take place in nature. - -At first glance one might be tempted to find an incompleteness in the -observation and description, when a conditional standpoint is adopted. -It might be thought that conditionalism were a purely _formal_ method -of observation, and only considered the _interdependence_ of things, -but not the _properties_, the _nature_ of the objects themselves. -Regarded more closely, however, it is seen that this objection does not -hold good. For what is a condition? - -A condition is in itself a _thing_ of quite distinct _properties_. -The properties of a thing are, however, determined by the specific -combination of conditions which characterize the thing. The conditions -by which a thing, that is to say, a state or process, is determined, -are _identical_ with its being and nature; in other words, they are -the thing itself. Purely formal relations without essence would be -altogether an absurd fiction _not_ in accord with reality, and which -even the science of mathematics does not acknowledge, for we cannot -have a conception without concrete content, just as in nature we do -not find a form existing independently of a thing. Every thing is -equal to the sum of all its conditions and depending upon the uniform -constancy in accordance with natural laws is solely determined by its -conditions. The problem of all scientific research consists wholly in -the ascertaining of the conditional interdependency. - -_A state or process is solely determined by the sum total of its -conditions. A state or process is identical with all of its conditions -in totality._ From this it follows that equal states or processes -are always the expression of equal conditions and wherever unequal -conditions exist, unequal states or processes will result; and further, -a state or process is completely investigated when the entire number of -its conditions is ascertained. - -This fundamental statement of conditionism should be engraved over the -portals to the entrance of every scientific investigation. - -That there is not the least difficulty in presenting scientific -observations strictly according to these principles of conditionism, -and that one can perfectly well do without the causal conception in a -scientific description, I have shown by a concrete example, namely, -in the fifth edition of my “General Physiology.” In the whole volume -the conception of cause is only mentioned in one place, where its -theoretical value is criticised, elsewhere not at all, and yet I do -not think that any one will miss this conception, and indeed, if -their attention is not especially called to the fact, even notice the -omission. - -These principles of an exact conditional investigation must also guide -us in the analysis of the processes of stimulation. The process of -stimulation is especially apt to tempt one to employ the old conception -of cause, for it belongs to that group of processes which originate -from an already existing system by the addition of a new factor. -An electric stimulus acts on the muscle. The muscle contracts. The -stimulus is considered the cause of the contraction. But what would I -explain if I were to prove that the stimulation is the cause of the -contraction? - -The history of physiology shows us that this subject has advanced long -since far beyond the stage of being satisfied with such an explanation. -Today the process would only then be fully investigated if we knew -the entire number of its conditions and had traced the dependency of -the individual partial constituents of the whole complex process upon -one another. For this, however, it is essential that we study the -conditions already existent in the entire system previous to the action -of the stimulus. - -That which we describe with the word life is an exceedingly complex -process. If we analyze life, it is found to be composed of an immense -number of separate constituent processes, each one being conditioned -by the others. These constituent processes are the vital conditions. A -vital process occurs, and must occur, where and when the whole sum of -vital conditions is realized. It is identical with the sum total of the -vital conditions. If only one condition is absent, then life does not -exist. It is then expedient to reserve the expression “life” for the -_entire sum_ of the vital conditions. When we speak of the individual -constituent processes as “_vital processes_” in the plural, we must -bear in mind that in reality each is not in itself life. Only the whole -complex “lives,” not an individual constituent of the same. Living -substance is rather the _whole_ system, and not a constituent part of -the same, not a piece of protoplasm, not a nucleus and not a specific -protein combination in the cell. - -A property of this system should receive our consideration at this -point. It is a characteristic of every system in the world, namely, -the fact that a system _is not isolated_ from its surroundings. It -is a deception resulting from the selective action of our sensory -organs, if we consider the bodies as separated and isolated from their -environment. This deception disappears upon further analysis and when -we assist our organs of sense, which only respond to certain parts -of the whole process, by experimental methods of investigation. Our -experience then shows us that an isolated system does not exist, but -that there are instead everywhere connections which extend further and -further into the infinity of the world. An organism is consequently -no delimitated system and the vital process cannot, therefore, be -sharply separated from the processes in the medium. We cannot draw -a sharp line between vital processes and say: on the right we have -factors which are necessary for the maintenance of life, and on the -left factors which are not necessary. The conditional connection -between individual processes extends to the entire world, and likewise -a great series of constituents, each influencing the others, extend -from the medium into the organism. The nature of our sense perception, -and consequently the knowledge derived therefrom, is such that we are -obliged to arbitrarily take into consideration merely _fragments_ from -the endless interdependence of all things in the world, and so we -separate the vital conditions of the organisms from their surrounding -factors, as though they were independent. A conscientious theoretical -analysis requires that we should never forget that in reality such an -isolation does not exist. Only with the recognition of this can we -distinguish for practical purposes between _internal_ and _external_ -vital conditions. In such a differentiation the _internal vital -conditions_ which compose the living system conceived to be isolated, -are the organs, the tissues, the cells, the protoplasm and the cell -nucleus, and within the protoplasm and the nucleus the arrangement and -quantitative relations of certain substances, such as proteins, salts, -water and the thousands of special components with their interactions -and continued alterations. On the other hand, the _external vital -conditions_, which act on the periphery, are the conditions of the -surrounding medium, as foodstuffs, water, oxygen, static and osmotic -pressure, temperature, light, etc. But this distinction has only a -_practical_ value for the study of the organism as an _independent_ -system. Theoretically it is as impossible to make a sharp distinction -between internal and external vital conditions, as to distinguish -between the vital conditions generally and the more remote conditions -of the environment. All these conditions form a widely branching -system of factors of which one is conditioned by the other reaching -continually from the interior of the vital system into the surrounding -medium, so that on the periphery of the system it cannot always be said -whether or not a component still belongs to life. Considering these -circumstances we can roughly for the present define the conception of -stimulus as follows: - -_A stimulus is every change in the vital conditions._ - -The most essential point in this definition is the relation of the -conception of stimulus to that of vital conditions. These relations, -however, call for a brief explanation. Here again the conditional -method of observation saves us from error, for it would be wrong to -place the conception of stimulus and vital conditions in contrast to -one another, one excluding the other. On the other hand, this method of -observation shows that the stimuli are likewise only conditions, but -conditions producing certain changes in the vital system. If a stimulus -acts, that is, if there is any change whatever in the vital conditions, -the whole complex of life in consequence of the dependency of the -constituent parts upon each other is also changed, and a new state -of living substance occurs. Stimuli are, therefore, also only vital -conditions, but vital conditions for new vital manifestations. The -_relation_ of _one_ given state to _another_, forms an indispensable -point in the understanding of vital conditions as well as that of the -stimulus. The stimulus becomes a vital condition for the new state -which it produces. It is only a stimulus _relatively_ to the original -state, which _previously_ existed. The essential point, therefore, -in the conception of the stimulus is that of alteration. An example -will serve to make this clearer. If _Amœba limax_ are bred in a hay -infusion they appear in countless masses. Observed in water in a -watch glass they show at first the well-known form of _Amœba proteus_ -with short, broad, lobate pseudopods. (Figure 1, A.) After a period -of rest, however, they gradually assume the characteristic elongated -_limax_ form. (Figure 1, B.) In this shape they constantly move about. -But if I add to the water only a faint trace of diluted solution of -caustic potash, the amœbæ first assume the shape of a ball (Figure -1, C), and then after a time, stretch out long, pointed pseudopods, -which give them the characteristic form of _Amœba radiosa_. (Figure 1, -D and E.) They remain permanently[16] in this form. I have observed -them for several hours at a time. They move in the same manner as -_Amœba radiosa_. They draw in one pseudopod, stretch out another and -float freely in the water in contrast to their _limax_ state, in which -they are always attached to some support. The long, pointed, often -threadlike pseudopods, yield to every movement of the water, bending -in consequence like whipcords. In this example the amœbæ under the -vital conditions existing in tap water have _limax_ form. The vital -conditions undergo a change by the addition of a solution of caustic -potash, which acts as a stimulus. The consequence is a reaction, in -which the animal assumes _radiosa_ form. By the action of the stimulus -a new state of the living substance is produced, and remains as long -as the solution of caustic potash is contained in the medium. The -solution of caustic potash is, therefore, a stimulus for the state of -the vital system, which is manifested in the _limax_ form, whilst for -the state of the system which shows itself in the _radiosa_ form, it -is a vital condition. If I place the amœbæ of the _radiosa_ form once -again in tap water, they assume the _proteus_ and then the _limax_ -form. The withdrawal of the solution of caustic potash, the presence of -which is a vital condition for the _radiosa_ state, acts as a stimulus, -which results in a transition of the vital system to another state. By -altering the medium I can at will bring about this change of form in -the same individuals. In this way one and the same factor can figure -as stimulus and vital condition, according to the state of the vital -system on which it acts. Whilst its addition acts as stimulus in the -one state, its withdrawal acts as a stimulus in the other state, which -it has produced. The same fact is shown by the well-known example of -_Artemia salina_, which on being placed in fresh water changes into -_Branchipus stagnalis_ and, when again introduced into sea water, -becomes once more _Artemia salina_. - - [16] _Max Verworn_: “Die polare Erregung der lebendigen Substanz - durch den galvanischen Strom.” In Pflügers Archiv. f. d. ges. - Physiologie Bd. 65, 1896. - -[Illustration: _A_ - -_B_ - -_C_ - -_D_ - -_E_ - -Fig. 1.] - -These facts show clearly that some stimuli can also be considered -as vital conditions. In the absence of certain stimuli, life could -not exist for any length of time. In the highly differentiated cell -community of the animal organism, for instance, as a result of the -coexistence of the cells and the tissues, many parts have forfeited -in a measure their independence. An example of this is the skeletal -muscle, which, in the absence of impulses from the nervous system, -reaches a low level of chemical change and energy transformation. Here -the nervous impulses which act as momentary stimuli, are also in the -course of time indispensable vital conditions. Without them the muscle -would gradually become atrophied from inactivity. The same applies -to all other tissues of our bodies. The functional stimuli are for -them at the same time vital conditions. These vital conditions undergo -fluctuations and interruptions but at each alteration from a given -state they act as stimuli. - -_Stimulus is every change in the vital conditions._ But is this -definition complete? Are we really justified in regarding _every_ -alteration in the vital conditions as a stimulus? - -In considering this question, one point must not be omitted. This is -the fact that one of the chief characteristics of the vital process -is, that it undergoes continuous change. A vital process involves not -simply an alteration in metabolism or transformation of energy in the -sense that the same chemical processes continuously reoccur in the same -manner. Such a view could only be admissible for the observation of -living substance during a limited period. An investigation over a long -period of time shows rather that every living system alters as long as -it exists, although this alteration is very gradual. The constituent -processes, in short, continuously undergo metabolic change both -quantitative and qualitative in nature. - -If we observe the occurrences in a living system at various moments -of the cycle of life, we will find that the condition differs -qualitatively at each period. The progressive alteration of the system -is such that every state of living substance conditions another, by -which it is followed. No state can permanently exist as such. Every -state is the product of the preceding, as it in turn conditions -its successor. Consequently the relations of the system to the -surrounding medium also undergo alteration, even when the external -factors themselves in no way alter. That which today is still a vital -condition, is not in consequence necessarily one tomorrow. These -progressive changes exist continuously until the death of the system -takes place. They characterize life. It is development, and life cannot -exist without development. Death is only the last phase of development. -The individual constituent processes of metabolism gradually change -to such a degree that they can no longer work harmoniously together. -Then the chain of processes is interrupted at one point or another. -The system develops into death or, on the other hand--and this, -as _Weissman_ especially emphasizes, is realized in the case of -unicellular organisms--a corrective process takes place, a process of -cell division by which the original state of the cell is restored and -development begins anew and in a similar manner. - -Ought we to designate these constant alterations in the inner vital -conditions as “stimuli”? Usage in this connection has already answered -in the negative, by applying to them the word “_development_.” And -this use is in a certain sense justified. Let us imagine an organism -or any other object for the purpose of investigation as isolated from -its surroundings. This conception, which we have already stated, proves -untenable on closer analysis, but it, however, is based on the nature -of the methods of human observation and is indispensable for practical -use within certain limits. Then the inner vital conditions belong to -the organism, the external to the medium. They differ in so far that -the external vital conditions can exist permanently without alteration, -that is, independently of the development of living systems, whilst -the inner vital conditions of every living organism continuously and -progressively undergo alteration. In this sense, but only in this, -there is evidently a difference between the inner and outer vital -conditions, which permits a separation of the two groups. But we should -always bear in mind that this separation cannot be sharply defined. On -the same basis we assume that the organism for purposes of study is -separated from its surroundings as an independent system, which leads -us in consequence to contrast the alterations in the internal with -those in the external vital conditions, in which we designate the first -as processes of _development_, the latter as stimuli. This distinction, -as all differentiations and separations in nature, gives us only a -practical working basis. - -In this way we confine the conception of the stimulus to all -alterations in the external vital conditions of a living system, -considered as isolated. This view does not exclude the fact that -stimuli can also occur and act within an organism. If a nervous impulse -is conducted from the cerebral cortex through the pyramidal tract -to a skeletal muscle, this impulse acts upon the muscle cells as a -stimulus. Although the explosion of the impulse is an alteration within -the body, nevertheless, as far as the muscle is concerned, it may be -looked upon as an external vital condition, therefore as a stimulus. -As the conception of stimulus involves the relation to a given state, -it likewise involves at the same time the relation to a given living -system, upon which it acts from the exterior. - -What is the value then of all this theoretical discussion? - -In presenting the conception of stimulation from a conditional -standpoint, I desired to show what difficulties stand in the way of -a theoretical isolation of a fundamental conception in the field of -physiology, which indeed is used in our practical research work at -every step. “_Natura non facit saltus._” I wished to demonstrate -that the sharp separation of the conception of stimulation, like all -artificial divisions which we make in nature, must always contain -an arbitrary note, as in reality isolated systems do not exist in -the world. I wished to show that, for this reason, the conception -of vital system, the conception of life, the conception of vital -conditions are not sharply defined. I wished likewise to show that -as a necessary consequence of this fact a sharp separation of the -conception of stimulation, which can only be made in relation to that -of vital conditions, cannot be maintained theoretically. I wished to -show further that there is no sharp line of division between inner and -outer vital conditions, and that we cannot, therefore, make a strictly -theoretical distinction between the conception of stimulation and that -of the processes of development. I wished to show that, for these -reasons, we must not expect from the conception of stimulation, as we -understand it, anything beyond its possibilities. But finally I wished -also to show that, whilst fully conscious of and with due consideration -of all these difficulties, it is possible to work out a definition of -stimulation which is of great _practical_ working value. The definition -in short is: “_Stimulus is every alteration in the external vital -conditions._” - -This definition gives to the conception of stimulation its most -complete, that is to say, its generally applicable and simplest form. -The great importance from a methodical standpoint of this definition -of stimulation for the research of life is evident. Our whole -experimental natural science always employs for investigation of any -state or process the same method: the state or process to be observed -is studied under systematically altered conditions. By stimulating the -living substance it is brought under changed external conditions. A -systematic employment of stimulus is, therefore, the experimental means -for the research of life. - - - - -CHAPTER III - -THE CHARACTERISTICS OF STIMULI - - _Contents_: The quality of the stimulus. Positive and negative - alterations of the factors which act as vital conditions. Extent of - the alteration in vital conditions or intensity of the stimulus. - Threshold stimuli, sub-threshold, submaximal, maximal and supermaximal - intensities of stimulus. Relations between the intensity of stimulus - and the amount of response. The _Weber_ and _Fechner_ law. All or - none law. Time relations of the course of the stimulus. Form of - individual stimulus. Absolute and relative rapidity in the course of - the stimulus. Duration of the stimulus after reaching its highest - point. Adaptation to persistent stimuli. Series of individual stimuli. - Rhythmical stimuli. The _Nernst_ law. - - -We have found that stimuli are alterations in the external vital -conditions and that the irritability of living substance consists in -the capability to respond to stimuli by changes of the vital processes. -It now behooves us in the interest of experimental research to -investigate the relations between the nature of the alterations in the -external vital conditions on the one hand, and that of the alterations -of the vital process on the other; that is to say, to systematically -study the effects of stimulation on the living organism. For this -purpose it is above all necessary to become acquainted with the almost -countless numbers of alterations which take place in the external -vital conditions of an organism, and to create a systematic scheme of -stimulation which differentiates and presents in comprehensive order -those various elementary factors which, among the innumerable varieties -of stimuli, would prove effectual. For this purpose it is necessary to -select the various factors which are involved in an alteration of the -external vital conditions. - -The first of these factors is the _quality of the stimulus_. The -external vital conditions are, in short, a series of chemical factors, -such as foodstuffs, water and oxygen; the presence of a certain -temperature; the existence of a certain light intensity; the existence -of a definite static pressure; and finally the presence of an equal -osmotic pressure. The stimulus according to its quality can be -differentiated into chemical, thermal, photic, mechanical and osmotic -varieties. To these must be added other forms of stimuli not ordinarily -operative, for instance, many uncommon chemicals, and certain kinds of -rays. The form of stimulation, par excellence, which has acquired the -greatest importance for the _experimental_ investigation of life, is -electricity. In its manifold forms it permits, as no other, of such -fine gradations of intensity and duration that it has become in the -hand of the physiologist an invaluable means of research. - -Alterations in those factors which act as vital conditions compose the -great mass of physiological stimuli which act continuously on every -living organism. The first point to be considered in every alteration -is its _direction_. The alterations produced by stimuli may be of -two different kinds, either positive or negative. The quantity of -foodstuffs, water or oxygen, in the surrounding medium, can undergo an -increase or diminution; as may the temperature, intensity of light, the -atmospheric and osmotic pressure. The strength of the electric current, -which may be applied, can also be regulated. In accordance with the -definition of stimulation already referred to, we must consider these -alterations, whether negative or positive, as forms of _stimulation_. -Now the question arises: Is this point of view justifiable? Should one -also consider, for example, the lessening or total removal of a vital -condition as a stimulus? Should one consider the removal of water or -oxygen, cooling or darkening, as a stimulus? It has, in point of fact, -been occasionally attempted _not_ to regard these negative deviations -as forms of stimuli. These observers permitted themselves to be led by -the dogma, that only that which produces an excitation, that is, an -increase of the processes in the living substance, should be regarded -as a stimulus. Such a limitation of the conception of stimuli would -only result from the one-sided consideration of an all too limited -circle of facts. Considered from the point of view which results from a -broader range of experience, this narrow view becomes untenable. - -In the first place it does not follow that only _positive_ fluctuations -of a factor, acting as a vital condition, result in _excitation_ in -the existing vital processes. The _withdrawal_ of water produces a -diametrically opposite effect. A muscle, from which water has been -removed, if exposed to dry air or placed in a hypertonic salt solution, -shows violent _excitation_, which manifests itself in great increase of -irritability and development of fibrillary contractions. The breaking -of a constant current which has for a long time flowed through a -nerve or muscle also elicits a momentary excitation. Further, the -abrupt removal of light may also bring about stimulation. To cite an -example from the physiology of the single cell, I should like to call -to your attention the interesting observations of _Engelmann_[17] on -the _Bacterium photometricum_, of which he was the discoverer. When -the field containing these organisms is suddenly darkened, all the -individuals contained in the drop immediately dart forward for some -distance, at the same time, as is usually the case, quickly rotating -around their own axis, and then after a moment of immobility, swim -on quickly in another direction. An analogous responsivity has also -been shown by other single cell organisms, as has been pointed out by -several observers and especially by _Jennings_.[18] In all these cases -the excitation was produced by a lessening or total withdrawal of the -factors which act as vital conditions; and even those who take the -standpoint that only such factors are to be considered as stimuli which -produce an _exciting_ effect, are compelled to regard these alterations -as stimuli, in spite of the fact that they are _negative_ variations of -external vital conditions. - - [17] _Th. W. Engelmann_: “Bacterium photometricum ein Beitrag zur - vergleichenden Physiologie des Licht-und Farbensinns.” In Pflügers - Archiv. Bd. 30. 1883. - - [18] _Jennings_: “Behavior of the lower organisms.” New York 1906. - -But further, the restriction of the term stimulation to those -alterations which increase the course of the changes in the living -substance involves the observer in still greater contradictions. It -can easily be shown that one and the same factor in one and the same -form of living substance has now an exciting, now a depressing effect -on the vital processes. This fact can be readily demonstrated[19] -by means of the infusoria _Colpidium colpoda_, which can be grown -without difficulty in a hay infusion. A number of individuals in a -drop of fluid may be placed in a warm stage and observed under the -microscope; one then sees that at room temperature they swim about -by moving their ciliary processes at a definite rate. Now if the -temperature is raised to about 35° C., the ciliary movement becomes -enormously increased. The infusoria swim madly through the field of -vision. They are in a state of violent excitement. The increase has, -therefore, acted as a strong, exciting stimulus. But if one allows -the temperature to further increase only a few degrees the ciliary -movements are suddenly greatly retarded. The infusoria now swim -sluggishly through the field of vision and finally remain stationary. -In this case the increase in the temperature has had a depressing -effect. If the infusoria are not quickly removed, the depression is -followed by death. Should the increase in temperature be regarded in -the _first_ instance as a stimulus, and _not as such_ in the _second_, -in which the temperature rises only a few degrees higher? Here the -change in the vital conditions concerned is in both instances positive. -In all cases of overstimulation we are confronted by the same question. -Nevertheless it is not at all necessary to refer to such strong or even -life-endangering stimuli for the observation of these conditions. In -this connection I would like to cite an even more striking instance and -which is of special interest for the understanding of the phenomena -in nerve centers. If the posterior spinal roots of a _Rana temporara_ -are severed, and the eighth root stimulated with a faradic current, -whilst the _musculus Gastrocnemius_ of the same side is connected -with a writing lever, one obtains, as _Vészi_[20] has found, at the -moment of the beginning of stimulation a contraction of the muscle. -The faradic stimulus has, therefore, produced an excitation reflexly. -If instead of the _eighth_ the _ninth_ posterior root is stimulated, -the result obtained is also an excitation of the muscle. In this case, -however, the excitation in the form of a tetanic contraction lasts -for some time, provided that the stimulation is not at once stopped. -If now during tetanic stimulation of the ninth root the eighth is at -the same time stimulated, with a strength of current equal to that -which previously brought about contraction of the muscle, instead of -an _increase_ and a _strengthening_ of contraction there is, on the -contrary, an _inhibition_ which continues throughout the time during -the stimulation of the eighth root. If the stimulation of the eighth -root is discontinued, the tetanic response of the ninth root reappears. -If, on the other hand, the faradic stimulation of the ninth root is -interrupted and the eighth root now again stimulated, one obtains once -more, as in the beginning, with each stimulation a contraction of the -muscle. This fact is illustrated by the accompanying tracings. (Figure -2.) In this investigation undertaken in the Göttingen laboratory it -was further shown that a faradic current of the same strength and the -same frequency had at one time an augmenting, at another an inhibitory -effect, and these effects could be produced alternately at will. Should -the faradic current at one time be called a stimulus, at another not? -It is here clearly shown to what absurd consequences it leads if the -conception of stimulation is limited solely to the cases in which an -external factor has an exciting effect; and yet an immense number of -instances of a like nature could be cited to show the untenability of -this view. - - [19] _Max Verworn_: “Physiologisches Prakticum für Medizinen.” Jena - 1907. - - [20] _Julius Vészi_: “Der einfachste Reflexbogen im Rückenmark.” In - Zeitschrift f. allgemeine Physiologie Bd. XI, 1910. - -[Illustration: Fig. 2. - -Lower thick line shows duration of stimulation of 9th root; upper thick -line that of 8th root.] - -It follows from this, that it is altogether impracticable to define -the stimulus itself in relation to the nature of the effects which -the stimulus has upon the substances in the living system. One can -only appreciate the nature of stimulation in relation to the vital -conditions and without considering the nature of the action of the -stimuli on the living substance. It is true that every stimulus is -followed by an alteration in living processes, but this is to be -expected when one clearly understands the nature of vital conditions. -A stimulus is in all cases an alteration in vital conditions and, in -that each of the vital conditions is necessary for the continuance -of life, it follows of necessity that every alteration in the vital -conditions, so intimately connected with the living processes, will -also be followed by an alteration in the processes occurring in the -living system. In short, response is produced. Nevertheless, a definite -alteration of an external vital condition, depending upon the state -of other vital conditions, that is, according to the state of living -substance at the moment, can produce quite opposite effects. Although -it may appear expedient to include in the conception of stimulation in -given instances, distinctions between stimuli according to the nature -of their effects upon the living substance, in all cases the conception -must under all circumstances be so formulated that it comprises _all_ -alterations in the external vital conditions, either positive or -negative, that is to say, an increase or decrease, an augmentation or -diminution in those factors, acting as vital conditions. - -Besides the quality there is another highly important factor to be -considered in the study of every alteration in the living process, -namely, its _amount_. The chemical concentration of the medium, -temperature, amount of light, the static and osmotic pressure may -undergo more or less variation. The electric stimulus can rise from -zero to great intensity and from great intensity can fall to zero. The -extent of the alteration determines the intensity of the stimulus. -In relation to the intensity, a differentiation of stimulation has -been introduced, which is not dependent upon the absolute intensity -of the stimulus, that is, upon the extent of the alterations in the -external vital conditions, but the intensity of the response that -can be observed. One refers frequently to threshold stimulation, -to stimulation beneath the threshold, to submaximal, maximal and -supermaximal stimulation. Such a classification is in many ways very -valuable. It is not only of practical value for the establishment of -definite intensities of stimulation, but also for the study of the -state of irritability in the living organisms. - -_The threshold of stimulation_ furnishes roughly a standard for the -degree of irritability of a living system. The threshold value of a -stimulus is then that degree of intensity which is just sufficient -to bring about a perceptible response. The threshold of stimulation -is low, that is, the irritability is great, when the intensity of -the threshold stimulus is small; the threshold is high, that is, the -irritability of a system is small, if the intensity of the threshold -stimulus is great. All intensities of stimuli beneath the threshold -are sub-threshold stimuli. Here a point must not be overlooked, which -in older physiology did not generally meet with sufficient attention. -From the fact that the sub-threshold stimuli produce no apparent -effects, the wrong deduction must not be made, that they have no effect -whatsoever. The conception of the threshold of stimulation originated -in the field of muscle physiology and that of the special senses. -Here the indicator of the response is, on the one hand, contraction -of the muscles, and on the other, conscious sensation. There was a -great temptation to consider the stimulus altogether ineffectual, if -it produced no conscious sensation or no contraction of the muscle. -Today with our finer and more sensitive indicators for the study of -the alterations in the living substance, we know in reality that -sub-threshold stimuli, which produce no apparent effect in the living -substance, can have an effect in reality. - -I will call your attention later to the fact that these sub-threshold -stimuli play a very important rôle under certain conditions in the -activities of the central nervous system. It only depends upon the -sensitivity of our special senses, or the indicators used for this -purpose, as to whether the alterations can be observed or not. The -conception of the threshold of stimulation, therefore, has meaning -only when used in relation to a certain indicator. The threshold of -the same living system may be different for different indicators. -When we use the term threshold we must necessarily know the indicator -employed in its determination. The threshold stimulus produces only -barely perceptible effects. The amount of response in most living -substances increases with the intensity to a certain limit. If this -limit is reached, that is, if the response is maximal, the stimulus -of the weakest strength necessary to produce this result is termed -the _maximal stimulus_, whereas all intensities lying between the -threshold and the maximal stimulus are termed _submaximal stimuli_. If -the intensity of the stimulus is increased _above_ that of the maximal, -the response, as in the case of the muscle, does not increase, and -therefore one could say that all intensities above the maximal could -also be called maximal stimuli. - -In realty, however, the response to stimuli of different intensities -is never equal, even though it may appear so, when measured by -an indicator, as for instance, the height of the maximal muscle -contractions. This is clearly shown, for example, when the electrical -stimulus is increased far beyond that intensity which is necessary -to produce maximal effect. Injury is thereby produced, which is -manifested, for instance, in the muscle contraction by the nature of -its course and also by its height. One is, therefore, justified in -a certain sense in calling the intensities of the stimulus, which -are above the value which barely produces maximal contraction, -“_supermaximal stimuli_,” notwithstanding this is logically far from -being a happy expression. The term “maximal stimulus,” then, is limited -to the intensity of the stimulus which just produces a maximal effect. -I wish to point out this distinction between maximal and supermaximal -stimulus, as there is often a lack of clearness in the use of these -terms. - -In that the nomenclature of intensity of stimulation is based upon the -intensity of response, the question arises as to the _relation between -the intensity of stimulus and the amount of response_. It is well known -that this question has met in one special field of physiology with a -very detailed and comprehensive treatment. I allude to the teaching -concerning sensation. _Ernst Heinrich Weber_[21] first called attention -to the relation between increase in sensation and that of the stimulus -in the case of the sense of touch. His observations, which have been -formulated into “_Weber’s law_,” have been the object of animated -discussion. A presentation of this law is the following: “The amount -of pressure necessary to produce a perceptible increase of sensation -always bears the same ratio to the amount of the stimulus already -applied.” - - [21] _Weber_: “Annotationes anatomicæ et physiologicæ.” Lips. - 1851. The same: “Der Tastsinn und das Gemeingefühl,” in Wagner’s - Handwörterbuch d. Physiologie Bd. III. 2. Braunschweig 1846. - -If in accordance with _Ziehen_[22] we designate the relative increase -in pressure to that already applied, which is necessary to produce -a perceptible increase in sensation, as the _threshold of relative -differentiation_, we can formulate the law in the simplest way thus: -The _relative threshold of differentiation is constant_. _Fechner_,[23] -who indeed attempted to apply this law, applicable to the sense of -pressure, to all the other special senses, has given us a mathematical -formula, based on the assumption that the just perceptible increase of -sensation has the same value at all levels. By this assumption he was -able to establish for the first time a relation between the intensity -of sensation and that of stimulus, for it follows that “_the sensation -increases in intensity in arithmetical progression, whereas the -intensity of the stimulus increases in geometrical progression_.” From -this _Fechner has_ worked out a psychophysical formula, which today is -generally termed the _Fechner law_. This is the law: _The intensity of -sensation varies with the logarithm of the intensity of the stimulus._ - - [22] _Ziehen_: “Leitfaden der physiologischen Psychologie in 15 - Vorlesungen.” VI Auflage. Jena 1902. - - [23] _Fechner_: “Elemente der Psychophysik.” Leipzig 1860. 2 Auflage - 1889. - -Soon the _Weber_ as well as the _Fechner_ law had been extended over -the whole field of sensation and stimulation. In this connection -_Preyer_[24] has formulated his “myophysical law,” which states -that there is the same relation between strength of stimulus and -the intensity of response of the muscle as is laid down by the -_Fechner_ law for stimulation and sensation. _Pfeffer_[25] has -found that _Weber’s_ law applied also to the relations of the -chemotaxis of bacteria, to the intensity of the chemical stimulus, -and likewise the attempt has been made to show that all living -substances respond in the manner laid down by the _Weber-Fechner -law_. Unfortunately the innumerable investigations in this field have -shown more and more clearly that it is not possible to formulate a -general mathematical law, which strictly fixes the relations of the -intensity of the stimulus and the intensity of response. Even in -the field of the physiology of the special senses many voices have -opposed the general application of the _Weber_ and the _Fechner law_. -_Lotze_, _G. Meissner_, _Dohrn_, _Hering_, _Biedermann_ and _Löwitt_, -_Funke_ and numerous other investigators have already demonstrated -for some decades, partly by means of critical inquiry, partly by -experimentation, that these laws are not strictly valid. Above all -these experiments have shown that logarithmic relations are not -tenable and likewise are not applicable to very strong stimuli. The -assumption made by _Fechner_, that is, the acceptance that all barely -perceptible increases of sensation have an equal value, has been set -aside as incorrect, and with this his mathematical formulation within -those boundaries of intensity of the stimulus, in which the _Weber_ -law has proven itself valid, must also be abandoned. That which we can -say today with certainty concerning the relation between the intensity -of stimulus and the amount of response is as follows: A law generally -applicable to the relation between the strength of the stimulus and the -amount of response cannot be mathematically formulated. For a great -number of living systems the rule which holds for the intensity of -stimulation within certain boundaries is the following: With increase -of the intensity of stimulation the _response_ at first increases -rapidly and later more and more slowly. - - [24] _Preyer_: “Das myophysische Gesetz.” Jena 1874. - - [25] _Pfeffer_: “Ueber chemotaktische Bewegungen von Bacterien, - Flagellaten und Volvocineen.” Untersuchungen aus dem botanischen - Institut zu Tübingen. Bd. II, 1888. - -This rule of course only applies within the boundaries of the -intensity between the threshold of stimulation and maximal stimulus. -The interval, however, between these intensities varies considerably -in different living substances. In this connection there are several -forms of living substance which call for our special attention. In -these the surprising condition seems to exist, that the interval -between the threshold and the maximal stimulus is zero; that is, -every stimulus which acts at all always produces a maximal response. -_Bowditch_[26] first observed this behavior in the frog’s heart and -this has also been confirmed by _Kronecker_.[27] The induction current -produces, as _Bowditch_ says, either a contraction or nothing. If -the former, it is the strongest contraction which can be produced -by an induction shock at the given time. Here for the first time a -constancy of response was discovered which has been termed the _all or -none law_. _McWilliams_[28] has later verified the same fact for the -mammalian heart. _Gotch_[29] has also arrived at the same conclusion -in connection with the nerve. He states that “the comparison of -submaximal with maximal responses shows that although there is an -obvious difference in the amount of E. M. F., there is little or no -difference between such time relations as the moment of commencement, -the moment of culmination of E. M. F. and the rate at which E. M. F. -disappears.” Further: “the rate of propagation of the excitatory wave -is the same whether this is maximal or submaximal.” He likewise assumes -that the “all or none law” is applicable to the constituent fibers, and -that the variations in the strength of response with weak and strong -stimulation are brought about in the first instance by stimulation of -a few, in the latter by a greater number of fibers in the nerve trunk. -The same conclusion has been reached by _Keith Lucas_[30] for the -single cross-striated fiber of the skeletal muscle, founded on the fact -that by direct stimulation of a bundle of curarized muscle fibers, -the contraction only increases inconstantly and not regularly with the -increasing intensity of the stimulus. This is only comprehensible if -one takes into consideration that, with the increasing intensity of -the stimulus, a greater and greater number of fibers are stimulated. -_Keith Lucas_[31] came to the same conclusion in the case of the -muscle stimulated indirectly through the nerve. He, therefore, sees, -because of the nature of the response of the single muscle cell, no -difference between heart muscle and skeletal muscle. The “_all or -none law_” applies to the individual muscle cells of both kinds. The -difference between the heart and skeletal muscle, according to him, -lies in the fact that in the heart the individual muscle cells in their -totality stand together as conductors of excitation, whereas in the -skeletal muscle the individual muscle fibers are separated, as far as -conduction of excitation is concerned, by the sarcolemma. Finally, the -recent investigations of _Vészi_[32] with strychnine poisoned ganglia -cells of the posterior horns of the spinal cord, have made it appear -probable that “the all or none law” can be applied likewise to the -individual ganglion cell. He draws this conclusion not only from the -fact that all reflex contractions of a muscle of a strychninized frog -are maximal, whether they are produced by weak or strong stimuli, but -also especially because of the loss in the strychninized spinal cord -of the capacity of the summation of irritability. The normal spinal -cord does not reflexly respond at all to weak single stimuli, but -responds to equally weak faradic stimulation very readily. Therefore, -the threshold lies very high for the individual induction shock and -very low for faradic shocks. But these differences are equalized in the -strychninized frog. This seems intelligible, when we assume that the -strychninized cell responds to every stimulus, to which it responds -at all, to the maximal extent which is permitted at that moment by -its stored up energy, otherwise the excitation would necessarily be -summated by faradic stimulation. - - [26] _Bowditch_: “Ueber die Eigentümlichkeiten der Reizbarkeit, - welche die Muskelfasern des Herzens zeigen.” In Arbeiten aus der - physiologischen Anstalt zu Leipzig VI. Jahrgang 1872. - - [27] _Kronecker_: “Das characteristische Merkmal der - Herzmuskelbewegung.” In Beiträge zur Anat. und Physiol. Als. Festgabe - Carl Ludwig gewidmet von seinen Schülern. Leipzig 1874. - - [28] _McWilliams_: “On the rhythm of the mammalian heart.” Journal of - Physiology, Vol. IX, 1888. - - [29] _Gotch_: “The submaximal electrical response of nerve to a - single stimulus.” Journal of Physiology, Vol. XXVIII, 1902. - - [30] _Keith Lucas_: “On the graduation of activity in a skeletal - muscle fibre.” Journal of Physiology, Vol. XXXIII, 1905–06. - - [31] _Keith Lucas_: “The all or none contraction of skeletal muscle - fibre.” Journal of Physiology, Vol. XXXVIII, 1909. - - [32] _Vészi_: “Zur Frage des Alles oder Nichts-Gesetzes beim - Strychninfrosch.” Zeitschrift für allgemeine Physiologie Bd. XII, - 1911. - -Such are the instances to which one has up to the present applied -the “all or none law.” The question if, as a matter of fact, such a -condition has ever been realized in any living substance has until now -found no final answer. Most authors, who accept the validity of the -“all or none law” for certain living substances, do so with a certain -reserve and speak only of the possibility or probability of such -behavior. The subject has, however, as will be shown later, a great -and even vital interest in another direction. For this reason I should -prefer to postpone the treatment of the same to a later occasion. Here -I wish simply to say, that _if_ the “all or none law” is valid in a -strict sense for certain structures, then there exists no general -constancy of the relations of the intensity of the stimulation and the -amount of response, applicable to all living organisms. - -We will now return from this digression concerning the relations -between the intensity of the stimulus and the response, to the -further characterization of the properties of the stimulus. Besides -the quality, the direction and the intensity of every alteration in -vital conditions, an equally important factor is the duration of -the alteration. The time relations, under which a deviation of the -external vital conditions takes place, present immense and manifold -variations in nature. In many cases the change is very complicated, as -for instance, the alteration of the static pressure or the temperature -under the influence of air or water currents, the osmotic pressure -or chemical factors in diffusion currents, and the light intensity -produced by the movement of clouds. These very irregular alterations -have practically little interest for us. Here we are concerned rather -with the differentiation of the time alterations of the processes of -the simplest fundamental types, which are of importance in studying -the course of the reaction. For it is of such simple elements that the -complicated and irregular alterations of the above-mentioned kinds are -composed. - -The simplest form of an individual change in the external vital -conditions would be a regular and constant alteration of intensity -which can be graphically represented as a straight line, wherein the -intensities are the ordinates and the time the abscissa. (Figure -3, A.) A regularly rising pressure would, for instance, represent a -stimulus in its simplest form. But such forms of stimuli are only very -rare in nature and are also experimentally very difficult to produce. -It is, for example, not easy to give the _electrical_ stimulus, so much -used for experimental purposes, this form. _Fleichl_ and _v. Kries_ -have only accomplished this by means of complicated apparatus. The -usual _form of the individual stimulus_ is not a straight line, but a -logarithmic curve. (Figure 3, B.) The alteration hardly ever progresses -with equal rapidity from its beginning until it reaches its highest -point, but as a rule, with decreasing rapidity. This is the usual -course of alterations of concentration, also of chemical and osmotic -stimuli, of changes of temperature and of electric stimulation. - -[Illustration: _A_ - -_B_ - -Fig. 3.] - -The _rapidity of alterations_ in vital conditions has quite an -important influence on the development of the response to stimulation. -It is well known that if a constant current, which reaches its highest -intensity rapidly, is permitted to act upon a muscle, the effect -differs from that following the application of a current of the same -intensity but in which this is reached very slowly. In the first case -there is a sudden strong twitch, in the second none at all. In spite -of this there can be no doubt whatever of the current in the last case -being effective. That the muscle is also excited when the current is -slowly increased is shown by the contracture, which grows more and more -plainly perceptible with the increasing intensity of the current and -in higher intensities by the so-called _Porret’s_ phenomenon, which -consists in a curious wave-like movement of the muscle-substance. In -reference to the rapidity of the alterations in the factors which -act as stimuli, the behavior varies greatly. Many stimuli because of -their nature never have a steep ascent or descent of intensity, as, for -instance, alterations in the concentrations of soluble substances, that -is, chemical or osmotic stimuli; likewise temperature variations may be -mentioned. They always act relatively slowly. On the contrary there are -forms of stimuli which have now a rapid, now a slow, ascent or descent -of their intensity, such as the photic and mechanical stimuli. Finally, -there are other stimuli that nearly always show a very abrupt change of -intensity, such as the electrical form. - -The most important factor to be considered in producing the response -to variations of intensity, is not the _absolute rapidity_, but rather -the _relative rapidity_; that is, the rapidity in relation to the -characteristic rapidity of reaction of the particular living substance -concerned. The rapidity of the reaction to stimuli is very different -in various forms of living substance. On the one hand, we have forms -reacting very quickly, as the nerve and the striated muscle; on the -other, those which respond very slowly, such as a great number of -unicellular organisms. Between these are a great number of living -substances which, as far as the rapidity of the reaction is concerned, -occupy intermediate positions of every varying degree. It is clear -that the adequate stimuli for slowly reacting substances must be those -having also a slow change of intensity; for quickly reacting, those -having a rapid change of intensity.[33] If a nerve muscle preparation -is simulated with the single induction shock, the “break” as well as -the “make” shock has effect. But even here a difference is noticeable. -The “make” shock has a weaker effect than the “break” shock. This -difference is due to the difference of abruptness in its course, which -when the current is made is less than that of opening, for, when the -current is made, the ascent of the primary current is retarded by -the extra current flowing in the opposite direction, whereas, when -broken, with the fall of the intensity of the primary current, the -extra current in the primary coil flows in the same direction. In -consequence of this there is a perceptible difference in the rapidity -of the alteration of the “make” and “break” shocks. (Figure 4.) - - [33] Vergl. _Julius Schott_: “Ein Beiträg zur electrischen Reigung - des quergestreiften Muskels von seinen Nerven aus.” Pflügers Archiv - Bd. 48, 1891. - -[Illustration: Fig. 4. - -Course of induction shocks. 1 and 2 make and break of the primary -current. 1_{1} and 2_{1} make and break induction shocks. (After -_Hermann_.)] - -Now slowly reacting forms of living substance, such as certain -foraminifera, in which the extended pseudopods are stimulated with -single induction shocks, the break as well as the make shocks are -wholly without effect, as both take place far too quickly for the -slow responsivity of these organisms. I have made such observations -on various forms of foraminifera of the Red Sea, on _Orbitolites_, -_Amphistegina_ and others. The movement of granules in the pseudopods -is not influenced by the induction shocks in the least. It also -continues without interruption when the pseudopods are extended. Even -with the strongest induction shocks at my disposal I could _not_ induce -them to contract; the faradic current, also, the intensity of which -I found quite unbearable, remained utterly without effect.[34] These -two extreme cases, the nerve and the foraminifera, show plainly that -the effect of a stimulus is not produced by the absolute rapidity of -the increase of intensity, but is solely influenced by the relative -rapidity of the same. - - [34] _Max Verworn_: “Untersuchungen über die polare Erregung der - lebendigen Substanz durch den constanten Strom.” III Mitteilung, - Pflügers Arch. Bd. 62, 1896. - -[Illustration: - - A B C - -Fig. 5.] - -A further point for consideration in the duration of an alteration in -a vital condition in producing a stimulant action is the _length of -time the stimulus remains after reaching its highest point_. In the -forms of stimuli occurring in nature the duration of the alteration -after reaching its highest level can vary considerably. The stimulus -may remain indefinitely at a certain level, when this is once reached. -(Figure 5, A.) The alteration likewise persists. This would be the -case, for instance, with the changes of concentration in the transfer -of an organism from fresh into sea water. The alteration can also, -however, immediately after attaining its highest level, return, so that -the original state is at once reestablished. (Figure 5, B and C.) Here -it is a case of a quick deviation in the external vital conditions. A -_sudden jar_ would be a case in point. Between these two extremes we -have all variations in the duration of all natural and experimental -forms of single stimuli. - -Now we arrive at the question: Has a prolonged stimulation really a -prolonged effect? This question might seem superfluous, as from a -conditional standpoint it is self-evident that every alteration in -any one of the conditions of a system is followed by an alteration in -the system. But this very question played an important rôle in older -physiology and led to prolonged discussions for the reason that a -special case was taken into consideration in this connection, which -at that time was not clearly understood. _Du Bois-Reymond_,[35] as a -result of his investigations on the nerve muscle preparation of the -frog, formulated a law of nerve excitation, according to which it is -not the _absolute value_ of the intensity of the constant current which -produces an excitation of the nerve and contraction of its muscle, but -an alteration of the intensity from one moment to another. The more -rapidly these changes are produced, the greater is the excitation. -His arguments were based upon the fact that a contraction can only -take place on the “making” or “breaking,” or by rapidly strengthening -or weakening the constant current; it is possible to subject a nerve -muscle preparation to a current of considerable strength without a -muscle contraction resulting, provided it is slowly increased. One -might be disposed to conclude from this that the constant current, -when showing no fluctuations, has no stimulating effect whatsoever. -Should this observation be carried even further and the attempt made to -extend it into a general law of excitation by assuming that the effects -of stimulation are only produced by variations in the intensity, not -by its continued duration, one would commit the error of judging the -occurrence of a stimulus only by the unsatisfactory criterion of an -abrupt muscle contraction. Today we know with positiveness that a -continued effect also exists during the uninterrupted flowing of a -constant current in nerve or muscle, though much weaker, however, than -in the case of the excitations produced by sudden fluctuations of the -intensity. This is shown in the nerve by an altered excitability, which -continues at the poles during the whole duration of the current. In -the region of the anode the excitability is diminished, in that of -the cathode it is increased. An excitation can also be demonstrated -which extends from the cathode through the nerve, which can easily -be detected by sufficiently delicate methods. Among other effects of -prolonged stimulation is that of cathodal contracture, which remains -localized in the region of the cathode and which excitation persists -as long as the current continues. This permanent excitation can be -particularly well observed in the single cells of the rhizopods. If a -constant current is allowed to flow through an _Actinosphærium_,[36] -the straight, smooth, ray-shaped pseudopods of the cell body at the -moment of “making,” show evidence of contraction by being drawn _in_, -particularly those directed towards the anodic and in less degree also -those towards the cathodic pole. This excitation, greatest at the time -of “making” of the current, though diminishing rapidly in intensity -during its continuance, remains, however, to a less degree, and leads -to a progressive disintegration of the protoplasm on the side towards -the anode, which lasts until the current is again broken. (Figure 6.) -Thus even though there can be no doubt, on the one hand, that the -effect of stimulation, which appears at the moment of the entrance, -is to produce alterations, which develop very rapidly, and that by a -continuation of this state there is a more or less rapid fall to a low -level; on the other hand, it is just as certain that the alterations -in the living system persist throughout the duration of the changed -external conditions, or to put it more concisely: the effect of the -stimulus never wholly disappears unless the changes in the external -vital conditions return to their original state. - - [35] _Du Bois-Reymond_: “Untersuchungen über tierische electricität.” - Bd. I. Berlin 1848, p. 258. - - [36] _Kühue_: “Untersuchungen über das Protoplasma und die - Contractilität.” Leipzig 1864. _Max Verworn_: “Die polare Erregung - der Protisten durch der galvanischen Strom.” Pflügers Arch. Bd. 35, - 45, 1889. - -[Illustration: Fig. 6. - -_Actinosphaerium eichhornii._ Four stages showing the progressive -influence of a constant current. Protoplasmic disintegration at the -side toward the anode.] - -But more, an effect of the stimulus cannot indeed take place _without_ -a certain duration of stimulation, which is related in _its_ turn to -the rapidity of reaction of particular living system. This can be much -more readily observed in more slowly reacting substances. _Fick_[37] -first proved this fact on the muscle of the _Anodonta_. I have also -been able to demonstrate the same fact in the slowly reacting sea -rhizopods[38] by the use of the constant current. When _Orbitolites_ -is stimulated with a constant current lasting approximately the tenth -of a second, no response is seen in its extended pseudopods, which -are directed towards the poles. The same is the case if the induction -current is employed. Only when the constant current of the uniform -strength lasts approximately .05 seconds, a barely perceptible response -occurs, manifested by the sudden stoppage of the centrifugal flowing of -granules in the anodic pseudopods, which, however, after the lapse of -one to three seconds continues again unaltered. Should the duration of -the constant current be still further prolonged, typical symptoms of -contraction are seen being manifested by a heaping up of the protoplasm -in the pseudopods in the form of spindles and balls, whilst the -protoplasm flows in a centripetal direction towards the central cell -body. (Figure 7.) - - [37] _A. Fick_: “Beiträge zur vergleichenden Physiologie der - irritablen Substanzen.” Braunschweig 1863. - - The same: “Untersuchungen über die electrische Nervenreizung.” - Braunschweig 1864. - - [38] _Max Verworn_: “Untersuchungen über die polare Erregung der - lebendigen Substanz,” etc. III Pflügers Arch. Bd. 62, 1896. - -Two effects can be realized by the alteration in the living system as -the result of prolonged stimulation. Either a new state of equilibrium -is established by the prolonged action, or sooner or later death -develops. In considering both results, however, we will ignore for -the present the fact that every living system in the absence of -such prolonged stimulation is always in a state of change, i.e., -development. Only with this restriction can an equilibrium of the -living system be spoken of. - -[Illustration: - - A Fig. 7. B - -_Orbitolites complanatus._ A--Before stimulation. B--Under influence of -a constant current.] - -It is sometimes the case that under the influence of a stimulus a new -equilibrium is developed, which may remain as long as the stimulus -persists. This most frequently occurs as a result of _weak_ stimuli. -That which is usually termed “individual adaptation” belongs in this -category. Likewise some of the natural and artificial immunizations may -also be included. The continued stimulation in such cases of adaptation -as we learned before in the example of _Amœba limax_ and _radiosa_ or -_Branchipus stagnalis_ and _Artemia salina_ becomes a vital condition -for the living substance in its new state. - -The other result, namely, that of death ensuing sooner or later, is -most frequently produced by stronger stimulation. Through the effect of -the prolonged stimulation, the change in the living system is so great -that all harmonious interaction of the various processes of life become -after a time impossible. The disturbance of this equilibrium after a -longer or shorter time becomes so great that life ceases. By far the -greater number of all diseases furnish examples of this kind. Disease -is nothing else but reaction to stimulation. Should a constant stimulus -persist and if the development of a new equilibrium of this system is -not established, the result is premature death. - -In most cases, as, for instance, the nerve impulses which move -toward an organ, or better still the electrical stimuli as used for -experimental purposes, it is not a question of a permanent but of a -temporary alteration in the external vital conditions. The stimulus -starts, then ceases after a longer or shorter period. In this way -there is added to the deviation at the start also the alteration at -its termination. The latter takes place with different degrees of -rapidity, in a manner analogous to that of the initial alteration, -and can bring about response. With this the curve of the duration of -the course of the stimulus becomes somewhat more complicated and in -consequence a like effect is observed in the response. The “making,” -duration and “breaking” of the constant current furnishes the example -of this type. The “making” of the current being a quick alteration -calls forth a strong and sudden excitation (in the muscle contraction); -the continuation of the current maintains weak excitation of equal -intensity (in the muscle a continued contraction) and the “breaking,” -being a sudden alteration, is followed again by a stronger excitation -(in the muscle a contraction). The duration of the change can, however, -be so short that its intensity does not remain at two periods of -time at the same height, but instead the ascent of the intensity is -immediately followed by its descent to zero. Induction shocks of short -duration, the duration of which have been observed more in detail -especially by _Grützner_,[39] offer typical examples. Here a single -effect of the stimulus results from the rise and fall of the intensity -curve. Hence the induction shocks as momentary stimuli are universally -used for experimental purposes. - - [39] _Grützner_: “Über die Reizwirkungen der Stöhrer’schen Maschine - auf Nerv und Muskel.” Pflügers Arch. Bd. 41, 1887. - -In contrast to the single stimuli, which find their ideal in induction -shocks, another form of stimulation should receive our attention, -namely, the series of stimuli which produce a rhythmical alteration -of vital conditions. These show among their complex combination of -simultaneous and successive actions of their single stimuli relatively -the simplest and most easily understood regularity in their effects. -They are of particular interest, because they develop in the normal -physiological happenings of the animal body in the form of rhythmical -intermittent impulses of the nervous system. - -Here again it is self-evident that with regard to the course of -response, we must first consider the character of the single stimulus -of the series, and this must be done from all those standpoints -already here discussed. However, a new factor is met with here, that -is, the frequency of the single stimuli of the series, or that which -has the same meaning, the duration of the intervals between them. -This is a feature upon which the result of stimulation depends in a -very high degree. But here, too, however, it is not a case of the -absolute frequency of the single stimulus, but simply of the relative -frequency in regard to the rapidity of reaction of the particular -living system. I should like to remark here that it is of greatest -importance whether the interval between the two single stimuli of the -series is sufficiently long or not to allow the living system time -to completely recover from the effect of the _preceding_ stimulus. -In the cases, for instance, where we have recovery, we have the same -rhythm of stimulation as that of response. When recovery _does not_ -occur, interferences of the response are developed, which are of great -physiological importance, with the analysis of which we shall later -on find occasion to occupy ourselves in detail. The physiological -example for these stimuli is the rhythmical discharge of impulses of -the nerve centers; the physical method, which is most widely used for -experiments, is the faradic current. - -It is apparent that the question of frequency must again be combined -with all those factors previously discussed in connection with the -_single_ stimulus. In consequence another complication arises and -with this another point must be taken into consideration, namely, the -fact that the duration of the single stimulus in a series undergoes -alteration by increasing frequency beyond a certain limit. Beyond -this limit the duration of the single stimulus must become less and -less. As the result of the fact that stimulation is, as we have seen, -dependent on the duration of stimulus, it is evident that, depending -upon the rapidity of response of the living system, sooner or later -the rhythmical stimulation must become ineffectual. Nevertheless, -this effect of shortening the duration of the single stimulus can be -compensated by a corresponding increase of its intensity. In this -connection _Nernst_[40] showed a very simple relation for induction -currents of higher frequency of interruption, which furnishes a law -according to which such a compensation takes place. In conjunction -with _Barratt_ he found, namely, that the intensity must increase -proportionately to the square root of the number of single stimuli if -the threshold value of the stimulus is to be maintained, that is, I : -√m = const., in which _I_ is the intensity of the current and _m_ the -frequency of interruptions. The limits of the validity of this law -cannot at present be conclusively established. - - [40] _Nernst und Barratt_: “Ueber electrische Nervenreizung durch - Wechselströme.” Zeitschrift für Electrochemie 1904. - -This exhausts the small number of elementary factors concerned in the -course of the stimulation, and which are of importance in considering -its effect. The combination of the different varieties of these single -factors, that is, the nature, the direction, the intensity, the -rapidity, the duration and number of alterations in the external vital -conditions of the organism produce the enormous variety of effects of -stimulation which we observe in the living world. - - - - -CHAPTER IV - -THE GENERAL EFFECT OF STIMULATION - - _Contents_: Various examples of the effects of stimulation. Metabolism - of rest and metabolism of stimulation. Metabolic equilibrium. - Disturbances of equilibrium by stimuli. Quantitative and qualitative - alterations of the metabolism of rest under the influence of stimuli. - Excitation and depression. Specific energy of living substance. - Qualitative alterations of the specific metabolism and their relations - to pathology. Functional and cytoplastic stimuli. Relations of the - cytoplastic effects of stimuli to the functional. Hypertrophy of - activity and atrophy of inactivity. Metabolic alterations during - growth of the cell. Primary and secondary effects of stimulation. - Scheme of effects of stimulation. - - -In the foregoing lectures we have had occasion to touch more or less -often on the subject of the effects of the stimuli. This was the -case, however, only when it appeared necessary to obtain a systematic -knowledge of the stimuli and the differentiation of the individual -factors. We will now proceed to consider the effect of stimulation in a -more systematic manner. The conditional method of observation, however, -will remain our guide. - -We have already pointed out the relations between the conception of -stimulation and that of vital conditions, now we will consider that of -the effect of stimulation with that of vital processes. Nevertheless, -the _effect_ of stimulation being a manifestation of the vital process -is not, therefore, in opposition to the latter as such. Hence the -question presents itself as to the connections between vital process -and the effect of stimulation. - -When we study the motile flagellate infusorium _Peranema_ swimming -undisturbed in water, we observe that the swimming movements are -absolutely regular in character. The elongated cell body remains -unaltered in shape. The long flagellum is extended in a perfectly -straight line in the axis of the body and only the extreme end lashes -with regularity through the water (Figure 8, A). There is majestic -grace in this perfect uniformity of motion. The picture suddenly alters -the moment the _Peranema_ is influenced by the slightest jar. The whole -flagellum at once executes a few violent movements (Figure 8, B), the -body draws together, soon stretches itself again and swims immediately -after, in another direction, with the same majestic calm as before. - -[Illustration: Fig. 8. - -_Peranema._ A--Swimming in non-stimulated condition. B--Mechanically -stimulated at the end of the flagellum.] - -Another instance. A number of fertilized eggs of the sea urchin are -placed in a watch glass in sea water. The temperature of the water -should correspond with the mean temperature in which the animals live -in the sea, averaging about 15° C. The eggs begin to form grooves and -to develop slowly by progressive division. In another glass we observe -a second sample of fertilized eggs of the same kind and under the same -conditions, but in this case we increase the temperature to 25° C. The -increased temperature brings about a decided increase of segmentation -and the same stage of development is reached in less than half the -time. The increased temperature, therefore, increases the development. -Further we take a third sample of the same urchin eggs in a watch glass -with sea water of 15° C. and add a little sea water mixed with ether. -The development of the eggs now comes to a standstill. The narcotic has -produced an inhibition of development. - -To quote another instance. _Bacterium phosphorescens_ having been bred -upon a putrid fish are exposed in the culture fluid to the air. In the -dark the bacteria give forth a phosphorescent light. Then the culture -fluid containing the bacteria is put into a glass receptacle, which can -be rendered air-tight and all oxygen excluded. After a short time the -light formation ceases completely. The absence of oxygen has here had -a depressing effect and it is only after air has been again introduced -that light is once more produced. - -Lastly, an example from the group of mammals may be cited. The -metabolism of a dog in complete rest is examined for a prolonged length -of time and we ascertain the values of the oxygen consumption, the -carbon dioxide production, and the nitrogen elimination in the urine. -Under the same nutritive conditions the animal is then allowed to -work from time to time in a treadmill. During these working periods -impulses of excitation are continually conducted to the muscles from -the nervous system. It is now found that under the influence of the -constantly recurring stimuli the quantity of nitrogen in the urine has -only very slightly augmented, whereas the consumption of oxygen and the -production of carbon dioxide has markedly increased. - -What conclusions can be drawn from these instances of response to -stimuli, of which any number could still be quoted? They show us, first -of all, that a state or process existing under given conditions, is -altered by the influence of the stimulus. This is a fact, however, -which could be expected from the beginning and is self-evident, for -stimuli are alterations in the vital conditions, and when these are -altered the state of the system or the happenings thereof must also -alter. The question with which we are here more closely concerned, -however, is a somewhat more detailed characterization of the state -or process itself, as well as that of alterations produced by the -influence of the stimulus. The instances of response to stimuli already -cited furnish us with information in both kinds. - -In all these examples, the living processes occur with equal constancy -and unaltered rapidity, provided a stimulus is not operative. Here, -however, the gradual alterations, the result of development, must -not be overlooked. An excellent example of this is seen in the eggs -of sea urchin, where the development is readily perceptible. In all -these instances, however, the condition is immediately changed by the -influence of the stimulus. The previous state of constancy in the vital -process is disturbed. The rapidity of its course is changed, being -either increased or decreased, and the specific vital manifestations -concerned are, therefore, augmented or diminished. We will now study -the vital process with the methods of chemical investigation and -consider the problem from the standpoint of metabolism. It may be -noted here, that other methods, such as the transformation of energy -or changes of form of the living system, would serve equally well as -indicators for this purpose. In every instance there is a uniformity -of the processes; the difference, however, is in the nature of the -indicators and the terms used. The methods and the terms used in -chemical investigation and description reach proportionately much -deeper than those employed when the transformation, energy or the -variations of form of the organisms are studied, and permit of the -finest differentiation of the processes. The atomistic terminology -is, for this reason, preëminently fitted for the description of vital -processes. When we study the vital process metabolically, we can, as -shown in the above-mentioned instance, divide the processes into a -_metabolism of stimulation_ in contradistinction to a _metabolism of -rest_. - -The comprehension of _the metabolism of rest_ demands a closer -consideration. On closer observation we must say that this much-used -conception is merely an abstraction nowhere realized in a strict sense. -In truth, there is nowhere in nature a metabolism of rest. No cell -exists which in a mathematical sense remains for even two successive -moments under absolutely the same external conditions. If we imagine -a single living cell of the simplest kind living in a fluid nutritive -medium, and if we suppose its body and surroundings so magnified that -the single molecules and atoms were respectively of the size of cannon -and rifle balls, the boundary between cell and medium would represent -a battlefield, on which a heavy bombardment is constantly taking -place. The rain of shot of food and oxygen molecules penetrating into -the cell from the medium, would produce an explosion in the existing -ammunition depots, now at one point, now at another, creating great -breaches through which new masses of shot would reach the interior. -The fragments of these exploding molecules would be flung out here -and there into the medium and would stem, now at this, now at that -point the besieging masses of shot. In this wild confusion on the -whole boundary line between cell and medium there can be no question -of rest or even equilibrium at any point. The human mind, superior to -the material world as we may deem it, is yet always dependent upon -the results of experience, and even in its highest flights cannot -become wholly emancipated from the concrete objects. For this reason -it is of great purport to conceive processes whose dimensions cannot -be observed even microscopically, as enlarged and transformed to that -method of expression most familiar to the human mind, namely, in the -field of optical presentation. This method is of great help in aiding -our understanding, and likewise here, even in the resting state, the -cell is constantly exposed to local effects of stimulation, now at one -point, now at the other. The conception of the metabolism of rest is, -therefore, in a strict sense fiction. - -Nevertheless, the conception of the metabolism of rest as an -abstraction can be of value provided always that it is strictly -and definitely limited. It must, for instance, not be applied to -short periods of time. The continued local and temporary responses -to stimulation constitute a mean value which, although composed -of numberless small sub-threshold responses, we can still call a -metabolism of rest. Weak stimuli have, however, as already seen, -the property, provided their influence is constant, of effecting an -adaptation to the stimulus on the part of the living organism, so -that the stimulus becomes a vital condition for this state of the -organism. Hence the continued existence of a vital process resulting -from the constant action of stimulation is made possible. That which -we are in the habit of calling metabolism of rest, would, therefore, -be metabolism of stimulation, but one that is characterized by a -constantly existing metabolic equilibrium. - -This “_equilibrium of metabolism_” distinguishes the metabolism of -rest from that form which is developed in response to temporary -stimulation, in that every temporary stimulation has the effect that -it disturbs the existing metabolic equilibrium for a longer or shorter -time. This disturbance of the equilibrium of metabolism can in contrast -to the metabolism of rest be termed “_metabolism of stimulation_.” -In this, but only in this sense, can these two conceptions be placed -in opposition and used to characterize the processes in the living -organism. The conception of the metabolism of stimulation must always -stand in relation to that of an equilibrium of metabolism characterized -by a constantly existing metabolism of rest, just as the conception -of stimulus can likewise only be defined relatively to that of vital -conditions. - -Nevertheless, the conception of the equilibrium of metabolism requires -a somewhat more accurate definition before we can feel justified in -using this term. Definitions are always trite, nevertheless they -are the basis of all our thinking and a definite understanding is -impossible unless we first clearly fix their contents. The history of -theology and philosophy even to the most recent times furnishes a long -line of instances in which the most eminent minds, for the want of -fixed definitions of the conceptions which they made use of, failed to -find a mutual basis for their ideas. Without a sharp definition every -conception is a mere word, which each individual, according to his -personal experiences and views, endows with a different meaning. To -such conceptions we may apply Mephisto’s ironical comment to his pupil: - - “Mit Worten lässt sich trefflich streiten, - Mit Worten ein System bereiten.” - -The natural sciences, if they are to retain their reputation for -exactness and precision, require the strictest and clearest definitions -of all conceptions. If we seek to penetrate more deeply into the -varied happenings in concrete conditions, we must reconcile ourselves -to dry pedantic definitions. In the case of that of the equilibrium -of metabolism indeed we have before us one of the most important -conceptions in physiology. - -The justification to speak of an equilibrium of metabolism arises from -investigations of metabolism in mammals. The classical experiments of -the previous century, as is well known, have shown that in the adult -mammal receiving a necessary quantity of nourishment and in a state of -rest, the intake and outgo of the constituent elements are the same. -The carbon, hydrogen, nitrogen, oxygen, sulphur, phosphorus, etc., -taken in during a lengthened period in the form of food and respired -air, appear again in equal quantity, in other combinations, in the -products of excretion of the organisms. Calorimetric experiments -likewise show an equilibrium of the consumption and elimination of -energy. If there thus exists an equilibrium of metabolism for the -whole cell community, it is clear that the same must also apply -to the individual cell, that is, for all living substance. The -quantitative relations of the foodstuffs taken _in_, and the excreted -metabolic products given _off_, are, however, merely a standard of the -metabolism. We know that the former are used to build up new living -substance and that the latter represent the result of disintegration -of that previously existing living substance; for we find, as in the -case of the plant, complicated protein combinations, which are built up -from comparatively simple constituents of the food and are again broken -down into comparatively simple substances. And so the building up and -breaking down processes form the two great processes of metabolism, -which with _Hering_[41] we can briefly call “_assimilation_” and -“_dissimilation_.” In the terms assimilation and dissimilation are -comprised the sum of _all_ processes of construction and disintegration -in the living organism. It is apparent that equilibrium of metabolism -occurs when assimilation and dissimilation are equal. The formula A : D, -that is, the relation of the sum of all assimilation to the sum -of that of all dissimilative processes, is a factor of fundamental -importance in the study of the course of the vital processes, for upon -its value depends individual vital manifestation, and, in fact, the -continuation of life. I have, therefore, designated the formula A = D -“_Biotonus_.” The equilibrium of metabolism would then be characterized -by the biotonus[42] of a living organism being equal to _one_. This -would be the metabolism of rest of a system, whilst its metabolism of -stimulation would consist in an alteration of the _biotonus_. But is -this state of living substance strictly speaking ever realized? - - [41] _E. Hering_: “Zur Theorie der Vorgänge in der lebendigen - Substanz.” In Lotos, Bd. 9, Prag. 1888. - - [42] _Max Verworn_: “Allgemeine Physiologie. Ein Grundriss der Lehre - vom Leben.” V. Aufl. Jena 1909. - -In considering the nature of the equilibrium of metabolism one factor -has been disregarded which must be taken into account at every point; -this is growth. Growth changes, although varying more or less, are -never absent during the life of the organism. An equilibrium of -metabolism never exists in a strictly mathematical sense, and here -again we are working with a conception which is faulty, because it is -an abstraction, originating from experience with rather too restricted -boundaries. But an error of which one is aware is not dangerous. -In mathematics we also consciously reckon with errors, without the -result being altered. In the before mentioned cases the equilibrium of -metabolism was maintained, because the investigations involved only a -short time in an adult mammal. In the adult mammal the growth processes -occur very slowly, so that alterations within a relatively short time -are not demonstrated. - -If it were possible to subject the adult mammal to metabolic or -calorimetric experiments, extending for years, it would be found that -the intake would be qualitatively and quantitatively different at the -end of the investigation and that the same would apply to the outgo. -In the growing egg cell this takes place with much more rapidity. In -the organism which rapidly grows, it can be seen at once that the -quantity of the outgo of the products of disintegration cannot be equal -to that of the intake of foodstuffs. If biotonus were equal to one, -the organism could not grow. Equilibrium of metabolism can only be -understood when we take into consideration a period of time in which -the alterations in growth take place with such imperceptible slowness -that the resultant error is inconsiderably minute. This period of -time is of greatly varying length in different living organisms and -this fact must be taken into account in every living form. Only with -this restriction can we justify the use of the term “equilibrium of -metabolism.” Then, however, its use is of great value. - -The _metabolism of stimulation_ is then a disturbance of the metabolism -of rest, that is, a disturbance of the equilibrium of metabolism -through the effect of stimuli. - -The question here follows: Is there a _constancy of this interruption -of the equilibrium of rest produced by the stimulus_ which can be -formulated into a general law? To begin with, the number of possible -responses are greater than the variety of forms of living substance, -for every living organism with its specific properties can undergo -alteration in its metabolism in various directions. Thereby results an -infinite number of manifold reactions to stimuli. However, in answer to -the question, in which direction the change in the specific metabolism -of rest in response to a stimulus takes place, we find a comparatively -simple scheme of general reaction. All phenomena can change in their -rapidity as well as in their nature. That is quantitatively and -qualitatively. In this way the specific vital process of an organism -can be altered by the stimulus, on the one hand, in its rapidity; on -the other, in the manner of its action. - -The majority of all temporary responses to stimuli consist in -_alterations of rapidity of the vital process_, and form either a -quickening or retardation of its course. The former is manifested in a -strengthening or an increase, the latter in a decrease or repression -of the specific action of the living organism. The stimuli have the -same effect as in the case of the catalysers in chemical processes. -According to _Ostwald’s_[43] well-known definition of catalysis -a catalyser is a substance which, without appearing in the final -product of a chemical reaction, alters its rapidity. This group of -reactions can, therefore, be referred to as “_catalytic stimulation and -response_.” When the response consists in _increase_, we speak, in a -physiological sense, of an excitation, and when there is decrease in -the vital processes, we speak of a depression. - - [43] _Ostwald_: “Ueber Katalyse.” Verhandl. d. Ges. Deutscher Naturf. - und Aerzte zu Hamburg 1901. - -The conception of _excitation_ and _depression_ are purely empirical. -They are terms for real things, referring, in fact, simply to -alterations in rapidity of life process, which can be as readily -observed as the process itself. I wish to lay particular stress on -this fact, for the reason that _Cremer_[44] has recently made the -extraordinary statement that I have introduced hypothetical processes -into the definition of the conception of excitation. I have always -considered excitation as merely an increase or change of intensity of -the specific actions of a living system, and as such is an established -process without a _trace_ of the hypothetical element.[45] If, however, -the excitation process is to be regarded as something _absolute_, -as a mysterious state _sui generis_, which is entirely independent -and totally unlike the metabolism of rest, then, of course, it would -appear utterly incomprehensible and would be without purpose. As an -_absolute_ process excitation is merely a meaningless word. Excitation -and depression are _relative_ conceptions and can only acquire meaning -when the process which is excitated or depressed is more closely -defined. This is the specific vital process of a given organism, and -the two conceptions only have meaning in relation to it. The conception -of the vital process, however, is one directly gained from experience. -However complex or difficult to analyze the process may be, it still -is as little hypothetical as that of the combustion of carbon into -carbon dioxide, or the revolving of the earth around the sun. It can -be looked upon as something positive and real. Quite another question -is the manner in which we are to consider the mechanism of the vital -process. In analyzing this mechanism we cannot, at least in the -present state of our knowledge, entirely dispense with hypothesis. But -these hypotheses are in no way involved in the _definition_ of the -process of excitation. If we look upon every excitation or depression -produced by a stimulus as an alteration in rapidity in the specific -vital process of a given organism, we are thereby expressing the same -fact which _Johannes Müller_ has termed “_specific energy_.” We give, -however, the doctrine of specific energy a more general application -in so far as it comprehends not only the increase but likewise the -decrease of activity in response to stimuli. _Johannes Müller’s_ -doctrine of specific energy of the living substance at all times has -been the subject of most animated discussion. When I refer here to the -specific energy of living substance, it is with the knowledge that -_Johannes Müller_ did not use this expression of “living substance” in -this connection. He was already acquainted, however, as we have seen, -with the fact of the existence of the specific energy of all living -structures. For appertaining to the muscle he says: “This is universal -in all organic reaction.” The reason why the doctrine of _sense energy_ -has become of importance in the discussion of the specific energy of -the living substance, is in consequence of the theoretical interest, -resulting from its connection with the nature of the specific energy -of our _sense substances_. The controversies on this subject are still -far from settled.[46] Indeed, according to the special philosophical -standpoint taken by an observer, the existence of a specific energy of -the senses is acknowledged or disputed. For any one acquainted with -the general physiological reaction to stimuli, such a discussion is -wholly without purport. The sense substances have as a matter of course -in common with all living substances their specific energy, that is, -the influence of stimuli can produce an increase or decrease of their -specific vital processes. “Specific energy” of “sense substance” in -this sense is like that of all other living substances, a fact. In that -the psychical capability of these sense substances, in which we include -not only the peripheral, but also the central portion, are dependent -upon their specific vital processes, it must be self-evident that the -excitation and the suppression of sense sensation can be brought about -by adequate and inadequate stimuli, no matter what one may think of -the relations between physical and psychical phenomena. - - [44] _Cremer_: “Die allgemeine Physiologie der Nerven.” In Nagels - Handbuch der Physiologie des Menschen. Bd. IV, Braunschweig 1909. - - [45] In the first edition of my “_General Physiology_” in 1895 I - have sharply and clearly defined it as such, stating in formulating - the general law of stimulation: that every excitation is an increase - either of individual parts or the whole of vital phenomena, - depression every decrease in the individual part or the whole of - vital phenomena. - - [46] Compare: _Rudolf Weinmann_: “Die Lehre von den specifischen - Sinnesenergien.” Hamburg 1895. - - Further: _Eugen Minkowski_: “Zur Müllerschen Lehre von den - specifischen Sinnesenergien.” In Zeitschrift f. Sinnesphysiologie, - Bd. 45, 1911. - -The only debatable question is that concerning the limits of the -validity of the doctrine of the specific energy of living substances. -This question will involve our attention when we have analyzed somewhat -more closely the happenings in the living substance taking place under -the influence of stimuli. We will, therefore, return later on to a -more detailed consideration of the last question. Nevertheless, we -will here refer to a fact which, upon a superficial observation, seems -to restrict the validity of the conception of the specific energy of -living substance. - -In contrast to those reactions to stimuli, which consist merely in the -changes of a rapidity of the specific vital process, are another group -of reactions in which the influence of stimuli leads to qualitative -alterations in the specific vital process. In these instances, the -influence of the stimulus directs the metabolism of rest into new -channels, so that chemical processes occur in the cell, which under -ordinary circumstances do not take place. This group of reactions, -which I wish to term “metamorphic stimulation and response,” are -chiefly observed where weak stimuli act continuously upon the living -substance. These are essentially weak chemical stimuli, which last -for a prolonged period or frequently reoccur in the life of the cell -community. Examples of this are found in the continual ingestion of -alcohol and other poisons by the human being, or in the formation of -metabolic products of bacteria, etc. The majority of _chronic_ diseases -belong to this group of reactions; disease being simply response to -stimulation. Disease is life under altered vital conditions and altered -vital conditions are stimuli. This simple and self-evident fact shows -the immense importance which the knowledge of the general laws of the -physiology of stimulation has for pathology. The pathologist, who -does not wish to confine his observations to a purely superficial -symptomatology or a merely histological morphology, must seek above -all to penetrate as deeply as possible into the nature of the general -reactions to stimulation in the living organism. It is the essential -point which meets him everywhere. In spite of their great interest -for pathology, however, it is just these qualitative alterations of -the normal vital process produced by continuous stimulation which -have up to now been least analyzed. In this field we expect much from -pathological investigation which alone has the immense amount of -material at its command. This will take place only when pathology adds -to the almost exclusively histological direction of investigation, that -also of experimental physiology. It is true that the problems of the -qualitative alterations of a vital process by chronic stimulation are -much more complicated than those of the rapid responses to temporary -stimuli, consisting simply in mere alterations of rapidity of the -specific vital process. An understanding of the nature of the former -can only be expected when a deeper knowledge of the latter is gained, -for, as will be seen presently, there is the closest relation between -the two groups. - -The reactions to catalytic stimuli of short duration, which produce -merely an alteration of rapidity in the specific phenomena of a living -organism, show on a closer analysis the interesting fact, that it is -not always the _entire_ metabolic processes of the cell which are -perceptibly quickened, but that only certain constituent processes -of the same are affected by the action of excitation. This is the -_more_ noticeable, as, considering the close correlation which all -the individual links of the chain of metabolism bear to each other, -it is to be expected that the alteration in rapidity of _one_ would -be followed at once by a corresponding change in all the others. An -example of the case in question, in which a special constituent process -may be predominately affected, is that of the specific activity of a -muscle which is repeatedly stimulated by nervous impulses. Since the -classical investigation of _Fick_ and _Wislicenus_[47] on themselves, -and of _Voit_[48] on the dog, we know that the nitrogen metabolism is -practically unaltered by the functional use of the muscle and there is -a remarkable increase only in the breaking down of the nitrogen-free -groups of the living substance. Sufficient importance has not as yet -been attached to this knowledge. This fact not only has a particular -interest for the much-discussed question of the source of muscle -energy, but also affords a deeper insight into the metabolic activity -of the living substance. It shows us that we must not imagine a purely -linear linking of the individual constituent metabolic processes, -but rather, at least at certain points, a branching formation, the -individual members spreading in various directions. An alteration in an -individual member can occur without an immediate change in the other -branches. This _would not_ be the case if there were only a linear -connection of the constituent processes, for the breaking of a single -member of the chain would be followed by a change in all the following -members. - - [47] _Fick und Wislicenus_: “Ueber die Entstehung der Muskelkraft.” - Vierteljahresschrift d. Züricher Naturforschenden Gesellschaft. Bd. - 10, 1865. - - [48] _Voit_: “Ueber die Entwicklung der Lehre der Quelle der - Muskelkraft and einiger Theile der Ernährung seit 25 Jahren.” - Zeitschrift f. Biologie Bd. VI, 1870. - - Derselbe: Physiologie des allgemeinen Stoffwechsels u. d. Ernährung. - In Hermanns Handbuch d. Physiologie, Bd. VI, 1881. - -It shows us, further, that certain branches are more labile than -others. In the case referred to here, the branches of this system, -which bring about the nitrogen metabolism, are relatively _firm_ and -_stable_, the branches, which are disturbed by the stimulus producing -functional activity of the muscle, are particularly _labile_. I should -like in passing to call here your attention to the fact that as is -well known, _Ehrlich_,[49] in another field involving other conditions -and other experiences and considerations, has arrived in analogous -manner at his “side chain theory.” In order to have an expression for -those stimuli which involve rapid alteration of the labile constituent -processes and which are connected with the specific action of the -particular organism, I have called them “_functional stimuli_,” and -contrasted with them the “_cytoplastic stimuli_.” In the latter the -alterations produced include all the constituent processes extending -even to the stable processes of nitrogen changes, and sometimes extend -to complete disintegration and rebuilding of living substance.[50] To -the first group belong all adequate stimuli within certain limits of -duration and intensity, and the greater part of inadequate stimuli of -brief duration so long as they do not exceed a certain intensity. -To the latter group belong in general all the stronger adequate and -inadequate stimuli of prolonged duration; such as extreme temperature, -the stronger electric currents, constant alteration in the supply of -food, water, oxygen, the prolonged or stronger influence of extraneous -chemical matter, etc. - - [49] _Ehrlich_: “Das Sauerstoffbedürfniss des Organismus. Eine - farbenanalytische Studie.” Berlin 1885. Compare further: _L. - Aschoff_: “Ehrlich’s Seitenkettentheorie und ihre Anwendung auf die - künstlichen Immunisierungsprozesse. Zusammenfassende Darstellung.” - Zeitschr. f. allgemeine Physiologie, Bd. I, 1902. - - [50] _Max Verworn_: “Die Biogenhypothese. Eine - kritisch-experimentelle Studie über die Vorgänge in der lebendigen - Substanz.” Jena 1905. - -Considering the close correlation of the individual part processes it -would appear very strange, however, if a single one of these could -undergo an alteration of its rapidity without the course of the rest -of the processes being in the least influenced. One cannot comprehend -such _absolute_ independence of a process brought about by functional -stimulation from all the other constituent processes, particularly when -this is of prolonged duration and involves to a considerable extent -the alterations in rapidity, for the individual constituent processes -are dependent in a high degree upon the quantity of the particular -chemical substances of which the living system is composed. The cycle -of the individual constituent processes of this system is determined in -the most delicate manner in its rapidity and extent, by the relative -quantities of the individual substances. Associated with an alteration -in the rapidity of an individual constituent process, there would also -be a relative alteration quantitatively of the substances. And with the -increase in the _quantity_ of the disintegration products, and also the -increase of the substances for their replacement, there would result, -during this time, an alteration in the amount of interaction of the -molecules of the other constituent processes, so that these processes -secondarily suffer an alteration in rapidity which is perceptible after -long continued involvement of the functional part of metabolism. - -In fact, in the previously mentioned case of the functional stimulation -of the muscle, the proof has been furnished that a long-continued -increase of the functional metabolism is followed, although to a -less extent, by an increase in the entire cytoplastic metabolism. -_Argutinski_ showed this on himself in 1890 in _Pflüger’s_ laboratory. -He found, namely, that after the exertion of a long walk in a hilly -district, a considerable increase of nitrogen excretion in the urine -took place, which extended over the succeeding two or three days. This -increase of the nitrogen metabolism in its totality is not nearly as -great as that of the breaking down of nitrogen-free substances, but -it is, nevertheless, present and shows us that functional metabolism -cannot experience a lasting excitation without being followed by -secondary results in the entire cytoplastic metabolism. This fact -is even more strikingly illustrated in the alteration of the entire -volume of a living organism as produced by the lengthened duration -of functional stimulation. It has been long known, that the muscle -as the result of frequent functional excitation by means of adequate -nerve impulses, that is, prolonged activity, is considerably increased -in size, whereas in the absence of such it loses more and more in -volume. A hypertrophy of activity, produced by functional stimuli, and -the atrophy of inactivity, the result of the discontinuance of the -functional excitation, is universal and can be observed in the various -tissues of our body. We see it, for example, in the glands; we see -it in the skin and we see it in the elements of the nervous system. -_Berger_,[51] for instance, established the fact that the ganglion -cells of the optic lobe in the cerebrum of newborn dogs only reach -their full development when functionally excitated by adequate light -stimuli (Figure 9, B), coming from the eye, whereas they remain in the -embryonic state when these light stimuli are eliminated. (Figure 9, A.) -The cytoplastic increase of volume of the neurons under the influence -of functional stimuli is a fact of fundamental importance for the -entire happenings of the nervous system and forms the physiological -basis for reinforcement of reflexes, which, in its turn, is essential -for all acts of memory and intelligence. For the increase in volume of -the ganglion cell body is, when functionally activated, accompanied at -the same time by an increase of specific capabilities and the intensity -of discharge. Its excitation impulses can, therefore, be conducted -through a greater number of neurons, with which it is connected, than -would be the case if development of the volume of the ganglion cell -increased to a less extent. - - [51] _Berger_: “Experimentell-anatomische Studien über die durch - den Mangel optischer Reize veranlassten Entwickelungschemmungen im - Occipitallappen des Hundes and der Katze.” Arch. f. Psychiatrie, Bd. - 33, 1909. - -[Illustration: A - -B - -Fig. 9. - -A--Undeveloped ganglia cells in the optic lobe of a dog, the eyes of -which have been sewn up immediately after birth. B--Fully developed -ganglia cells in the same region of a normal dog of the same age. -(After _Berger_.)] - -The increase in volume under the influence of stimuli further shows -the relation between the group of those solely catalytic effects -of stimulation consisting in mere alterations of rapidity of the -specific vital process, and that of the metamorphotic effects of -stimulation, which manifest themselves in qualitative alterations of -the vital process. Simple observation shows us that a qualitative -change of individual constituent processes must necessarily result -from the increase of volume of a cell, and that considering the close -correlation of all the individual processes a profound alteration of -the entire metabolism must be produced. I have already at another -place[52], [53] treated these conditions more in detail and will, -therefore, only briefly refer to them here. If we study the growth of a -ball-shaped cell, we find that the surface then increases as a square, -and the volume as the cube. It therefore follows that, by progressive -volume increase, the conditions for the interchange of substance with -the surrounding medium must become more and more unfavorable for -those cell portions situated in the interior, whereas those at the -exterior are at much greater advantage. This must lead to a constantly -increasing difference of the rapidity of the metabolic processes -between the peripheral and central portions. Accordingly, the intricate -interworkings of the individual constituent processes, the rapidity of -action of all which is intimately connected, are, therefore, followed -by corresponding alterations in the entire metabolism. Sooner or later -a stage is reached in which the individual constituent processes become -so limited that certain metabolic products, which previously were -broken down as soon as formed, can be no longer eliminated and remain -in the cell acting as foreign bodies. In this way the relative quantity -of the individual cell substances become more and more altered, and -as the course of chemical processes occurs in accordance with the -law of mass action, the whole metabolism is directed into another -channel, so that finally new constituent processes take place, which -were formerly not possible. These in their turn produce deep-seated -alterations of the relations of the cell to its surrounding medium, -etc. Hence this mere increase of volume of the cell in growth forms -the source of an infinite mass of alterations in the activities of -cell metabolism, which we briefly term its “_development_,” and which -by constant progression, leads either to a process of cell division, -and with this to a correction of existing disorder, or finally to -irreparable disturbances ending in death. In this way an inseparable -relation exists between increase of volume and the development of -living substance. We have seen, however, that the catalytic reactions -of stimulation, which at first only produce an alteration of rapidity -of the individual constituent processes, if of prolonged duration -or of frequent recurrence, secondarily effect a change of volume of -the entire living organism. One can, therefore, hardly reject the -conclusion that seeing the close interworkings of the individual part -process of metabolism, every change of rapidity of a single member, -if of prolonged duration or of frequent occurrence, must finally lead -to qualitative alterations of the entire metabolism. In consequence -there results an important dependence between catalytic stimulation and -metamorphic reaction. Indeed, it is not unlikely that the metamorphic -reactions, which are especially seen in the continued effect of weak -stimuli, result from alterations of rapidity, which the individual -members of the vital processes have primarily undergone from this -influence. - - [52] _Max Verworn_: “Die cellularphysiologische Grundlage des - Gedächtnisses.” Zeitschrift f. allgemeine Physiologie, Bd. VI, 1907. - - [53] _Max Verworn_: “Allgemeine Physiologie.” V. Aufl. 1909, pages - 649–671. - -It is perhaps expedient to cite a concrete instance in illustration. -A simple example is furnished by asphyxiation. If oxygen is withdrawn -from any living organism, the result is a depression of its oxydation -processes. Here there is primarily only a change in rapidity, -especially a retardation of oxydation processes. The metabolism, -however, proceeds, the disintegration of living substance continues, -although at a slower rate, but produces an accumulation of other -products. Whereas formerly during the existence of a sufficient supply -of oxygen an oxydative disintegration of nitrogen-free groups into -carbon dioxide and water took place, both of which could easily be -eliminated from the cell, the anaërobic disintegration furnishes only -complex products, having a higher carbon content, such as lactic acid, -fatty acids, aceton, etc. These, being more difficult to excrete from -the cell, accumulate. These asphyxiation products have in their turn a -depressing effect and so on. In this way the whole metabolism is forced -into a wrong course. The accumulation of fat in those tissue-cells -with an insufficient blood supply, as we have seen in the case of the -fat metamorphosis, is doubtless brought about in the same manner by -relative oxygen insufficiency. The fatty acids accumulate as products -of an incomplete combustion and combine with glycerine to form neutral -fats. In like manner it may be that the accumulation of amyloid -substance in amyloid metamorphosis, of lime salts in arteriosclerosis, -etc., is produced by a primary depression of the individual constituent -processes of the particular cells. - -The relation here described, of the catalytic stimuli to the production -of the metamorphic processes, leads us to the distinctions between -primary and secondary effects of stimulation. Should the general fact -be established, which has up to now only been pointed out in individual -cases, that all the metamorphic processes are merely secondary results -of primary alterations in rapidity of individual metabolic constituent -processes, _then the primary reactions of every stimulus would consist -purely in the excitation or depression of the directly concerned -constituent_. Whether or not, as may be assumed, this primary effect -of stimulation applies to _all_ stimuli, is a question which only the -future can answer. - -The metamorphic processes are not, however, the only secondary effects -of stimulation. The influence of long-continued excitation of the -functional constituent processes upon the entire cytoplastic metabolism -can be looked upon as a secondary response. Therefore, they may be -considered as a _secondary_ effect of stimulation which, in contrast to -this _primary excitation_, may be called the _secondary excitation_. - -Further: While the secondary excitation and metamorphic processes -are generally produced by the continued existing effects of weak -stimulation, we also observe as the result of a stimulus of short -duration or frequently repeated at brief intervals, but otherwise -not exceeding the physiological limits of intensity, a secondary -effect, which plays a very important part in the activity of the -organism. I refer to fatigue. Here a secondary depression is developed -in connection with the primary excitation, for fatigue of a living -organism must be characterized as a depression of activity. This case -shows that we have to distinguish between a _primary depression_, -as for example, produced by temperature reduction, withdrawal of -food, deficiency of oxygen, etc., which occurs as a direct effect of -stimulation, and _secondary depression_, which as in fatigue is an -_indirect_ result of primary excitation. - -After the cessation of a briefly catalytic stimulus, not exceeding the -physiological limit of intensity, another secondary result is observed, -which is of the greatest importance for the continued existence of the -living substance. The catalytic stimulus brings about a disturbance of -the equilibrium of metabolism, which after cessation of the stimulus is -reestablished by the living substance. In other words: recovery takes -place. This fundamental principle has been known for a long time as -the result of observation. If a skeletal muscle of our body has been -activated for a prolonged period by nerve impulses, until it has become -completely fatigued and incapable of work, a recovery takes place on -the cessation of these impulses and the muscle is again capable of -action. Likewise, as the result of strong mental activity during the -day, we are mentally fatigued in the evening; recovery, however, occurs -during the night, which results from the removal of the source of -activity. The next morning finds us refreshed. This restitution occurs -in every cell, and the return of its former capability of action, -which had disappeared under the influence of stimulation, shows that -compensation has taken place of the metabolism of rest, disturbed -by the effects of the stimulus. _Hering_[54] has aptly termed this -restitution as “_the internal self-regulation of metabolism_.” All -recovery after disease is based on this self-regulation. The physician -simply provides, by means of therapy, for the possibility of its taking -place. Healing itself is brought about by the organism. “_Natura sanat, -medicus curat._” - - [54] _Ewald Hering_: “Zur Theorie der Vorgänge in der lebendigen - Substanz.” In Lotos, Bd. 19, Prag. 1888. - -Finally, a third kind of secondary effect of stimulation claims -our interest. This is the _secondary extension of the result of -stimulation_ from the part of a living organism directly and primarily -affected by the stimulus, to the surrounding structures. All living -substance has the capability of conducting an excitation, which is -produced locally through a catalytic stimulus, to a neighboring part, -not directly affected by the stimulus. It finds its highest development -in the nerve, but in no living structure is it completely absent. This -capability has been frequently termed “_conductivity of stimulation_.” -It is more precise, however, to speak of conductivity of excitation, -for it is not the primary influencing external stimulus which is -conducted in the living substance, but the excitation which it has -produced. I have intentionally considered only the excitating effects -of stimulation, and not those of the depressing reactions, as only -excitations, not depressions, are conducted by the living substance. -These questions, however, demand a closer analysis. Here we were -concerned only with a survey of the general effects of stimulation. If -I, therefore, once more summarize the results which have been gained, -this is most clearly demonstrated by the following scheme: - - PRIMARY EFFECTS OF STIMULATION - - Excitation Depression - - Functional Cytoplastic Functional - - SECONDARY EFFECTS OF STIMULATION - - Secondary excitation Secondary depression - - Conduction of excitation, Metamorphic processes, Self-regulation of - metabolism - -This, however, is simply a scheme, like all other schemes, having for -its purpose a superficial survey of the subject. - -It brings to some extent order into the overwhelming mass of manifold -effects of stimulation but tells us nothing of the mechanism and -genesis. Our further task must, therefore, be a more thorough analysis -of this field. - - - - -CHAPTER V - -THE ANALYSIS OF THE PROCESS OF EXCITATION - - _Contents_: Indicators for the investigation of the process of - excitation. Latent period. The question of the existence of - assimilatory excitations. Dissimilatory excitations. Excitations of - the partial components of functional metabolism. Production of energy - in the chemical splitting up processes. Oxydative and anoxydative - disintegration. Theory of oxydative disintegration. Dependence - of irritability on oxygen. Experiments on unicellular organisms, - nerve centers and nerve fibers. Restitution after disintegration by - metabolic self-regulation. Organic reserve supplies of the cell. - The question of a reserve supply of oxygen of the cell. Metabolic - self-regulation as a form of the law of mass effect, and metabolic - equilibrium as a condition of chemical equilibrium. Functional - hypertrophy. - - -If it is true that all primary effects of stimulation consist either -in an excitation or depression of the metabolism, and that all other -effects of stimulation secondarily follow this primary alteration of -the metabolism of rest, then every thorough analysis of the mechanics -of reaction must have its beginning in the investigation of these -primary processes. I desire to adopt this method here and will analyze -somewhat further the _primary process of excitation_ and its immediate -and remote sequences. This will be followed later by the analysis of -the process of primary depression and its results. - -The investigation of the more obscure processes in the living substance -places us in a difficult position, for their details cannot be -observed by the unaided senses. That which we can perceive is merely -the grosser vital action, consisting of a complex combination of the -individual processes, the total result of a multitude of different -components. For this reason the conception of excitation can only be -established by observations based upon the combined vital actions, -which are produced by the effect of stimulation upon the complex -system. In the beginning, the process of excitation was studied -exclusively on the muscle and nervous system. A physical factor served -as indicator, such as muscle contraction or production of electricity. -These showed, besides the direct and primary effect of stimulation, -the secondary process of conductivity. Even graphic registration is -merely an expression of the phenomena composed of a great mass of -individual elements. The visible course of the phenomena, as shown, -for instance, by the latent period by the ascent and descent of the -curve of contraction, represents as it were a reflected picture of the -actual excitation processes similar to an object seen in a distorting -mirror; the first and the last parts of the process are not even -perceptible. Later, when organ physiology was extended into a cell -physiology the processes of excitation were studied in numerous simple -organisms, such as the plant cell, the rhizopoda, the infusoria, etc. -Later, in this way, by the use of comparative methods many essential -facts were discovered. However, even the single cell, in spite of -its minuteness, is, compared with the size of a molecule, a gigantic -system, and it would be a grave error if we should consider this system -even in its simplest aspect as homogeneous. In order, therefore, -to analyze the vital activities in the cell, cell physiology must -endeavor to penetrate into molecular conditions. For this purpose the -indicators employed must be essentially of a chemical nature, capable -of magnifying the processes of molecular dimension to such a degree -that we are enabled to base conclusions upon these not otherwise -directly perceptible phenomena. To obtain a sufficient magnification we -must necessarily place somewhat larger quantities of living substance -under observation and apply a stimulus of such frequency or length -of duration that the chemical alterations as a result of excitation -are so increased as to be plainly perceptible with the aid of our -chemical indicators. Unfortunately, we do not possess specific chemical -indicators for every individual molecular constituent process of the -cell and so cannot dispose with the help of indicators of the combined -happenings in a greater quantity of living substance. It remains for -us to obtain data concerning the cycle of excitation processes in the -living substances by the aid of the combined employment of the most -varied kinds of physical as well as chemical indicators. If we use the -most varied types of living substance of widely differing properties, -showing us the greatest variety of vital manifestations, we may hope -by the use of comparative physiological methods, even though with -difficulty, to separate more and more the essential details of the -general processes of excitation. At present we are still at the very -beginning of this task and vast fields of unexplored regions are yet -before us. But it is the unknown which has a particular fascination, -especially if we succeed from time to time in making new advances. - -If we suppose a living system in a state of metabolism of rest -influenced by an instantaneously excitating stimulus, the entire -course of excitation extends from the first alteration produced by -the stimulation until the complete restitution of the metabolic -equilibrium, and we will, therefore, differentiate individually the -successive stages of this whole process. - -The very beginning of the chain of alterations produced by the -excitating stimulus cannot be studied by any indicator. The changes -must first reach a certain dimension by conduction from the point of -stimulation before they influence even the most delicate indicators. -The application of the stimulus is, therefore, followed at first by a -measurable “_latent period_,” in which the living substance remains -apparently at rest. This latent period has been particularly studied in -muscle. After its discovery by _Helmholtz_[55] it was made the object -of innumerable investigations and met with an interest which can only -be explained by the exactness of the methods employed. Among others -_Tigerstedt_[56] has made the most thorough study of the influence of -various factors on the duration of the latent period. These experiments -have established the fact that the duration of the latent period varies -according to the intensity of the stimulus, temperature, loading or -fatigue. This is apparent when it is understood that the amount of -the alterations produced by the stimulus must ascend from the value -zero to a certain height before the changes are perceptible, and that -under various conditions this amount is, on the one hand, attained -in different lengths of time and, on the other, must reach a varying -amount before it is perceptible by means of the indicator. - - [55] _Helmholtz_: “Messungen über den zeitlichen Verlauf der - Zuckungen animalischer Muskeln and die Fortpflanzungsgeschwindigkeit - der Reizung in den Nerven.” Archiv für Physiologie Jahrgang 1850. - - [56] _Robert Tigerstedt_: “Untersuchungen über die Latenzdauer der - Muskelzuckung in ihrer Abhängigkeit von verschiedenen Variablen.” - Arch. f. Physiologie Jahrgang 1885 Suppl. - -The facts concerning the whole latent period and its dependence on -various factors would be incomprehensible if it were assumed that no -alterations whatever take place during the latent period although the -stimulus is already operative. In reality, the alterations following a -stimulus occur with imperceptible rapidity in the form of a molecular -interchange, and the latent period is simply an expression of the -fact that the primary alterations, being limited in nature, are not -registered by our indicators. - -The question first arises, In what do these first imperceptible -alterations consist? _Nernst_[57] has evolved the theory for electric -stimulus, that the primary effect produced by the electric current is -an alteration in the ion concentration on the surface of the living -substance. In fact, we know that the surfaces of all protoplasm -possess the property of semi-permeable membranes and that changes -in the concentration of ions invariably occur when an electric -current flows through two electrolytes separated by a semi-permeable -membrane, in which the anions and cations have a different rapidity -of movement. It is apparent, therefore, that such an alteration in -the ion concentration must be followed by further chemical processes -in the living substance. According to the theory of _Nernst_ the -first impetus for all further alterations, which the electrical -stimulus brings about in the metabolism of rest, is the alteration -in the concentration of the ions on both sides of the semi-permeable -membrane, which represents the surface of the protoplasm. In view of -the present findings of physical chemistry, objections can hardly be -made to this theory of _Nernst’s_. It is a question, however, in how -far this theory, especially established for the _electric_ stimuli, -can be applied to other forms of stimuli and their action. It cannot -be denied that the degree of dissociation of an electrolyte can be -altered by very different factors, such as heat, light, chemical -processes, etc., and in that the surfaces of the protoplasm, acting -as semi-permeable membranes, bring about a selective action on the -passage of the ions, there arises the opportunity for the development -of difference of electrical potential on both sides, and for further -chemical alterations in the protoplasm. These observations, however, -require further experimental investigations in many fields, before -we are justified in extending the _Nernst_ theory of the manner of -action of the electric stimuli to a general explanation of the primary -alterations produced by all stimuli in the living substance. For the -present we must confine our observations to _those_ alterations which -are known to be responses to an excitating stimulus; these are the -chemical alterations in the metabolism of rest in the living substance. - - [57] _Nernst_: “Zur Theorie der electrischen Reizung.” Nachrichten - der Königl. Gesellsch. d. Wissensch. zu Göttingen. Math. physik. - Klasse 1899. - -If it is asked, which members of the entire metabolic chain are -increased primarily by the stimulating excitation of a vital system, we -should not be able to answer this question generally for _all_ living -systems. To begin with, it appears highly probable that the various -forms of vital substances in this respect act quite differently. It is -to be regretted that, up to the present, this question has not been -treated from a comparative standpoint. This inquiry should be extended -to the greatest possible number of organisms. Still there is enough -material at hand, obtained from the muscles, glands, ganglion cells, -nerve fibers and plants, to show that the complexity is by no means so -great as one might at first assume. - -In considering the two stages of metabolism, assimilation and -dissimilation, in their entirety, it appears as a very remarkable fact, -that nearly all stimuli produce primarily a _dissimilative_ excitation. -We are only acquainted with a primary _assimilative_ excitation, -that is, an augmentation of the building up processes, in short, the -_formation_ of living substance, occurring as a primary result of -stimulation, following increased introduction of _foodstuffs_ extending -over a prolonged length of time. With this exception it cannot be -proved that _any_ other stimuli, either especially those operative -in the activity of the animal organism or any of the physiological -nerve impulses which regulate the actions of the different organs and -tissues, bring about primarily an assimilative excitation, which leads -to an increase of new formation of living substance. The much-discussed -teaching of the existence of the trophic nerves has not given us a -single case in which there was positive proof that a nerve impulse -brought about a primarily assimilative excitation. I have endeavored -for nearly fifteen years to discover such a case. My efforts have -been, however, without avail. In the most recent critical review by -_Jensen_[58] on the subject of the trophic nerves, the same conclusion -is reached although certain facts, as, for instance, the excitation -of assimilative processes in the green plant cell, produced by light, -seems at the first glance to clearly demonstrate a primary excitation -of the building up processes resulting from a stimulation. Nevertheless -closer observation invariably shows that these conditions are much more -complicated and that primarily assimilative excitating reaction of -the stimulus cannot be conclusively shown. There remains, therefore, -as a primary assimilative excitating stimulus only the increased -introduction of nutrition in a living organism. This excitating effect -on the assimilative portion of metabolism is, as we shall see later, a -simple manifestation of the law of mass action. - - [58] _Paul Jensen_: “Das Problem der trophischen Nerven.” - Medicinisch-naturwissen-schaftliches Archiv. Bd. II, 1910. - -As a result manifold effects of excitating stimulation, which seemed -possible at a first glance, are already considerably restricted. -The great mass of excitating stimuli produce an acceleration of the -dissimilative processes of the metabolic chain. But here our former -observations have already shown that certain constituent processes -are especially responsive and very readily increase as a result -of the most varied adequate and inadequate stimuli. These are the -“_functional_” members of metabolism. These members are particularly -labile, so that they are always affected by every influence to which -the system is subjected in the form of a stimulus. The functional -portion of metabolism of the muscle, which is particularly labile -and is always primarily affected by stimulation, consists as -demonstrated in increase of formation of carbon dioxide and water, and -in the disintegration of the nitrogen-free groups. The innumerable -observations on metabolism during the stage of the activity of the -muscle, as those of _Hermann_, _v. Frey_, _Fletcher_, _Johannson_, -_Thunberg_, and many others on the individual muscle, and those -by _Voit_, _Fick_ and _Wislicenus_, _Pflüger_, _Rubner_, _Zuntz_, -_Lehmann_ and _Hagemann_, _Bernstein_ and _Löwy_ and others on the -muscle of the entire organisms, have sufficiently proved this fact. -However, we should not apply in detail the conditions existing in -the _muscle_ to _all_ living substance. Comparative methods show us, -rather, that the functional portion of metabolism is very differently -involved in various forms of living substance. The formation of carbon -dioxide and water is constant in nearly all forms of living substance. -We must, however, exclude certain micro-organisms, which have adapted -themselves to unusual vital conditions. Further, there appear in -some forms manifold special constituent processes consisting in a -disintegration of living substance which are in part converted into -very complex combinations. In the gland cells this type is represented -in an especially high degree. Here the functional disintegration leads -to excretion of proteins, glycoproteins, nucleoproteins, cholic acid, -enzymes of various kinds, all of which are complex and at the same time -nitrogenous organic combinations. This fact must not be lost sight -of. The origin of these special members, however, for the present is -completely unknown, while on the other hand, it is self-evident that -the general and constant constituents of the process of excitation -must claim a first place in our interest. It is just at this point, -therefore, that we must endeavor to penetrate somewhat more deeply into -the mechanism of the excitation process and analyze in greater detail -the acceleration of the functional constituent parts of metabolism -produced by the stimulus bringing about the formation of carbon dioxide -and water. - -The question arises: _By what means is the particular labile state of -just this constituent part of functional metabolism conditioned?_ The -lability of the functional portion of metabolism, excitated by the -stimulus, resembles the processes in the disintegration of explosive -combinations. Iodide of nitrogen, for instance, in a manner similar -to the living substance in the state of the metabolism of rest, -constantly disintegrates even without the influence of an impact. The -disintegration is suddenly enormously increased by the result of a jar. -An explosion follows. In a like manner the functional metabolism of -rest is explosively excitated by the stimulus, the transformation of -the energy involved likewise bears a similar relation. - -In both instances the transformation of energy, _constant_ in the -resting state, is by the impact of the stimulus suddenly increased. -The dynamic method of investigation of the excitation process with its -physical indicators, forms, therefore, in many respects an excellent -addition to the chemical analysis. A development, that is, exothermic -formation, of energy can only occur in a chemical process when the -chemical affinities which are to be combined are stronger than those -which have been separated. When this process is brought about by a -simple impact, the energy value of which bears no relation to that of -the quantity of energy in the process itself and which occurs with -explosive rapidity, then it can be simply a question of a liberation -process, that is, a process by which the impact brought about a -conversion of latent chemical energy into that of kinetic energy. -The comparison of the functional excitation process with that of an -explosion does not, therefore, consist in a merely superficial analogy, -but is founded on the same dynamic principles. - -When we study the chemical process which occurs in the explosive -transformation of potential into kinetic energy we find two types of -chemical processes. The first type includes the synthetic processes. -For this, the synthesis of water from explosive gas may serve as a -simple example. Here the weaker affinities in comparatively simple -molecules (H + H and O + O) are separated and stronger affinities -are combined in the formation of more complicated molecules (H + O + -H). The second type represents the process of cleavage. As example -for the latter, the explosive disintegration of nitroglycerine may -be quoted. Here the atoms, held together in a complex molecule by -weaker affinities, are changed by transposition of nitroglycerine. For -instance, the hydrogen atoms loosely combined with carbon enter into -strong combinations with oxygen and the oxygen loosely combined with -the nitrogen enters into strong combination with carbon, so that water -and carbon dioxide are formed and nitrogen and oxygen set free. - -[Illustration] - -In the functional disintegration of living substance, the last type is -realized. Living substance contains loose complex combinations, and we -know that functional disintegration is accompanied by the consumption -of these organic combinations. In the functional disintegration of -muscle substance the nitrogen-free groups are concerned, and we must, -consequently, first consider the carbohydrates. However, without -further study we should not generalize from that which is true in -the case of muscle. There are other forms of living substances which -contain different combinations, which disintegrate as a result of the -contact of a stimulus and yield carbon dioxide. A clue as to which -combinations in individual cases undergo disintegration as a result -of excitating stimulation, is furnished by the metabolism of rest -in the particular substance. Plants and micro-organisms have been -investigated more thoroughly in this connection than animals. Plant -physiology has demonstrated that the material employed for the CO_{2} -formation and with it the production of energy is carbohydrate, but -that, on the other hand, various plant organisms and protistæ also use -a quantity of other substances, such as fats and protein, indeed even -such comparatively simple organic combinations as alcohol, formic acid -and methane. It may be accepted that in all these various instances of -excitation of the functional metabolism as a result of stimulation, -the specific respiratory material of the substance concerned is used -in greater amount in the decomposition and likewise invariably yields -carbon dioxide. - -The point of most essential interest for the analysis of the excitation -processes is, above all, the _mechanism_ of the organic combustion and -the associated energy production. Here we may base our observations -on the disintegration of carbohydrates, which is most extensive in -the animal as well as in the vegetable kingdom. We may now ask how -dextrose, for instance, disintegrates in the living system into carbon -dioxide, for it is this, or a sugar of similar chemical nature, which -is generally concerned. Plant physiology, which here, as in many other -respects, is in advance of animal physiology, has indicated two ways -by which this can be accomplished in the living substance. One is -oxydative, the other, _an_oxydative disintegration. - -In the _oxydative disintegration_ of dextrose, taking place in -aërobic organisms, if sufficient quantities of oxygen are present, -there occurs a splitting up of the carbohydrate molecule, as a result -of the introduction of oxygen, into simpler substances and finally -into carbon dioxide and water, just as the dextrose molecule, when -subjected to oxydative processes, is split up into simpler molecules. -In the living substance the oxydases play the important rôle of oxygen -carriers. It cannot be denied, however, that up to now no carbohydrate -splitting oxydases have been obtained from living substance. This, -of course, does not prove its nonexistence. But this deserves -consideration in connection with an assumption very widely spread -among plant physiologists in regard to the aërobic disintegration of -the carbohydrate molecule, which I shall touch upon presently. If we -suppose that oxydases exist, which bring about primarily the oxydative -disintegration of the dextrose molecule, its first point of attack -must obviously be sought in the aldehyde group. Here would be situated -the activator, as it were, for the whole carbon chain, from which, as -by a spark, the entire series of links would be ignited. - -In an _anoxydative disintegration_ of dextrose as observed in -anaërobic as well as in aërobic organisms, provided the latter have -an insufficient supply of oxygen, the dextrose molecule, by enzymic -action as a result of the splitting off of carbon dioxide, is converted -into substances having a comparatively large carbon content. The -best-known example of this anoxydative disintegration is the formation -of alcohol by fermentation in which the dextrose molecule is split -up by the yeast into alcohol and carbon dioxide. (C_{6}H_{12}O_{6} = -2C_{2}H_{5}OH + 2CO_{2}.) Instead of the production of alcohol and -CO_{2} we may have other enzymic actions with the formation of other -carbon-containing disintegration products, such as lactic acid, fatty -acids, hydrogen, etc. Of course in such an anoxydative disintegration, -which does not lead to the formation of such simple combinations as -carbon dioxide and water, the _quantity_ of energy set free is much -less in amount than in complete _oxydative_ decomposition, the energy -production of the alcohol fermentation being only 11 per cent of the -latter. In order to produce the same amount of energy as in the former, -a much greater number of molecules is required. We find, therefore, -that the anoxydative type of disintegration develops either only where -the respiratory substances are present in sufficient amounts, as for -instance, in the case of yeast cells, existing in nutritive solutions -rich in sugar; or where the chemical and energy transformations occur -only to a limited extent, as, for example, in the presence of low -temperature. In this respect _Pütter_[59] has demonstrated in the -leech that at a higher temperature, the oxydative, at a lower, the -anoxydative, decomposition predominates. These are important facts -in that they show us the superiority of oxydative to that of the -anoxydative disintegration in the cell economy. This is of particular -interest when we consider those organisms in which great demands are -made upon the capability of movement, above all, in homothermous -forms, the metabolism of which takes place on a continuously high -level. For this reason, in homothermous animals the respiration of -oxygen is the almost exclusive source of energy production. - - [59] _A Pütter_: “Der Stoffwechsel des Blutegels (Hirudo medicinalis - L).” I Theil. Zeitschrift für allgemeine Physiologie Bd. VI, 1907. II - Teil. ebenda Bd. VII, 1908. - -The previously mentioned facts make it clear that in one and the same -form of living substance both oxydative and anoxydative decomposition -processes are found, depending upon the conditions. This does not -apply merely to the individual organic forms, such as the facultative -anaërobic organisms, but generally to all aërobic living substance. -If oxygen is withdrawn from an aërobic organism the disintegration -does not cease in consequence. In place of the oxydative we have -anoxydative decomposition. The various aërobic organisms are, however, -adapted in very different degrees to the possibility of an anaërobic -existence. While the facultative anaërobic organisms can continue to -exist without oxygen, the homothermous animals become asphyxiated in -a very short time in the absence of oxygen, in that they are poisoned -by the products of the anoxydative decomposition, which are eliminated -with much more difficulty than carbon dioxide and water. The fact, -however, that disintegration also continues in an anoxydative form, -if oxygen is withdrawn, has given rise to the thought, which has been -accepted especially by plant physiologists with great readiness, that -the decomposition of organic respiratory substances of the aërobic -organisms invariably takes place in two stages; in that the dextrose -molecule--to again use this as an example--is split up first by an -enzyme into larger fragments, which then in the second stage of the -process undergo combustion to the formation of carbon dioxide and -water. Such a possibility cannot be repudiated. I wish, however, to -state that one should be very reluctant in generalization of this -assumption for all aërobic organisms. The types of metabolism in -the different organisms are so manifold and of such immense variety -that we should be very careful in our generalizations before being -in possession of material extending over a great number of groups of -organisms. Above all, it does not seem justifiable to also accept -this type for life existing at higher temperatures, and still less -to apply it to those instances in which the production of energy -following stimulation is suddenly increased to great amounts. Let us -suppose that the disintegration process occurs in two phases, the first -of which after the type of the fermentation of dextrose separates -the molecule into larger fragments, while in the second phase these -fragments are split up through oxydation into the formation of carbon -dioxide and water. We can then say with certainty that in the first -stage only a comparatively _small_ amount of energy production occurs, -for energy production by enzymic processes of this kind is never -great; the second phase, on the other hand, must be associated with -a very considerable energy production, for by the addition of oxygen -and the formation of carbon dioxide and water the strongest affinities -possible are combined. With this assumption in certain cases, as, for -instance, in the sudden production of energy in muscle contraction, -which necessarily occurs in the purely oxydative phase of the whole -process, the view is forced upon us, that, in these cases, the entrance -of oxygen into the molecule from the very beginning, even the first -impact, produces oxydative decomposition of the whole molecule. The -view that, in the reactions of warm-blooded animals, which occur with -great rapidity and considerable energy production, the oxygen primarily -explosively breaks up the whole carbon chain, certainly presents no -more difficulties than the supposition that the simpler substances -are attacked secondarily, provided sufficient oxygen be present. -This method would be obviously the simplest. This is, however, mere -speculation and a definite decision between the two possibilities -cannot be made at present. However, whether the process takes place in -two phases, an anoxydative and an oxydative, or simply in an oxydative -phase, in _any case, the sudden discharge of energy in the aërobic -organism set free by the stimulus, is brought about by the addition of -oxygen_. - -This is a highly important fact and as such requires the most thorough -confirmation, and is best accomplished by the investigation of the -state of excitation of aërobic substances on the withdrawal of oxygen. -Experience gained by observation in this respect on a great number -of living substances shows that excitability decreases upon the -withdrawal of oxygen. In this connection I should like to cite some -particularly significant instances. - -[Illustration: A - -B - -Fig. 10. - -_Rhizoplasma kaiseri._ A--Under normal conditions. B--In an atmosphere -of pure hydrogen.] - -During a sojourn at the Red Sea in 1894–95 I was able to establish this -dependence in the single-celled organism, the _Rhizoplasma Kaiseri_, -a large naked orange-colored rhizopod. (Figure 10, A.) Mechanical -stimulation, which under normal vital conditions of these organisms -brings about contraction in the long-branched pseudopods, becomes -ineffective with a cessation of the movement of protoplasm, when -oxygen is removed and is replaced by a stream of hydrogen. (Figure -10, B.) With renewed introduction of oxygen there is a return of the -protoplasmic movement and entire recovery takes place. - -This dependence of irritability upon oxygen is most clearly -demonstrated in the _nerve centers_. For this purpose I have employed -the spinal cord of the frog.[60] A canula is introduced and fixed -into the aorta of the animal and the blood is replaced by a current -of oxygen-free saline solution. The centers of the spinal cord are -thereby wholly isolated from the supply of oxygen. The indicator for -the irritability here used is reflex excitation from the skin to the -gastrocnemius, or better, stimulation of the central stump of the -sciatic nerve with single induction shocks, bringing about reflex -response of the triceps. The reflex may be considerably augmented by -increasing the reflex excitability of the spinal cord by poisoning -the animal with strychnine. On testing the reflex excitability at the -beginning of the experiment it will be found that the reaction to -each individual stimulus consists, in consequence of the strychnine -poisoning, of a long-continued maximal tetanus. The longer the -deficiency of oxygen continues, the briefer become the tetanic -reflex contractions following a single stimulus. Soon reflex tetanic -responses are merely short single contractions, which decrease more -and more with the continuance of oxygen deficiency. Finally, the same -stimuli which previously produced strong tetanic contractions of -long duration are altogether without effect. Although by increasing -the intensity of stimulation brief contractions can again be brought -about, irritability decreases more and more, until at last even the -strongest stimuli remain without result. If the oxygen-free saline -solution is now replaced by one saturated with oxygen, or blood of the -ox, rendered arterial, the excitability returns within a few minutes -and soon reaches the maximal height which it possessed under the -influence of the strychnine poison. Even the weakest single stimuli now -again produce tetanus. The same process reoccurs, if the fluid used -for transfusion containing oxygen is again replaced by an oxygen-free -saline solution. In this way, by repeated change of the perfusing -fluid, we can demonstrate in the most positive manner this alteration -in irritability, the result of the alternate presence and removal of -oxygen. This is perhaps the best example of the close dependence of -irritability on oxygen. - - [60] _Max Verworn_: “Ermüdung Erschöpfung und Erholung der nervösen - Centren des Rückenmarks. Ein Beitrag zur Kenntniss der Lebensvorgänge - in den Neuronen.” Archiv. f. Anat. u. Physiologie. physiol. Abteil. - 1900 Suppl. - - The same: “Ermüdung und Erholung.” In Berliner Klin. Wochenschrift - 1901. - -This same fact can be observed with equal clearness in the nerve. At my -suggestion _H. v. Baeyer_[61] showed as the result of investigations -made in the Göttingen laboratory the dependence of irritability of the -nerve upon oxygen for the first time. By employing as the method the -ascertainment of the threshold of stimulation I then made a closer -study of the alterations in irritability during asphyxiation. These -observations were soon after continued by _Fröhlich_.[62] The method -is as follows: the nerve of a nerve-muscle preparation of the frog -is drawn through a glass chamber which is made completely air-tight -and containing platinum electrodes. The air in the chamber is then -displaced by a stream of pure nitrogen. (Figure 11.) On testing that -part of the nerve situated within the glass chamber with single break -induction shocks it can be observed that its irritability, measured by -the threshold of stimulation for muscle contraction, decreases more and -more, until after the lapse of some hours, the stimulation required is -so strong as to reach the region of the “Stromschleifengrenze.” If in -place of the stream of nitrogen, air or pure oxygen is now allowed to -flow through the chamber, the nerve recovers almost instantaneously. -Within the space of a minute its irritability has risen again to -its full height and the same experiment, with the same result, can -be repeated. Finally, as _Fillié_[63] has shown, the like result is -obtained when the nerve is asphyxiated in a fluid medium. - - [61] _H. v. Baeyer_: “Das Sauerstoffbedürfniss des Nerven.” - Zeitschrift f. allgemeine Physiologie Bd. II, 1903. - - [62] _Fr. W. Fröhlich_: “Das Sauerstoffbedürfniss des Nerven.” - Zeitschrift f. allgem. Physiologie Bd. III, 1904. - - [63] _H. Fillié_: “Studien über die Erstickung des Nerven in - Flüsigkeiten.” Zeitschrift f. allgemeine Physiologie, Bd. VIII, 1908. - -[Illustration: Fig. 11. - -Arrangement for asphyxiating the nerve. A--Gasometer containing pure -nitrogen. B and B_{1}--Vessels for washing the gas. C--Ether chamber -for eventual experiments with narcosis. D, D_{1} and E--Glass faucets. -F--Moist chamber. G--Asphyxiation chamber. H and H_{1}--Two pairs of -electrodes over which the nerve is laid. I--Nerve muscle preparation. ] - -All these facts, the number of which indeed could be increased greatly -for other aërobic forms, suffice to establish the fundamental -importance of oxygen to the maintenance of irritability of living -substance. _Oxygen is of greatest importance for a high degree of -irritability in all aërobic organisms._ All living systems which are -characterized by a great capability of activity and evince strong -responses under the influence of stimulation, such as the vertebrates -and insects, are necessarily aërobic, whereas the living organisms -of pronounced anaërobic character, as some bacteria, yeast cells, -parasitic organisms, etc., manifest on the average much less capability -of activity. - -Finally, to briefly summarize the foregoing, the following picture -presents itself of disintegration produced by a momentarily acting -stimulus. It is immaterial how the stimulus produces an excitating -effect in the given case, whether through changes in the ion -concentration of the living system, by increase of intramolecular -atomic movement or in any other manner, it invariably accelerates -the disintegration of the complex molecules concerned in functional -metabolism, the nature of which varies in the special cases. In the -great majority of instances nitrogen-free organic combinations serve as -material for the functional constituent members of metabolic processes. -In the anaërobic organisms this decomposition takes place anoxydatively -with the coöperation of enzymic processes, and as larger fragments -generally result from the disintegration of the complex molecule, -the production of energy is accordingly smaller. The disintegration -of aërobic organisms, on the other hand, occurs in the form of an -oxydative splitting up of the complex molecules into carbon dioxide -and water so that the production of energy attains a high value. -The details concerning the manner in which the individual stages of -this decomposition take place and the interactions by which its end -products are reached is at present beyond our knowledge. It would be a -mistake to generalize in this connection from the behavior of certain -groups of organisms. The assumption that under certain conditions the -disintegration occurs in two phases, the splitting up resulting from -enzymic action of the complex molecule into larger fragments, followed -by an oxydative splitting up of these into carbon dioxide and water, -can in no case as yet be justifiably applied to all conditions and all -aërobic organisms. This is more or less the impression which we derive -of the functional excitation process as seen today. - -Under normal conditions the functional excitation is at once followed -by a succession of secondary processes, the “_self-regulation of -metabolism_.” Self-regulation after a functional excitation is a fact -demonstrated by experience. But in what manner does it take place in -detail? - -As the functional constituent members of metabolism involve a -disintegration of the nitrogen-free atom groups, the functional -self-regulation must necessarily furnish in sufficient quantity and -in proper form the carbon, hydrogen and oxygen atoms, which have -been removed in the production of carbon dioxide and water. This is -accomplished, as is well known, by the food and the intake of oxygen. -It is of importance to the maintenance of living substance that after -every functional activity it is as soon as possible again capable of -reaction. Therefore, it is absolutely necessary that this material is -in the proper place, where building up is essential, and is at the same -time constantly in proper form. Indeed, the restitution of the original -state follows under favorable conditions with lightning rapidity, -although varying in different forms of living substance. This occurs in -the nerve in an extremely short time. From this it might be supposed -that the living system by accumulating a store of the necessary -compensation substances in suitable form, had made itself independent -to a certain degree of the frequently varying supply of material -obtained from the medium. - -This may be held as the proper view, first with regard to compensation -substances. The fact that living organisms can under some conditions -remain for a lengthened period in a state of starvation, without losing -their capability of activity, can only be explained by the presence -of a great quantity of reserve supplies of compensation substances. -In the course of work in the laboratory every physiologist has become -acquainted with the fact that frogs which have been kept without food -for a year, although much reduced in weight, are still capable of some -muscular activity. - -[Illustration: A - -B - -Fig. 12. - -Motor ganglia cells from the spinal cord of the frog. A--In normal -state. B--After an asphyxiation lasting 8 to 9 hours. (After _Gordon -Holmes_.)] - -[Illustration: Fig. 13 - -_Paramecium aurelia._ A--In normal state. B--In a state of starvation.] - -Organs and tissue, which are cut off from all food supply through the -blood and lymph, may remain active for many hours. _H. v. Baeyer_[64] -has shown that the ganglion cells in the frog, in which saline -solution was transfused at room temperature and containing no trace of -organic substances and where irritability has been increased to the -maximal by means of strychnine, were capable of strenuous work for -nine or ten hours before losing responsivity. The nerves and muscles -of the animal retain their excitability for even a longer period -under the same conditions. Indeed, we have histological evidence of -the existence of organic reserve material in the various cells in -the form of embedded bodies in the protoplasm. As for instance the -disappearance of the _Nissl_ granules in the ganglion cells following -great activity,[65] (Figure 12), or that of the granules in infusoria -cells during starvation.[66] (Figure 13.) We assume that a certain -amount of organic foodstuffs in a state properly prepared is present in -the cell. As the amount of these prepared substances is consumed, new -quantities of stores, having undergone various preparatory processes, -among which the enzymic actions may be considered to play a chief rôle, -are brought into that form in which they appear suited to fill the gap -produced by disintegration. Plant physiologists in particular have here -again furnished us with some essential data for the assumption of -the existence of such processes which regulate the transformation of -reserve substances as well as its extent. _Pfeffer_[67] has found in -several fungi and bacteria that there exists a compensation between the -diastatic breaking down of the carbohydrates stored as reserve material -and the quantity of dextrose introduced. He further found that the more -the reserve substance is split up into dextrose the less of the latter -is introduced from without and _vice versa_. _De Bary_[68] some time -ago also observed in the _bacillus amylobacter_ an analogous relation -between the enzymatic cellular digestion and the quantity of dextrose -introduced with the food. An equilibrium, therefore, exists between -the required amount of dextrose and the extent of enzymic splitting up -processes of the reserve material. A great number of similar processes -have been observed. Even though the details of the whole preparatory -assimilative processes are beyond our knowledge we can still say with -certainty that, on the one hand, everywhere great quantities of organic -reserve substances are always present in the cell, and on the other, -that these substances are subjected to a transformation into suitable -material for building-up processes, the extent of which is controlled -according to need, by the processes of self-regulation. - - [64] _H. v. Baeyer_: “Zur Kenntniss des Stoffwechsels in den nervösen - Centren.” Zeitschr. f. allgem. Physiol. Bd. I, 1902. - - [65] _Gustav Mann_: “Histological changes induced in sympathetic - motor and sensory nerve cells by functional activity.” In Journ. of - Anat. and Physiol. 1894. Further: _Gordon Holmes_: “On morphological - changes in exhausted ganglion cells.” Zeitschrift f. allgem. Physiol. - Bd. II, 1903. - - [66] _Wallengren_: “Inanitionserscheinungen der Zelle.” Zeitschrift - f. allgem. Physiol. Bd. I, 1902. - - [67] _W. Pfeffer_: “Ueber die regulatorische Bildung von Diastase.” - In der math. phys. Klasse d. Königl. Sächs Ges. d. Wiss. zu Leipzig - 1896. - - [68] _De Bary_: “Sur la fermentation de la cellulose.” In Bull. de la - Soc. bot. de France 1879. - -Entirely different is the question if the cell also possesses a -reserve store of oxygen. In this respect views have widely differed, -and even today no conformity of opinions has been arrived at. The -fact that many purely aërobic organisms and tissues can exist under -complete exclusion of oxygen for a longer or shorter period, retaining -their excitability and producing carbon dioxide, has for a long time -led a great number of investigators, such as _Liebig_, _Matteucci_, -_Engelmann_, _Pettenkofer_ and _Voit_, _Claude Bernard_, _Verworn_, -_H. v. Baeyer_ and others, to the supposition that a reserve store -of oxygen must exist in the living substance which maintains its -excitability for a time. More recent information, however, of the -transition of the oxydative to the anoxydative disintegration under -a deficiency of oxygen, as can be observed in plants and certain -invertebrate animals, indicates that here also there is the possibility -of another explanation of these facts. Various attempts have been made -to solve the problem if reserve oxygen is present in the cell or not. -The experiments of _Rosenthal_,[69] carried out with his respiration -calorimeter, seemed to point directly to an oxygen reserve in the -organism of the mammal. He observed that during respiration in an -atmosphere rich in oxygen the respiratory quotient (CO_{2} : O_{2}) -became lower than in ordinary air, that is, that oxygen, and that -indeed in considerable quantity, must be retained in the organism. -Nevertheless _Falloise_[70] found that when rabbits, which had -been kept in an atmosphere containing 80 per cent of oxygen, were -asphyxiated, the time necessary to produce death was no longer than in -animals which had been kept previously in ordinary air. The correctness -of the observations of _Rosenthal_ have been disputed by _Durig_.[71] -_Winterstein_[72] also, employing the microrespiration methods of -_Thunberg_ upon the spinal cord of the frog, believed that he had found -proof that an oxygen reserve cannot take place. He reasoned thus: If -the cells of the spinal cord contain reserve oxygen, which is used up -when pure nitrogen only is breathed, then it necessarily follows that -after reintroduction of oxygen, following asphyxiation, a definite -quantity must be stored up again as reserve. In consequence, the -respiratory quotient following the intake of oxygen after asphyxiation -should be smaller than when the animal is in air. He found, however, -that the respiratory quotient does not essentially change and concluded -from this that storage of oxygen does not take place. In these -experiments, however, there exists no certain indicator as to the state -of the spinal cord during asphyxiation and recovery in the given case. -The spinal cord may be severely injured and even undergo degeneration -during asphyxiation, and the recovery following the reintroduction of -oxygen may be either incomplete or nil, without there being a method -for its determination. Apart from this, _Lesser_[73] has already -emphasized, in opposition to these experiments, that the respiratory -quotient in recovery is no criterion to guide us. It is immaterial -whether during asphyxiation oxygen respiration occurs following a -reserve supply, or that an anoxydative formation of carbon dioxide has -taken place, for in both instances the respiratory quotient would be -less _after_ asphyxiation when there is again an oxygen supply. It is, -therefore, quite impossible to decide the question by the employment -of this method. For this reason _Lesser_ has attempted to solve the -problem by means of quite another method, and was convinced that he -had refuted finally the belief in the existence of reserve oxygen. His -method consists in the employment of the _Bunsen_ ice calorimeter, by -which he determines the heat production of frogs, kept first in air, -then in nitrogen, and at the end of each experiment ascertaining the -amount of output of carbon dioxide, respectively in air and nitrogen. -He found that the quantity of heat, calculated in terms of 100 grms. -body weight per hour, produced in nitrogen was considerably less than -that under corresponding conditions in air, but that the production -of carbon dioxide, on the other hand, during the first hours in -nitrogen was doubled in amount, as compared to that in air. From this -he concludes that the carbon dioxide formation in nitrogen must be -different from that in air, as it is associated with a reduced heat -production. In other words, carbon dioxide formation, while the animal -is in a nitrogen atmosphere, does not have its origin in oxydative -processes at the cost of stored up oxygen. I regret that I am unable to -accept these arguments as conclusive evidence against the assumption -of an oxygen reserve, as this question cannot be decided by the use of -such methods. _Lesser_ does not measure the amount of carbon dioxide -until the end of his experiments, that is, he learns merely the -entire carbon dioxide production during a period of many hours. No -conclusions can be drawn from this as to the conditions existing in the -first period of time, directly after the animals have been subjected -to an atmosphere of nitrogen. It is quite possible that subsequent to -the change to nitrogen an oxydative carbon dioxide formation may have -continued in decreasing degree, without this being shown in the final -result. The problem of the existence of a reserve supply of oxygen is -in no way solved by these experiments. - - [69] _Rosenthal_: “Untersuchungen über den respiratorischen - Stoffwechsel.” Arch. f. Anat. u. Physiologie physiolog. Abt. 1902 und - Suppl. 1902. - - [70] _Falloise_: “Influence de la réspiration d’une atmosphère - suroxygéné sur l’absorption d’oxygène.” Traveaux du laborat. de - physiol. de L. Fredéric Liège, T. VI. - - [71] _Durig_: “Ueber Aufnahme und Verbrauch von Sauerstoff bei - Aenderung seines Partialdruckes in der Alveolarluft.” Arch. f. Anat. - u. Physiol. physiol. Abt. 1903 Suppl. - - [72] _Winterstein_: “Ueber den Mechanismus der Gewebeatmung.” - Zeitschr. f. allgem. Physiol. Bd. VI, 1907. - - [73] _Lesser_: “Die Wärmeabgabe der Frösche in Luft and - sauerstofffreien Medien. Ein experimenteller Beweis dass die CO_{2} - Production der Frösche im sauerstofffreien Raum nicht auf Kosten - gespeicherten Sauerstoffs geschieht.” Zeitschr. f. Biologie Bd. 51, - 1908. - -In assuming the presence of a reserve supply of oxygen in the cell we -must above all entertain no false conception as to its amount. This -must be, as I have often had occasion to emphasize, exceedingly small -and in no way comparable with the great masses of organic reserve -substances contained in the cell. The assumption, especially for the -_nerve centers_ of the frog, that the excitability remains after -complete exclusion of oxygen must be looked upon as demonstrating a -reserve supply of oxygen, would oblige one to suppose the presence of -such a small store of oxygen that it would be completely exhausted -by continued activity in room temperature within ten to twenty-five -minutes. Strychninized frogs, in which the blood has been replaced -by an oxygen-free saline solution, lose, as I have shown,[74] their -excitability completely within ten to twenty-five minutes after the -blood has been displaced. Nevertheless the assumption of the existence -of a small oxygen supply in the cell can hardly be evaded. It must not -be imagined that the moment the blood of the frog has been replaced -with an oxygen-free solution, there is not a trace of oxygen left in -the organism. Were such the case, the irritability, if measured by the -extent of the response, would sink _momentarily_ to a very low level, -for the anoxydative disintegration processes are associated with an -incomparably smaller production of energy than those of oxydative -disintegration. We see, however, that the irritability in the muscles, -nerves and nerve centers of the frog even after the complete withdrawal -of oxygen at first remains practically at the former height and only -very gradually decreases. Above all it would seem to me to be in the -interest of the preservation of the organism and especially of those -parts in which there is a high energy production and particularly those -substances in which energy production predominates, that the material -necessary for its formation is always at its disposal in sufficient -quantity. Otherwise the capability of action of the organism would be -impaired at every moment or at least suffer great fluctuations. - - [74] _Max Verworn_: “Ermüdung, Erschöpfung and Erholung der nervösen - Centra des Rückenmarks.” Arch. f. Anat. u. Physiol. physiol. Abt. - Suppl. 1900. - -In accordance with this we must suppose that under physiological -conditions all those substances required to replace the disintegrated -molecules are always present in the cell in sufficient quantity and -suitable form to replace at once those lost by excitation. Further, -without doubt, in the organism which is always aërobic, oxygen must -be present in certain quantities to assure at any moment oxygen -replacement following oxydative disintegration, to guarantee sufficient -amount for succeeding stimulation. - -A further question arises: How is it that the material lost in -disintegration is always replaced in just sufficient quantity to -establish the metabolic equilibrium? In short, how are we to understand -in a mechanical sense the self-regulation of metabolism? - -In the preservation of metabolic equilibrium, we have a process before -us, the principle of which is nowadays restricted to living substance. -In my “Biogen hypothesis,”[75] I have associated the self-regulation -of metabolism with the chemical equilibrium in interreacting masses. -I have considered the metabolic self-regulation as the expression of -the formation of a mass equilibrium between the quantity of foodstuffs -and the quantity of a hypothetical combination of living substance, -the _biogen_, which continuously disintegrates and builds up again of -its own accord. In fact, however, we have in the chemical equilibrium -of reacting mixtures in the non-living world, a principle which is -completely analogous to the self-regulation in living substance. The -chemical facts are, indeed, well known. If we take the classical -example of the formation of ethylacetat from acetic acid and alcohol, -we have a case of an inanimate system, in which the amounts of the -reacting substances are in constant equilibrium. The reaction following -the mixture of equal amounts of alcohol and acetic acid is as follows: - - [75] _Max Verworn_: “Die Biogenhypothese.” Jena 1903. Compare also - _Max Verworn_: “Allgemeine Physiologie.” V. Aufl. Jena 1909. - - 1/3 Mol. C_{2}H_{5}OH + 1/3 Mol. CH_{3}COOH - = 2/3 Mol. CH_{3}COOC_{2}H_{5} + 2/3 Mol. H_{2}O. - -In this reaction there is an alteration only in the absolute quantity -of the individual constituents but never in the relative amount. In the -living system we have a completely analogous instance, which apart from -its course differs from the inanimate example merely in the following -points: In the first place, certain quantities of substances reacting -on each other are continually introduced into and certain reaction -products continually removed from the living system. Secondly, the -reacting mixture of the living substance is not homogeneous, and at -the same time is more complicated than that of the inanimate example. -Thirdly, the sum total of the reaction is not reversible in its -entirety. The question arises, should any essential difference between -metabolic self-regulation and the maintenance of chemical equilibrium -be assumed upon this statement? I must confess that this does not -appear to me to be the case. The fact that organisms exist in a stream -of substances by which their nutrition is introduced and the metabolic -products removed, cannot have any influence on the state of equilibrium -so long as the conditions are again and again replaced in the same -manner. The equilibrium can only be influenced when the introduction -of foodstuffs or the output of metabolic products is changed in value. -Then they occur as the inanimate example, when various amounts of -material are brought together. A new equilibrium takes place, having -a higher or a lower mass level. This is also true in the living -substance, in growth and in atrophy. The equilibrium is disturbed as -happens in the inanimate reacting mixture, where different quantities -of reacting substances are brought together. In both instances we -have in principle a conformity of behavior of the inanimate and -the living system. Secondly, as far as the greater complexity and -inhomogeneity of the living reacting mixture is concerned, it is -self-evident that this likewise does not constitute an essential -difference, for we are acquainted with conditions of equilibrium in -chemical reactions possessing a number of members and in inhomogeneous -mixtures. Finally, the fact that the reaction in the living system -is not totally reversible, forms no barrier to the assumption in -principle of metabolic self-regulation as a chemical equilibrium. It -is quite possible to conceive of a chemical equilibrium in a reacting -mixture, of which only certain constituent processes are reversible, -without the totality of the reactions as a whole being necessarily so. -Let us assume, by way of example, that the assimilative processes of -the metabolic chain are reversible, then under constant quantitative -relations of foodstuffs, following every disintegration of assimilative -products with removal of the decomposition products, the same amount -of assimilatory processes is required for building up. And this is -just that which we observe in metabolic equilibrium. Accordingly, -we may look upon the metabolic equilibrium as a special, although a -very highly complicated, instance of chemical equilibrium, and we -may explain the metabolic self-regulation following a dissimilative -excitation of the same, by those principles on which the rebuilding of -chemical equilibrium is founded. It is true that the special details -of this process can be differentiated in only that degree in which it -is possible to penetrate at all into the details of metabolism of the -given cell form. In this, as is well known, the advance is extremely -slow. - -The rebuilding process following decomposition of living substance -in response to an excitating stimulus consists not merely in -compensation for the decomposed atom groups but also in the removal -of disintegration products. This removal can be accomplished, in -so far as simple chemical substances such as carbon dioxide and -water are concerned, by diffusion. Observations have shown that the -semi-permeable protoplasm surface is pervious to water and carbon -dioxide. The latter can, therefore, depending upon the amount of -concentration, be eliminated from the living substance. Output of water -likewise takes place in so far as the specific water content of the -living substance is exceeded and which is osmotically regulated by its -amount of salt content. When, finally, osmotic pressure within the -living cell and in the surrounding medium is equal, the interchange -of water ceases. All these processes are explained by diffusion. -Self-regulation takes place in this regard simply by osmotic means. -The conditions in respect to those decomposition products consisting -in more complicated organic combinations, such as lactic acid, fatty -acids and nitrogen derivatives of protein disintegration, are somewhat -different in that the protoplasm surface possesses the property of -hindering the passage of these substances into the medium. These are, -as is well known, first transformed by secondary chemical processes -into transfusable substances. In this transference the oxydative -decomposition with the formation of simpler substances plays the most -important rôle, so that the substances thereby formed, namely, carbon -dioxide, water and ammonia, are osmotically eliminated as the result of -the selective permeability of the surface of the protoplasm. In this -way the living cell rids itself of the useless products of metabolism. - -Finally, the question remains, is the original state, as it existed -before the influence of the stimulus, really completely recovered by -metabolic self-regulation, or does even individual excitation of brief -duration produce a continued change in the protoplasm? It is quite -impossible to prove that such an effect follows the momentarily acting -single stimulus, if stimulation has not exceeded the physiological -limits of intensity. Should it exist, it must be imperceptible. -Nevertheless, it ought to be possible by frequently repeated -application of the stimulus to increase this which is imperceptible to -an extent in which it is perceptible. This is, indeed, the case and -is manifested as we have already seen in the increase of the volume -of living substance by frequently recurring functional excitation. We -can, therefore, assume with great probability that even the momentarily -acting individual stimulus produces, although not perceptible _per se_, -lasting effect in the cell. The functional excitation must be followed -secondarily by an increase of the assimilative phase of the entire -cytoplastic metabolism. Otherwise the taking place of the increase -of volume of the living system following frequent excitation of the -functional constituent members of metabolism, is unintelligible. -But how are we to interpret these secondary results from a physical -standpoint? First of all, it must be stated that we do not know of -such hypertrophy following activity in unicellular organisms, but only -in the tissues and organs of multi-cellular forms, in muscles, nerve -cells, glands, etc. In the cell community of the vertebrates, however, -the studies on the relations between activity and the blood supply of -the particular tissue or organ furnish a physical interpretation for -the existence of the functional hypertrophy. The active portions show a -dilation of the blood vessels, therefore an increased supply of blood -and consequently an increase in the circulation of lymph. In other -words: the supply of nourishment to the individual cell and the removal -of the metabolic products in a unit of time is increased. The preceding -discussion of the dependence of the conditions of equilibrium upon the -quantitative relations of the reacting substances makes it clear that -under these conditions a metabolic equilibrium on a higher quantitative -level must occur; that is, the living substance must increase in amount -just as in the inanimate example the absolute amount of the æthylacetat -increases if more alcohol and acetic acid are introduced to an equal -degree. Some time ago[76] I expressed the opinion that the increase -of the blood supply in a functionally active organ must be based on a -physical self-regulation, which takes place as a result of the fact -that metabolic products of the tissue cells influence the cells of -the vessel walls in that part, so that the vessels dilate and more -lymph is formed. In the meantime this has been proved to be indeed -the case. _Schwarz und Lemberger_[77] and _Ishikawa_[78] have shown -that especially the weak acids, which are produced in larger amount -as a result of strong activity of the cells, bring about vessels’ -dilation. By the demonstration of this highly important process -of self-regulation the last link has been added for the physical -understanding of the hypertrophy of activity of the tissue cells by -continued functional excitation. Whether or not the same applies to -the single living cell, if the unicellular organism likewise undergoes -a quantitative increase by a continuous functional excitation, and -if the single cell possesses in itself a corresponding mechanism of -self-regulation similar to the cell community in the vertebrates, -cannot be answered, for concerning all these problems information is -lacking for the present. - - [76] _Max Verworn_: “Die cellularphysiologische Grundlage des - Gedächtnisses.” Zeitschr. f. allgem. Physiol. Bd. VI, 1907. - - [77] _Schwarz und Lemberger_: “Über die Wirkung Kleinster Säuremengen - auf die Blutgefässe.” Pflügers Arch. Bd. 141, 1911. - - [78] These investigations have not yet been published. - - - - -CHAPTER VI - -CONDUCTIVITY - - _Contents_: Only processes of excitation are conducted, not processes - of depression. Conduction of excitation in its two extreme instances. - Conduction in undifferentiated pseudopod protoplasm of rhizopoda. - Conduction of excitation with decrement of intensity and rapidity. - Conduction of excitation in the nerve. Rapidity of conduction of - excitation without decrement. Relation between irritability and - conductivity. Conduction of excitation with decrement of the nerve - after artificial depression of irritability by narcosis. Theory of the - decrementless conduction of the normal nerve. Proof of the validity of - the “all or none law” in the medullated nerve. Theory of the process - of the conductivity of excitation. Theory of core model (Kernleiter). - Electrochemical theory of conduction based on the properties of - semi-permeable surfaces. - - -When the response to a stimulus is studied in a living system, whether -it be a single cell, a tissue, or a complex organism, the indicator -used, either that of movement, current of action, production of certain -substances, the development of light, of heat or the alteration of -form, is the result of two distinct processes. The first of these is -primary excitation, brought about by the stimulus at a local point, and -the second is an extension of the excitation to the surrounding tissue. -We are not in a position to experimentally bring about a response -to stimulation, in which the primary excitation occurs and not the -secondary process, that of conductivity. All living substance contains -this property, although to a very different degree, as all living -substance possesses irritability, and this presents the condition not -only for the taking place of the process of excitation but also that of -its conduction. - -If I here speak only specifically of the conduction of excitation -instead of the conductivity of response to stimulation this is not -only primarily for the reason that we intend especially to analyze the -conductivity of excitation on this occasion, but also because no other -effects of stimulation except those of excitation can be conducted from -the part affected by the stimulus to the surroundings. - -Although considered on theoretical grounds it appears more or less -improbable that depression is extended from the place of its origin, -it is very easy to convince one’s self experimentally of the fact -that depression following a stimulus is invariably localized to that -portion directly affected by the stimulus. The nerve furnishes a very -favorable object for this purpose. If a nerve muscle preparation of the -frog is made and introduced in the glass chamber previously described -containing platinum electrodes, and another pair is applied to the -nerve between the chamber and the muscle, it is possible to subject -the stretch of nerve in the chamber to various agents, producing a -paralyzing effect. In this way it may be exposed to an atmosphere of -pure nitrogen for example, or to narcosis as by ether, chloroform, -carbon dioxide and other gases, to an increase in temperature or to -other agents, without these in any way affecting the irritability of -the nerve stretch situated over the electrode between the chamber and -the muscle. The contractions of the muscle, which are produced by -stimulation of the periphery region of the nerve with stimuli of a -definite strength, remain unaltered, even when the asphyxiated stretch -of nerve in the chamber is already completely degenerated. The central -depression of a ganglion cell of a motory neuron is likewise wholly -without influence on the degree of excitability of its nerve fiber, as -I was able to demonstrate[79] in the reflex inhibition of the motor -neurons of the spinal cord of the dog. (Figure 14.) That which is -conducted by the nerves is solely the process of excitation. - - [79] _Max Verworn_: “Zur Physiologie der nervösen - Hemmungserscheinungen.” Arch. f. Anat. u. Physiol. physiol. Abt. - Suppl. 1900. - -It is our task to analyze in detail the conditions involved in the -conduction of excitation in order to obtain a deeper insight into the -physics of this process. A comparative survey of a series of various -types of living substance shows us that they differ in respect to the -conduction of excitation in the following points: In regard to the -rapidity with which the excitation is conducted, the extent of the area -over which it spreads, and the intensity with which it extends. These -conditions may be best illustrated by citing two extreme examples. The -one is formed by the rhizopods, the other by the nerve fibers. Between -these two extremes we have manifold gradations in the conditions of -conductivity. Not all cell forms are suitable objects for the study of -conductivity. There are forms of rhizopods which are as favorable to -investigation as the nerve; this is due to the fact that, although -they are often of microscopic dimensions, they possess elongated -fingerlike or threadlike pseudopods. - -[Illustration: Fig. 14. - -Contractions of the musculus extensor digitorum communis longus of the -dog, brought about by rhythmic stimulation of the nervus peroneus. The -muscle is in the condition of tonic excitation which proceeds from -the center. The arrows indicate the point where reflex inhibition of -the central tonus is produced. The height of the single contraction -undergoes no diminution. ] - -Indeed, a rhizopod cell, with its straight, elongated pseudopods, -is preëminently fitted as an object of comparison with a neuron. -Although the difference in respect to the individual points is so -far-reaching, still, based on their outward morphological similarity -various physiological parallels in both are forced on our observation. -A comparison of the rhizopod cell with the neuron can consequently -guard us from many erroneous generalizations which we might be -inclined to deduce from a one-sided investigation of the nerve. This -is especially the case in regard to the conductivity of excitation, -which was formerly studied almost exclusively on the nerve and only -occasionally on the muscle, which offers similar conditions. The nerve, -in which the function of the conductivity of excitation is particularly -highly developed, was considered at the same time as the type in which -this process could be most readily analyzed, and from which it was -believed general information of the process of the conductivity of -excitation could first be gained. This view has led to serious errors, -as the nerve, resulting from the high development of its conductive -capability, shows quite one-sided specialized conditions, which can by -no means be transferred to other forms of living substance. - -A very suitable object among rhizopods for the study of conductivity, -and which is everywhere easily procured, is _Difflugia_. This species -living in small pools has a delicate urn-shaped, pear-shaped or -flask-shaped capsule built up of sand grains, diatomes or material -produced by the organism itself. From the opening the protoplasm -extends often to a considerable length its finger-shaped hyaline -pseudopods. When _Difflugia_ is placed in a flat dish in water and -observed under the microscope, it is frequently seen to extend from the -opening long pseudopods in exactly opposite directions, which reach -for a considerable distance on the bottom. These offer particularly -favorable conditions for the study of the conduction of excitation. -When this animal is placed under a microscope, the pseudopods are -very readily stimulated at any position to a desired extent by means -of a sharp needle, to which fat has been previously applied and -subsequently the excess removed. The extension of the response from -one point toward the other can then be followed with great ease. -The pseudopod of the rhizopod has the great advantage over the -nerve that its excitation can be directly observed. The excitation -following weaker stimulation is manifested by a wrinkling of the -previously completely smooth surface; stronger stimulation produces -differentiation of the hyaline protoplasm to a strongly refractive -strand in the axis and a turbid myelinlike mass at the periphery, the -pseudopod at the same time retracting toward the central cell body. In -spite of all these occurrences being of microscopic dimensions, still -with some practice it is quite possible to experiment on them under the -microscope. In this way I found it comparatively simple to study the -fundamental principles of conductivity.[80] - - [80] _Max Verworn_: “Psycho-physiologische Protistenstudien. - Experimentelle Untersuchungen.” Jena 1889. - -[Illustration: Fig. 15. - -_Difflugia urceolata._ A--Weak local stimulation at the end of a long -extended pseudopod. B--Stronger local stimulation applied to the end of -a long pseudopod.] - -[Illustration: Fig. 16. - -_Difflugia urceolata._ A--In non-stimulated condition. B--The same -individual locally stimulated in the middle of a long extended -pseudopod. The excitation spreads in both directions, centripetal as -well as centrifugal. ] - -All these factors, the intensity with which the excitation extends from -the point of stimulation, the rapidity of the extension, and finally -the area over which conduction takes place, are manifestations of the -intensity of stimulus, and as such alter with these in corresponding -manner. If the end of a pseudopod is barely touched and thereby weakly -stimulated, the response is restricted to a slight wrinkling of the -surface, which slowly extends to the immediate neighborhood, whilst -the more distant parts of the pseudopod are not affected at all by -the excitation. (Figure 15, A.) On a stronger stimulation of the -pseudopod by slight pressure, the response is likewise stronger, and -the characteristic differentiation of the protoplasm, consisting in -the strongly refractive strand in the axis and the turbid myelinlike -outer mass, appears at the point of stimulation. From here a peculiar -alteration spreads gradually further over the pseudopod, in that -first upon its smooth surface a few myelinlike droplets are seen, -which become larger and with the development of the strand in the -axis, dissolve into a wrinkled mass on the surface. The further this -process extends from the point of stimulation, the weaker it becomes -and the more slowly it proceeds, until at last there is complete -disappearance. (Figure 15, B.) The pseudopod has at the same time -retracted to a considerable degree. If a still stronger stimulus is -applied by firm pressure at the end of the pseudopod the process takes -place with much greater violence. The differentiation of the protoplasm -spreads centripetally from the point of stimulation over the whole -pseudopod with great rapidity, and produces a quick retraction in the -same, then involves the oppositely directed pseudopod, in which it -then extends more and more slowly, until, proceeding in a centrifugal -direction, it is at last gradually completely obliterated. When strong -stimulation is applied, the process occurs with such rapidity that the -contraction of the pseudopod is almost twitchlike. As the rapidity of -the conduction alters within a wide limit according to the strength -of the stimulus and the distance from the point of stimulation, it -is self-evident that no constant figure can be stated. To give a -general idea of the rapidity, they might be estimated according to -observations I have made with second watch and ocular-micrometer as -from within a slight fraction to that of a millimeter in the second. -When a very long extended pseudopod is locally stimulated in the -middle, the response spreads from the point affected in both directions -diminishing in intensity and rapidity. The excitation extends equally -in all directions. (Figure 16.) These facts show very clearly that -in _Difflugia_ the excitation following a localized stimulus is -dependent on the intensity of the stimulus, and that according to -the degree of this, the wave progresses in either stronger, more -rapid and extended, or weaker, slower and more limited manner. With -the greater distance from the point of stimulation the excitation -undergoes an increasing decrement of its intensity and rapidity of -conduction. Different species of _Difflugia_ which I have investigated, -_Difflugia lobostoma_, _urceolata_, _pyriformis_, have shown a -complete conformity in this respect. A great number of other fresh -water and marine rhizopods, the pseudopods of which I have used for -analogous experiments, although differing in the manner of reaction -in regard to the extent and rapidity of the course of excitation, -manifest exactly the same fundamental principles. A very favorable -form is, for instance, the much smaller _Cyphoderia margaritacea_, -which is distinguished by a somewhat higher degree of excitability and -rapidity of reaction.[81] The long straightly extended pseudopods are -thinner and more threadlike than those of _Difflugia_ and show upon -stimulation as a result of their local excitation a simple contraction -into clumps of the stimulated protoplasm without the characteristic -differentiation of that of _Difflugia_. (Figure 17.) In the case of -the marine rhizopods, _Orbitolites_ (Figure 19), _Amphistegina_, etc., -which I investigated at the Red Sea, the conduction of excitation takes -place also as in _Difflugia_ with a decrement of intensity and rapidity -becoming larger with the distance from the point of stimulation until -the wave of excitation is obliterated. - - [81] _Max Verworn_: “Die Bewegung der lebendigen Substanz. - Eine vergleichend physiologische Untersuchung der - Contractionserscheinungen.” Jena 1892. - -[Illustration: Fig. 17. - -_Cyphoderia margaritacea._ Result of localized mechanical stimulation -at the end of a long extended pseudopod. A, B, C--three successive -stages.] - -[Illustration: Fig. 18. - -_Cyphoderia margaritacea._ Result of localized mechanical stimulation -in the middle of a long extended pseudopod.] - -[Illustration: Fig. 19. - -A pseudopod of Orbitolites complanatus (cf. Fig. 7). _a_--In normal -condition. _b_--Severed by a cross section near the end. _b-f_--Five -successive stages of the effect. _b-d_--The pseudopod retracts by -centripetal flowing of the protoplasm contracted in the shape of -microscopic balls and spindles. _e_ and _f_--The pseudopod begins to -extend again. The centripetal flowing balls and spindles begin to -disappear. ] - -A sharp contrast to this type is formed by the other extreme as -represented by that of the medullated nerve. As an indicator of the -course of excitation we will take the action current in an isolated -nerve of the frog. If this is stimulated at one end, we can test the -intensity of the conducted excitation by leading off the action current -from two points at varying distances from the one influenced by the -stimulus. Since the classical discovery of _Du Bois-Reymond_ of the -action current of the nerve, we know that in the fresh medullated -nerve, if observed under favorable experimental conditions, no -decrement of intensity of excitation during its course from the point -of stimulation along the length of the nerve can be demonstrated.[82] -If unpolarizable electrodes are applied to a nerve in such a position -that they are equidistant from the cross section and are connected with -apparatus for testing the current, it will be found that there exists -an “unwirksame Ableitung” in the sense of _Du Bois-Reymond_, that is, -in which there is no demarcation current. When a tetanizing current is -applied to one end of the nerve, no difference of potential between the -two nonpolarizable electrodes is observed, which indeed would be the -case if excitation with its current of action would have a decrement -on its way from one to the other point of leading _off_ the current. -_This fact, which has been repeatedly confirmed, shows us that the -medullated nerve, under normal conditions, conducts excitation without -a perceptible decrement of the intensity._ - - [82] _Du Bois-Reymond_: “Untersuchungen über tierische Electricität.” - II Band. 1849. - -This specific property of a medullated nerve is in conformity with -the conditions in connection with the rapidity of conductivity. Since -_Helmholtz_[83] has devised the method for measuring the rapidity of -conduction in the nerve, this investigator himself and numerous others -have studied the rate in different nerves.[84] _Helmholtz_ found the -rate for motor nerves of the frog to be 27 meters per second, for -the sensory nerves of man 60 meters, and the motor nerves of man 34 -meters. Other investigators have obtained quite different results; -_Hirsch_, for the sensory nerves of man, 34 meters; _Schelske_, for the -same, 25–33 meters; _De Jaager_, 26 meters; _v. Wittich_, 34–44 meters, -and _Kohlrausch_, 56–225 meters; _v. Wittich_ for the motor nerves of -man, 30 meters; _Piper_[85] finally in the most recent investigations -about 120 meters in the second. - - [83] _H. Helmholtz_: “Messungen über den zeitlichen Verlauf der - Zuckung animalischer Muskeln und die Fortpflanzungsgeschwindigkeit - der Reizung des Nerven.” Müller’s Archiv. 1850. - - The same: “Messungen über die Fortpflanzungsgeschwindigkeit der - Reizung in den Nerven.” Zweite Reihe, Müller’s Arch. 1852. - - [84] Compare: _Hermann_: “Handbuch der Physiologie.” II, 1 Leipzig - 1879. - - [85] _Piper_: “Ueber die Leitungsgeschwindigkeit in dem markhaltigen - menschlichen Nerven.” - - The same: “Weitere Mitteilungen über die Geschwindigkeit der - Erregungsleitung im markhaltigen menschlichen Nerven.” Pflügers Arch. - Bd. 127, 1909. - -These differences may be explained in a _large_ measure by the variety -of the methods used, in part also by the difference in the structures. -The methods employed for the study of the velocity have also been used -to solve the question, whether the velocity of the excitation wave in -its course over the nerve meets with a decrement as it moves further -and further away from the point of stimulation. Here the endeavor was -made to study the difference in time of the latent period, which is -observed by the indicator, when the nerve is stimulated at two points -at different distances from the muscle, used as an indicator, or -from the wires leading the current to the indicator. The more recent -investigators, as _René Du Bois-Reymond_,[86] _Engelmann_,[87] _G. -Weiss_,[88] have arrived at the same conclusion, that the rate of -conductivity in the medullated nerve under normal conditions is the -same at all distances from the point of stimulation. (Figure 20.) - - [86] _R. Du Bois-Reymond_: “Ueber die Geschwindigkeit des - Nervenprincips.” Arch. f. Anat. u. Physiol. physiol. Abt. Suppl. 1900. - - [87] _Engelmann_: “Graphische Untersuchungen über die - Fortpflanzungsgeschwindigkeit der Nervenerregung.” Arch. f. Anat. u. - Physiol. physiol. Abt. 1901. - - [88] _G. Weiss_: “La conductibilité et l’excitabilité des nerfs.” In - Journ. de Physiol. et de Pathol. générale 1903. - -The medullated nerve shows, therefore, under normal conditions -neither a decrement of its conductivity, nor of its _irritability_, -as the distance of the wave of excitation increases from that of the -position of stimulation; this means, in other words, that excitation is -conducted with the same intensity with which it is started, and with a -constant rate throughout the entire course of the nerve. - -[Illustration: Fig. 20. - -Curves of muscle contraction obtained by stimulation of 3 and 4 points -situated at equal distances from each other on the sciatic nerve of the -frog. The increase of length of the nerve stretch corresponds with an -equal increase of the latent period of contraction. From this follows, -that the rapidity of the wave of excitation is the same at all points -of the entire length of the nerve. (After _Engelmann_.) ] - -There is, nevertheless, a third point of considerable difference -between the types of conduction of excitation in the rhizopods and -in the nerve. Whereas in the rhizopods the rapidity of conduction -is dependent upon the _intensity_ of the stimulus, it has been long -known as the result of investigation by _Rosenthal_, _Brücke_ and -_Lautenbach_ and at a more recent date by _Gotch_[89] and _Piper_,[90] -that in the nerve of the frog, as well as in man, the velocity is _not_ -dependent upon the intensity of stimulation. (Figure 21.) Contrary -results have been obtained by a few early observers wherein the latent -period was shorter when the stimulation was strong. _Nicolai_[91] -explains this shortening of the latent period, resulting from the -application of strong electrical stimuli, to a spreading out of the -“Stromschleifen” from the point of application and consequently -there is a shortening of the stretch of nerve between the point of -stimulation and the indicator. - - [89] _Gotch_: “The submaximal electric response of nerve to a single - stimulus.” Journal of Physiology, Vol. XXVIII, 1902. - - [90] _Piper_: Ueber die Leitungsgeschwindigkeit in den markhaltigen - menschlichen Nerven. Pflügers Arch. Bd. 124, 1908, und Bd. 127, 1909. - - [91] _Nicolai_: “Ueber Ungleichförmigkeiten in der - Fortpflanzungsgeschwindigkeit des Nervenprincips, nach Untersuchungen - am marklosen Riechnerven des Hechts.” Arch. f. Physiologie 1905. - -[Illustration: Fig. 21. - -Course of the action current of the nerve. The thin line indicates the -action current produced by a weak, the thick line the action current -produced by a strong stimulus. The duration of the action current is -the same in both cases. (After _Gotch_.) ] - -This conspicuous difference in the conduction of the two extreme types -of living substance, which we have already observed, arouses the -question as to what properties of living substance bring about these -differences. In order to answer this question, it is necessary, first -of all, to make some general statements concerning the processes of -conductivity. - -As already emphasized, all living substance possesses the capability of -conducting excitations to a definite degree. We may, therefore, assume -that the same fundamental _property_ of conductivity exists in all -substances. A fact to be considered in the conduction of excitation, is -that the primary breaking down of the complex molecules at the position -of stimulation act in turn as exciting stimuli upon the neighboring -portion of the living substance, which in turn undergoes a similar -decomposition. And so this process continues. This fact is evident from -the observations on the process of excitation. But the nature of the -stimulus which produces the breaking down of the complex molecules -upon the surrounding molecules is a problem which can only be studied -later. Here only one point will be mentioned in advance concerning the -intensity of the stimulus. It is apparent from the experiments on the -rhizopods, that the greater the intensity of the stimulus the more -extensive must be the breaking down of the living substance. A stronger -primary stimulation must also secondarily produce a stronger stimulus -in the neighborhood. In other words: the _conduction of excitation_ -is a function of irritability. The greater the irritability, that is, -the greater the number of molecules broken down in a unit of time -and space by a stimulus of a certain intensity, the greater also is -the conductivity of the living system, that is, the stronger, the -more rapidly and the further excitation is extended. Conductivity -of excitation is, therefore, unthinkable without irritability. Both -are inseparably connected. The conclusion forced upon us by this -chain of reasoning admits of no argument. Nevertheless the endeavor -has been made, because of certain evidence at hand, to show that -the property of conductivity could exist without irritability. A -number of authors, such as _Schiff_,[92] _Erb_,[93] _Grünhagen_,[94] -_Effron_,[95] _Hirschberg_[96] and _G. Weiss_,[97] have observed the -fact that in spite of a more or less strong decrease of _excitability_ -of a stretch of nerve, stimuli applied above this stretch can still -produce a conduction of excitation through the affected part. They have -concluded from this that it is possible to separate the conductivity -from irritability. _Erb_ and _G. Weiss_ have even gone so far as -to directly express the opinion that capability of conduction and -irritability involve two different histological elements. In contrast -to this, other investigators, such as _Hermann_,[98] _Szpilmann_ and -_Luchsinger_,[99] _Gad_,[100] _Piotrowski_[101] and _Wedenski_,[102] -have more or less decidedly taken the stand that an actual separation -of irritability and of conductivity does not exist. The apparently -contradictory evidence as well as the conflicting theoretical views -have been cleared up by _Werigo_,[103] _Dendrinos_,[104] _Noll_[105] -and _Fröhlich_.[106] These investigators have shown that the length -of the narcotized stretch of the nerve plays an important rôle in the -obliteration of conductivity. It has been found by the application -of a stimulus above the narcotized stretch of nerve, that the longer -this stretch is, the less is the reduction of irritability which -obliterates the excitation wave reaching this area. Further: The -shorter the stretch, the greater must be the reduction in irritability -before this result is brought about. (Figure 22.) In other words, the -conductivity in the narcotized nerve is dependent upon the length and -the irritability of the narcotized stretch. From this observation the -important fact is evolved, that the wave of excitation meets with a -decrement of its intensity in the narcotized area. This decrement -becomes larger as the wave progresses through the involved stretch. -Further it is progressively increased as the amount of the irritability -is reduced. Finally, when the stretch is long enough, the wave of -excitation is obliterated. This important fact has been further -established by the experiments of _Boruttau_ and _Fröhlich_,[107] in -which they studied the intensity of the current of action, produced by -a wave of excitation, from two points in the narcotized stretch. The -wave of negative variation, brought about by the excitation, gradually -decreases in the narcotized stretch as the electrode is further removed -from the point of entrance. Beside a decrement of _intensity_, as -the investigations of _Fröhlich_[108] prove, the wave of excitation -shows a decrement of the velocity in the narcotized stretch. And it -is probable that the wave of excitation extends with _progressive_ -reduction in the velocity, corresponding to the decrement of intensity. -The work of _Koike_[109] under the direction of _Garten_, in which the -conclusion arrived at is that the reduction in the velocity is the same -throughout the narcotized area, should not be accepted as conclusive -in spite of the delicate method employed. These investigations are -extremely difficult, being in the field of the most delicate of -present-day methods. The decrement, which the wave of excitation meets -with in its progress in the narcotized stretch, makes the conflicting -testimony concerning the apparent separation of irritability and -conductivity intelligible. It depends entirely upon the length of -the narcotized area, and the amount of reduction in irritability on -the one hand, and the strength of the stimulus used for testing the -irritability on the other, whether the conductivity will disappear -_before_ the irritability or _vice versa_. If I test the irritability -in the narcotized stretch with a weak stimulus, just slightly _above_ -the threshold, then by slight reduction in the irritability complete -absence of response occurs, when the same stimulus is applied. This -occurs at a time when excitation reaches the narcotized area from -above and meets with a decrement so slight that it can pass through -the whole narcotized stretch, that is, when the narcotized stretch is -short enough. If I test the irritability of the narcotized area with a -strong stimulus, far above that of the threshold, irritability will be -found to be present at a time when the conductivity for the excitation, -coming from above, is already obliterated. This is due to the fact that -the decrement in the narcotized area is already great enough to bring -about the complete disappearance of the wave of excitation coming -from above. This, of course, only occurs provided the length of the -narcotized stretch is great enough. The separation of conductivity -and irritability is, therefore, only an apparent one. In reality, the -facts obtained from experimentation indicate that with the reduction of -irritability the decrement of the wave of excitation increases, whilst -the shorter the stretch, the smaller is the decrement. This shows that -_conductivity is a manifestation of irritability_. - - [92] _Schiff_: “Über die Verschiedenheit der Aufnahmsfähigkeit und - Leitungsfähigkeit in dem peripherischen Nervensystem.” Henle u. - Pflügers Zeitschr. 1866. - - [93] _Erb_: “Zur Pathologie und pathologischen Anatomie - peripherischer Paralysen.” Deutsches Arch. f. Klin. Med. 1869. - - [94] _Grünhagen_: “Versuche über intermittierende Nervenreizung.” - Pflügers Archiv. Bd. 6, 1872.--_Funke-Grünhagen._ Lehrbuch der - Physiologie Bd. I, 1876. - - [95] _Effron_: “Beiträge zur allgemeinen Nervenphysiologie.” Pflügers - Arch. Bd. 36, 1885. - - [96] _Hirschberg_: “In welcher Beziehung stehen Leitung und Erregung - der Nervenfaser zu einander?” Pflügers Arch. Bd. 39, 1886. - - [97] _G. Weiss_: “La conductibilité et l’excitabilité des nerfs.” - Journ. de physiol. et de pathol. générale. T. V. 1903.--“Influence - des variations de temperature et des actions méchaniques sur - l’excitabilité et la conductibilité des nerfs.” _Ibidem._ - - [98] _Hermann_: “Handbuch der Physiologie.” Bd. II, I Leipzig 1879. - - [99] _Szpilmann und Luchsinger_: “Zur Beziehung von Leitungs- und - Erregungsvermögen der Nervenfaser.” Pflügers Arch. Bd. 24, 1881. - - [100] _Gad_: “Ueber Trennung von Reizbarkeit und Leitungsfähigkeit - des Nerven.” (Nach Versuchen des Herrn Sawyers) Arch. f. Anat. u. - Physiol. physiol. Abt. 1888. - - Derselbe: “Ueber Leitungsfähigkeit und Reizbarkeit des Nerven in - ihren Beziehungen zur Längs- und Querschnitts erregbarkeit.” Nach - Versuchen des Herrn Piotrowski Arch. f. Anat. und Physiol. physiol. - Abt. 1889. - - [101] _Piotrowski_: “Ueber Trennung von Reizbarkeit und - Leitungsfähigkeit des Nerven.” Arch. f. Anat. u. Physiol. physiol. - Abt. 1893. - - [102] _Wedenski_: “Die fundamentalen Eigenschaften des Nerven unter - Einwirkung einiger Gifte.” Pflügers Arch. Bd. 82, 1900. - - The same: “Excitation, inhibition et narcose.” Compt. rendus du v. - Congres internat. de Physiologie à Turin 1901. - - [103] _Werigo_: “Zur Frage über die Beziehungen zwischen Erregbarkeit - und Leitungsfähigkeit des Nerven.” (Nach Versuchen von stud. - Rajmist.) Pflügers Arch. Bd. 76, 1899. - - [104] _Dendrinos_: “Ueber das Leitungsvermögen des motorischen - Froschnerven.” - - [105] _Noll_: “Ueber Erregbarkeit und Leitungsvermögen des - motorischen Nerven unter dem Einfluss von Giften und Kälte.” Zeitsch. - f. Allgem. Physiol. Bd. III, 1907. - - [106] _Fr. W. Fröhlich_: “Erregbarkeit und Leitfähigkeit des Nerven.” - Zeitschr. f. allgem. Physiol. Bd. III, 1904. - - [107] _Boruttau und Fröhlich_: “Erregbarkeit und Leitfähigkeit des - Nerven.” Zeitschrift f. allgem. Physiologie Bd. IV, 1904. The same: - “Electropathologische Untersuchungen ueber die Veränderungen der - Erregungswelle durch Schädigung des Nerven.” Pflügers Arch. Bd. 105, - 1904. - - [108] _Fröhlich_: “Die Verringerung der Fortpflanzungsgeschwindigkeit - der Nervenerregung durch Narkose and Erstickung des Nerven.” - Zeitschrift allgem. Physiologie Bd. III, 1904. - - [109] _Izuo Koike_: “Ueber die Fortleitung des Erregungsvorgangs in - einer narkotisierten Nervenstrecke.” Zeitsch. f. Biologie Bd. 5, 1910. - -[Illustration: Fig. 22. - -Scheme of the decrement of the excitation wave in the narcotized -stretch of a nerve. A--The narcotized stretch (indicated by the cross -section of the chamber) is 30 mm. long. The ordinates of the dotted -lines indicate the amount of the decrement. If the decrement is slight -(upper dotted line), the excitation wave passes the narcotized stretch -and increases again on entering the normal stretch. If the decrement is -great (lower dotted line), the excitation wave is obliterated towards -the end of the narcotized stretch and the muscle remains at rest. -B--The narcotized stretch is 15 mm. long. The decrement is slight. -The excitation wave can therefore pass into the normal stretch and -here increase again. C--The narcotized stretch is 15 mm. long. The -decrement is great. The excitation wave is obliterated, therefore, in -the narcotized stretch, and the muscle remains at rest. ] - -The facts just mentioned have, however, a much deeper meaning. They -show us that it is possible by means of narcosis to convert an extreme -type of a living system, with decrementless conductivity, into another -extreme type of living substance, in which excitation in its progress -meets with a strong decrement, like that seen in the rhizopods. The -same results may also be obtained by asphyxiation and other forms of -temporary and permanent injury of the nerve. We are, therefore, in the -fortunate position in the case of the medullated nerve of having a -substance to study, which, depending upon conditions which are under -our control, may become a type in which conductivity occurs with -or without the presence of a decrement. We can likewise reduce the -irritability to various degrees, producing all intermediate gradations -between the two extremes. This latter is particularly valuable in that -it permits us to study the conditions in one and the same substance -necessary to bring about the various peculiarities of conductivity. The -great differences in the conductivity of excitation are conditioned by -variations in the degree of irritability. If the irritability of the -nerve is at the normal level the wave of excitation progresses to the -end of the nerve without manifesting a decrement of its intensity or -rapidity. - -If the level of irritability of the intact nerve is artificially -reduced, the wave of excitation meets with a greater decrement and -reduces in velocity, and in fact disappears the more quickly in the -stretch of nerve, as the reduction in irritability is increased. -These three factors, irritability, intensity and velocity of the -progress of the wave of excitation, are inseparable. All living -substances may be grouped according to their capability of conducting -excitation into a long series, starting with those possessing the -least irritability, as we found in the rhizopods, then those having -greater irritability, as the smooth muscle and ganglion cells, then -those with still greater irritability, as the striped muscle, and -finally those having the greatest degree of irritability, as the -medullated nerves of the warm-blooded animal. Should the processes of -excitation, as we saw, result from the energy production following the -disintegration of the labile molecules of the living substance, then -the degree of irritability is determined by the chemical constitution -of the disintegrating molecules, by the number of molecules which are -broken down in a definite space and a given time, and by the nature -of the disintegration itself. All of these individual components, if -we observe the problem from the physical standpoint, are manifested -by the quantity of energy production. The higher the irritability of -a living system, the greater is the amount of energy production in a -given time and space which the stimulus produces. This has particular -interest from the standpoint of the extreme cases of medullated nerves -of the vertebrates with their most highly developed conductivity, -and which will be analyzed in somewhat greater detail. How are we to -explain their decrementless conductivity? When we study the decrement -of the excitation wave in the series of living substances, before -alluded to, we see that this reduces with a progressive increase of -irritability. Consequently the extreme irritability of the nerve is -a manifestation of its decrementless conductivity. If we study the -course of a process of excitation and its conduction in its molecular -details, the fact of the decrementless conduction indicates that -in excitation, produced by a stimulus, the same number of specific -molecules capable of disintegration are broken down in the same manner -at every following cross section, as at the point of stimulation; or -in other words: an equal amount of energy is set free at every cross -section, which, in its turn, acts as stimulus to the next, etc. Such a -condition presupposes, however, in an elementary fiber of the nerve, -that by the conduction of the wave of excitation from cross section -to cross section, all those molecules capable of disintegration are -broken down. If it is assumed that the entire number of molecules -capable of disintegration do not break down, but only a certain per -cent. of the same, then it would not be possible to conceive of a -molecular structure of the nerve in which this would take place -without decrement of the wave of excitation. With the assumption of -a generally homogeneous molecular structure (Figure 23, a) of the -elementary fibers it would be entirely incomprehensible how, with the -decrementless extension of the excitation, individual molecules capable -of breaking down could escape disintegration. If, on the contrary, the -molecular structure is not homogeneous it only is possible to explain -a conduction, on each cross section of which an equal per cent. of -irritable molecules break down, by the hypothesis that the irritable -molecules are in their turn ordered in fiber-shaped series (Figure 23, -b) within the elementary fiber and are thus protected to a certain -degree from one another and from transverse conduction of excitation. -This hypothesis would, therefore, only mean that the elementary fiber -is not such in reality and would thus transfer the difficulty to -the ultimate fiber unit, for which a homogeneous molecular structure -would have to be presumed. In short, whatever may be the assumption on -which molecular structure of elementary fibers is based, the fact of -the decrementless conduction peremptorily demands, from the physical -standpoint, that from cross section to cross section the entire number -of irritable molecules are broken down. This conclusion is highly -important, for it indicates very clearly that the “all or none law” is -applicable to the nerve. - -[Illustration: Fig. 23.] - -This gives us occasion to return to the discussion of the question, if -living systems really exist which respond in accordance with the “all -or none law.” The medullated nerve forms an object particularly suited -to serve as a starting point for the treatment of this especially -important problem. The question arises in this connection, if the -validity of this law for the nerve can be tested by other means. - -At first it would seem as if the application of the “all or none law” -to the nerve were in contradiction to the well-known fact that a -weak stimulation of the nerve produces a weak, a strong stimulation, -a strong response. In this connection _Gotch_[110] has pointed out, -as the result of experimental studies of the wave of activity of the -nerve, that the difference in response, following the application of -stimuli of varying strengths, is understandable from the fact that -threshold stimuli stimulate only a few of the fibers of the nerve -trunk, whereas progressively increasing the intensity of the current -involves more and more fibers. There can be no doubt that this factor -explains the difference in the strength of the response. Therefore, in -reality we do not find here a contradiction of the “all or none law.” -On the other hand, the fact that the nerve, in contradistinction to -many other forms of living substance, the ganglion cell, for example, -upon a weak stimulation does not show the phenomena of summation, even -when the stimuli follow each other in a rapid succession, indicates -very strongly that the weakest operable stimulus produces maximal -excitation, so that the response cannot be further increased. But -above all, there is a series of facts, which have been gained in the -Göttingen laboratory, which demonstrate apparently without doubt the -validity of the “all or none law” for the medullated nerve. These -observations I wish now to consider in greater detail. - - [110] _Gotch_: “The submaximal electrical response of nerve to a - single stimulus.” Journal of Physiology, Vol. XXVIII, 1902. - -If a nerve of a nerve muscle preparation is drawn through a specially -devised glass chamber so that the middle portion can be narcotized or -asphyxiated and the nerve so arranged that it rests upon a pair of -electrodes in the chamber and upon a second pair without the chamber -and centrally located, then the nerve can be narcotized or asphyxiated -and thereby the alterations in the irritability as well as the -conductivity can be followed. In order to obtain as distinct a picture -of this alteration as possible, I tested continuously the threshold of -stimulation, which just produced minimal contraction in the muscle, and -_Fröhlich_[111] continued these observations. As a result the following -very remarkable conditions were observed. During the increase of the -depth of narcosis or asphyxia the irritability sinks more and more with -regularity. The conductivity remains unaltered for a long time, as the -strength of the threshold stimulus is not changed until irritability -has fallen to a definite point. When this is reached, conductivity -disappears. (Figure 24.) The most important point in this connection, -however, is, that the conductivity disappears simultaneously and -practically momentarily for the excitation produced by both weak and -strong stimuli. When the stimulation at the electrode placed centrally -to the chamber does not bring about response for threshold stimuli, -maximal stimuli at the same time also become inoperative. This is a -very interesting point, the importance of which has not until now been -recognized. This fact is not in harmony with the view held until now, -that in the nerve fiber different strengths of stimuli bring about -excitation of different intensity, and are then conducted. Let us now -clearly comprehend this problem. - - [111] _Fröhlich_: “Erregbarkeit und Leitfähigkeit des Nerven.” - Zeitschr. f. allgem. Physiologie, Bd. III, 1904. - -[Illustration: Fig. 24. - -Curves of the changes in irritability (p) and conductivity (c) of -a nerve under the influence of narcosis or asphyxiation. (After -_Fröhlich_.)] - -We have already seen that the wave of excitation meets with a decrement -of its intensity in the narcotized stretch, which increases in -strength as the irritability diminishes. If the value of the threshold -is learned by stimulating the nerve at the electrodes centrally placed -to the chamber with minimal stimuli, it would necessarily follow that -this weak stimulus would bring about a corresponding weak excitation -of the individual fibers and the wave of excitation already in the -beginning of narcosis would be obliterated, for it would meet with a -decrement, the result of the reduction in the irritability. A wave of -excitation of minimal strength could under these conditions no longer -reach the muscle, even in the beginning of narcosis. In spite of this -the excitation, even when produced with threshold stimuli, passes -through for a long time, even when the irritability in the chamber is -greatly reduced, as shown by testing with the electrodes within the -chamber. This is not consistent with the assumption that a threshold -stimulus brings about the minimal excitation, even in the individual -nerve fiber. But further: with a definite decrease of irritability of -the narcotized stretch the capability of conductivity disappears, and -indeed simultaneously for the weakest as well as the strongest stimuli. -If it is assumed that weak stimuli bring about weak excitations in the -nerve fiber, it must most certainly be expected that on the cessation -of the response, weak stimuli applied at the central nerve end would -still, by slight increase of the intensity of stimulation, be followed -anew by reaction in the muscle. This is all the more to be expected, -because the irritability of the narcotized stretch, as shown by -stimulation with the electrodes inside the chamber, very gradually -decreases, so that within the chamber stimuli of moderate strength are -still effective. Instead the capability of conduction is completely -obliterated, and even the strongest stimuli, applied to the end of -the nerve, produce no response in the muscle. This in turn does not -agree with the assumption that the intensity of excitation varies with -the strength of the stimulus in the individual nerve fiber. The facts -here alluded to are, therefore, either not correct, or the intensity -of excitation in the individual nerve fibers is independent of the -strength of the stimulus, and the view which we have entertained up to -the present in this respect is incorrect. - -[Illustration: Fig. 24.] - -In order to examine these facts once more on an extensive scale, and -at the same time obtain an understanding of the development of the -decrement in the narcotized stretch, I have requested _Dr. Lodholz_ to -register as many accurate curves as possible in which the positions of -the secondary coil of an inductorium are the ordinates indicating the -threshold of stimulation at four points of a nerve stretch. Of these -points three are situated at prescribed distances from each other in -the narcotized or asphyxiated stretch; the fourth is centrally placed. -(Figure 24.) As might be expected the result was the same as in former -investigations. They show however even more strikingly the abruptness -of the disappearance of conductivity simultaneously for the weakest -and the strongest stimuli. The curve produced by the centrally placed -electrode remains at the same height for a considerable period, then -suddenly abruptly declines. Those of the electrodes within the chamber -likewise sink, at first slowly, then with increasing rapidity in -successive order corresponding to the distance which they are situated -from the point of exit of the nerve, so that the curve of the most -distant electrode reaches the abscissa first, that of the electrode -nearest the muscle in the chamber, last. The experiments demonstrate -with complete clearness that in contrast to all those points within the -affected stretch, where the conductivity, though already obliterated -for weaker stimuli, still exists for stronger, that with stimulation -of a point towards the center _above_ the affected stretch, conduction -ceases simultaneously for all different strengths of stimuli. This -last state at the points within the affected stretch might be ascribed -to the diminution of the excitability of this stretch, and the idea -entertained that the weak stimuli no longer produce excitation capable -of further conduction. - -This assumption is contradicted, however, by the fact that subsequently -to the disappearance of the response at a point situated at the -_greatest distance_ from the place of exit, an effect of stimulation -can be obtained at the _nearest_ point to the exit with the same or -even less strength of the current. As the irritability in the affected -stretch is reduced at all points in equal measure, the fact of a weaker -stimulus becoming inoperative whilst a stronger remains effective can -only be attributed to the circumstance that the wave of excitation -set free at some point of the influenced stretch by a weaker stimulus -is sooner obliterated on its way to the muscle than that produced at -the same point by a stronger stimulus. These experiments, in which -the manifestations of the nerves in response to stimuli applied -centrally above the chamber in the normal stretch are compared to those -in response to a stimulus acting on the affected stretch, clearly -demonstrate the totally different effect in both cases. In stimulation -of the centrally situated normal stretch, the wave of excitation, which -enters from here into the influenced stretch, is obliterated at the -same point simultaneously for the weakest as well as for the strongest -stimulus; stimulation of the affected stretch, the wave of excitation -which is set free at one point by a weak stimulus, is obliterated -sooner and after passing through a shorter stretch than that which is -produced by a stronger stimulus. It is self-evident that in the first -instance, in which the stimulus acts on the centrally situated normal -stretch, the wave of excitation, thereby set free, must in passing -through the affected stretch undergo a decrement of its intensity. If, -therefore, the wave of excitation, coming from above, is obliterated -exactly at the same point, whether brought about by weak or strong -stimuli, the inevitable conclusion must be drawn that, whether either -a weak or a strong stimulus is operative, the wave of excitation must -have entered into the influenced stretch from the normal stretch with -exactly the same intensity. In other words: the weakest as well as the -strongest stimuli produce excitations of equal intensity in the normal -nerve, that is, the “_all or none law_” is _valid for the nerve_. - -This information can no longer be doubted in the presence of such -evidence as was presented above. This indeed is a fact of far-reaching -importance in the understanding of the functional activity of our -nervous system, for it is evident that the difference of intensity in -the conduction of excitation is not, as has been assumed until now, the -result of the conduction of varying strengths of a single excitation -in the same elementary fibers, but rather the involvement of a various -number of fibers, and that a series of processes which we have to the -present attributed to the varying intensities are now to be explained -by difference in the duration and form of excitation. This gives us -an entirely different but nevertheless a more definite picture of the -physiological character of the processes in the nervous system. Still, -this question belongs to another chapter of physiology. Here we are -interested in the fact that we have in the nerve a form of living -substance, in which irritability has reached a high degree, and every -stimulus which is at all operative brings about disintegration of all -the material involved in excitation, and consequently the property of -conductivity in the nerve reaches the state of highest development -of all living structures, in that the medullated nerve conducts with -the greatest rapidity on the one hand, and on the other, there is -no decrement of the velocity and intensity of excitation. All these -characteristics: the existence of the “all or none law,” the rapidity -of the conduction of excitation, the absence of a decrement in the -velocity, the absence of a decrement of the intensity of the excitation -wave, the want of the capability of summation of excitation, are all -dependent upon one another, for they are the combined expression of -one and the same factor, that of the high state of irritability. When -the irritability is artificially reduced, then the nerve approaches -more and more, depending upon the amount of reduction, to the series -of living substances in which we found the protoplasm of the rhizopoda -to occupy the other extreme. Between the normal medullary nerve with -its maximal, and the pseudopods of the rhizopods with their minimal -capability of reaction, we find innumerable gradations in groups of -living substances. Whether or not other forms of living substances -follow the type of the nerve, whether for example the “all or none law” -can be applied to the skeletal muscle as the investigations of _Keith -Lucas_[112] seem to show, requires further investigation. - - [112] _Keith Lucas_: “On the gradation of activity in a skeletal - muscle fiber.” Journal of Physiology, Vol. IX, 1888. The same: The - “all or none” contractions of the amphibian skeletal muscle-fiber. - Journ. of Physiology, Vol. XXXVIII, 1909. - -Finally, there arises the important question as to the finer mechanism -of conductivity. The progression of excitation from cross section to -cross section in a living system is brought about by the decomposition -of the molecules in one region acting as a stimulus and producing -a disintegration of the molecules in another region, etc. We have -already seen that the intensity is dependent upon the amount of energy -produced by the disintegration of the molecules following the stimulus, -that is, upon the amount liberated in a definite space in a definite -time. The question which now arises is this: What form of energy is -produced by the stimulus at the point of stimulation, which acts upon -the neighboring molecules? The conduction of excitation is a property -of all living substance, and we may presume that this occurs in all -living systems in the same manner. If one examines the forms of energy -which are produced in a living substance by the breaking down of the -molecules, we find that chiefly three forms of energy may be taken in -consideration in the problem of conductivity: heat, electricity and -osmotic energy. Light cannot be looked upon as a form of energy which -is produced by all living substance, and the other forms of energy, -as the chemical energy and surface tension, remain local. At a first -glance one is inclined to assume that heat is the form of energy -which is liberated by the breaking down of the stimulated molecule -and which spreads to the neighboring molecules and brings about their -decomposition. For we know that heat facilitates dissociation, and the -analogy between living substance and explosive material is very close. -In both instances the decomposition, which extends over a great mass -of molecules, is accomplished by the heat produced in the breaking -down of a few molecules. In fact, the conduction of excitation of a -nerve can in many respects be compared with the burning of a fuse.[113] -Nevertheless, it must not be forgotten that this analogy, which on -first glance seems so apt, upon closer observation presents serious -difficulties. It can be experimentally shown that an increase in the -temperature in the living substance follows stimulation, but it is -also known that in momentary excitation following a single stimulus, -as in the muscle after the application of an induction shock, the heat -production is extremely small. This difficulty becomes particularly -apparent if we endeavor to gain an approximate idea of the numerical -proportions of the irritable, that is the disintegrating molecules to -the remaining mass of a living system. The water content above all -represents an enormous proportion. If we calculate this to be for -the nerve, for instance, roughly about 75 per cent., which is a low -estimate, only 25 per cent. of dry substances remain. Even of this -25 per cent. by far the largest part is apportioned to connective -tissue, for which 15 per cent. is certainly not too high a figure. -Neither can the remaining 10 per cent. of dry substances be regarded -as consisting entirely of molecules capable of decomposition. For in -this is also included the organic reserve material of the axis cylinder -protoplasm, which is doubtless of very considerable amount. Further, -the salts and products of disintegration, for which the estimate for -the sum total would probably not be too low if we assume the amount to -be equal to that of the group specially concerned in the process of -excitation. As, however, a constant metabolism of rest takes place, -these last molecules or atom groups are certainly not at the moment -of entrance of the stimulus in their entirety in a condition capable -of decomposition. It is quite certain, therefore, that we are still -overestimating the amount of the molecules capable of disintegration, -if we put them down as 5 per cent. of the entire nerve substance. -If we now suppose that this 5 per cent. of irritable molecules are -broken down as a result of stimulation, 95 per cent. of nonirritable -substance, separating these irritable molecules, must become heated to -such a degree by the disintegration of the latter that the amount of -heat suffices to bring about decomposition of the nearest surrounding -molecules or atom groups, for otherwise conduction of disintegration -could not take place in this manner. This condition presents a -serious difficulty for the assumption that heat is the form of energy -responsible for the conduction of disintegration. It is true that we -cannot reject this view at once as being completely incorrect, as the -possibility of conduction does not depend upon the absolute amount of -heat which reaches the next molecule capable of decomposition, but -upon the relative amount of heat in regard to the degree of lability -of the irritable molecules, of which we cannot even approximately make -an estimate. However, by a comparison with other highly explosive -substances, such as iodide of nitrogen, we find that a slight trace -of water applied to the iodide of nitrogen suffices to prevent the -extension of the disintegration process, and with this the explosion of -the whole mass. Nor does the view of _Pflüger_ remove this difficulty, -which assumes that the atom groups capable of breaking down are joined -together by a chemical linking of atoms to long fiber-shaped giant -molecules through the whole nerve fiber, for this assumption of a firm -structure can hardly be reconciled with the principles concerned of -metabolism. - - [113] Compare _Pflüger_: “Ueber die physiologische Verbrennung - in den lebendigen Organismen.” In Pflügers Archiv. Bd. 10, 1875. - Further: _L. Hermann_: “Handbuch der Physiologie, Bd. II, Allgemeine - Nervenphysiologie,” 1879. - -In consideration of this difficulty it seems easier to assign the -rôle of mediator of disintegration not to heat but to electricity. -Production of electricity is likewise a property of all living -substance. Differences of electrical potential between two points may -be equalized in the stretch by conduction through the intervening -space. Electricity would then fulfil the important conditions, which -must be demanded for the form of energy, acting as mediator for the -conduction of disintegration from cross section to cross section. - -[Illustration: Fig. 25. - -Model of a “Kernleiter.” A, B--Glass tube, with a number of side tubes -filled with saline solution, through which a wire is passed. _c_ and -_d_--Side tubes with electrodes for stimulation. _e_ and _f_--Tubes for -connection with a galvanometer. (After _Hermann_.) ] - -Physiologists even at an early date, misled by the apparent likeness -in the conduction of excitation, especially in the nerve, to that of -electricity in a metal wire, regarded both processes as identical. -When, however, _Helmholtz_ first demonstrated experimentally the -rapidity of the conduction in the nerve, the thought that electrical -conduction was concerned, such as takes place in a metal wire, had to -be abandoned, as the velocity shows too great a difference in the two -cases. - -[Illustration: Fig. 26. - -Scheme of the conduction by local electric currents in a “Kernleiter.” -(After _Hermann_.)] - -The observations, on the other hand, on the conductivity in the -so-called “core model,” seemed to offer another possibility of -attributing the conduction of excitation in the nerve to electric -processes. _Matteucci_, later _Hermann_ and finally _Boruttau_[114] -have endeavored to apply the results obtained when electricity is -introduced in a wire covered with a moist envelope (saline solution), -to the explanation of conductivity in the nerve. (Figure 25.) The fact -has been shown, that in such a model the application of electricity -to a point, as a result of polarization between the moist envelope -and the metal, produces a weak local current, which in turn disturbs -the electrical potential in the next cross section and consequently -a new local current is produced and so on through the whole length -of the wire. (Figure 26.) This fact, in connection with the apparent -similarity in the differentiation of the axial fibers and peripheral -envelope in the nerve, has led _Boruttau_ to apply the principles of -conductivity in the “core model” to that of the nerve. Then, however, -_Nernst_ and _Zeyneck_ brought forward their theory, according to which -the galvanic current is operative as a stimulus in that it brings -about an alteration in the concentration of the ions at the junction -of two different electrolites which, in turn, produce local currents. -_Boruttau_ then dropped the assumption of the existence of a simple -physical polarization between the wire and the envelope and replaced it -by the assumption of an alteration in the concentration of the ions at -this position. Thereby the “core model explanation” was already altered -in principle, in that only the differentiation of a central fibrilla -and a peripheral enveloping substance was appropriated. It seems to me -that this factor can likewise be considered as completely dispensable -and may, therefore, be omitted; thus nothing remains of the “core model -explanation” of the conduction of excitation in the nerve. - - [114] The enormously extensive literature on this subject up to the - most recent date is quoted in _Cremer_: “Die allgemeine Physiologie - der Nerven.” In _Nagels_ Handbuch der Physiologie des Menschen, Bd. - IV, 1909. Braunschweig. - -The results of continually increasing numbers of investigation in -recent times make it appear almost as a certainty that the elementary -fibrillæ in the axis cylinder are nothing else but skeletal substances. -_Wolff_,[115] _Verworn_[116] and others have first expressed the -view that the neurofibrillæ must be looked upon as skeletal fibers -for the soft neuroplasm, and more recently _Lenhossek_[117] and -especially _Goldschmidt_[118] have confirmed this assumption in detail. -_Goldschmidt_ has shown by extensive comparative studies of cell -mechanism the rôle played by the neurofibrillæ in a physical connection -as internal skeletal formations, and has proved at the same time, in -complete unanimity with other investigators, their continuity with -other undoubted skeletal fibrillæ. By this the numerous combinations -and speculations of _Apathy_ and _Bethe_ concerning the part taken by -the neurofibrillæ have been rendered untenable. In no case is there the -slightest justification to regard the apparent “Kernleiterstructur” of -the nerve as the principal condition for the process of conductivity, -for should we dispense completely with this point for the theory of the -conduction of the nerve, we can obtain, solely by the aid of the facts -known today in physical chemistry, the foundations for a theory of the -conductions of excitation which not merely renders the specific case of -the conduction of the nerve intelligible, but contains at the same time -the principles of the process of the conduction of excitation for all -living substance. - - [115] _M. Wolff_: “Ueber die fibrillaren Structuren in der Leber des - Frosches.” Anatom. Anzeiger Bd. 26, 1905. - - [116] _Max Verworn_: “Bemerkungen zum heutigen Stand der - Neuronlehre.” Medicin. Klinik, Jahrg. IV, 1908. - - [117] _M. v. Lenhossek_: “Ueber die physiologische Bedeutung der - Neurofibrillen.” Anatom. Anzeiger Bd. 36, 1910. - - [118] _Richard Goldschmidt_: “Das Nervensystem von Ascaris - lumbricoides und megalocephala. Ein Versuch in den Aufbau eines - einfachen Nervensystems einzudringen.” III Teil. Festschrift zum 60 - Geburtstage Richard Hertwigs Bd. II, 1910, Jena. - -[Illustration: Fig. 27. - -Scheme of the foam structure of living substance. A--In -undifferentiated protoplasm. B--In fibrillae protoplasm.] - -On the basis of investigation in the physical chemistry on the -properties of semi-permeable membranes, we know that such membranes -produce an elective effect on the diffusion of dissolved substances. -This is in the way that the two different solutions, separated by a -semi-permeable surface, do not follow the known laws of diffusion, but -are altered in that certain substances in contrast to their rapidity -of diffusion pass through the membrane or are prevented from entering -by the latter. This applies likewise to the two kinds of ions, which -are dissociated in diluted substances. If the surface exercises a -selection in the way, for instance, that the positive kations are -allowed to pass through, whilst the negative anions are held back, a -difference of potential must exist between the two. In this manner, -wherever two different solutions are separated from each other by a -semi-permeable surface, an opportunity occurs for the taking place -of galvanic currents. As we know, living protoplasm by reason of -its colloidal components possesses, in common with all colloidal -substances, on its surface the properties of semi-permeable membranes. -Between the cell and the medium, therefore, there is always the -opportunity for the occurrence of differences of electric potential. -But more. We likewise know that protoplasm itself represents a -mixture of colloid substances and actual solutions. Frequently, if -not always, living structure presents a morphological differentiation -of two types, when seen under the microscope, in the form of a foam -structure described by _Bütschli_. (Figures 27 and 28.) If we suppose -that with the disintegration of complex molecules, which we must assume -as taking place in the material of the walls of the protoplasm network, -substances are formed which are subjected to electrolytic dissociation, -the anions and kations hereby liberated must be diffused from the place -of their separation into the surroundings. Their diffusion, however, -is restricted by the protoplasmic network. The positive ions may pass -through, but the negative ions may not. As a result: the reticulated -substance is the seat of electric discharge, which in turn gives the -impact to the breaking down of new molecules and with this to the -occurrence of new potential differences, and so on, consequently the -disintegration is extended further and further through the connected -masses of the protoplasmic framework. - -[Illustration: Fig. 28. - -Protoplasm of different cells, showing foam structures. A--Pseudopod -of a marine rhizopod. The protoplasm only shows foam structure at the -point of stimulation. B--Epidermic cell of lumbricus. C--Nerve fiber. -D--Part of the cell body of a ganglia cell. (A-C after _Bütschli_, D -after _Held_.) ] - -This theory, founded on facts gained entirely from investigation, would -involve those forms of energy which play the rôle of activator in the -extension of the breaking down of the molecule from cross section to -cross section, namely, the osmotic and the electrical energy. Based on -the general properties of physical chemistry and those of morphology -of the living substances, they would be applicable to all vital -systems. It would be premature to attempt to extend this assumption and -further develop its specific details, above all to make it responsible -for the specific differences in the process of the conduction of -excitation in various forms of living substance. For this our knowledge -of the properties of living substance is still far too incomplete. -Nevertheless, it furnishes us even now with various points of view -for the further analysis of a series of vital manifestations, as, -for instance, the facts concerning the production of electricity, of -galvanotaxis, chemotaxis and so on. This, however, exceeds the limits -of the task we have here mapped out. We are concerned here solely with -the general principle on which the conductivity of excitation in the -living substance is founded. - - - - -CHAPTER VII - -THE REFRACTORY PERIOD AND FATIGUE - - _Contents_: Conception of specific irritability. Alteration of - specific irritability during and after excitation. Refractory period - in various forms of living substance. Absolute and relative refractory - period. Curve of irritability during refractory period. Dependence of - the duration of the refractory period on the rapidity of the course - of the metabolic processes in the living substance. Dependence on - temperature. Dependence on supply of oxygen. Theory of refractory - period. Refractory period as basis of fatigue. Fatigue as a form of - asphyxiation. Alterations of irritability and the course of excitation - in fatigue. Recovery from fatigue. The rôle played by oxygen in - recovery. Fatigue as an expression of the prolongation of the - refractory period conditioned by the relative want of oxygen. Fatigue - of the nerve. - - -Every living system possesses, as we know, a peculiar and -characteristic manner of reacting to stimulation. The muscle responds -with a contraction, the salivary cell with production of saliva, the -luminous cell with the emission of light. This is the _specific energy_ -in the sense of _Johannes Müller_. Every living system is likewise -characterized by a certain degree of irritability, which can be -expressed by the threshold value of the stimulus at which the specific -reaction is just perceptible. This degree of irritability, by which -the system concerned is distinguished, may be termed its _specific -irritability_. - -From the standpoint of the conditional method of investigation it is at -once apparent that specific energy, as well as specific irritability, -must be solely determined by the specific conditions existing in the -particular system. It follows from this that every alteration in -the conditions of the system, that is, every change of its state, -likewise entails a corresponding alteration of its specific energy and -its specific irritability. It is, therefore, self-evident that the -alteration of the state, which is undergone by the living system in -the process of excitation, brings about an alteration of its specific -irritability. Likewise as the original state of the system is restored -by the metabolic self-regulation after the course of an excitation, the -specific irritability of the system must be reestablished. The specific -irritability is, therefore, a property of the living system, which, -like the metabolic equilibrium, undergoes restitution by the process of -self-regulation after variation produced by a stimulus of any kind. It -is scarcely necessary to repeat each time that this is only applicable -within the physiological variations and for a limited period, during -which the alterations in development need not be considered. - -These alterations of the specific irritability following an excitation -and their compensation through the metabolic self-regulation will now -claim our attention. - -That the specific irritability of a living system undergoes a -diminution as the result of a stimulus of long duration has been -long known through the study of fatigue. This is especially so with -frequently recurring excitating stimuli. It is only within the last -decade, however, that the observation has been made in a few instances -that a single momentary excitation is likewise followed by such a -reduction of the specific irritability. But that this is a fact of -general physiological fundamental importance for the whole field -of response to stimulation in the living substance has only been -recognized within the last few years. - -[Illustration: Fig. 29. - -Eight series of heart contractions. The dotted lines _e_ show -the moment of an artificial stimulus. The artificial stimulus is -ineffective if it is applied before the height of a systole. The -artificial stimulus becomes the more effective in producing an extra -systole, followed by a compensatory pause, the later it is applied -after the height of the systolic contraction. (After _Marey_.) ] - -In 1876 _Marey_[119] found that the irritability of the heart in -response to artificial stimulation was greatly reduced during the -systole, and that recovery took place during the following diastole. -(Figure 29.) This fact was already apparent from the observations made -by _Bowditch_[120] and _Kronecker_,[121] that by stimulation of the -isolated frog’s heart with single induction shocks, an artificial -systole can only be produced with certainty when the stimuli succeed -each other at certain intervals, which must be the longer as the -strength of the stimulation is weaker. _Marey_ calls this period -of reduced irritability “_phase réfractaire_” of the heart. The -refractory period of the heart has been made the subject of a great -number of investigations, especially by _Engelmann_ and his pupils. -It was _Engelmann_[122] especially who determined more exactly the -duration of the course of the refractory period. He found, namely, that -irritability disappears immediately before each systole and reappears -shortly before the beginning of the diastole, and again reaches its -original height at the end of the diastole. For a long time, however, -this refractory period was looked upon as a special peculiarity of the -heart. It was not until _Broca_ and _Richet_,[123] twenty years after -_Marey’s_ investigations, discovered an analogous refractory period for -the motor centers of the cerebral cortex of the dog. They first made -this observation on a dog affected with chorea, in which the choreic -movements rhythmically occurred in intervals of one second. They found -that after each movement electrical stimulation of the cortex remained -without result for about .5 seconds. During the next .25 seconds -stimulation was followed by a weak response and it was not until the -last .25 seconds before the next movement that a strong effect was -produced. They also found in the normal dog a refractory period after -every artificial stimulation equal to .1 second, so that the number of -contractions brought about by rhythmical electrical stimulation were -only ten per second. Following this, numerous other investigations of -the refractory period have been made on the central nervous system. -_Zwaardemaker_[124] and _Lans_ have observed a refractory period in -the eyelid reflex of the human being which, on stimulation of the -optic nerve, amounts to about .5–1 second; on the stimulation of -the trigeminus produced by blowing on the cornea on the other hand, -it is somewhat shorter, less than .25 seconds. _Zwaardemaker_[125] -also was able to demonstrate an analogous refractory period for the -swallowing reflex of the cat. Further a refractory period was found -and closely analyzed by _Verworn_[126] for the reflexes in the spinal -cord of the strychninized frog. _Dodge_[127] found a refractory period -in the knee jerk reflex of man. _Gotch_ and _Burch_[128] showed, by -two induction shocks following each other in quick succession, a -refractory period of the nerve, which is characterized by its extremely -brief duration. They found, depending upon the temperature, a period -of nonirritability of .001-.008 seconds after every stimulus. The -investigations of Miss _Buchanan_[129] lead us to conclude that there -is a refractory period for the cross striated skeletal muscle. Miss -_Buchanan_ stimulated the muscle at times through the nerve, at other -times directly after elimination of the nervous element, with very -frequent electrical stimuli (about 1000 in the second) and found by -means of the capillary electrometer a rhythmical reaction of the muscle -of about 50–100 excitation shocks per second. Likewise the _Ritter_ -tetanus produced by the breaking of an increasing current proved to -be a rhythmical reaction of an analogous nature. In a more direct -manner _Keith Lucas_[130] has determined the refractory stage for the -musculus sartorius of the frog. He allowed two induction shocks to act -successively on the muscle at intervals of varied duration and then -registered the action currents by means of the capillary electrometer. -He then found that the second stimulus was ineffective for about .005 -seconds after the application of the first stimulus. If the second -stimulus follows somewhat later, it produces a contraction which is -weaker and has a longer latent period the nearer the second stimulus -approaches the first in point of time. (Figure 30.) _Massart_[131] -and _Jennings_[132] likewise observed the existence of a refractory -period for the myoids of unicellular organisms brought about by -mechanical stimuli. _Massart_ attributes this cessation of reaction -to stimuli following each other at certain intervals, to fatigue, an -explanation which has been disputed by _Jennings_ as the result of -his investigations made on Stentor and Vorticella. _Jennings_ looks -upon the behavior of the infusoria rather as an “adaptation” to the -stimulus. _Pütter_ was the first to see in this the existence of a -refractory period. His experiments on Spirostomun ambiguum in 1900 -showed a refractory period in the reaction to rhythmical mechanical -stimuli. I wish to state, however, that these observations of _Pütter_ -have not as yet been published. Thus the existence of a refractory -period has even today been proved for a whole series of very different -kinds of substances. - - [119] _Marey_: “Des excitations artificielles du cœur.” Travaux du - lab. de M. _Marey_ II, 1875. The same: “Des mouvements qui produit le - cœur lorsqu’il est soumis à des excitations artificielles.” Comptes - rendues de l’academie des sciences T. L. XXXII, 1876. - - [120] _Bowditch_: “Ueber die Eigenthümlichkeiten der Reizbarkeit - welche die Muskelfasern des Herzens Zeigen.” Arbeiten aus der - physiologischen Anstalt zu Leipzig, 1872. - - [121] _Kronecker_: “Das charakteristische Merkmal der - Herzmuskelbewegung.” Beiträge zur Anatomie und Physiologie als - Festgabe f. Carl Ludwig zum 15, Oct. 1874, gewidmet von seinen - Schülern. Leipzig 1874. - - [122] _Th. W. Engelmann_: “Beobachtungen und Versuche am - suspendierten Herzen III. Refractäre Phase und compensatorische Ruhe - in ihrer Bedeutung für den Herzrhythmus.” Pflügers Arch. Bd. 59, 1895. - - [123] _Broca et Richet_: “Période réfractaire dans les centres - nerveux.” Comptes rendus de l’academie des sciences 1897. Further - _Richet_: “La vibration nerveuse.” Revue scientific Déc. 1899. - - [124] _Zwaardemaker und Lans_: “Ueber das Stadium relativer - Unerregbarkeit als Ursache des intermittierenden Charakters des - Lidschlagreflexes.” Centralblatt für Physiol. XIII, 1899. - - [125] _Zwaardemaker_: “Sur une phase réfractaire du reflex - déglutition.” Arch. international de physiologie Vol. I, 1900. - - [126] _Max Verworn_: “Zur Kenntniss der physiologischen Wirkungen - des Strychnins.” Arch. f. Anat. u. Physiol. physiol. Abth., - 1900. “Ermüdung Erschöpfung and Erholung der nervösen Centra des - Rückenmarks.” Ibidem, 1900. “Die Biogenhypothese.” Jena 1903. “Die - Vorgänge in den Elementen des Nervensystems.” Zeitsch. f. allgem. - Physiologie Bd. VI, 1907. - - [127] _Dodge_: “A systematic exploration of a normal knee jerk, its - technique, the form of the muscle contraction, its amplitude, its - latent time and its theory.” Zeitsch. f. allgem. Physiol. Bd. XII, - 1911. - - [128] _Gotch and Burch_: “The electrical response of nerve to two - stimuli.” Journ. of Physiology, Vol. XXIV, 1899. - - [129] _Florence Buchanan_: “The electrical response of muscle in - different kinds of persistent contraction.” Journ. of Physiology, - Vol. XXVII, 1901–1902. - - [130] _Keith Lucas_: “On the refractory period of muscle and nerve.” - Journ. of Physiology, Vol. XXXIX, 1909–1910. - - [131] _Massart_: Annales de l’Institut Pasteur 1901. - - [132] _Jennings_: “Studies on reactions to stimuli in unicellular - organisms.” IX. American Journal of Physiology, 1902. - -[Illustration: Fig. 30. - -Curve of action current of the musculus sartorius excitated by two -successive stimuli (St. 1 and St. 2). The effect of the second stimulus -is the less and the latent period is the longer the more quickly the -first stimulus is followed by the second. (_Keith Lucas._) ] - -We will now examine the alterations of irritability which are -perceptible during the refractory period to complete restitution of the -specific irritability of the particular system, and endeavor by the -analysis of their special conditions to render them comprehensible from -a physical standpoint of view. - -The first fact to take into consideration is, that, as is shown in the -heart, the refractory period begins at the moment of the appearance -of the systolic excitation. The irritability of the heart is absent -and remains so until the excitation has reached its highest point, -that is, shortly before the beginning of the diastole. From this point -the restitution of irritability begins, which does not reach the -maximum until the end of the diastole. In other words: irritability -undergoes the greatest reduction by disintegration produced by the -stimulus and is restored by the metabolic self-regulation following the -decomposition. - -This point of view enables us to interpret this state from a physical -standpoint. In this discussion on the relations between irritability -and the extension of excitation, I have taken the amount of energy -which is produced during the time unit and space unit in a living -system as the general standard for the degree of irritability, at the -same time duly regarding the individual components involved. This -amount of energy is determined in a given system by the quantity -of substance broken down by a stimulus of a given intensity. It -is, therefore, clear that during the time in which an increased -disintegration produced by a stimulus takes place, the irritability in -response to a second stimulus must be reduced, as during this period -the second stimulus has less of necessary decomposable substances -at its disposal, and at the same time there are more products of -disintegration in a given space. If a living organism is the subject -of consideration, to which the “all or none law” is applicable, as, -for instance, the heart at the moment of the beginning of excitation, -irritability is completely obliterated, as shown by the fact that the -second stimulus of any strength remains without response, for during -the excitation there is a complete breaking down of all the substances -capable of decomposition. If, on the contrary, a system is the subject -of observation, for which the “all or none law” is not valid, then -irritability is merely reduced but not wholly obliterated during an -excitation, and whether or not a response is obtained to the stimulus -depends upon its strength. To impress the relations between the degree -of irritability and the intensity of the stimulus, I have, therefore, -employed the term “_relative refractory period_” in contrast to the -“_absolute refractory period_,” in which irritability is obliterated -even for the strongest stimuli. It is self-evident that irritability -must again increase in the same degree as the restitution of the -living system by metabolic self-regulation takes place, for the -more molecules capable of disintegrating are restored and the more -products of disintegration removed, the more molecules necessary for -decomposition in the unit of space are attacked and broken down by the -stimulus. All these are self-evident facts which are in accordance -with the conception we have here developed of the course of the -process of excitation and its physical nature. But another important -point is evolved from the observations we have made of the nature of -the process of self-regulation. The process of self-regulation is -founded on the same principle as that which governs the taking place -of all chemical equilibrium, for metabolic equilibrium is merely a -special kind of a chemical equilibrium. The development of a chemical -equilibrium between reacting substances and reaction products has, -as known, a characteristic course in regard to its duration. If the -rapidity with which the equilibrium is reached is expressed by a curve -in which the abscissa represents the time, while the ordinates signify -the number of contacts of the interacting molecules, the rapidity -of reaction is altered with the approach to the equilibrium in the -form of a logarithmic curve; that is, the approach to the state of -equilibrium, which is represented by ordinate value zero, takes place -at first very rapidly, then with more and more decreasing speed, for -with the decrease of the number of reacting molecules and the increase -of the amount of products of reaction, the contact of the interacting -molecules and with this the opportunity for the reaction occurs -less and less frequently. Although the self-regulation of metabolic -equilibrium is by no means such a simple process as, for instance, that -of the well-known example of the forming of ethylester from acetic -acid and æthyl alcohol, we have still in every case to deal with the -taking place of a chemical mass equilibrium. Hence the progress to -the metabolic equilibrium must likewise correspond with a logarithmic -curve, i.e., restitution after a disturbance of the equilibrium must -take place at first rapidly, then at a constantly decreasing rate. For -reasons readily to be understood the special form of this restitution -curve has so far not been accurately ascertained for any kind of living -substance. Even in those cases where the restitution occurs very slowly -we meet with the difficulty that, when the tests are applied which -are necessary to determine the restitution at different intervals, -with each testing stimulus irritability is each time reduced. Hence -the construction of the restitution curve can only be achieved by -indirect means, and we must content ourselves with the ascertainment -of a smaller number of its points from which by interpolation its form -can be constructed. Indeed in this connection a certain number of -results have already been gained quite sufficient to experimentally -confirm the correctness of these types of curves, primarily obtained -by purely theoretical deductions. That irritability very gradually -reaches its maximal height has been already shown, as previously -mentioned by _Bowditch_[133] in his investigations on the influence -of rhythmical induction shocks on the apex of the heart of the frog. -He found that in order to produce response, the weaker the stimuli -the longer must be the intervals between them. It follows from this, -that after a discharge the irritability in response to strong stimuli -reappears more rapidly than for weak, i.e., that they only _gradually_ -regain their maximum. The exact periods of time for the course of the -return of irritability for the heart have unfortunately not been so far -ascertained. On the other hand, the investigations of _Ishikawa_[134] -furnish the material for the construction of the restitution curve -for the centers of the spinal cord of the frog. _Ishikawa_ did not -employ the threshold of stimulation as an indicator for the course -of restitution, but used instead the duration of the reflex time -following on a stimulus of a certain strength. The reflex time is -greatly prolonged after an excitation of extended duration and only -regains its normal value in the same degree as restitution takes place. -By a great number of painstaking experiments _Ishikawa_ ascertained -the duration of the reflex time at intervals of thirty seconds to one -minute, and obtained figures which show that restitution does actually -take place, at first rapidly and then with constantly decreasing speed. -The detailed study of the course of self-regulation of the individual -forms of living substance will doubtless be more exactly determined -in the near future. But even at the present we are fully justified in -describing the form of restitution curve as a _logarithmic_ in type. -Therefore, a relative refractory period must be present in every -metabolic self-regulation after an excitation, during which stronger -stimuli produce response, while weaker are still without result. This -is a fact which, as we shall see later, is of fundamental importance -for the comprehension of the various kinds of interference responses to -stimuli. - - [133] _Bowditch_, 1. c. - - [134] _Hidetsurumaru Ishikawa_: “Ueber die scheinbare Bahnung.” - Zeitschrift f. allgem. Physiologie Bd. XI, 1910. - -From the information here gained on the nature and origin of the -refractory period the conclusion must inevitably be drawn that in all -living substance there must exist, directly following an excitation, -a period of time in which its irritability is reduced, that is, under -proper conditions a refractory period can be demonstrated for every -living organism. Every living system possessing irritability undergoes -a period of reduced irritability at the time of and subsequent to every -excitation, for every excitation momentarily decreases the amount of -products capable of disintegration and increases the disintegration -products in the unit of space. As restitution involves time, a -stimulus occurring in the phase preceding complete restitution cannot -break down the same quantity of molecules as would be the case after -the establishment of complete restitution, that is, the response is -weaker, the irritability is decreased. The refractory period during and -subsequent to excitation is as much a general property of the living -substance as irritability and metabolic self-regulation. - -This conclusion appears so self-evident that it would seem hardly -to call for emphasis were it not that even at the present time the -view is still widely held that the refractory period is a special -characteristic of certain forms of living substance. This assumption -is explained on the one hand by the fact that our information -concerning the refractory period is still of comparatively recent -date and that few physiologists are in the habit of connecting -special observations with general physiological conceptions, but also -for the reason that some investigators have vainly tried to find a -refractory period in certain forms of living substance. _Langendorff_ -and _Winterstein_,[135] for instance, have not succeeded in proving -a refractory period for the spinal cord of the frog. _Langendorff_ -stimulated the central sciatic stump with two stimuli in quick -succession and used the contractions of the triceps as indicator of -the response. He found that when the stimuli, if consisting in either -single induction shocks or faradic shocks, followed each other even at -intervals of .004 seconds the second stimulus was still operative, this -being perceptible in an increase of the contraction or with greater -intervals of time in a summation of two contractions. _Winterstein_ -concludes from this that the development of a refractory period after -a stimulation is not a general property of all nerve centers. If -the experiments of _Langendorff_ failed to show the presence of a -refractory period it is not for the reason that this does not take -place in the centers of the spinal cord but rather results from the -fact that the conditions for the investigation were not suited for its -demonstration. In fact, _Fröhlich_[136] and especially _Vészi_[137] -have incontestably proved the existence of relative refractory periods -in the normal spinal cord. - - [135] _Langendorff u. Winterstein_: “Beiträge zur Reflexlehre.” - Pflüger’s Arch. Bd. 127, 1909. - - [136] _Fr. W. Fröhlich_: “Beiträge zur Analyse der Reflexfunction des - Rückenmarks mit besonderer Berücksichtigung von Tonus, Bahnung und - Hemmung.” Zeitschrift f. allgem. Physiologie Bd. IX, 1909. - - [137] _Julius Vészi_: “Der einfachste Reflexbogen im Rückenmark.” - Zeitschr. f. allgem. Physiologie Bd. XI, 1910. - -If the existence of the refractory period is based on the fact that -during the time of and subsequent to an excitation the quantity of -substances necessary for disintegration is decreased and that of -the breaking down products increased, and if it is limited by the -restitution of the substances required for decomposition and the -elimination of the disintegration products, its duration must be -dependent upon the length of these processes. All factors which -lessen the decomposition and hasten the metabolic self-regulation -must, therefore, shorten its duration. This is completely confirmed -by experimental investigations. As can be understood, the factors of -special interest for us are those which influence the duration of the -refractory period in the physiological occurrences of the organism. - -One of these factors is temperature. As we know, the rapidity of -chemical reactions increases with ascending and decreases with falling -temperature. As in the disintegration as well as in the restitution, -processes are chemical in nature, it is to be expected that the -duration of the refractory period is influenced in like manner by -temperature. Indeed, _Kronecker_[138] found some time ago that in -the isolated frog’s heart a much more frequent rhythm of stimulation -is effective at a higher than at a lower temperature. When the heart -is stimulated at a temperature of 11–12° C. with twelve rhythmical -induction shocks in the second, every stimulus is operative and -produces a systole. If a stimulus of the same frequency is used at -a temperature of 5° C., the heart responds merely to every second -stimulus. This shows that the refractory period is of longer duration -at a lower than at a higher temperature. - - [138] _H. Kronecker_: “Das charakteristische Merkmal der - Herzmuskelbewegung.” Beiträge zur Anatomie and Physiologie als - Festgabe Carl Ludwig zum 15 October 1874 gewidmet. Leipzig 1874. - -A factor of particular interest is the supply of oxygen, for we know -its fundamental importance in all aërobic organisms in the breaking -down of the living substance. The life of these organisms is primarily -dependent upon the supply of oxygen from without. Organic reserve -substances for restitution after disintegration are contained in ample -quantity in the reserve stores in the living cell substance, whereas -oxygen is present in very small quantities in relation to the former. -It is, therefore, self-evident that the rapidity of the breaking down -processes is very closely dependent upon the amount of available oxygen -at hand. Nevertheless it is not the absolute quantity but the relative -amount of oxygen in relation to the momentary requirement which is of -importance. For instance, the quantity of oxygen present may completely -suffice for the oxydative disintegration in the metabolism of rest or -at lower temperature, whereas the same amount would be much too small -to meet the demand increased by excitation or at higher temperature. -In the latter case “_a relative deficiency of oxygen_” occurs. I have -introduced the term “_relative deficiency of oxygen_”[139] for I have -found that a number of authors by neglecting the relations of the -available oxygen to that which is required at the moment have been -led to false conclusions. There is no living object so preëminently -fitted to demonstrate in such a striking manner the dependence of -the duration of the refractory period upon the supply of oxygen as -the spinal cord centers of the frog, when their irritability has been -increased to the maximum by strychnine.[140] Various observers, such -as _Loven_, _Buchanan_, _H. von Baeyer_ and others, investigated the -action current by the capillary electrometer. As a means of studying -the number of impulses in the strychnine tetanus, we can upon the basis -of their figures roughly assume the number of impulses to equal ten -per second at room temperature. In short, in the freshly strychninized -frog the duration of the refractory period is about .1 second. By means -of the method of artificial circulation already mentioned a deficiency -of oxygen can readily be brought about. It has been demonstrated that -the rhythmic in contrast to the continuous method of introduction -of circulatory fluid is superior in that the former reproduces more -closely the natural conditions of the circulation of the blood and -renders the smallest capillaries more permeable. In consequence I have -recently constructed a small appliance for artificial circulation, -which accomplishes this in a manner as simple as it is complete. -(Figure 31.) - -[Illustration: Fig. 31. - -Arrangement for an artificial circulation in the frog. A--Accumulator. -B--Metronom. C--Mercury key. D--Electromagnetic apparatus for -compressing the rubber tube: 1, wire spool with magnet; 2, anchor for -the magnet; 3, spiral spring which pulls back the anchor; 4, axis on -which the anchor turns; 5, plate for arresting the anchor. E--Vessel -containing saline solution. F--Slab of cork with frog. ] - -The fluid flows from a vessel, E, provided with an outlet tube through -a thin rubber tube into a glass canula, which is introduced into the -general aorta of the frog, F. The tube is automatically occluded by the -rhythmical movement of the armative of an electromagnet, D, produced by -a metronome, B. The pressure of the circulating fluid can be readily -changed at will by varying the level of the vessel and the frequency -of the pulse by the rhythm of the metronome, which makes and breaks -the current to the electromagnet.[141] In this way it is possible -to artificially replace the normal circulation with satisfactory -exactitude and substitute for the blood, circulating in the vessels of -the frog, any desired fluid. If the entire quantity of blood of a frog -is displaced by a continuous stream of oxygen-free saline solution and -a weak strychnine solution is injected with a Pravaz syringe, a violent -strychnine tetanus appears after the lapse of a few seconds. (Figure -32, A.) If the artificial circulation with oxygen-free saline solution -is now contained in the rhythm of the natural heart beat, the further -reactions can then be readily observed. The first long-continued -tetanic attack, which can be produced by a slight touch of the skin, -is followed by a whole series of tetanic convulsions of prolonged -duration, which are repeatedly followed by periods of exhaustion. I -wish to emphasize this fact once more, as it appears to me as not -without interest for the understanding of the question of reserve -substances. - -[Illustration: Fig. 32. - -Muscle curve of strychnine tetanus in a frog with artificial -oxygen-free circulation. Lower line indicates seconds. Upper line -indicates stimulation by induction shocks. A--A single shock produces -a long tetanic contraction. B--In a more advanced stage each shock -produces a tetanus only of short duration. C--In a still more advanced -stage each shock brings about only a single contraction if the stimuli -do not succeed each other too rapidly. If they succeed more rapidly, -as, for instance, in a faradic current, only the first shock is -effective. ] - -If we assume that at the moment when the entire amount of blood is -removed from the vascular system, no oxygen remains in the cells of the -spinal cord and muscle, then disintegration of the living substance -could from this instant take place exclusively anoxydatively, and there -would be no further oxydative breaking down into carbon dioxide and -water. The energy production compared in equal number of molecules, -taking the figures of _Lesser_ for the fermentation of sugar, would -approximately amount to about 3.8 per cent. of that of the energy -production in the oxydative disintegration of dextrose into carbon -dioxide and water. In reality, however, the tetanic convulsions are -at first exactly as violent as in the frog with a normal circulation. -There simply remains the assumption, therefore, that either the -disintegration as soon as it becomes _an_oxydative involves relatively -greater number of molecules than would be the case if it were oxydative -in nature, or to suppose that even after the complete displacement -of the blood a certain, though relatively small, amount of oxygen is -present in the cells which for a short time suffices for the taking -place of oxydative disintegration and with this an almost maximal -production of energy which naturally decreases as the oxygen is -consumed. It seems to me that the latter supposition contains more -probability than the first. To return, however, from this observation -to a further consideration of the animal we are studying, we see how -the complete tetanic convulsions in the refractory period which we -assumed to be .1 second are gradually transformed into incomplete -tetanus. After a time the tetanic convulsions become shorter after each -stimulus (Figure 32, B) and permit us to distinguish their individual -movements, even though the latter at first succeed each other still -very rapidly. Gradually this incomplete tetanic convulsion assumes the -form of a short series of individual contractions, distinctly separated -from each other and soon a stage is reached in which each reaction -to a peripheral stimulus consists merely in a single contraction. -(Figure 32, C.) The refractory period is, however, even now less than -a second. Nevertheless, with a further continuation of the experiment, -the refractory period becomes more and more prolonged, so that stimuli -succeeding each other at intervals of less than a second are without -effect. It is possible at this stage, as _Tiedemann_[142] did, to -graphically record the reactions. He severed the sciatic nerve on one -side and stimulated its central stump, at the same time connecting the -triceps with a writing lever. It is then found that when the single -induction shocks follow each other at intervals of a second or more -every stimulus produces a contraction, but that on the contrary only -the first stimulus of a rhythmical series is operative and all those -succeeding ineffectual, if the stimuli follow each other at shorter -intervals. The refractory period becomes, however, more and more -prolonged. The rhythm of the stimulus must become continually slower -if each individual stimulus is to remain effective. If the rhythm is -even slightly too rapid only the first few stimuli of a rhythmical -series are effective and this with decreasing response and later no -contraction at all is observed. With a further continuance of the -experiment, the stimuli are only effective when following each other -at long intervals. It is necessary that a period of recovery lasting -several seconds must take place before the following stimulus can -meet with response. (Figure 33.) The refractory period can gradually -be prolonged for the space of a minute or longer, until finally -irritability does not reappear at all, and even the strongest stimuli -fail to produce the least contraction. The continuous manner in which -the refractory period is, in the absence of oxygen, more and more -prolonged until eventually a prolonged state of nonirritability is -developed, can be better followed by observing the experiment than when -described in words. If at this stage instead of the oxygen-free saline -solution, defibered blood of the ox shaken in air or a saline solution -saturated with oxygen is circulated in the frog, restitution is often -within a few minutes so complete that tetanic attacks are once more -produced by a single stimulus, that is, the refractory period has from -being practically nil returned to the normal. This experiment can be -repeated several times on the same animal. It is invariably found that -the refractory period is prolonged by the withdrawal of oxygen and -shortened with a renewed supply. - - [139] _Max Verworn_: “Allgemeine Physiologie.” V. Auflage. Jena 1909. - - [140] _Max Verworn_: “Ermüdung Erschöpfung und Erholung der nervösen - Centra des Rückenmarks.” Arch. f. Anat. u. Physiol. physiol. Abt. - Suppl. 1900. The same: Ermüdung und Erholung. Berliner Klin. - Wochenschrift 1901. - - [141] As I have not yet described this method elsewhere the above - figure will suffice for demonstration. - - [142] _Tiedemann_: “Untersuchungen über das absolute - Refractäerstadium and die Hemmungsvorgaenge im Rückenmark des - Strychninfrosches.” Zeitschrift f. allgem. Physiologie Bd. X, 1910. - -[Illustration: Fig. 33. - -Development of the refractory period in the spinal cord of a -strychninized frog. Lower line indicates seconds; upper line stimuli. -Of a series of stimuli only the first ones are operative with -decreasing effect. ] - -I have described this experiment somewhat in detail as it contains -facts which are the key for the comprehension of a general -physiological process of paramount importance. I refer to fatigue. The -refractory period and fatigue are inseparably connected, for fatigue is -founded on the existence of the refractory period and is an expression -of prolongation of the former, brought about by want of oxygen. This is -shown at once by closer analysis. It is here necessary to differentiate -somewhat more in detail the factors which bring about the _prolongation -of the refractory period in deficiency of oxygen_. - -If we first turn our attention to the normal refractory period -which occurs in a system in metabolic equilibrium of rest in direct -connection with dissimilatory excitation, following a momentary -stimulus, we find that reduction of irritability or, more exactly -expressed, the lessening of the response is, as we have seen, -determined by the time involved in the metabolic decomposition and -recovery. Both these processes require time and until their completion -the quantity of substance demanded for the oxydative disintegration -is decreased in a given space, and every stimulus must consequently -be followed by a weaker response. Our conceptions of the physical -details of these processes depend essentially upon the question, if -the oxydative disintegration itself in the given living system occurs -in one single phase, in that the oxygen is the activator for the -oxydative splitting up of the carbon chain, or if this takes place in -two periods, in which the carbon chain is first anoxydatively split -up into larger fragments by the stimulus, which are then seized upon -by the oxygen to be split up into carbon dioxide and water. As we -have seen, this question must remain for the present undecided as far -as the metabolism of rest as well as the excitation produced by a -single momentary stimulus is concerned. It is highly probable that a -uniformity of the process for all living systems does not exist. We -are, therefore, not justified in assuming that these special chemical -processes resulting from single stimuli are uniform throughout the -refractory period. - -On the contrary it is different in the case of oxygen deficiency. Here -we see with increasing want of oxygen a constantly increasing duration -of the refractory period, a prolongation which may be attributed to the -retardation of the oxydative disintegration. It is necessary, however, -that we now study more clearly these alterations brought about by the -deficiency of oxygen. - -If we follow the course of the changes from that of the normal state of -equilibrium of metabolism, wherein oxygen is sufficient to bring about -complete disintegration of the molecules to the formation of carbon -dioxide and water, we must assume in spite of the great explosive -rapidity of this process on the basis of our chemical knowledge, that -first a series of intermediate products are produced before finally -the end products are formed. In this way the oxydative disintegration -produced by a stimulus becomes more and more prolonged by an increasing -want of oxygen. If, as I have previously suggested, the amount of -energy which is liberated in a given space and time by an excitating -stimulus is taken as a standard of irritability, it is apparent that -the more the oxydative disintegration following a stimulus is retarded, -the greater must be the decrease in irritability. The less oxygen there -is at disposal and the more incomplete the oxydative breaking down, -the smaller is the degree of irritability, the weaker the response and -the slower the return of irritability after every stimulus. In other -words, with the increasing deficiency of oxygen, the response is not -merely reduced for every stimulus, but the duration of the refractory -period is likewise progressively prolonged until finally with an -absolute want of oxygen, constant and complete depression takes place. -In the genesis of this process another factor, however, has the same -effect. - -While with a sufficient supply of oxygen disintegration leads to the -formation of carbon dioxide and water, therefore to end products, which -can quickly and easily be removed by diffusion, the want of oxygen -produces complex products of incomplete combustion and finally of -anoxydative decomposition, such as lactic acid, fatty acids and even -more complex substances in constantly increasing quantities. These -products permeate the protoplasmic surfaces with great difficulty, -if at all, and as they cannot subsequently be oxydatively split up, -constantly accumulate. These asphyxiation substances, as they may be -briefly termed, produce a depressing effect on further disintegration. -This can be experimentally demonstrated. - -For this purpose I have modified the experiment previously described -in the way that after every introduction into the blood of oxygen-free -saline solution and after the injection of strychnine, the artificial -circulation was stopped so that stagnation of the oxygen-free saline -solution took place in the vascular system. The processes then occurred -in exactly the same manner with the exception that the state of -non-irritability appeared somewhat earlier. If after the beginning of -complete depression artificial circulation with oxygen-free saline -solution was again started, a certain degree of recovery took place -within one or more minutes. The stimuli were once more effective -and produced a number of contractions. At times, several single -contractions, following each other in more or less quick succession, -could be brought about. But complete recovery or the appearance of even -incomplete tetanic convulsions was never again obtained, whereas by -the introduction of oxygen complete recovery could at once be brought -about. If, however, the circulation with oxygen-free saline solution -was continued, irritability gradually decreased. The refractory -periods after the individual stimuli became longer, and in spite of -continuous artificial circulation irritability _again_ disappeared. -The experiment shows that by the circulation of oxygen-free solution -irritability can simply be reduced up to a certain degree. This partial -restitution is produced by washing out the depressing metabolic -products. Being desirous to verify the results of this investigation -with greater exactitude I have requested _Dr. Lipschütz_[143] to repeat -the experiments, taking the utmost possible precaution in respect to -the absolute exclusion of oxygen. _Lipschütz_ has tested the normal -saline solution made oxygen free with the sensitive _Winkler_ method, -in which the slightest trace of oxygen is shown by the oxydation of -manganous chloride to manganic chloride in which the latter in a -saline solution sets free an amount of iodide from iodide of potassium -corresponding to that of the consumed oxygen. These experiments of -_Lipschütz_ have shown that even with the absolute exclusion of the -slightest trace of oxygen a partial recovery can be brought about by -artificial circulation. There can be, therefore, no doubt that recovery -is actually founded on the removal of the depressing asphyxiation -substances by artificial circulation. Moreover _Fillié_[144] has -previously succeeded in the laboratory at Göttingen in obtaining -by the same methods a corresponding result for the nerve. In both -cases the experiments are extremely complicated and must be carried -out with the most painstaking care. The depressing influence of the -asphyxiation products need not be regarded as a specific effect of -poisoning. It can be solely an expression of mass relations, if we -assume that the anoxydative decomposition is controlled by a chemical -equilibrium between masses capable of disintegrating and products of -the disintegration. It is not possible to give any detailed account -as to the part taken by accumulating asphyxiation substances in -the prolongation of the refractory period. Indeed, we must for the -present relinquish the attempt to delimitate quantitatively the part -taken by the individual constituent processes in the symptoms of -depression resulting from the deficiency of oxygen. We can merely -say, the individual alterations produced by the want of oxygen, that -is, the restriction and retardation of the oxydative disintegration, -the corresponding increase of the anoxydative decomposition and the -accumulation of the products of incomplete oxydation and anoxydative -breaking down have the same influence in that they decrease the -strength of the response and retard the rapidity of the decomposition -process. These are the general effects perceptible in the refractory -period by the deficiency of oxygen. - - [143] _Alexander Lipschütz_: “Ermüdung und Erholung des Rückenmarks.” - Zeitschr. f. allgem. Physiologie Bd. VIII, 1908. - - [144] _Fillié_: “Studien über die Erstickung und Erholung des Nerven - in Flüssigkeiten.” Zeitschr. f. allgem. Physiologie Bd. VIII, 1908. - -The establishment of these facts of the dependence of the refractory -period upon oxygen are of the utmost importance for the genesis -of fatigue, for the state of fatigue in all aërobic organisms is -invariably brought about by deficiency of oxygen. In other words: -_fatigue is invariably asphyxiation_. A deficiency of organic -reserve substances never occurs in fatigue before the effect of -oxygen deficiency leads to complete depression, for the quantity of -organic reserve substances at the disposal of the cells is greater -comparatively than that of oxygen. This is shown by transfusion -experiments in which the time involved before complete paralysis was -brought about in the frog by the introduction of an oxygen-free saline -solution was ascertained and compared with the period which elapsed -before complete paralysis took place, when the same solution saturated -with oxygen was used. - -Although the previously described experiments on the strychninized -frog show clearly the relations of fatigue to the refractory period, I -should, nevertheless, like to illustrate them somewhat further. - -The state of fatigue as it is developed in a living system by a -continuous functional activity is characterized by a series of symptoms -which can be best studied in the fatigue of the muscle, the nervous -centers, and the peripheral nerves. - -If the muscle of the frog is isolated and rhythmically stimulated -with single induction shocks and the muscle contractions graphically -recorded, it will be found that the first perceptible alteration during -the course of stimulation is the increasing height in the curve, -which appears directly after the first contraction and becomes more -and more noticeable after every succeeding one. With the isolated -apex preparation of the frog’s heart an effect is produced which -_Bowditch_[145] has termed the “Treppe” and _Tiegel_,[146] _Minot_[147] -and others have obtained the same result for the skeletal muscle. The -_Treppe_ has been often regarded as an expression of increasing of -capability of the muscle following each succeeding stimulus in spite of -the fact that it is physiologically incomprehensible that an isolated -muscle can become more capable by increased demands. _Fröhlich_[148] -first threw light on this seeming contradiction by showing that the -increase in height of the muscle contraction in the _Treppe_ is in -reality the first indication of the beginning of fatigue, and _Fr. -Lee_[149] arrived at the same result. The increase in height of the -contraction curve depends upon the retardation of the course of -contraction. As the contraction extends over the muscle substance in -the form of a wave, a longer stretch of the muscle will be in a state -of contraction when the wave is more extended than when it is shorter, -that is, the shortening of the muscle will be greater, the contraction -curve higher, when the wave is more extended. With increasing fatigue -the retardation in the course of contraction, as _Rollet_[150] already -has shown, becomes continuously greater. (Figure 34.) The consequence -of this retardation in the course of contraction is, therefore, -perceptible in the rhythmically activated muscle in the form of -contracture. As fatigue increases, the muscle requires an increasing -length of time to relax to its full extent and in consequence the -period between the two stimuli is very soon insufficient for this to -occur. There remains a certain amount of shortening, when the next -contraction begins. This characteristic extension of the individual -contraction curve of the fatigued muscle is an expression of the -retardation of the oxydative disintegrating processes and of the -_Treppe_. It shows us that fatigue is perceptible to a slight degree -even after the first excitation. After every succeeding stimulus -the oxydative decomposition in the fatigued muscle is increasingly -prolonged. It is, therefore, self-evident that the capability of -action of the muscle likewise becomes less with increasing fatigue. -Every state of fatigue is, in fact, distinguished by the decrease of -response. This is perceptible in the later stages by the decline of -the height of contraction. Hence all symptoms of fatigue which we -observe form the expression of one single process; it is the constantly -increasing slowness of oxydative disintegration with increasing fatigue. - - [145] _Bowditch_: “Ueber die Eigenthümlichkeiten der Reizbarkeit, - welche die Muskelfasern des Herzens zeigen.” Arbeiten aus der - physiologischen Anstalt zu Leipzig VI Jahrgang 1871, Leipzig 1872. - - [146] _Tiegel_: “Ueber den Einfluss einiger willkürlichen - Veränderungen auf die Zuckungshöhe des untermaximal gereizten - Muskels.” Arbeiten aus der physiol. Anst. zu Leipzig X Jahrgang 1875, - Leipzig 1876. - - [147] Minot: “Experiments on tetanus.” Journ. of Anat. and Physiol. - Vol. XII. - - [148] _Fr. W. Fröhlich_: “Ueber die scheinbare Steigerung der - Leistungsfähigkeit des quergestreiften Muskels im Beginn der - Ermüdung. (Muskel Treppe), der Kohlensäurewirkung und der Wirkung - anderer Narcotica (Aether, Alkohol).” Zeitschr. f. allgem. - Physiologie Bd. V, 1905. - - [149] _Frederic S. Lee_: “The cause of the Treppe.” Americ. Journ. of - Physiol. Vol. XVIII, 1907. - - [150] _Alexander Rollet_: “Ueber die Veränderlichkeit des - Zuckungsverlaufs quergestreifter Muskeln bei fortgesetzter - periodischer Erregung und bei der Erholung nach derselben.” Pflügers - Arch. Bd. 64, 1896. - -[Illustration: Fig. 34. - -Series of muscle curves graphically recorded one over the other, -showing the retardation in the course of contraction with increasing -fatigue. (After _Rollet_.) ] - -Exactly similar conditions as those of the muscle are seen in the -central nervous system. The reflex contraction of the triceps of the -frog produced by stimulation of the central end of the sciatic nerve -with single induction shocks demonstrates clearly as _Ishikawa_[151] -has proved in certain stages of fatigue, an increase in height and a -strong relaxation which does not depend upon the fatigue of the muscle -but on that of the centers. If the fatigue is greater, the height of -the contraction then decreases, whereas the extension of the course -of relaxation increases further. The possibility of fatigue of the -muscle during these experiments was, of course, precluded by proper -precautionary measures. Irritability and the course of excitation in -fatigue of the centers show exactly the same alterations as developed -in fatigue of the muscle. The processes of oxydative breaking down -are retarded more and more with increasing fatigue, that is, fatigue -is characterized by exactly the same processes as is the prolongation -of the refractory period by the deficiency of oxygen, and likewise in -fatigue this retardation of the oxydative disintegration processes is -conditioned by the relative deficiency of oxygen. This is shown by the -rôle played by oxygen in recovery after fatigue. - - [151] _Hidetsurumaru Ishikawa_: “Ueber die scheinbare Bahnung.” - Zeitschr. f. allgem. Physiologie Bd. XI, 1910. - -It was found by _Hermann_[152] in 1867 and confirmed by Mademoiselle -_Joteyko_[153] in _Richet’s_ laboratory, that the isolated muscle -of the frog, which was completely nonirritable as the result of -fatigue, does not regain irritability in an oxygen-free medium, -but does so when oxygen is introduced. The previously described -experiments of artificial circulation in the frog show clearly how -dependent the centers are upon the oxygen supply for the restoration -of irritability. In consequence of the strychnine poisoning the -irritability of the centers is so enormously increased that the “all -or none law” is applicable to the centers of the spinal cord under -these conditions.[154] These are the best conditions for the production -of fatigue. One can readily demonstrate the importance of the oxygen -supply for the rapidity with which irritability returns after fatigue -if in the strychninized frog an artificial circulation is used, at -the same time varying on one hand the amount of oxygen, on the other -the activity of the centers. If a saline solution containing merely -a trace of oxygen is circulated, the centers recover very slowly -and incompletely after every fatigue. Subsequent to every reaction -produced by a stimulus, an increasing length of time is required until -irritability is so far recovered that a new stimulus can meet with -response. If, however, a saline solution is circulated which has been -saturated by being shaken with oxygen and is continuously in a pure -atmosphere of oxygen, recovery takes place in comparison with far -greater rapidity and completeness. If the supply of oxygen is ample and -the stimuli act at longer intervals on the frog, irritability always -is quickly restored in the periods of rest between the stimuli. With -continuous stimulation of quickly succeeding stimuli, irritability is -soon completely obliterated, even though an abundant oxygen supply be -present, and it is not until a pause is interpolated that oxygen is -capable of bringing about a recovery. By manifold variations of these -experiments the connection between fatigue and the refractory period -can be more and more clearly recognized. _Fatigue is simply the -refractory period prolonged by deficiency of oxygen._ In both cases -there is a diminution of irritability. In both cases this diminution -is conditioned by a retardation of oxydative disintegration following -every stimulation. In both cases it is the relative deficiency -of oxygen which produces this delay. In both cases the oxydative -decomposition can be quickened and irritability restored, that is, -the refractory period lessened and fatigue removed by a sufficient -supply of oxygen. The amount of oxygen which suffices to constantly -maintain the specific irritability of a living system in an undisturbed -metabolism of rest is not sufficient if the system is continuously -functionally activated by stimulation. The refractory period increases -after excitation and merges, although very gradually, finally into -permanent nonirritability, that is, into complete fatigue. - - [152] _Hermann_: “Untersuchungen über den Stoffwechsel der Muskeln - ausgehend vom Gaswechsel derselben.” Berlin 1867. - - [153] _Joteyko_: “La fatigue et la respiration élémentaire du - muscle.” Paris 1896. - - [154] _Julius Vészi_: “Zur Frage des Alles oder Nichts Gesetzes beim - Strychninfrosch.” Zeitschr. fur allgem. Physiologie Bd. XII, 1911. - -[Illustration: Fig. 35. - -Double glass chamber for comparative experiments on fatigue of the -nerve (_n n_). A and B--Wires of the electrodes. (After _Thörner_.) ] - -[Illustration: Fig. 36. - -Curve of action current of two nerves, one of which is stimulated -(plain line) whilst the other remains at rest (dotted line). After -decrease of irritability of the stimulated nerve in nitrogen, oxygen is -introduced into the chamber and irritability increases again. Then the -previously resting nerve is stimulated in nitrogen and the stimulated -nerve remains at rest. (After _Thörner_.) ] - -The knowledge that fatigue represents a prolonged refractory period -resulting from relative deficiency of oxygen has enabled me with the -aid of my coworkers to demonstrate the existence of fatigue and produce -the typical symptoms experimentally for a living tissue, which up to -then was considered indefatigable: I refer to the medullated nerve. -After having found that the condition necessary for the production of -fatigue in the nervous centers is a deficiency of oxygen, I arrived at -the conclusion that fatigue could only be obtained in the medullated -nerve when subjected to a deficiency of oxygen. Up to that time, -however, no consumption of oxygen was known for the nerve. It was, -therefore, necessary to first ascertain if the nerve possessed an -oxydative metabolism. At my request, _H. von Baeyer_ investigated -these questions. After many vain attempts to obtain absolutely pure -nitrogen, we finally succeeded in finding a method by which it is -possible to gain nitrogen gas, which is, one might almost say, in a -mathematical sense absolutely pure. It was then possible for _H. von -Baeyer_[155] to asphyxiate the nerve and subsequently to bring about -complete restoration by the introduction of oxygen. It was shown -that the nerve requires merely a minute quantity of oxygen and only -completely asphyxiates when the last trace of oxygen is removed, -and further that recovery takes place within a fraction of a minute -if the oxygen is again supplied. These experiments which have been -carried further by _Fröhlich_[156] were afterwards confirmed in other -laboratories,[157] and _form_ the basis for proving the existence of -fatigue of the medullated nerve. Shortly after, _Fröhlich_[158] was -able to demonstrate symptoms of fatigue in the medullated nerve. He -found that the refractory period of the nerve, which, as previously -mentioned, _Gotch_ and _Burch_ fixed at about .005 second duration, -was prolonged by oxygen deficiency to .1 second, so that stimuli -following each other oftener than ten times per minute produced -merely single initial contractions in the muscle concerned, that -is, in a series of stimuli of which the intervals are less than .1 -per second, only the first produces response, whereas the following -occur in the refractory period, brought about by those preceding, -and are, therefore, inoperative. The nerve is fatigued by the quick -succession of stimuli. The normal nerve on the contrary invariably -responds, as known, to an even more rapid succession of stimuli with -a rhythmical excitation corresponding to the number of stimuli and -which is manifest in the muscle by a tetanus. This again confirmed the -identity of fatigue with the prolonged refractory period, conditioned -by the relative want of oxygen. It likewise explained the conditions -of the analogous behavior that _Wedensky_[159] had observed in the -narcotized nerve, but had neither recognized as manifestation of the -prolonged refractory period nor as fatigue. A further advance was made -by the investigations of _Thörner_. He placed two nerves of the same -frog in a double chamber under completely identical conditions with -the exception that one remained in a state of rest, whilst to the -other tetanic stimuli were applied. (Figure 35.) If this took place in -nitrogen, the irritability of the stimulated nerve invariably sank with -much greater velocity than that of the nonstimulated, whereas after an -introduction of oxygen, even when the stimulation was continuous, both -again recovered. In these experiments of _Thörner_[160] the action -current and not the muscle contraction served as indicator. Here the -fatigue of the medullated nerve brought about by the deficiency of -oxygen during prolonged stimulation is demonstrated in the most obvious -manner. (Figure 36.) _Thörner_[161] further succeeded by a continuous -stimulation of the nerve in obtaining even in atmospheric air the -indications of primary fatigue. The symptoms were exactly the same -as those characterizing fatigue of the muscle; the extension of the -course of excitation and, as a consequence of this, the appearance of -a summation of excitation produced by tetanic currents and a reduction -of irritability in response to single stimuli. The form of the curve, -resulting from alteration of irritability in fatigue and recovery, -likewise shows complete conformity with that of the muscle. (Figure -37.) Finally _Thörner_[162] proved that the nerve, when fatigued by -continuous tetanic stimulation in nitrogen, could also partially -recover in the latter if the stimulation was interrupted, whereas a -complete recovery could not take place unless a supply of oxygen was -introduced. (Figure 38.) This fact is in perfect accordance with the -relations found by _Verworn_, _Lipschütz_, in fatigue of the nervous -centers. It is the expression for the accumulation and removal of -fatigue substances, the depressing effect of which _Ranke_[163] first -established for the fatigued muscle. The fact that the nerve could also -partially recover in an atmosphere of nitrogen would seem to likewise -contain the proof that among the fatigue substances products in the -form of gas must be present. It is probable that an escape of carbon -dioxide has taken place. - - [155] _Hidetsurumaru Ishikawa_: “Ueber die scheinbare Bahnung.” - Zeitschr. f. allgem. Physiologie Bd. III, 1904. - - [156] _Fr. W. Fröhlich_: “Das Sauerstoffbedürfniss des Nerven.” - Zeitschr. f. allgem. Physiologie Bd. III, 1904. - - [157] _K. H. Baas_: “Zur Frage nach dem Sauerstoffbedürfniss des - Froschnerven.” Pflügers Arch. Bd. 103, 1904. - -_K. Frick_: “Die Abhängigkeit der Erregbarkeit des peripherischen -Nerven vom Sauerstoff.” Inaugural Dissertation vorgelegt der -medicinischen Facultät der Univers. Berlin (Aus dem physiologischen -Institut der Univers.). Berlin 1904. - -_Uchtomsky und Dernoff_: “Zur Frage nach dem Sauerstoffbedürfniss der -Nerven.” Travaux du laboratoire de Physiologie a l’université de St. -Petersbourg II Année 1907. - - [158] _Fr. W. Fröhlich_: “Die Ermüdung des markhaltigen Nerven.” - Zeitschr. f. allgem. Physiologie Bd. III, 1904. - - [159] _Wedensky_: “Die fundamentalen Eigenschaften des Nerven unter - Einwirkung einiger Gifte.” Pflügers Arch. Bd. 82, 1900. - - The same: “Erregung, Hemmung und Narkose.” In the same place. Bd. - 100, 1903. - - [160] _Thörner_: “Die Ermüdung des markhaltigen Nerven.” Zeitschr. f. - allgem. Physiologie Bd. VIII, 1908. - - [161] _Thörner_: “Weitere Untersuchungen über die Ermüdung des - markhaltigen Nerven. Die Ermüdung in Luft und die scheinbare - Erregbarkeitssteigerung.” Zeitschr. f. allgem. Physiologie Bd. X, - 1910. - - [162] _Thörner_: “Weitere Untersuchungen über die Ermüdung des - markhaltigen Nerven. Die Ermüdung und Erholung unter Ausschluss von - Sauerstoff.” Zeitschr. f. allgem. Physiologie Bd. X, 1910. - - [163] _Ranke_: “Untersuchungen über die chemischen Bedingungen der - Ermüdung des Muskels.” Arch. f. Anat. u. Physiol. 1863 u. 1864. - -[Illustration: A - -Scheme showing course of fatigue (plain line) and recovery (dotted -line) of the nerve as it is manifested on testing the irritability -with tetanic stimuli, when fatigue and recovery alternate at equal -intervals. The curve shows at the beginning an apparent increase of -irritability corresponding to the “Treppe” of the muscle. (After -_Thörner_.) ] - -[Illustration: B - -Fig. 37. - -Scheme showing course of fatigue (plain line) and recovery (dotted -line) on testing the irritability of the nerve by single induction -shocks. In fatigue irritability sinks at first rapidly, then more and -more slowly until a state of equilibrium is reached. Recovery shows the -same in reverse succession. (After _Thörner_.) ] - -As a result of all these investigations, linked together in a -systematic series, the proof has now been obtained that the nerve like -all other living substances is fatigable. Its fatigue is solely the -manifestation of a prolonged refractory period and the extension of the -latter by continuous stimulation is, as in all aërobic substances, a -result of relative deficiency of oxygen. - -[Illustration: Fig. 38. - -Curve of irritability as demonstrated by action current of two nerves -in nitrogen, which are alternatively stimulated (plain line) and at -rest (dotted line). Recovery in nitrogen is always merely partial -and relative. It only increases on introduction of oxygen. (After -_Thörner_.) ] - -To briefly summarize in conclusion, I will repeat that just as all -living systems show a refractory period after an excitation, in which -irritability is reduced, all living systems are likewise capable of -fatigue. Both are most intimately connected and are based fundamentally -on the facts of metabolism. - -An excitating stimulus disturbs the metabolic equilibrium of rest -by suddenly bringing about increased decomposition of certain -substances. During and directly after the breaking down, irritability -is reduced in the same degree as the amount of substances required -for disintegration in response to a succeeding stimulus is decreased -and the quantity of the decomposition products is increased. This is -the refractory period. By the metabolic self-regulation in accordance -with the principle of chemical equilibrium, the original metabolic -equilibrium is restored after every excitation. Irritability, -therefore, increases in the same measure as this occurs, that is, in -the form of a logarithmic curve, until it again reaches the specific -degree of irritability of the particular system. The refractory period -diminishes. If the processes of disintegration and self-regulation are -delayed, either by want of substance necessary for breaking down or -the accumulation of decomposition substances, the refractory period is -prolonged and the response to every further stimulation decreased, that -is, the system is fatigued. In all aërobic organisms the retardation -of the course of excitation and self-regulation under a continuous -influence of stimuli is the result of the relative want of oxygen. The -processes of oxydative disintegration are prolonged and restricted by -relative deficiency of oxygen and merge more and more into anoxydative -decomposition. The products of incomplete oxydative and anoxydative -decomposition accumulate. Both factors decrease the strength of the -response after every stimulation. Thus the want of oxygen leads to -reduced activity. In the anaërobic organisms the refractory period and -symptoms of fatigue are, of course, produced by the relative deficiency -of other substances. Fatigue in the anaërobic systems has, however, so -far not been investigated. We advance very slowly, step by step, in -physiology, and, as in every science, an acquirement of a new knowledge -means a new problem. In this lies the inexhaustible charm of our -scientific research. - - - - -CHAPTER VIII - -INTERFERENCE OF EXCITATIONS - - _Contents_: Examples of effects of interference of stimuli in - unicellular organisms. Interference of galvanic and thermic stimuli in - Paramecia. Interference of galvanic and thermic stimuli and narcotics. - Interference of galvanic and mechanical stimuli. Interference of - galvanotaxis and thigmotaxis in Paramecia and hypotrii infusoria. - Real or homotop interference, apparent or heterotop interference. The - two effects of homotop interference of excitations: Summation and - inhibition of excitations. Theory of the processes of inhibition. - _Hering-Gaskell_ theory. Inhibition as an expression of the refractory - period. Individual possibilities of interference of two stimuli. - Interference of an excitating and a depressing stimulus. Interference - of two depressing stimuli. Interference of two excitating stimuli. - Analysis of the interference of two excitations. Interference of two - single stimuli. Conditions upon which the result of interference is - dependent. Heterobole and isobole living systems. Intensity of the - two stimuli. Interval between the stimuli. Specific irritability and - rapidity of reaction of the living system. Latent period. Interference - of single stimuli in a series. General scheme of the development - of the effect of interference. Summation and inhibition. Apparent - increase of irritability. Conditions of summation. Tonic excitations. - Conditions of inhibition. Various types of inhibition. Interference of - two series of stimuli. Relations in the nervous system. Peculiarities - of the nerve fibers. Conversion of the nerve by relative fatigue from - an isobolic into a heterobolic system. - - -Until now the mechanism of the single excitation has received the major -portion of our attention. It was not until we reached the subject -of the origin of fatigue that we became acquainted with the effects -of repeated stimulation. Here we found a case of interference of -individual excitations. But fatigue is simply a special instance of -such interference, for the subject of interference action occupies a -much greater field. - -Every cell of the larger organisms, and more especially the single -celled organisms, is subjected to manifold stimuli. It is indeed, -quite common that two stimuli interfere with each other and manifold -effects follow, depending upon the specific reaction of the cell -and the quality, intensity and duration of the interfering stimuli. -Sometimes the interference effect is readily understandable from a -knowledge of the specific effect of the individual stimuli concerned. -At other times, however, the specific reaction seems entirely different -in nature than would be expected from a study of the effects of the -individual stimuli. - -[Illustration: Fig. 39. - -Galvanotaxis of Paramaecium aurelia.] - -When I place a drop of Paramecium culture on a slide having on two -sides parallel pieces of baked clay which serve as electrodes and -allow a constant current of about .2 milliampère to flow through, it -will be seen that the infusoria at room temperature move toward the -negative pole at a rate averaging 1–1.4 mm. per second. (Figure 39.) -If I increase the temperature, the rate of movement is increased. Here -the galvanic and the thermal stimuli influence each other in such a -manner that the reaction to the galvanic is increased by the thermal -stimulation. This summation of excitation is readily understood on -the basis of the laws concerning the effect of temperature upon the -velocity of chemical change established by _van’t Hoff_. If, however, -the Paramecia are in a 1 per cent. alcoholic solution, then, as was -shown by _Nagai_,[164] the rapidity of movement following galvanic -stimulation is decidedly reduced. The interference effect between the -galvanic and chemical stimulation is, because of the depressing effect -of the latter, likewise readily understood. - - [164] _Nagai_: “Der Einfluss verschiedener Narcotica, Gase and Salze - auf die Schwimmgeschwindigkeit von Paramæcium.” Zeitschr. f. allgem. - Physiologie Bd. VI, 1907. - -[Illustration: Fig. 40. - -Thigmotaxis of Paramaecium aurelia. (After _Jennings_.)] - -Greater difficulty meets us, however, in the following instance. The -forward movements of the Paramecia follow in consequence of the fact -that the individual cilia of the body lash more powerfully backward -than forward. If now the Paramecia, while moving forward, meet with a -resisting body, they withdraw sideways while executing a sudden strong -forward ciliary stroke. The strong mechanical stimulation brings about -retraction of the organism. Entirely different are the results when the -impact is weak. If Paramecia while slowly swimming touch a resisting -object with the anterior portion of the body, withdrawal does not -occur. The infusoria remain under proper conditions in contact with the -resistance, and the rhythmic activity of the cilia directly against -resistance, as well as those on the other side toward the posterior -portion of the body, are more or less inhibited. (Figure 40.) The -degree of inhibition brought about by this weak mechanical stimulation -may vary considerably. At times the cilia of the whole body suddenly -cease their movement. (Figure 41, A.) At other times, this cessation -is limited to the cilia in the anterior portion of the body (Figure -41, B), while the movements of those on the posterior portion of the -body are of less amplitude or are irregular and weak. In all cases -the infusorium remains quiescent in the water in contact with the -resistance, and it is not uncommon to find numerous individuals in -apposition with particles of ground, slimy detritus, plant fibers and -so forth. (Figure 41, C.) In short, the rhythmic activity of the cilia -of the Paramecia receiving their normal impulses of excitation from the -ectoplasm of the cell body interfere with strong mechanical stimuli -in such a manner that a negative thigmotaxis develops; following weak -mechanical stimuli a positive thigmotaxis results. Here is an instance -of the relation between the intensity of the stimulus and the manner in -which its effects interfere with an already existing excitation. - -[Illustration: - - _A_ _B_ _C_ - -Fig. 41. - -Thigmotaxis of Paramaecium aurelia.] - -However, the strength of the inhibitory effect of a weak contact -stimulus upon another excitation is best appreciated when positive -thigmotaxis is interfered with by the effect of a thermal or galvanic -stimulus. _Jennings_[165] and especially _Pütter_[166] have, at my -request, more thoroughly investigated my original observations and -have given us a complete analysis of these interesting interference -effects. If the freely swimming Paramecia are subjected to a constantly -increasing temperature, the movements of these infusoria become more -and more active. At 30° C., the rapidity is very violent and at -about 37° C. they reach their maximal. If now the same experiment is -repeated with Paramecia which have in consequence of thigmotaxis fixed -themselves to particles of slime, the temperature may be increased to -30° C. without an observable effect. The infusoria remain throughout -in contact with the resistance. Only when the temperature is 37° C. -do they release their contact and move violently through the water. -If a drop containing Paramecia is placed on a slide, between parallel -pieces of fired clay which serve as electrodes, it will be seen that -some freely swim about, whereas others remain thigmotactically in -contact with particles of slime. When a constant current of about .2 -of a milliampère is passed through, it is observed that the freely -swimming individuals hasten towards the cathode. Those attached -to objects, on the contrary, do not respond in this manner to the -electrical current. (Figure 42.) The intensity of the current can be -greatly increased without bringing about detachment of the individuals -from their position of fixation. The typical influence of the strong -current upon the movement of the cilia of the thigmotactically fixed -individuals can be clearly seen. Nevertheless, the inhibition, brought -about by the contact stimulus, predominates over that of the excitating -effect of the current, so that a freeing of the organisms from their -position does not occur. Not until the current becomes very strong is -the excitation thereby produced sufficient to bring about a separation -of the infusoria, whereupon they immediately swim toward the cathode. -In this interference between the contact stimulus, on the one hand, -and the thermal or galvanic on the other, the inhibitory effect of the -former may overpower the strong excitation of the latter. - - [165] _Herbert S. Jennings_: “Studies on reactions to stimuli - in unicellular organisms. I. Reactions to chemical, osmotic and - mechanical stimuli in the ciliate infusoria.” Journal of Physiology, - Vol. XXI, 189 F. - - [166] _Pütter_: “Studien über Thigmotaxis bei Protisten.” Arch. f. - Anat. and Physiologie, physiol. Abt. Suppl. 1900. - -[Illustration: Fig. 42. - -Interference of galvanotaxis and thigmotaxis in Paramaecium aurelia. -The individuals which are thigmotactically attached to slime particles -remain at rest while the freely swimming individuals move toward the -cathodic pole. ] - -[Illustration: A - -B - -Fig. 43. - -_Hypotrichous infusoria._ A--Stylonychia. B--Urostyla.] - -Still more complex and striking is finally the following case of -interference between thigmotaxis and galvanotaxis. The hypotrichous -infusoria as _Stylonychia_, _Urostyla_, _Oxytricha_, etc., have a -marked functional and morphological differentiation of their cilia. -They possess a bow-like row of perioral cilia, which sweep in the food; -a number of cilia on the ventral surface used for locomotion by which -they move about upon objects in the water; a row of border cilia on -each side, which, during swimming, contribute the propelling force. The -perioral cilia also form the elements which bring about a screw-like -movement on the axis. They further possess several cilia, which -permit a rebounding of the organism, and finally certain forms have -anal cilia, which probably serve as breaks and to steer the organism. -(Figure 43.) Their usual mode of locomotion is that of creeping, moving -by means of the cilia on the ventral surface. These movements depend -upon the positive thigmotaxis of the cilia of locomotion. At the same -time there is inhibition of the cilia on the sides. When the infusoria -are excitated by a new stimulus, the cilia used for rebounding become -active, the body frees itself from its position of attachment and -begins to swim, wherein the cilia on the sides, as well as the perioral -cilia, act in the manner mentioned above. I have made the striking -observation that the hypotrichous infusoria respond differently to the -galvanic current, depending on whether they are swimming or in a fixed -position. If one places a drop of water with numerous Urostyla on a -slide between parallel pieces of fired clay which serve as electrodes, -it will be seen, upon the closing of a current, that all of the -individuals which are freely swimming and turning in a screw-like -manner around their axis, steer immediately toward the cathode, exactly -as in the case of the Paramecia. On the other hand, those which are -fixed to the bottom of the slide as a result of thigmotaxis, upon -closing of the current, make a short turn and assume a position wherein -the long axis is at right angles to the direction of the current, and -the perioral rim is directed toward the cathode. In this position they -move through the field. (Figure 44.) When the current is broken the -individuals draw backwards, distribute themselves and creep and swim -in all directions in the water. If during the course of the passage of -the current, an individual which has been swimming begins to creep, the -axis immediately assumes the position above described in the case of -the organisms which are in contact with the bottom and _vice versa_. -The thigmotaxis, therefore, influences galvanotactically swimming -organisms in a most characteristic manner. As a consequence of the -interference of thigmotaxis and galvanotaxis, the organisms move in -a direction transversely to the direction of the current. This most -striking reaction has been cleared up by _Pütter_,[167] the explanation -being based upon an accurate investigation of the mechanism of ciliary -activity. The galvanotactic swimming toward the cathode is explained -by the same principle as that applicable to all galvanotaxis.[168] As -a result of the excitation produced by the anode, the cell body must -assume a position wherein the border cilia, which are of greatest -importance in swimming, are equally stimulated on both sides of that -part of the body directed toward the anode. It is only in this position -that forward swimming is possible, for as a result of unsymmetrical -excitation of the border cilia a turning must at once occur, which -automatically brings about a resumption of the position of the long -axis. The perioral cilia bring about the screw-like movement around the -axis during swimming. It follows that the freely swimming individuals -must necessarily move towards the cathode. In the case of the -thigmotactically moving individuals the activity of the border cilia -is inhibited. The perioral and the locomotion cilia bring about the -assumption of the position of the axis, above described. The perioral -cilia during movement bring about a turning of the body on the vertical -axis toward the side opposite that of the orifice and it follows that -the body can occupy only that axial position wherein the perioral cilia -are least excitated. This is, however, only the case when the long axis -of the body is transverse to the direction of the current, and the -perioral cilia are directed toward the cathode, for stimulation arises -from the anode. The reason why the infusoria do not turn toward the -anode from this transverse position of the axis is to be found in the -fact that the anterior locomotion cilia are stimulated to a greater -extent by the turning toward the anode, and bring about a movement in -the contrary direction. The transverse position of the axis is thus -the result of an antagonistic action between the perioral and the -anterior locomotion cilia. It therefore follows that the characteristic -position, which is necessarily assumed by the thigmotactically creeping -individuals, is brought about by an interference action between tactile -and galvanic stimulation. - - [167] _Pütter_: l. c. - - [168] _Max Verworn_: “Allgemeine Physiologie.” V Aufl. Jena 1909. - -[Illustration: Fig. 44. - -_Urostyla grandis._ Interference of galvanotaxis and thigmotaxis. The -freely swimming individuals move towards the cathode (left side). The -creeping individuals move in transverse direction. ] - -These, then, are a few examples of the interference action of various -stimuli on the single cell. They show us in part fairly simple, and -in part very complex states. It now behooves us to obtain a general -understanding of interference action, to learn the fundamental _laws_ -in connection with these complex actions, to shell out, as it were, the -general factors involved in the special conditions. In this connection -the examples already referred to furnish all of the data necessary for -our first orientation. In the simple instance in which the effect of -galvanic stimulation was augmented by increase of temperature and again -in the case where there was a diminution of excitation resulting from -the alcohol, the interference of the two stimuli is consequent upon -the fact that the location of attack is the same. The constant current -acts upon a portion of the infusorium, which also responds to elevation -of temperature. We have a _real_, or, as I may term it, “_homotopic -interference_,” for it is an interference in which the general point of -attack is the same for both stimuli. - -In contradistinction to this case, we have the examples of the -interference of thigmotaxis and galvanotaxis in the hypotrichous -infusoria. Here the effect of interference, the characteristic position -of the axis of the cell body, is brought about by the fact that the -galvanic stimulus affects different elements than the mechanical. -The turning of a creeping Stylonychia or Urostyla, when the current -is closed, in which the anterior portion of the body was previously -directed towards the anode, results from excitation of the perioral -cilia from the anodic pole. The mechanical stimulation, on the -contrary, exerts its effect upon the locomotion and border cilia. Only -when there is a turning of the anterior portion of the body towards the -anode, would the galvanic stimulus affect also the anterior locomotion -cilia and thereby counteract turning towards the anode. Therefore, -we have before us in this case of the assuming of a characteristic -position of the axis of the cell body the expression of an _apparent_, -or, as I prefer to express it, a “_heterotopic interference_,” in which -the two stimuli do not actually interfere in their action, but rather -influence the final result, in that the condition for the state of the -system in its totality is dependent upon its individual components. -This heterotopic interference is of particular importance in the -bringing about of the movements of the living system. The locomotion -of the animal and especially the direction is in part a manifestation -of heterotopic interference of response. At the same time, however, -especially in the coördinated movements of nervous origin, the -homotopic interference _also_ plays an important rôle and, not rarely, -is combined with heterotopic interference. - -Although the physical analysis of heterotopic interference is extremely -attractive, we must, however, temporarily set aside its consideration, -for at this point the question arises as to what happens when there -is interference of two stimuli at the same point. In the heterotopic -interference the effect of each stimulus is the same as if it were -applied singly. In the homotopic interference the interfering effects -of stimulation influence each other. - -The above examples of homotopic interference introduce us to the two -principal types of these manifold kinds of interference effects; the -excitation brought about by galvanic stimulation is summated by the -excitation produced by temperature. The other type consists of an -inhibition of one effect of stimulation brought about by another. The -depression produced by alcohol on the Paramecia weakens the excitation -of the galvanic current. These examples of the two principal types -of interference effects are quite simple; nevertheless, in other -cases, the conditions are very complex. This is especially true in -the field of nervous inhibition, so important in the functionation of -the nervous system, and which has presented the greatest difficulties -to physiological investigators until the last few years. That a -stimulus bringing about excitation in a ganglion cell can be inhibited -by another exciting stimulus, or that the development of excitation -in a ganglion cell may be prevented by another exciting stimulus -cannot be easily understood. The problem as to how two interfering -excitations can bring about inhibition is one that has received many -explanations. An interesting incident in the history of physiology is -that the first explanation of the principles of inhibitory processes -was close on the track of being a correct one, but was subsequently -abandoned by its originator. _Schiff_[169] (1858) has endeavored to -explain this inhibition as a manifestation of fatigue, and this idea -he defended with the greatest tenacity for a long time, until finally, -twenty-five years after, in a treatise which he called “Abschied von -der Ershöpfungstheorie,” he renounced the idea as untenable. - - [169] _M. Schiff_: “Lehrbuch der Physiologie des Menschen.” Bd. I, - Lahr 1858. - -Among other investigations, which since this time have been made -to explain the mechanism of inhibition, those of _Gaskell_,[170] -_Hering_[171] and _Meltzer_[172] have received widest consideration. -These theories are built upon the existence of the two phases of -metabolism, and assume that inhibition, in contradistinction to -dissimilatory excitation processes, depends upon an increase of -the assimilative processes. The principal evidence which _Gaskell_ -advances is that when the vagus nerve of the tortoise heart, a -typical inhibitory nerve, is stimulated, a positive variation of the -demarcation current of the heart muscle occurs, whereas when a motor -nerve of a skeleton muscle is stimulated the attached muscle shows a -negative variation of the demarcation current. I must confess that -this explanation of inhibitory processes, from the standpoint of -an interpretation of processes in the living substance, seems very -plausible, and I have accepted this even in my address on excitation -and depression before the Frankfurter Naturforscher Versammlung.[173] -I have since then endeavored to obtain experimental evidence to -substantiate this theory, in that I attempted to prove that increase -of the assimilatory processes brought about by stimulation would be -associated with a reduction of the specific irritability. For this -purpose I have sought for such cases in which a stimulus primarily and -momentarily increases assimilative processes in a system in a state -of metabolic equilibrium. I was disappointed, when, after years of -investigation, I could not find such cases. There is only one kind -of stimulus of which we can say with positiveness that it primarily -increases the assimilative processes, that is, increased supply of -food. But here the increase in the processes of assimilation never -occurs momentarily, and indeed this increase is so extremely slight -that it can only be demonstrated over a long course of time. These -totally negative results of my investigation had awakened strong doubts -concerning the assimilation hypothesis of inhibition. Above all, this -explanation seemed to me to be impossible for the nervous system. I -searched, therefore, for another explanation for the processes of -inhibition in the nervous system. If the increase of energy production -resulting from the application of a stimulus is dependent upon an -excitation of a dissimilative nature, then one is justified to look -upon the reduction of functional energy production as an expression of -an antagonistic process to that of dissimilatory excitation. In this -respect the _Gaskell-Hering_ hypothesis of inhibition rests upon a -firm foundation. When, however, this hypothesis assumes an antagonism -between dissimilatory and assimilatory excitation, then it must not be -overlooked that a second antagonism is possible between dissimilatory -excitation and dissimilatory depression. The antagonism need not -involve the two types of metabolism, it may depend upon variations of -_one_ type. When, therefore, the hypothesis that inhibition is brought -about by assimilatory excitation meets with insuperable difficulties, -the possibility should be considered if it is not more likely -dependent upon dissimilatory depression. These reflections induced -me to investigate if conditions could not be produced experimentally -wherein dissimilatory depression could bring about inhibitory processes -in the nervous system. The most essential requirement was, that -dissimilatory depression should quickly develop and pass away with like -rapidity, for inhibition of the nervous system sets in momentarily -and disappears again momentarily. Another important requisite is, -that both interference stimuli are individually capable of producing -dissimilatory excitation, for the inhibitory processes of the nervous -type may be assumed to be the result of dissimilatory excitation which -produce by their interference inhibition, for the nerve fibers, as -already stated, are capable of conducting only dissimilatory excitation -to the responding organ. As I studied the problem in this manner, -it became clear to me that all the conditions necessary for the -genesis of inhibition are realized in the existence of the refractory -period, and that I had already produced inhibition by prolonging the -refractory period, by oxygen withdrawal, in the strychninized frog. -If we take a strychninized frog in which the refractory period has -been somewhat prolonged by oxygen withdrawal, so that the reaction -is simply a short reflex contraction, and rhythmically stimulate -the skin, a reaction is only obtained with the first few stimuli, -which reactions rapidly decrease until a stage is reached wherein -the succeeding stimuli are completely inoperative. (Figure 45.)[174] -This inhibition is demonstrated even more clearly by the following -experiment. Contractions of the triceps muscle of a strychninized -frog are recorded which reflexly follow from stimulation of the -central end of the cut sciatic nerve. Oxygen is withdrawn in the -manner already referred to. At the proper stage of oxygen deficiency, -rhythmic induction shocks applied to the central end of the nerve, the -interval between the individual stimuli of which being longer than the -duration of the refractory period, elicit reflex contractions of the -muscles of the posterior extremity on the opposite side following each -individual stimulus. If, however, in the same stage the central end of -the nerve is stimulated with induction shocks at intervals briefer than -the duration of the refractory period, a contraction is only observed -during the very beginning, being brought about by the _first_ stimulus, -whereas the subsequent stimuli are ineffective, the muscles remaining -at rest during their entire application. (Figure 46.) _Tiedemann_[175] -at a later date continued these observations and analyzed them more in -detail. In all these experiments, therefore, there is an interference -of the frequent stimulus, because each succeeding stimulus occurs in -the refractory period of the proceeding. In consequence there is a -strong reduction of irritability and reaction is absent. That is, the -centers during application of the frequent current are _inhibited_. If -cessation of stimulation by frequent shocks takes place, stimulation -by slowly succeeding individual shocks becomes effective again in a -few seconds. This is the simplest example of the process of inhibition -and by it I was led to seek in the refractory period the key of -the mechanisms of the process of inhibition. This principle once -recognized, further material for the more detailed working out and -extension of the theory was gathered from the experiences already -gained during the course of the preceding years in the researches on -fatigue and the refractory period in the nerve. Here it became apparent -that the processes resembling inhibition discovered by _Schiff_ in -the nerve preparation and which were studied anew at a later date by -_Wedenski_, _F. B. Hofmann_ and _Amaja_ and in part attributed by -_Hofmann_ to fatigue of the nerve endings, by _Fröhlich_ to fatigue -of the nerve itself, were in principle of the same nature as the -central inhibitions themselves. _Fröhlich_,[176] by his analysis of -the observations of _Richet_, _Luchsinger_, _Fick_, _Biedermann_ and -_Piotrowski_ on inhibition in the claw of the crab, then showed that -inhibition can be influenced by the alteration of the intensity of -the stimulus as well as its frequency. In a series of experimental -researches he could then demonstrate that the widely extended -antagonistic inhibitions and other special processes of inhibitions in -the centers could on the basis of the same principle be physiologically -explained. Here the supposition was confirmed that the development -of a relative refractory period plays a very important rôle in the -inhibition of the nervous centers. Thus, the relations of the processes -of inhibition to the refractory period, once established, their entire -field, up to then shrouded in darkness, has gradually in the course of -years been completely elucidated. - - [170] _Gaskell_: “On the innervation of the heart with especial - reference to the heart of the tortoise.” Journ. of Physiology, Vol. - IV, 1884. - - [171] _Ewald Hering_: “Zur Theorie der Vorgänge in der lebendigen - Substanz.” Lotos IX. Prag 1888. - - [172] _Meltzer_: “Inhibition.” New York Medical Journal, 1899. - - [173] _Max Verworn_: “Erregung und Lähmung. Vortrag gehalten in der - allgemeinen Sitz. der Gesellsch.” Deutsch. Naturf. u. Aerzte zu - Frankfurt a. M. 1896. Verh. d. Ges. Deutsch. Nat. u. Aerzte 1896. - - [174] _Max Verworn_: “Zur Kenntniss der physiologischen Wirkungen des - Strychnins.” Arch. f. Anat. u. Physiol. physiolog. Abth. 1900. The - same: “Ermüdung, Erschöpfung and Erbolung.” Ibidem Suppl. 1900. - - [175] _Tiedemann_: “Untersuchungen über das absolute Refractärstadium - und die Hemmungsvorgänge im Rückenmark des Strychninfrosches.” - Zeitschr. f. allgem. Physiologie Bd. X, 1910. - - [176] _Fr. W. Fröhlich_: “Die Analyse der an der Krebsschere - auftretenden Hemmungen.” Zeitschr. f. allgem. Physiologie Bd. VII, - 1907. The same: “Der Mechanismus der nervösen Hemmungsvorgänge.” - Medizin. naturwiss. Arch. Bd. I, 1907. The same: “Beiträge - zur Analyse der Reflexfunction des Rückenmarks mit besonderer - Berücksichtigung von Tonus, Bahnung und Hemmung.” Zeitschr. f. - allgem. Physiologie Bd. IX, 1909. The same: “Experimentelle Studien - am Nervensystem der Mollusken 12. Summation und scheinbane Bahnung, - Tonus, Hemmung und Rhythmus am Nervensystem von Aplysia limacina.” - Zeitschr. f. allgem. Physiol. Bd. XI, 1910. - -[Illustration: Fig. 45. - -Lower line indicates stimuli.] - -[Illustration: Fig. 46. - -Reflex inhibition in the strychninized frog. Lower line indicates -seconds, upper line stimuli. When stimulation with single shocks at -longer intervals is applied, each single stimulus is effective. When -faradic stimulation is used, only the first stimulus is operative, and -during the further continuance of stimulation inhibition takes place in -the spinal cord. ] - -Before going back to the cases of inhibition and explaining them by -this general principle, it is necessary that we penetrate more deeply -into the details of the characteristic course of the refractory period. -By this means we will find the conditions which universally determine -the interference in the effects of stimulation. - -First of all, it is self-evident that the occurrence of interference -of stimulation in a living system can only take place when the -succeeding stimulus is applied before the effects of the previous -one have completely disappeared. Within the interval, however, which -is involved from the moment of the beginning of a stimulus until its -effect disappears through the self-regulation of metabolism, there is -the possibility of various interference results from stimulation. - -If we take into consideration the various instances which can arise, -perhaps we may best start with that type wherein the first stimulation -produces depression, whereas the second has an exciting effect on -disintegration. In this type the response to the second stimulus is -weaker than when the second stimulus alone is applied. As a concrete -example of this type, we may refer to the interference of an induction -shock in a nerve during the relative want of oxygen. We arrange a -nerve of a nerve muscle preparation of a frog in a glass chamber, -as already described, and determine the threshold of stimulation of -the stretch within the chamber by the weakest induction shocks which -produce response. The oxygen is then removed and the effect on the -threshold determined. As shown by _Baeyer_ it is found that with -increasing asphyxia the threshold of stimulation for induction shocks -becomes continually higher. The irritability is likewise decreased. -This occurs, as the investigations of _Lodholz_ show, at first slowly, -then more and more rapidly. The curve of the decrease of irritability -has a logarithmic form. During the continuation of the depressing -stimulus, i.e., the want of oxygen, the exciting stimulus has less and -less effect. If oxygen is again brought in contact with the nerve, -irritability immediately returns to its original height. The cessation -of the depressing stimulus has, therefore, the effect that the exciting -stimulus again brings about its original response. - -A second type of interference is produced when both stimuli bring -about depression. As an example, we may select the interference of -cold and deficiency of oxygen. If we assume, for instance, that each -of these stimuli of itself brings about only a partial reduction of -living processes and not a _complete_ suppression, then it would be -possible to think of a summation of both depressions. Nevertheless, the -conditions for the summation of depression have never been carefully -analyzed. Quantitative investigations upon the interference of -depressing stimuli are entirely lacking. One should not, however, in -physiology presuppose what may happen under certain given conditions -without first making the necessary experiments. The strength of -scientific investigation depends upon the fact that every deduction, no -matter how small, must be substantiated by experience before further -progress can be made. So, likewise, we must await the results of -thorough experimentation upon the interference of depressing stimuli -before we can establish a law. The conditions are not as simple as they -appear on first observation, for the point of attack of the various -kinds of the depressing stimuli upon the chain of metabolic processes -may be very different. In such a case it is not at once possible to -understand the results of the interference. - -There is a third type in which two dissimilatory excitations interfere -with each other. Fortunately there is a great amount of experimental -data at our command so that today we have a clear understanding of -the essential points of the conditions necessary for the development -of summation of excitation on the one hand, and inhibition on the -other. If we take an instance of a momentary dissimilatory excitation -operating upon an aërobic system in metabolic equilibrium, it is -necessary to recall the two effects thereby produced. The stimulus -brings about an oxydative decomposition of the living substance. -Likewise there is a reduction of irritability. Both of these -alterations are the foundation of interference. Both processes have -a specific time of occurrence. The disintegration, determined by -energy production, reaches a maximum suddenly, then diminishes, at -first rapidly, then more and more slowly until the zero point is -reached. In an analogous manner the irritability abruptly reaches a -minimum, then increases rapidly, then more slowly, until it again -reaches its previous value. When we represent these processes by a -curve, they assume the following form. (Figure 47.) In this diagram -the abscissa is the time, the ordinate value zero is the level of the -metabolism of rest and the specific irritability. The points above the -abscissa represent disintegration, that is, energy production, those -under the abscissa, the reduction of irritability. A consideration -of the latent period may be omitted. At the end of the curve the -effect of stimulation may be assumed to have disappeared and the -state of metabolic equilibrium reestablished. If we base our further -observations upon this curve of excitation, we can study in them the -factors upon which responsivity is dependent when a second exciting -stimulus is operative during the course of the first. - -[Illustration: Fig. 47.] - -[Illustration: Fig. 48.] - -[Illustration: Fig. 49.] - -[Illustration: Fig. 50.] - -It is from the beginning apparent that the response to the second -stimulus is determined by the intensity of the second stimulus in -relation to the degree of irritability which exists at the moment -when this is effective. This relation is dependent first upon the -absolute intensity of the second stimulus. In the following diagram the -intensity of the existing threshold value is fixed for convenience as -ordinates beneath the abscissa. If, for example, at the time point _x_, -a stimulus of weak intensity R_{1} acts, this stimulus being under the -existing threshold, produces no perceptible effect. (Figure 48.) If now -instead of a weak stimulus, one of stronger intensity acts at the time -point _x_, this stimulus will produce an appreciable response. (Figure -49.) If the second stimulus is of the same strength as the first, -this second stimulus will bring about relatively less disintegration, -because the system is then in a state in which irritability is still -reduced. But this lessened disintegration in that it summates the -excitation still existing as the result of the first stimulus can -produce an absolute increase of the height above that of the abscissa. -Here then we see the possibility of an increase of response resulting -from summation. Accordingly the increase of disintegration must occur -simultaneously with a diminution of irritability and this must fall -below the level of the reduction of irritability produced by the -first stimulus. This augmentation of the response through summation -above the level of that produced by the first stimulus acting upon an -unexcitated system is, however, connected with another condition. The -above example refers to systems in which weak stimuli bring about weak -response and strong stimuli strong response, that is, the response -is capable of increase. In systems in which the “all or none law” is -applicable, such an alteration in the absolute height of excitation, -as results in summation, is not possible. In order to characterize -these two types of living systems by a short expression rather than -by a long sentence, we will call the first a “_heterobolic system_,” -the latter in which the “all or none law” is operative an “_isobolic -system_.” The former term expresses various degrees of discharge -depending upon the intensity of the stimulus, the latter term refers to -the constancy of discharge following stimuli of various intensities. -Isobolic systems are in contradistinction to the heterobolic systems -not capable of summation. The response to the second stimulus of equal -intensity cannot be greater than that of the first, it may be equal -to the first (Figure 50) or be less in extent, but it can never be -greater than that resulting when a single stimulus is applied. These -facts have been known for a long time in the case of the heart muscle. -A word is necessary, however, concerning the effect of stimuli beneath -the threshold in heterobolic systems. We must here distinguish between -the _“ideal” threshold_, beneath which the influence of a stimulus -is nil, and the _threshold of perceptible effect_, beneath which a -stimulus apparently has no effect; nevertheless a weak effect does -occur, as is shown by succeeding reactions. This effect is manifested -by a sub-threshold disintegration and a corresponding slight reduction -of irritability. (Figure 51.) The presence of such a sub-threshold -effect is recognized by various facts as, for example, the summation of -the sub-threshold stimuli to production of a perceptible result. Thus -stimulation of a sensory spinal cord root with a single sub-threshold -induction shock will not produce any evidence of a reflex excitation, -whereas, when induction shocks of the same strength and of sufficient -frequency are applied, a strong reflex contraction results. The fact -that sub-threshold stimuli can bring about sub-threshold effects is -also important in consideration of the result of interference. The -relation between the intensity of the second stimulus and the degree -of irritability of the system, the intensity of the stimulus being -absolutely constant, depends, secondly, upon the momentary amount of -irritability which exists just at the time when the second stimulus -produces its effects. It is, therefore, clear that the response -produced by interference must also alter with the momentary degree of -irritability in a manner analogous with variations of the intensity -of the second stimulus. One must, therefore, know the factors which -control the momentary degree of excitation. - -[Illustration: Fig. 51. - -Effect of sub-threshold stimuli. _o_--Level of the ideal threshold. -_s_--Level of the threshold of perceptible effect.] - -[Illustration: Fig. 52.] - -The first factor to be considered is the moment of time in which the -second stimulus is applied, that is, the interval between the first -and the second stimulus. If, for example, a weak second stimulus -follows very quickly after the first, the stimulus will bring about -no response, as the system at the time of its application is in a -relative refractory period. (Figure 48.) The stimulus is, therefore, -under the threshold. If, however, a stimulus of the same strength is -applied somewhat later, when the irritability has already increased to -a somewhat greater extent, then at this moment the stimulus is above -that of the threshold and a response is obtained which, on account -of the state of irritability existing, is summated. (Figure 52.) But -further, it is not a question of the _absolute_ interval between -the stimuli, but rather to the _relative_ interval to the _specific -rapidity of the reaction of the living substance under consideration_. -There are living substances, as we have seen, in which the refractory -period is unusually short, as, for instance, the nerve. There are -other substances wherein this period lasts a considerable time after -stimulation, that is, before the irritability returns to the original -level, as, for example, the smooth muscle. Indeed, depending upon the -specific properties of a system, a short or a long interval is required -before a stimulus of a given intensity is again operative. Finally, in -one and the same living system the duration of the refractory period -can be very different, depending upon the _momentary state of the -system_. Above all we know that the refractory period is considerably -prolonged in fatigue and likewise after the influence of other agents, -as narcotics, lowering of the temperature, etc. In such states a second -stimulus remains inoperative when it follows at a definite interval -from the first, whereas under normal conditions the same stimulus -applied at the same interval would be operative. - -Finally, there is another factor to be considered, namely, that the -latent period of the second stimulus is more and more prolonged as the -second stimulus approaches more closely to the absolute refractory -period of the first. In the above schemes the latent period was not -taken into consideration because practically for all the intervals -of stimulation considered at that time it could be assumed to be the -same. When, however, a decrease of the intervals between the individual -stimuli takes place, the prolongation of the latent period can then not -be overlooked, as it leads to a retardation of response. (Figures 29, -30.) This fact was shown in the classic investigations of _Marey_[177] -upon the refractory period of the heart, and more recently has been -the subject of study by _Samojloff_,[178] _Keith Lucas_[179] and -_Gotch_[180] in the muscle and nerve. These, then, are the essential -factors which bring about interference, and although there are special -details which deserve more close analysis, nevertheless, we are in a -position to attribute to them the origins of summation and inhibitory -processes, which occur in all living systems, especially the nervous -system. - - [177] _Marey_: “Des excitations artificielles du cœur.” Trav. du lab. - de M. _Marey_ II, 1875. The same: “Des mouvements que produit le cœur - lorsqu’il est soumis à des excitations artificielles.” Compt. rend. - de l’acad. des sciences T. LXXXVII, 1876. - - [178] _Samojloff_: “Actionsströme bei summierten Muskelzuckungen.” - Arch. f. Physiologie Suppl. 1908. The same: “Über die - Actionsstromkurve des quergestreiften Muskels bei zwei rasch - aufeinanderfolgenden Reizen.” Zentralblatt f. Physiol. 1910. - - [179] _Keith Lucas_: “On the refractory period of muscle and nerve.” - Journ. of Physiology, XXXIX, 1909–10. The same: “On the recovery of - muscle and nerve after the passage of a propagated disturbance.” - _Ibid._ XXXXI, 1910–11. - - [180] _Gotch_: “The delay of the electrical response of nerve to a - second stimulus.” Journ. of Physiology, XXXX, 1910. - -For the analysis of summation and the inhibitory processes which occur -in the physiologically active organisms or which are experimentally -produced, a very important point should be observed, that is, the fact -that the stimuli which bring about these phenomena are practically -always a _series_ of _single_ stimuli. The nerve impulses, for example, -consist of a shorter or a longer series of single discharges which -follow each other in rapid rhythmic sequence. Here, then, we have the -conditions necessary for the production of interference effects when -these single stimuli follow each other with sufficient frequency and -also when there is the combined action of _two_ series. - -[Illustration: Fig. 53. - -Curve showing the general development of the effect produced by -interference of the stimuli of the same series in an heterobolic -system. The effect is first summation and then inhibition. _R_ -indicates the intensity of the stimuli, _S_ the level of the threshold -of perceptible effect. ] - -We will first direct our attention to the simplest case brought -about by an interference between the individual effects of stimuli -in the same series. We will study the effect, which here occurs, -in the accompanying diagram, which shows the facts involved in the -interference of _two_ stimuli of a _series_ of stimuli. (Figure 53.) -The curve shows the development of summation and inhibition. The single -stimuli of equal intensity follow at the same intervals, so that the -succeeding stimuli meet with an incomplete recovery of excitation -and accordingly a decreased state of irritability. In spite of the -diminution of the relative response to each stimulus the summation -of excitation brings about an absolute increase of the same. At the -same time the irritability decreases more and more, for after each -stimulation the oxydative disintegration as well as restitution require -a progressively greater time and a relative fatigue must, therefore, -necessarily develop. The summation, consequently, reaches its limit -very soon and then decreases progressively, for, as a result of the -increase of fatigue, the oxydative decomposition which occurs at -the instant of every stimulation reduces and with this the energy -production becomes less and less. The system is relatively refractory -for the given intensity of stimulus. Accordingly the response to -stimulation falls below the threshold of perceptible response -(dotted line S) and finally an equilibrium between disintegration -and restitution occurs, wherein the small amount of material used at -each stimulation by oxydative decomposition is again replaced before -the next stimulus. In other words, the irritability is reduced at -each stimulation to an amount equal to that of the recovery in the -interval. If this all takes place beneath the threshold of perceptible -response, the system during the continuance of the stimulation seems -responseless, that is, inhibited. The _inhibition_ consists then of a -reduction of irritability below the perceptible threshold of response -of the stimulus concerned. It depends upon a continued lessening of -dissimilative excitation to a low level through the delay of the -oxydative decomposition processes. The inhibition is according to -this a relative fatigue, which is conditioned, as is true of every -fatigue, by a lengthening of the refractory period following a relative -deficiency of oxygen. _The processes of inhibition are simply and -solely an expression of a refractory period persisting as a result of -dissimilatory excitating stimuli._ - -Accordingly the general conditions requisite for summation on the one -side and inhibition on the other may be formulated as follows: - -A _summation_ may develop in a heterobolic system and by the use of -submaximal stimuli. It always develops when the following stimulus -is applied before there is complete recovery of excitation from the -previous stimulus. The absolute increase of excitation as a result of -summation is, however, limited by the diminution of irritability. By -continuation of the series of stimuli the state of equilibrium between -the amount of excitation and the irritability will be established -on a higher or lower level. There occurs then, depending on whether -the feeble persistent excitation remains above or below the level of -perceptible effect, either a tonus or an inhibition. - -Summation can be transformed into inhibition by the continuance of -stimuli of constant intensity. The principles which underlie both -processes are in no way antagonistic and indeed are not separated by -distinct boundaries. The diagram here shown (Figure 53) illustrates -this development of summation and inhibition. The time required for -this development is in manifold ways influenced by variations of the -above-stated factors which control the occurrence of interference. -Thereby results an immense number of special cases which differentiate -themselves in characteristic manner depending on whether an isobolic or -heterobolic system is involved, depending on whether the irritability -of the system, as measured by the threshold of stimulation, is high or -low, depending on whether fatigability is great or small, depending -upon the intensity and frequency of the stimuli, etc. Analysis of every -instance shows us different combinations of the interaction of the -individual factors. It is, therefore, self-evident that we cannot here -analyze a greater number of these cases of summation and inhibition. I -wish only to refer to a few typical examples at this time. - -It is known that summation of excitation in the normal nerve does not -occur. As already stated, the nerve is a system in which the “all -or none law” is operative. Such isobolic systems do not summate, -having no power of summation because each individual stimulus brings -about a maximum response. But we have seen that the nerve, as a -result of depressing factors, such as deficiency of oxygen, narcosis, -fatigue, etc., which decrease its irritability, can be transformed -from an isobolic into a heterobolic system. In this state the nerve -possesses the capability of summating excitations. _Waller_,[181] -_Boruttau_,[182] _Boruttau_ and _Fröhlich_,[183] _Thörner_[184] and -others have shown that the action current of the nerve during the -application of tetanic stimulation becomes decidedly greater during -a certain stage of narcosis or asphyxiation, so that the wave of -negative variation is higher than when the nerve is excitated by a -single induction shock. _Fröhlich_[185] first threw light upon this -subject in that he made the observation that here a principle is -involved which has far-reaching importance in the phenomena occurring -in the organism. He showed that as a result of fatigue, cold and -narcosis, etc., the course of excitation brought about by the single -stimulation undergoes retardation. These conditions within certain -limits become more favorable for the production of summation, because -each succeeding stimulus meets with a more incomplete recovery of -excitation than the one previously applied. In consequence of this, the -irritability of the system in the beginning of fatigue, or narcosis, -or immediately after the application of cold, is apparently increased. -This “_apparent excitation_,” as it was called by _Fröhlich_, depends, -however, in reality upon a beginning depression which is evident in -that the course of the individual excitations are lengthened by this -means. The irritability is likewise also reduced. _Reinecke_[186] -later studied in further detail the retardation of excitation in the -muscle and attributed to this the characteristic property shown in -muscle in the so-called “reaction of degeneration.” Fatigue, asphyxia, -cold, degeneration, in fact all factors which retard the course of -excitation, are favorable to the summation of excitation, provided -their influence does not exceed certain limits. - - [181] _Waller_: “Observations on isolated nerve.” Croonian Lecture, - Philosophical transactions. 1897. - - [182] _Boruttau_: “Die Actionsströme und die Theorie der - Nervenleitung.” Pflügers Arch. Bd. 84, 1901. - - [183] _Boruttau und Fröhlich_: “Electropathologische Untersuchungen. - Ueber die Aenderung der Erregungswelle durch Schädigung des Nerven.” - Pflügers Arch. Bd. 105, 1904. - - [184] _Thörner_: “Die Ermüdung des markhaltigen Nerven.” Zeitschr. f. - allgem. Physiologie Bd. VIII, 1908, und Bd. N, 1910. - - [185] _Fr. W. Fröhlich_: “Ueber die scheinbare Steigerung der - Leistungsfähigkeit des quergestreiften Muskels im Beginn der Ermüdung - (Muskeltreppe), der Kohlensäurewirkung und Wirkung anderer Narkotica - (Aether, Alkohol).” Zeitschr. f. allgem. Physiologie Bd. V, 1905. - The same: “Das Princip der scheinbaren Erregbarkeitssteigerung.” - Zeitschr. f. allgem. Physiologie Bd. IX, 1909. - - [186] _Fr. Reinecke_: “Ueber die Entartungsreaction und eine Reihe - mit ihr verwandter Reactionen.” Zeitschr. f. allgem. Physiologie Bd. - VIII, 1908. - -Although the nerve as an isobolic system can only be rendered capable -of exhibiting summation when artificially influenced, there are other -forms of living substance which normally are systems with a slow -course of excitation, in which excitation may be summated, for this -type possesses at the same time a heterobolic character. For example, -a single mechanical excitation elicits a hardly perceptible response -in _Amœba_, _Actinosphærium_, _Orbitolites_. When it is perceptible -at all, there occurs a short interruption of the centrifugal movement -of the protoplasm. After a pause the movement of the protoplasm and -the stretching out of the pseudopods again return. But if the organism -is agitated one or more minutes by rhythmically shaking the edge of -the slide by a special device, as a result of the summation of weak -excitations there occurs a complete drawing in of the pseudopods and -the amœbæ become bell-shaped.[187] The ganglion cells also possess a -great capability for summation. We have already alluded to the fact -that single induction shocks below that of the threshold produce no -evident effect, whereas when rapidly repeated, summation occurs with -reflex reaction. - - [187] _Max Verworn_: “Psychophysiologische Protistenstudien. - Experimentelle Untersuchungen.” Jena 1889. - - The same: “Die physiologische Bedeutung des Zellkerns.” Pflügers - Arch. Bd. 51, 1892. - -[Illustration: Fig. 54. - -Development of tonus by interference of sub-threshold stimuli. -_S_--Level of the threshold of perceptible effect.] - -The summation of sub-threshold excitation to a certain height offers -very favorable conditions for the development of _tonus_. (Figure -54.) This fact has been established for many kinds of centers -(cardio-inhibitory center, vasomotor center, etc.). During the -continuance of a series of stimuli, as we have already seen, an -equilibrium between disintegration and replacement soon takes place. -The level of this state of equilibrium depends upon the relative -intensity of the stimuli. It is lower in the case of strong and -higher in that of weak stimuli. This fact becomes apparent from the -researches of _Thörner_[188] on the fatigue of medullated nerves in -air. This investigator showed that during continued tetanic stimulation -of the nerve, the irritability fell to a certain level, at which it -remained so long as stimulation persisted. The irritability decreased -to a new level when the strength of the stimulus was increased. These -interesting experiments of _Thörner_ show that the level reached when -stimulation is continued is higher as the intensity is weaker. It is, -therefore, clear that this level in summation of stimulation beneath -the threshold can be above that of the threshold of perceptible -response, that is, a perceptible tonic excitation may result. In the -genesis of tonus in the muscle, there is another point to be taken into -consideration. Here we have a combination of a heterotopic interference -with a homotopic interference, for the total shortening of the muscle -is brought about in part by several contraction waves which occur at -various points at the same time and which follow each other, therefore -have a heterotopic sequence. If we consider a long stretch of muscle, -to one end of which a stimulus is applied, it will be found that -the contraction wave moves throughout the entire length. If after a -certain interval of time a second stimulus is applied, the resultant -wave moves along the muscle but does not necessarily homotopically -interfere with the first. In short, there are two waves of contraction -occurring coincidently in the muscle, the muscle is now more strongly -contracted. _Fröhlich_[189] has made the fact intelligible by this -means that tetanic shortening of a muscle is greater than that of -maximal shortening which can be produced by strong single stimulation. -This heterotopic interference dare not be overlooked in the genesis -of muscle tonus. If it is true, as appears from the investigations of -_Keith Lucas_,[190] that the “all or none law” applies to striated -muscle, then an increase of the contraction from homotopic summation -cannot occur, because an isobolic system cannot show an increase of its -already maximal excitation by summation. Such being the case, the tonic -shortening of striated muscle can only be explained as an expression of -a heterotopic interference. - - [188] _Thörner_: “Weitere Untersuchungen über die Ermüdung des - markhaltigen Nerven. Die Ermüdung in Luft.” Zeitschr. f. allgem. - Physiologie Bd. X, 1910. - - [189] _Fr. W. Fröhlich_: “Ueber die scheinbare Steigerung,” etc. - Zeitschr. f. allgem. Physiol. Bd. V, 1905. - - [190] _Keith Lucas_: “On the gradation of activity in a skeletal - muscle fiber.” Journ. of Physiology, Vol. XXXIII, 1905–06. The same: - “The all or none law of contraction of the skeletal muscle-fiber.” - Journ. of Physiology, Vol. XXXIII, 1909. - -If we assume that the summation of sub-threshold stimulation, by -increasing excitation, brings about a state of equilibrium from below, -as it were, so also inhibition may be assumed to be the reverse, the -level of equilibrium being reached from above, as it were, by decrease -of the primary excitation from strong stimulation. This is expressed -in our general scheme of the development of summation and inhibition -resulting from the effect of a series of stimuli. At the same time -the first part of the curve to the fall of irritation to the level -of the sub-threshold equilibrium can be shortened to a minimum by -strong stimulation or greater frequency of the same, and we have then -the type of _inhibition with primary excitation_. As example of this -I wish to again recall the strychninized frog which was used in the -fundamental experiments for understanding of the theory of inhibition. -If we stimulate a sensory nerve of a strychninized frog, in which -the refractory period is already lengthened, with rhythmic single -induction shocks of slow frequency, the muscle arranged to make a -graphic record will show reflex contraction following each stimulus. -If, on the other hand, we apply a series of stimuli, consisting of -single stimuli rapidly repeated, contraction is produced only by the -first, or the first few stimuli (Figures 45 and 46, pages 202, 203). -For the succeeding stimuli the centers remain inhibited, because each -succeeding stimulus occurs in the refractory period of the former. -The origin of this inhibition shows us with particular clearness -how excitation produced by each single stimulus depending upon the -frequency of the same, falls rapidly or slowly beneath the threshold of -perceptible response. In this case, the state of equilibrium is reached -which is maintained by the following stimuli. That a single stimulus is -not entirely without effect upon this state of equilibrium follows from -the fact that during the continuation of the stimulus a recovery to the -point of observable response does not occur, whereas such is the case -immediately upon the discontinuation of the stimulus. In inhibition, -then, the dissimilatory excitation produced by a single stimulus falls -to a low level as a result of the reduction of irritability and remains -at this level continuously. _Inhibition as well as tonus is based -upon the development of a state of equilibrium between excitation and -recovery, or disintegration and restitution of the living substance -under the continuous effect of a rhythmic series of stimuli. They -differentiate themselves essentially by the height of this equilibrium, -which is dependent upon the intensity of the stimulus._ - -We have to the present considered only the _simplest_ conditions -existing as a result of the effect of a _single_ series of stimuli and -also of the interference of its individual members. These elementary -conditions are at the basis of an understanding of complicated -_interference effects which arise when two series of stimuli interact_. -In that these processes can be readily explained by the elementary -processes previously described, I will, therefore, dwell but briefly -on this subject. From the standpoint already taken it may be readily -presumed what will happen when two series of stimuli act upon the same -system. - -When there is interference of _two series of stimuli_, there are -two resultant possibilities. In one type the stimuli of the one are -active simultaneously with that of the other. In this instance both -stimuli would act as a single stimulus of greater intensity, and we -have essentially the same condition as exists when a single series is -operative. Nevertheless, such cases are practically hardly realized -in the physiological happenings of the organism. More often a state -exists wherein the single stimuli of one series occur in the intervals -of the stimuli of the other. In these cases there is an increase in -the frequency of the stimuli applied in a given length of time. We -have here, then, in principle the same conditions as when a series -of greater frequency is operative. (Figure 55.) The effect of such -alteration in the frequency consists in an increase of the velocity -of the development of summation or inhibition, as the general scheme -(Figure 55) has shown us. Depending upon the special combination -of the factors involved in interference, we may have a summation -of the exciting effect of each series of stimuli or an inhibition -of one series by the exciting effects of the other series. If the -frequency of both series is essentially different, we may have here -the conditions for periodically increasing and decreasing excitations. -Nevertheless these conditions have not been systematically analyzed and -experimentally studied. - -[Illustration: A B - -Fig. 55. - -Interference of two series of stimuli. A--Effect of the one series -alone. Development of tonus by summation. The dots below the curve -indicate the points of time at which the stimuli of the second series -will operate. B--Effect resulting from the interference of both series. -By the addition of the second series the frequency has been doubled. -The result consists in an inhibition. ] - -The greatest number of instances of the interference of two series -of stimuli have been given to us by investigation of the physiology -of the nervous system. In the functionation of the nervous system -the fact that two series of stimuli from different tracks affect -the same ganglia plays a very important rôle. It is this to which -_Sherrington_[191] has alluded as “_the principle of the common path_.” -Where two nervous excitations involve the same paths, there arises -an interference of the effect of the two series of stimuli, for the -impulses in the nervous system, as already stated, possess a rhythmic -character. This principle has a broad application in the phenomena of -association in the cerebral cortex. The simpler and, therefore, the -most easily understood cases are, however, in the spinal cord. The -motor neurons of the anterior horns of the spinal cord are the junction -of a great number of tracks, for example, the sensory neurons of the -spinal cord at different levels, the neurons of the cerebellum, the -pyramidal tracks from the motor areas of the cerebral cortex, etc. -On the contrary, for example, the sensory neurons of the spinal cord -are strictly “_private_ paths” in the sense of _Sherrington_, for -excitation can enter by this means only from the special paths of the -spinal ganglia and, therefore, from the periphery. The motor neurons -of the anterior horns offer, therefore, excellent opportunities for -the experimental investigation of the interference of two series -of excitations which enter by different paths. The spinal cord -consequently has become a much-used object of investigation for this -purpose. In fact, we can observe and produce all types of interference -in the spinal cord. These conditions have been quite thoroughly -investigated by _Sherrington_[192] and his coworkers on the dog, and -_Fröhlich_,[193] _Vészi_,[194] _Tiedemann_[195] and _Satake_[196] on -the frog. - - [191] _Sherrington_: “Ueber das Zusammenwirken der Rückenmarksreflexe - and das Princip der gemeinsamen Strecke.” Ergebnisse der Physiologie. - Jahr. IV, 1905. - - [192] _Sherrington_: “The integrative action of the nervous system.” - New York 1906. - - [193] _Fr. W. Fröhlich_: “Der Mechanismus der nervösen - Hemmungsvorgänge.” Med. Natur. Arch. Bd. I, 1907. The same: “Beiträge - zur Analyse der Reflexfunction des Rückenmarks, etc.” Zeitschr. - f. allgem. Physiologie Bd. IX, 1909. The same: “Das Princip der - scheinbaren Erregbarkeitssteigerung.” _Ibid._ - - [194] _Julius Vészi_: “Der einfachste Reflexbogen im Rückenmark.” - Zeitschr. für allgem. Physiol. Bd. IX, 1910. - - [195] _Tiedemann_: “Untersuchungen über das absolute Refractärstadium - und die Hemmungsvorgänge im Rückenmark des Strychninfrosches.” - Zeitschr. f. allgem. Physiologie Bd. X, 1910. - - [196] _Satake_: The researches are not yet published. - -A _summation of two excitations_ was observed already by _Exner_. This -investigator connected the abductor pollicis of the rabbit with an -apparatus for making graphic records. He then stimulated first the paw -and then the motor areas of the cerebral cortex with faradic shocks, -the intensity of which was just sufficient to bring about perceptible -effect. If both stimuli were simultaneously operative, an increase in -the response was observed. Even when the stimuli were sub-threshold -in type, as a result of summation there was a perceptible muscle -contraction. (Figure 56.) _Exner_ had at that time referred to this -increase of the response as “Bahnung” (reinforcement). However, the -word “Bahnung” has more than one meaning, for processes of various -types are involved in this term. Thus writers have differentiated real -and apparent “Bahnungen.” On account of this lack of clearness in the -meaning of the term “Bahnung,” I wish to discard its use as it is not -at all essential. We will speak simply of a _summation of excitation_, -for here it is simply a question of summation of two excitations of the -motor cells of the spinal cord. - -[Illustration: Fig. 56. - -Summation of two excitations in the rabbit. The one proceeds from the -paw, the other from the motor sphere of the cerebral cortex. _S_--Time -in seconds. _Pf_--Stimulation of the paw. _H_--Stimulation of the motor -sphere. _M_--Contractions of the abductor pollicis. (After _Exner_.) ] - -_Fröhlich_ has shown that summation of two excitations upon a motor -cell of the anterior horn coming by way of different paths is more -readily obtained when the stimuli are somewhat strong, or when the -duration of the excitation processes in the ganglion cells are somewhat -prolonged by fatigue. - -[Illustration: A B - -Fig. 57. - -Summation of two excitations in the spinal cord produced by stimulation -of the ninth and tenth posterior root. Lower line indicates faradic -stimulation of the tenth, upper line of the ninth root. ] - -[Illustration: A B - -Fig. 58.] - -[Illustration: Fig. 59.] - -On the other hand, the conditions for the production of _inhibition_ -are favored when the intensity of the series of stimuli is weak. Here -it is a question of the development of a relative refractory period for -the weak stimuli by increase in their frequency. A relative fatigue of -the motor ganglion cells for weak stimuli rapidly occurs, and there -develops a state of equilibrium beneath that of the threshold of -perceptible effect throughout the continuation of stimulation. _Vészi_ -succeeded in isolating these types of summation and inhibition in the -spinal cord. His method consisted in cutting the posterior roots of -the spinal cord of the frog and stimulating faradically the central -ends, and at the same time graphically recording the response of the -gastrocnemius muscle. Upon faradic stimulation of the ninth posterior -root, one obtains tetanic reflex contraction of this muscle. When the -tenth posterior root is then stimulated, tetanus is also produced but -of somewhat shorter duration. If, while obtaining tetanus reflexly by -stimulation of the ninth root, a faradic current of short duration -and not too weak is applied to the tenth root, then a summation of -excitation occurs, an increase in the reflex contraction. (Figure -57, A and B.) When, on the other hand, the tenth root is stimulated -with weak shocks, one can obtain an increase of the tetanus of short -duration followed by inhibition. Here, as the result of interference, -we have an instance of inhibition with primary tetanus. (Figure 58.) -When the tenth root is stimulated with very weak shocks, inhibition -of the tetanus produced simultaneously from the ninth root occurs -without primary summation. (Figure 59.) The fact that two series of -stimuli, both of which produce dissimilative excitation, bring about -an inhibition by their combined action, is sufficient to show the -untenability of the _Gaskell-Hering_ hypothesis, that inhibitory -processes result from assimilatory excitation. It would be impossible -to understand how two dissimilatory exciting stimuli, by their -simultaneous action, could bring about assimilatory excitation. When -the eighth or the seventh root is stimulated with stronger faradic -shocks during the time when tetanus is produced reflexly by faradic -stimulation of the ninth, an inhibition is practically always obtained. -Indeed, faradic currents that are so weak as to be _far_ below the -threshold of perceptible response bring about when applied to the -seventh or eighth root a decided inhibition of the tetanus, brought -about by simultaneous stimulation of the ninth root. The inhibitory -effect of weak sub-threshold excitations are here particularly -apparent. This inhibition resulting from excitation far below that of -the threshold of perceptible response is a common occurrence in the -functional activities of the central nervous system. In various parts -of the nervous system, the excitation in its conduction is weakened -when passing through intervening ganglion stations so that it has -undergone a strong decrement before reaching the responding structure, -where an inhibitory effect may be manifested. In this connection it is -of interest that the reciprocal “antagonistic reflexes” discovered by -_Sherrington_,[197] who recognized their importance in the functional -processes of the nervous system, can be explained, as _Fröhlich_ -showed, upon this principle of inhibition resulting from weakened -excitation. On the basis of numerous investigations in the Göttingen -laboratory as well as that of Bonn[198] we have come to look upon the -reflex arc in the spinal cord as consisting of the following elements: -a neurone in the spinal ganglion, a neurone in the posterior horn and -a motor neurone in the anterior horn. This is the most direct route -between the point of stimulation and that of the responding organ of -a unilateral reflex. (Figure 60.) It is known that the excitation -becomes weaker in passing from the entrance of the excitation into -the spinal cord to the motor elements of a lower level on the same -side or to those on the opposite side. In order to obtain a response a -stronger stimulus is necessary. Here the weakening of the excitation -as well as the prolongation of the reaction time is brought about by -the introduction of intercalated neurones. The reflex arc contains -more stations. (Figure 61.) If we accept the most plausible assumption -that the central connection of antagonistic muscles possesses -like relations, then the effects discovered by _Sherrington_ are -self-explanatory. In this case stimulation of the sensory path, which -brings about a strong reflex excitation of the motor neurons of the -anterior horns controlling a muscle, at the same time stimulates -the antagonistic muscle with sub-threshold stimuli. The result of -this as shown by the experiments of _Vészi_ is not a motor response -of the antagonists, but an inhibition if the motor neurons of the -antagonists are at the time in a state of excitation. It is, therefore, -understandable that reflex excitation of a muscle under normal -conditions of irritability has an inhibitory effect on its antagonist. - - [197] _Sherrington_: “Experimental note on two movements of the - eye.” Journ. of Physiology XVII, 1895. The same: “On the reciprocal - Innervation of antagonistic muscles.” Proceed. of the Royal Soc., - 1897. - - [198] _Max Verworn_: “Die einfachsten Reflexwege im Rückenmark.” - Zentralblatt f. Physiologie Bd. XXIII. _Tiedemann_: “Untersuchungen - über das absolute Refractärstadium und die Hemmungsvorgänge im - Rückenmark des Strychninfrosches.” Zeitschr. f. allgem. Physiologie - Bd. X, 1910. _Julius Vészi_: “Der einfachste Reflexbogen im - Rückenmark.” Zeitschr. f. allgem. Physiologie Bd. XI, 1910. _Oinuma_: - “Ueber die asphyktische Lähmung des Rückenmarks strychninisierter - Frösche.” Zeitschr. f. allgem. Physiol. Bd. XII, 1911. _Satake_: Not - yet published. - -[Illustration: Fig. 60. - -Scheme of the simplest unilateral reflex arc of the spinal cord.] - -[Illustration: Fig. 61. - -Scheme of the simplest reflex arc from one to the other side, and from -a higher to a lower level.] - -Finally, I wish to conclude this discussion on the origin of central -inhibition and its dependence upon the strength of the stimulus by -referring to a point which apparently is contradictory. We have already -met with the fact that series of stimuli by their interference in -the nervous system may have different effects depending upon their -intensity; if this is strong, we obtain summation of excitation, if -weak an inhibition. The question may be asked, how is it possible -that a weak stimulus can have a different effect when it is believed -that the nerve as an isobolic system responds to intensities of all -gradations to the same extent, namely, with maximum excitation? If the -“all or none law” is applicable, then the same intensity of excitation -is always carried to the centers and yet we see that various kinds of -responses follow various intensities of stimulation. Here, indeed, is a -difficulty which has not as yet been explained. Naturally between the -two facts there can be no contradiction. But the question arises, how -are we to bring them into harmony? Two entirely different possibilities -present themselves. If the various intensities of stimulation always -bring about excitation of the same strength and we see in spite of -this that various intensities of stimulation produce various kinds of -effects, then we must think of the possibility that various intensities -of stimulation bring about some other effect than that of variations in -intensity in the course of the wave of excitation. In this connection -variations in the time involved must be taken into consideration. -One might think that _strong_ stimuli may develop a longer wave of -excitation than such of _weak_ intensity. _Gotch_[199] tested these -questions experimentally with completely negative results. A single -strong stimulus does not result in an excitation differing in its -course from that of a weak stimulus. But there is another possibility -that requires testing. This was brought to light by the investigation -of _Thörner_[200] on the fatigue of the nerve. His investigations -showed that in a normal nerve in air the first typical beginning of -fatigue resulting from faradic stimulation can be demonstrated in the -characteristic summation of excitations. This is shown by the nerve -after fifteen minutes of stimulation with faradic shocks applied for -short intervals. The irritability, when tested with single induction -shocks, is at the same time reduced. Thereby the amount of fatigue of -the nerve, that is, the amount of the reduction of irritability, is -dependent upon the strength and frequency of stimulation producing -fatigue. When the nerve is stimulated with weak faradic shocks of a -slow rate of frequency, there is a slight or a complete absence of the -reduction of irritability. On the other hand, if the nerve is fatigued -with strong faradic shocks of great frequency, the irritability falls -very considerably. This shows that when the nerve is stimulated for a -longer time, even under conditions favorable to the supply of oxygen, -a diminution of irritability occurs and with it naturally an actual -diminution of the wave of excitation, a diminution the intensity of -which becomes greater as the strength of the stimulus increases. In -other words, long-continued faradic stimulation converts the nerve -from a system isobolic in character to that which is heterobolic -in that the intensity of the excitation which is conducted differs -depending upon the intensity of the stimulus. We have found other cases -in the investigation of the nervous system in which, as in fatigue, -an isobolic is converted into a heterobolic system. _Vészi_[201] has -shown that the centers of the strychninized frog, which are isobolic -in character, when fatigued by _weak_ faradic stimuli can be brought -to react again when the faradic stimulation is increased. According -to this and other experiments of a like nature, it is beyond doubt -that an isobolic system during the refractory period may assume a -heterobolic character, and only after completion of the refractory -period and entire recovery of the equilibrium of metabolism does -the isobolic character return. This permits us to understand the -characteristic properties of an isobolic system more accurately and -precisely than has thus far been possible. The “all or none law” with -its associated properties, such as the conductivity without decrement -and the incapability of summating excitations, have in a system of this -character only relative validity. They are realized only in the state -of an equilibrium of metabolism. Only when the stimuli follow each -other at intervals greater than the duration of the refractory period -is there a response of equal extent to stimuli of all intensities which -are above the threshold. During the refractory period and consequently -in fatigue, asphyxia, cooling and narcosis, etc., in short, in all -states in which the refractory period is prolonged this system loses -its isobolic properties and becomes heterobolic. In order that there -may not be a misunderstanding, we will consider more in detail the -capability in this state of summation of excitations. When we refer -to a summation of excitation of such a system under the influence of -one of these factors, we, of course, at no time mean an increase of -response beyond that of the degree of excitation which exists in an -isobolic system in a normal state consequent upon the application of -a single stimulus, for this degree of excitation is maximal. We refer -rather to a summation which has become reduced as a result of fatigue. - - [199] _Gotch_: “The submaximal electrical response of nerve to a - single stimulus.” Journ. of Physiology, Vol. XXVIII, 1902. - - [200] _Thörner_: “Weitere Untersuchungen über die Ermüdung des - markhaltigen Nerven: Die Ermüdung in Luft,” etc. Zeitschr. f. allgem. - Physiologie Bd. X, 1910. - - [201] _Vészi_: “Zur Frage des Alles oder Nichtsgetzes beim - Strychninfrosche.” Zeitschr. f. allgem. Physiologie Bd. XII, 1911. - -On the basis of these facts it is readily understood when a level -of equilibrium of lower intensity has been reached that excitation -produced by weak faradic stimulation must have weaker effects than when -strong stimuli are applied, for when the system assumes a heterobolic -type as the result of relative fatigue weak stimuli bring about weak, -and strong, stronger excitation. Consequently, during interference -induced by a second series of excitations, in the first case we have -the conditions favorable for inhibition, in the second for those of -summation. If we also assume that this characteristic alteration of -the isobolic character of the elementary nerve fibers which has been -shown to occur in fatigue, as seen when continued faradic stimulation -is employed, develops immediately after the beginning of stimulation -then we can readily understand the various kinds of effects produced -by interference observed in the reflex response following weak and -strong faradic stimulation to the different nerves in spite of the -fact that the nerve in the state of rest is a system isobolic in type. -Experimental evidence, therefore, must be brought forward to show that -faradic stimulation of short duration produces the above-mentioned -alteration in the character of the system. _Thörner_ in his experiments -on the nerve stimulated it faradically at least four minutes and always -found after this that excitation was reduced. After shorter intervals -of stimulation _Thörner_ made no test of the state of excitation. It -is, however, highly probable that a reduction of excitation is much -more quickly reached. Indeed, we are unavoidably compelled to accept -the assumption that even after the first single stimulus of the faradic -current, alterations of a slight degree are present which, after -repeated stimulation, become constantly greater and give to the system -a heterobolic character. As a result of fatigue, as we have already -seen, the refractory period becomes more and more prolonged. As the -individual shocks in faradic stimulation follow each other at regular -intervals, a necessary consequence is that the shocks are operative -before the refractory period has completely disappeared, otherwise -_Thörner_ could not have obtained fatigue produced by continued -stimulation. The intervals of the individual shocks must be somewhat -shorter than the duration of the refractory period, even in fatigue -of a very slight degree. It is very interesting in this connection -that _Thörner_ invariably obtained positive evidences of fatigue by -the application of stimuli at the rate of 10–12 per second. When the -number of stimuli per second was less than this the above-mentioned -result was not always obtained. From this we can easily estimate the -refractory period of the nerve, which is present after reaching a state -of equilibrium under certain conditions. If we assume ten stimuli -per second to be the number required to produce slight fatigue when -stimulation is prolonged, we can conclude that the refractory period in -this state is somewhat longer than one tenth of a second. Even though -_Gotch_ in his investigations already cited placed the refractory -period of the normal nerve at about .005 second, this statement is in -no way contradictory to the figure which we have just given. _Gotch_ -measured simply the duration of the absolute refractory period of -the normal nerve, in other words, the duration of the period in -which no excitation at all could be brought about. On the contrary, -my estimate, based upon the investigations of _Thörner_, refers to -the _total_ refractory period of the nerve, that is, to the point -of _complete_ recovery of the equilibrium of metabolism and of the -specific irritability. Experimental proof of this assumption is already -under way. - -I have endeavored to show the elementary principles at the basis -of these extremely varied interference effects and to make a few -generalizations concerning the complicated conditions here concerned. -It has been shown that a great number of interference effects possess -characteristics in common if one takes into consideration the process -occurring in the course of a single excitation. The altered state -which exists in living substance until the complete disappearance of -excitation is the basis upon which to explain the altered effects -produced by a second stimulus. This state alters during the whole -course of the first stimulus until the original equilibrium of the -metabolism of rest is, by self-regulation, again reached. It is, -therefore, self-evident that the second stimulus must have different -effects depending upon the momentary state of the living system at the -time of its application. The state of the system differs depending on -the length of the interval in which the second stimulation follows the -first. The most important factor is the phase of the excitation period -and the reduction of irritability. The second important factor is the -intensity of the second stimulus; the relation of the two with each -other determines the response. But the specific properties of the given -systems must also be taken into consideration. It is important to know -if the living system possesses isobolic properties, that is, every -intensity of stimulation produces a _maximal_ liberation of energy, or -if it possesses a heterobolic character, that is, stimuli of different -strength bring about the liberation of _different_ amounts of energy. -It is further important to know the rapidity of reaction, whether the -system rapidly or slowly fatigues. In all cases it depends whether the -second stimulus produces a perceptible excitation or whether it occurs -in the refractory period and produces no perceptible effect. Upon -these factors depend the results of the interference of two rhythmic -series of stimuli, whether a summation or inhibition of excitation -takes place. Here is the key to the understanding of the great variety -of interference effects. By determination of these various factors in -a given case and their sequence, we can anticipate the nature of the -interference which will follow. The complex actions brought about by -the various factors, which we cannot at first clearly understand, can -be at once interpreted as soon as we convert them into their elements. - - - - -CHAPTER IX - -THE PROCESSES OF DEPRESSION - - _Contents_: Necessity of cellular physiological analysis of toxic - depressions by pharmacology. Apparent variety of processes of - depression. Depression of oxydative disintegration as the most - extended principle in the processes of depression. Asphyxiation, - fatigue, heat depression, as a consequence of restriction of oxydative - disintegration. Narcosis. Theories of narcosis. The alteration of - specific irritability and conductivity in narcosis. Depression of - oxydative processes in narcosis. Asphyxiation of living substance - when oxygen is present during narcosis. Persistence of anoxydative - disintegration in narcosis. Increase of the same by stimuli. - Depression by narcosis as a form of acute asphyxiation. Hypothesis - on the mechanism of depression of oxygen exchange by narcotics. - Possibility of combining the facts with the observations of _Meyer_ - and _Overton_. - - -The processes of _excitation_ of all the effects of stimulation -are those which have invariably claimed place in the interest of -physiologists. The study of the processes of _depression_, on the other -hand, has remained more or less in the background. This is readily -understood when it is considered how much more apparent the processes -of excitation are than those of depression. Nevertheless, these latter -possess no less importance for the course of vital phenomena than -those of excitation. Without depression no excitation can take place -in the vital activity of the organism, for, as we have seen, every -excitation is secondarily followed by a refractory period. To this -must be added the great number of _primary_ depressions, directly -brought about by the most varied stimuli, such as cold, want of oxygen, -poisons, etc., without the presence of a preceding excitation. Thus -it is essential that the processes of depression should be studied -with no less interest than those of excitation, and it is much to be -desired that the former should receive a more detailed analysis than -has up to now been the case. Even as it is, extensive material has -been obtained for the analysis of this group of reactions. With the -closer study of the process of excitation the facts in connection with -the refractory period and fatigue make it necessary that the processes -of depression be taken into consideration. Toxicology and pharmacology -likewise furnish innumerable effects of depression produced by poisons -and drugs. Unfortunately the investigation of these reactions has -been in the main purely superficial. This arises from the recency of -the development of these sciences. Even later than physiology they -are only now beginning to extend their investigations, directed up -to the present to the grosser organic reactions, to the cellular -analysis of the effects of poisons. How rarely we find instances in -which the effect of some drug is studied at the point of attack and -systematically followed to the specific cell form, and its primary -excitating or depressing effect on this or that constituent process -of the metabolic activities ascertained. And how great, on the other -hand, is the number of “medicines” making their appearance each year -in pharmacology of which nothing further is known than a few secondary -effects on the action of the heart, the blood pressure, the secretion -and excretion and on some other outwardly perceptible organic actions! -This deplorable condition of present-day pharmacology must be ascribed -to the regrettable circumstances that pharmacological research is only -in a very small degree the result of careful investigations, carried -out by biologically and chemically trained pharmacologists, but is for -the most part undertaken at the instigation of chemical manufacturers. -This eager haste to obtain superficially practical results has lessened -in great degree the interest in the close and painstaking theoretical -analysis of reaction to poisons. Thus it happens that, in spite of the -numberless examples of the depressing effects of poisons discovered by -pharmacologists, it is only in rare instances that the physical nature -of these processes is more closely studied. Therefore, investigation -in pharmacology and toxicology in so far as they are carried out in a -purely scientific spirit and not influenced by the desire for merely -superficial results, may find here a wide field of research work, rich -in future promise. It is from such investigation that we may expect -an abundance of material for the closer analysis of the processes of -depression. For the present, however, we must restrict ourselves to the -consideration of some individual cases which have been studied somewhat -more in detail by physiologists. - -Simple reflection shows the possibility that depression, that is, -the retardation of the normal vital processes, can be brought about -in various ways. As on the one hand the normal metabolism of rest is -composed of very numerous chemical constituent processes, and on the -other hand the closest interdependence exists between these individual -constituent processes, it follows that every factor which increases -or retards even one of these must secondarily influence the course of -the entire activity. Hence a wide range of possibilities exists for -the processes of depression. As the complicated works of a clock can, -by the stopping of a single moving part, be brought to a standstill, -so in like manner the metabolic activity can be depressed by very -different constituent members. In spite of this we have every reason to -assume that the greater number of all processes of depression result -from the primary effect of one or a few constituent members. A primary -simultaneous depression of all or at least of numerous constituent -processes of the entire metabolism may only be assumed as possible, -resulting from decrease of temperature within certain limits. But -even in the case of “_cold depression_” it is not probable, owing to -the great effect of every alteration in the relations of masses in -the cell, that depression is solely the manifestation of a _uniform_ -retardation of all individual constituent metabolic processes. If, -therefore, the greater part of the processes of depression are brought -about by the primary effects of an individual constituent process, -then the possibility must be admitted that _any_ component of the -chain can by the means of some specific external influence form the -starting point for a depression. The number of the various kinds of -processes of depression would be, therefore, enormous. The knowledge -obtained up to the present shows, however, that this variety is not -quite as great as the above facts might lead one to expect. Even -though future investigation will certainly not do away with the -assumption of the existence of the most manifold physical types of -depression, the analysis of a few processes which have been studied -up to now demonstrates the singular fact that a number of these which -are brought about by quite different external factors, are based on -an absolute uniformity of their mechanism. As we have previously -seen, a certain constituent of the metabolic chain can be _excitated_ -primarily by very different kinds of stimuli. In like manner there -exists in metabolic activity a certain point of predilection for -different kinds of stimuli, from which their _depressing_ effects -proceed. Here the highly interesting fact is shown that this point of -predilection, which represents that of the most frequent attack, is -the same for _excitating_ as for _depressing_ stimuli. These are the -_oxydative_ processes. As our knowledge of the reactions to stimuli in -anaërobic organisms is still almost nil it is not possible at present -to ascertain which component in the metabolism of these organisms, -adapted to life without oxygen, plays an analogous rôle to that of the -oxydative in aërobic systems. Our investigations must, therefore, be -restricted to the world of aërobic organisms. Here we have seen that -the different stimuli which produce an excitating effect invariably -increase the oxydative disintegration of the living system and we now -find that these constituent processes of metabolism likewise form a -point from which _depressing_ responses to stimuli very readily proceed. - -The prototype of this group of processes of depression in which -this is manifested in a most striking manner, is that of a simple -_asphyxiation_ by the withdrawal of the oxygen supply from the -exterior. If the supply of oxygen is withheld from an aërobic organism, -oxydative disintegration is gradually found to be more and more -decreased and further breaking down takes place _an_oxydatively, as -oxydative decomposition forms the chief source of energy production, -and energy production consequently undergoes a gradual decrease. -Excitating stimuli, therefore, meet with less response than when a -sufficient supply of oxygen is present, that is, _irritability is -diminished_. As a result of this decrease, a corresponding decrement -in the extension of excitation takes place, which, in turn, is -likewise manifested by the restriction of the perceptible response -to stimulation. In the same degree in which oxydative disintegration -becomes less, _an_oxydative breaking down products are accumulated. -The accumulation of these products likewise plays a part in the -production of depression and increases the decrement in the conduction -of excitation. The decrease of energy production by decline of the -oxydative decomposition, as well as the accumulation of anoxydative -breaking down products, therefore, similarly reduce irritability; -that is, their effect is depressing. This whole series of processes, -which we have previously considered in detail, takes place on the -withdrawal of oxygen and leads to the depression of asphyxiation. It -can readily be observed in the most varied kinds of aërobic organisms -in rhizopods and infusoria, in plant and ganglion cells, but finds its -most complete demonstration in the nerves. Here these processes can be -easily produced with any rapidity desired, accordingly as a relative -or absolute want of oxygen is brought about. These same typical -results are likewise shown in numerous processes in which the external -conditions are quite different in nature. - -We have previously become acquainted with such a case and studied -it in detail. This is the state of _fatigue_. Fatigue is a typical -state of depression, that is, a state in which the vital process is -retarded and irritability in response to stimuli correspondingly -decreased. Fatigue is, however, as we have found, the result of a -relative deficiency of oxygen. The amount of oxygen at disposal is not -sufficient to allow of disintegration, increased by constant functional -activity oxydatively taking place, to develop to its full extent. In -consequence the previously cited sequence of processes takes place. A -“depression of activity” is produced. Fatigue is true asphyxiation and -it is here evident that depression proceeds from the same constituent -processes of metabolism as excitation, brought about by a single -stimulus. Excitation produced by constant stimuli gradually merges -into depression as the amount of oxygen at disposal, even if augmented -in the intact organism by the increased blood supply, for instance, -is still insufficient to meet the demand made by the increased oxygen -consumption as a result of continuous functional activity. - -A further very interesting example of depression produced by oxygen -deficiency is furnished by _heat depression_. It has long been known -that with increasing temperature the vital manifestations of all -poikilothermic organisms at first undergo a heightening of their -intensity. If, however, after a maximum is reached, the temperature is -still further increased a sudden depression sets in. The increase in -the rapidity of the vital process as a result of increased temperature -is readily understood when based on the well-known law discovered by -_van’t Hoff_. Numerous investigations on the rapidity of the course of -special vital manifestations, as, for instance the growth of the eggs -of the frog and sea urchin, the assimilation of carbon dioxide in green -plant cells, the number of vacuole pulsations in the infusoria cells, -the frequency of the heart rate of the frog and of the mammal, etc., -have shown that their increase does in fact follow the _van’t Hoff_ -law, being doubled or tripled in amount with every increase of ten -degrees of temperature. The genesis of depression produced by _heat_, -developed in different organisms at various heights of temperature, -requires a closer analysis. This depression takes place at temperatures -below that in which coagulation of proteins occurs. Therefore, under -certain conditions, with which we shall presently become acquainted, it -is capable of being recovered from, whereas in higher temperatures, in -which albumen coagulates, vital activity is permanently obliterated. -Depression produced by heat is, therefore, in itself not a necrobiotic -process, which, as such, must necessarily lead to death. But rather -like fatigue it must be looked upon as an asphyxiation process. -Its relations to oxygen exchange have been chiefly demonstrated by -_Winterstein_[202] by his investigations on the central nervous system -of frogs and on medusæ. He found that when placed in a heated chamber -in a temperature of 32–40° the activity and reflex excitability of -the frog are at first augmented. Within the lapse of a short time -this increase has become so great that the slightest touch produces -tetanic contractions, similar to those characteristic of strychnine -poisoning. Very soon, however, this state of high excitation is -followed by one of depression, in which no response to stimuli can be -obtained. The animal remains entirely motionless in any position in -which it is placed, in the same manner as a frog whose nerve centers -have been completely exhausted by strenuous activity. On the basis -of our knowledge of the rôle played by the deficiency of oxygen in -the bringing about of exhaustion the thought arose, if in this heat -depression exhaustion might not likewise be the result of oxygen -deficiency. This assumption has been most strikingly confirmed by the -investigations of _Winterstein_. It has been demonstrated that recovery -of the animal in a state of heat depression cannot be obtained by mere -cooling, but is only brought about when at the same time a renewed -oxygen supply is provided. For instance, a frog is depressed in the -warm chamber and even when a strychnine injection has been introduced, -does not show the slightest reaction to stimuli. In the warm water -bath artificial circulation is now applied in the previously described -manner with an oxygen-free saline solution at 30° C., so that the blood -is displaced and thus the renewed oxygen supply to the nervous centers -prevented. The animal can now be cooled and the warm saline solution -be replaced by a cooled one without the least recovery taking place. -If, however, blood of the ox with contained oxygen is substituted for -the oxygen-free saline solution, the frog shows signs of recovery -within a few minutes and after ten or fifteen minutes responds as a -result of the strychnine to the merest touch with tetanic contractions -of the whole body. By modifying these methods of investigation to a -certain extent _Bondy_[203] has confirmed these results to the fullest -extent. Later _Winterstein_ by quantitative determinations of oxygen -consumption on medusæ showed that at 30–35° C., at which temperature -heat depression sets in, the consumption of oxygen shows an increase -of about three and a half times compared to that in a temperature of -11–12° C. These facts show that we have in heat depression a process -which, as far as its genesis is concerned, is completely analogous to -that of fatigue. In fatigue, a relative want of oxygen is produced -by the increased consumption following functional activity, in heat -depression by the increase of the entire metabolism producing a -corresponding increase of oxygen requirement. In both instances we have -an excitation produced by external stimuli which result in an increase -in the amount of oxygen required, and in both instances the oxygen at -disposal is not sufficient to permanently meet the augmented demand. -In both types, therefore, decomposition must become more and more -anoxydative and the well-known series of processes is developed, which -find their expression in depression. - - [202] _H. Winterstein_: “Ueber die Wirkung der Wärme auf den Biotonus - der Nervenzentren.” Zeitschr. f. allgem. Physiol. Bd. I, 1902. The - same: “Wärmelähmung und Narkose.” _Ibid._ - - [203] _Oskar Bondy_: “Untersuchungen über die - Sauerstoffaufspeicherung in den Nervenzentren.” Zeitschr. f. allgem. - Physiol. Bd. II, 1904. - -In another direction likewise heat depression is of special interest, -that is, in regard to the theory of nature of the processes in the -living substance. According to the _van’t Hoff_ law we may assume that -every individual constituent metabolic process, if we imagine it as -isolated and taking place in a test tube, undergoes in more or less the -same degree as all others an increased rapidity of reaction as a result -of increased temperature. At the same time, in living substance we -find on the contrary that the _van’t Hoff_ law is only within certain -narrow limits more or less applicable to the sum total of all metabolic -processes. Beyond certain degrees of temperature no further increase -of the vital process takes place, instead a retardation occurs. The -analysis of depression produced by heat shows us in the clearest and -simplest manner the reason for this apparent deviation from the general -law of _van’t Hoff_. This reasoning is based on the fact that the -rapidity of reaction of a chemical process is not merely dependent upon -the temperature, but likewise upon the mass relations of the reacting -substances. In spite of the effect of the temperature in increasing -the rapidity of reactions, the process undergoes retardation which -extends to a complete cessation if the supply of material necessary -to its existence does not keep pace with the increase produced by -temperature. In the present instance the amount of reserve supplies for -the building up of the disintegrating molecules exists in abundance, -and it is merely the available oxygen which is in relatively a very -small quantity. As soon, however, as metabolism in its entirety, or -even merely in those parts in which oxygen is directly required, is -increased by whatever means, the oxydative processes would be the -first to fail and it must be from this point that the disturbance of -the harmony in the interacting of the individual metabolic processes -proceeds. This principle which we here see manifested in its simplest -form in the effect of temperature on oxygen exchange in the form of a -disturbance in the correlations of the individual constituent processes -based on an alteration of the mass relation and the rapidity of -reactions of individual members is, however, not merely restricted to -effects of temperature and the results quickly following on a relative -oxygen deficiency. It has, indeed, a much more general significance for -all manner of constituent metabolic processes, for it is applicable to -all nutrition and to all growth, and forms one of the most important -factors which influence the process of development, that is, the -gradual “metachronic” alterations in metabolism to which all living -systems are subjected as long as life endures. - -A very extensive group of depression processes is produced by the -action of chemical stimuli. Among these the processes to which we apply -the collective term of “_narcosis_” must claim our special interest. -As is well known, an enormous number of substances of very different -chemical nature, such as carbon dioxide, alcohol, ether, chloroform, -chloral hydrate, etc., exist, which, possessing the property of -producing cessation of the vital activities in all living systems, -after withdrawal of their application, if it has not been too prolonged -or intense, permit a complete restoration to normal vitality. These are -the _general_ narcotics. Besides these there are a series of substances -which have a depressing effect only upon certain forms of living -substance, and which we may, therefore, term _special_ narcotics. As, -however, the particular nature of depression following the application -of chemical substances has hitherto been closely studied only in a -very few instances, we are not, at present, in a position to sharply -define the limitations of the conception of narcosis, a conception -which originally had hardly any further meaning than the production -of unconsciousness by chemical means. In the following discussion, -therefore, we shall deal merely with narcosis produced by the -well-known general narcotics, such as carbon dioxide, alcohol, ether, -chloroform, etc. From the time of the introduction of ether narcosis -into medical practice by _Jackson_ and _Morton_ in the year 1848 up to -the present day, the theory of this process has awakened the liveliest -interest. Many attempts have since been made to explain the physical -nature of this interesting process without, however, any generally -acknowledged theory of narcosis being established. I will refrain -from entering into these former theories in detail as they have been -exhaustively treated by _Overton_[204] in his studies on narcosis. - - [204] _E. Overton_: “Studien über die Narkose, zugleich ein Beitrag - zur allgemeinen Pharmakologie.” Jena 1901. - -In connection with our present observations, however, I will more -closely analyze the process itself, following the results of -investigations extending over more than ten years carried out by my -coworkers and myself. In these investigations it has been found that -narcosis belongs to this group of depressing processes. A satisfactory -theory of narcosis, however, and this I must explain from the first, -can even today not be arrived at. Such a theory would require the -ascertainment of all primary and secondary alterations produced by the -narcotic in the course of normal vital activity. For this, however, a -number of minute details are still lacking. Nevertheless, the careful -and detailed investigations during the last ten years have acquainted -us with a large number of alterations, which, acting as conditioning -factors for the process of narcosis, must be taken into consideration, -and which to a certain extent give us an idea of the mechanism of -this process. They are equally interesting from a theoretical as well -as from a practical point of view. The presentation will become more -detailed as more of such conditioning factors are established by the -deeper penetrating of future analysis. I will deal here with the facts -found up to the present and then proceed to the deductions which these -furnish for the theory of narcosis. - -In the first place narcosis is stamped as a typical process of -depression, being characterized by a _decrease of irritability -with a corresponding decrement of the extent of excitation_. The -chief feature of all narcotized systems is, that in slight narcosis -excitating stimuli produce a greatly weakened excitation, and that in -deep narcosis no perceptible response is obtained. This can readily -be ascertained in the various forms of living substance. According -to the previous observations on the inseparable relations between -conduction of excitation and irritability, it is self-evident that -with decrease of irritability there must be a corresponding decrease -in the capability of the conduction of excitation from the point of -stimulation. This decrease in conductivity must, therefore, be the -greater the more irritability is reduced; that is, the deeper the -narcosis, the greater must be the decrement undergone by the wave -of excitation in its extension from the point of stimulation. These -facts can be observed in the highest perfection in the nerve, and -have, as we have seen, been demonstrated by the investigations of -_Werigo_, _Dendrinos_, _Noll_, _Boruttau_ and _Fröhlich_.[205] Upon -deeper analysis of this process of depression, the next task for the -investigator must be the ascertainment of the special components of the -metabolic activity, which are depressed as a result of the narcotic. - - [205] I have previously on another occasion briefly communicated the - conclusions derived from the investigations made at the Göttingen - laboratory by my coworkers and myself. Compare: _Max Verworn_: “Ueber - Narkose.” Deutsche medicin. Wochenschrift, 1909. - -As a consequence of the result of my investigations on fatigue, the -idea occurred to me to test if possibly oxygen exchange likewise -undergoes depression during narcosis. The spinal cord centers of the -frog, which had served me in ascertaining the rôle played by oxygen in -the bringing about of the depression of activity, appeared likewise -a favorable object for this investigation. Indeed, the question -if consumption of oxygen takes place during narcosis, could be -experimentally determined in direct connection with the investigations -on fatigue. This was based on the following consideration. If an -oxygen-free saline solution is introduced into the aorta of a frog and -in order to increase the activity of the spinal cord centers to the -maximum the animal is poisoned with strychnine, after a very short -time complete exhaustion takes place as a result of oxygen deficiency. -This exhaustion can only be removed by the introduction of oxygen. In -this condition the oxygen requirement of the centers is enormously -increased. If the centers are narcotized by adding a narcotic to the -oxygen-free circulating fluid in amounts which, as experience has -found, would produce complete loss of reaction in the normal animal, -for example, about 5 per cent. of alcohol, it can then be tested if, in -this state of narcosis, the centers are capable of oxygen consumption. -It is merely necessary to replace the oxygen-free saline solution -containing alcohol by blood rich in oxygen, containing alcohol in an -amount sufficient to continue the narcosis, but supplying an abundance -of oxygen. If, after this artificial circulation has lasted for a -sufficient period, the blood is then displaced by an oxygen-free saline -solution containing alcohol, and then this, in turn, is replaced by -an oxygen- and alcohol-free saline solution, so that cessation of the -narcosis is now produced, it can be ascertained by the responses of -the animal if consumption of the oxygen, when at the disposal of the -centers during narcosis, has taken place or not. If the former is the -case, then on the cessation of narcosis reflex contraction must occur -in the same manner as in every strychninized frog totally exhausted by -oxygen deficiency and into which a saline solution containing oxygen -is reintroduced. If during narcosis, on the other hand, oxygen has not -been consumed by the centers, depression must continue to be present -after cessation of narcosis. Testing the recovery of the animal on -the introduction of blood, rich in oxygen, serves as an indicator -for the vital activity and capability of recovery of the centers. A -great number of experiments based on this scheme of investigation -were undertaken at my request by _Winterstein_.[206] These were -carried out with alcohol, ether, chloroform and also carbon dioxide. -His experiments have shown in the most uniform manner that, in spite -of the requirement of oxygen by the centers being increased to its -highest extent, and notwithstanding the most ample oxygen supply -during narcosis, after cessation of the same and the introduction -of an oxygen-free saline solution _no trace of recovery occurred_, -whereas after a supply of oxygen was introduced tetanic contractions -reappeared at once. _During narcosis, therefore, the centers, in -spite of their great requirement of oxygen, lose their capability of -oxydative splitting up and consumption of oxygen._ - - [206] _H. Winterstein_: “Zur Kenntniss der Narkose.” Zeitschr. für - allgem. Physiol. Bd. I, 1902. - -After the methods for asphyxiation of the _nerve_ had been worked -out and perfected the wish arose likewise to carry out for these -structures an analogous series of experiments to that employed for the -centers and based on the same chain of reasoning. These investigations -have the advantage of essentially simpler conditions. After having -convinced myself by experiments, that the results on the nerve were in -complete conformity with those on the spinal cord, at my suggestion -_Fröhlich_[207] repeated and continued these experiments on a more -extended scale. A nerve was asphyxiated by the previously described -method. This is accomplished in the simplest manner by the opening or -closing of stop cocks in the apparatus I have employed which permit of -pure nitrogen, or nitrogen with ether, and finally also oxygen with -ether or pure oxygen being conducted at will through the glass chamber. -If the nerve was so far depressed in pure nitrogen that conductivity -became obliterated for about two cm. of the asphyxiated stretch, it -was then narcotized in nitrogen. Following this oxygen with ether was -supplied for a time. Then the oxygen-ether mixture was displaced by -one of nitrogen and ether and finally by pure nitrogen. Even after -a prolonged period, a recovery in pure nitrogen never took place. -On the other hand, the nerve recovered at once, as soon as oxygen -without ether was introduced. The results of these investigations -are, therefore, completely in harmony with those undertaken by -_Winterstein_ on the nervous centers. They were later likewise -entirely confirmed by similar experiments of _Heaton_.[208] All these -investigations furnished the proof _that in narcosis, living substance, -notwithstanding even the greatest oxygen deficiency, is not capable of -producing oxydation, neither can consumption of oxygen take place, with -which, after cessation of the narcosis, oxydative splitting up can be -carried out_. - - [207] _Fr. W. Fröhlich_: “Zur Kenntniss der Narkose des Nerven.” - Zeitschr. f. allgem. Physiol. Bd. III, 1904. - - [208] _Trevor B. Heaton_: “Zur Kenntniss der Narkose.” Zeitschr. f. - allgem. Physiol. Bo. 1910. - -Recently _Warburg_[209] has likewise found an oxydative depression -during narcosis in the eggs of the sea urchin and in the red corpuscles -of geese, and the same fact has lately been also demonstrated by -_Joannovics und Pick_[210] for the oxydative activity of the liver -cells of the dog. - - [209] _Otto Warburg_: “Ueber die Oxydationen in lebenden Zellen.” - Zeitschr. f. physiol. Chemie Bd. 66, 1910. The same: “Ueber - Beeinflussung der Oxydationen in lebenden Zellen nach Versuchen an - roten Blutkörperchen.” Zeitschr. f. physiol. Chemie Bd. 69, 1910. - - [210] _Joannovics und Pick_: “Intravitale Oxydationshemmung in der - Leber durch Narkotica.” Pflügers Arch. Bd. 140, 1911. - -This fundamental establishment of the fact that narcosis prevents -oxydations in living substance is at once followed by the further -problem, in what _manner_ do the disintegration processes undergo -alterations during narcosis? _That_ they must be altered, and this -in the form of a reduced energy production, is clearly shown by the -decrease of irritability and the increase of the decrement of the -conduction of excitation. Both become the greater the deeper the -narcosis. The observations just discussed render these facts at -once self-evident. They follow as a simple and necessary result of -the elimination of the oxydative processes. If these are suppressed -further breaking down, if not influenced by addition of other factors, -proceeds anoxydatively. The previously observed series of processes is -developed, which invariably take place when oxygen deficiency occurs -and which produce in the clearest form the results of asphyxiation on -the withdrawal of oxygen supply. If, therefore, the disintegration -processes are not influenced in some other manner during narcosis, -they must then take place in the same way as in the withdrawal of the -oxygen supply. The question, if this is actually the case, can be -experimentally decided by comparing, on the one hand, the development -of the course of asphyxiation during narcosis, and on the other, the -withdrawal of the oxygen supply. We have carried out this comparison -for the spinal cord centers as well as for the medullated nerve. A -prolonged series of experiments have been made by _Bondy_[211] with the -apparatus constructed for this purpose by _Baglioni_.[212] Two frogs -under uniform conditions of temperature were submitted to artificial -circulation, the one merely with an oxygen-free fluid, the other with -the same, but with the addition of 5 per cent. of alcohol. In order -to render the least trace of irritability perceptible, responsivity -was increased in both animals by the employment of strychnine. It -then appeared that, on the average, irritability was obliterated in -the narcotized frog in about the same time as in the animal simply -asphyxiated. These experiments were controlled by introducing at their -conclusion a saline solution containing oxygen into both frogs and by -ascertaining the degree of recovery. In like manner _Fröhlich_[213] has -established the same fact for the nerve. The period of asphyxiation -for the nerve in a nitrogen-ether mixture is approximately the same -as in pure nitrogen. Analogous experiments have been carried out in -amœbæ by _Ishikawa_.[214] Here also it has been shown that living -substance becomes asphyxiated in narcosis and can finally recover only -when oxygen is supplied. In more than a hundred experiments _Ishikawa_ -has, however, obtained the uniform result that amœbæ asphyxiate rather -sooner in narcosis than in pure nitrogen. The most striking experiments -are those which _Heaton_[215] has carried out on the nerve. Using -both sciatic nerves of the same frog, he passed each one through a -separate glass chamber, as previously described, and laid the central -stumps projecting from the chamber over a pair of platinum electrodes, -while the stretch within was likewise placed on platinum electrodes. -The muscles served as indicator of the capability of conduction and -irritability. The alterations thereof were tested by the ascertainment -of the threshold of stimulation. The nerve in the _one_ chamber -was then subjected to a pure nitrogen current, that in the _other_ -merely to one of pure air with ether. In order to test the degree of -asphyxiation the air-ether current in the latter chamber was replaced -from time to time by an ether-nitrogen current, and then by one of pure -nitrogen, so that the narcosis was interrupted without the entrance of -oxygen being possible in the mean time. During this suspension of the -narcosis, the nerve recovered each time in nitrogen, its irritability -again increasing and its capability of conduction returning with every -test. However, recovery showed itself as less and less complete. -Finally irritability had sunk so low that the capability of conduction -disappeared entirely. At the end of the experiment as control, nitrogen -was displaced by air in the two chambers and in both nerves recovery -took place. - - [211] _Bondy_: “Untersuchungen über die Sauerstoffspeicherung in den - Nervencentren.” Zeitschr. f. allgem. Physiol. Bd. III, 1904. - - [212] _Baglioni_: “Bezichungenzwishen physiologischer Wirkung und - chemischer Constitution.” Zeitschr. f. allgem. Physiologie Bd. III, - 1904. - - [213] _Fr. W. Fröhlich_: “Zur Kenntniss der Narkose des Nerven.” - Zeitschr. f. allgem. Physiologie Bd. III, 1904. - - [214] The experiments of _Ishikawa_ have not as yet been published. - - [215] _Trevors B. Heaton_: “Zur Kenntniss der Narkose.” Zeitschr. f. - allgem. Physiologie Bd. X, 1910. - -In both cases recovery could only be brought about by an introduction -of oxygen. From the sum of all these experiments it results that -during narcosis in air the nerve, even when a sufficiency of oxygen is -present, gradually asphyxiates and loses its capability of conduction, -and this in about the same length of time as the other nerve in pure -nitrogen. These investigations furnish two important facts for the -theory of narcosis. First, that in narcosis living substance becomes -asphyxiated notwithstanding the presence of an ample oxygen supply, -and secondly, that asphyxiation occurs in the same time, or somewhat -more rapidly, in pure nitrogen under otherwise similar conditions -than without narcosis. In other words, it is shown that the breaking -down processes of metabolism continue in narcosis as anoxydative -disintegration. _In narcosis, therefore, asphyxiation takes place with -approximately the same or a somewhat greater rapidity than that in an -oxygen-free medium._ - -The fact here established explains in the simplest manner the often -described observation that in the human being and in mammals during -prolonged anæsthesia typical products of insufficient combustion, -such as fatty acids, lactic acid and above all aceton, in not -inconsiderable quantities are eliminated, as the case may be, by the -urine or the respiratory air.[216] If, as has been shown by the -foregoing experiments, the processes of disintegration can continue -to anoxydatively take place during narcosis, the problem arises, if -this anoxydative breaking down can be further increased by excitating -stimuli. This question has been answered likewise by means of -experiments on the nerve made by _Heaton_.[217] The two sciatic nerves -of the same frog were drawn through a double glass chamber of the form -previously described so that each nerve lay on an electrode and with -the central stump protruding out of the chamber hanging likewise over -an electrode. As in the former instances the muscle contraction of the -shank again served as indicator. Both nerves were then subjected to -the same current of nitrogen-ether. When, as a result of the narcosis, -their irritability has sunk to the level of “stromschleifen” the -central stump of the one nerve was continuously stimulated with faradic -shocks during a prolonged period, while the other nerve remained at -rest. Finally, by displacement of the current of nitrogen-ether with -one of pure nitrogen, cessation of narcosis was brought about. It was -then seen that the irritability of the continuously stimulated nerve -showed a much greater decrease than that of the nonstimulated. The -control made by introduction of air demonstrated that both nerves -recovered in an oxygen supply. _There can, therefore, be no doubt, -by comparative experiments we find, that during narcosis anoxydative -disintegration can be still further increased by the action of stimuli._ - - [216] For the very extensive literature on this subject see - _Reicher_: “Chemischexperimentelle Studien zur Kenntniss der - Narkose.” Zeitschr. f. klinische Medicin Bd. 65, 1908. - - [217] _Heaton_: l. c. - -In view of this knowledge of the influence of narcotics on oxygen -exchange it may be considered as a firmly established fact, that -a process of depression is developed during narcosis, which can -be classified with the large group of depressions, resulting from -deficiency of oxygen. This is followed by the important problem, is it -possible to attribute the whole series of alterations, produced by the -narcotic, solely to this _one_ factor? In other words, is narcosis the -result of acute suppression of the oxydative processes? - -If the individual symptoms which characterize narcosis are investigated -from this point of view, one must indeed confess that they are all -readily understood when regarded as the results of suppression of -the oxydative processes. Indeed, the disappearance of the perceptible -vital activities, the decrease of irritability, the restriction of the -conduction of excitation, the continuance of an anoxydative breaking -down, the recovery on cessation of narcosis, provided oxygen is -present, etc., in short, all the characteristics of narcosis so far -known must be expected and _demanded_ if a suppression of the oxydative -processes exists during narcosis. - -There is only _one_ point which at the first glance would not seem to -agree entirely with the assumption. This is the fact that depression -sets in with a relatively greater rapidity in narcosis than when the -supply of oxygen is completely withdrawn. Depression of the centers -in the spinal cord, which begins in about five to ten minutes after -artificial circulation of an oxygen-free, alcohol-containing, saline -solution, is not brought about for more than an hour when the same -saline solution but without alcohol is introduced. This difference -is still more strikingly apparent in the nerve. The same degree of -depression, which is produced in the nerve in a nitrogen-ether mixture -within about _five_ minutes, is not reached in pure nitrogen without -ether until after the lapse of from _two_ to _four_ hours. In order -to investigate this relation somewhat more closely I have questioned -if it is possible for a living system, which has been narcotized to a -certain extent, to regain its irritability in a completely oxygen-free -medium, if cessation of the narcosis takes place after a period -essentially shorter than the time of asphyxiation of the system under -equal conditions. If the depression of narcosis is founded exclusively -on asphyxiation, it would be expected that no recovery could occur. -Experiments which I have made on the spinal cord centers as well as -on the peripheral nerves have, however, demonstrated exactly the -contrary. If a frog is subjected to an artificial circulation of an -oxygen-free saline solution containing 5 per cent. of alcohol until -reaction is lost, being certain of this by the injection of a weak -dose of strychnine, and if now a cessation of the narcosis is brought -about by the transfusion of oxygen-free saline solution, the centers -of the animal recover completely within ten to fifteen minutes, as -shown by typical strychnine tetanus. If a nerve is placed in a gas -chamber through which a mixture of nitrogen and ether is allowed to -flow until irritability is greatly decreased, and is then displaced by -pure nitrogen, irritability increases more or less completely according -to the time which has passed from the beginning of asphyxiation. This -investigation proves that living substance, even after the deepest -narcotic depression, may recover on cessation of the narcosis, although -in an entirely oxygen-free medium. _Fröhlich_, _Bondy_ and _Heaton_, -by the methods of their experiments above described, have proved this -fact in a great number of instances. On the other hand, _Ishikawa_ -could not observe a pronounced recovery in amœbæ from narcosis in pure -nitrogen. But it is possible that here the difference is perhaps merely -quantitative. - -What position should be taken in the face of these facts? Does recovery -of a deeply narcotized tissue in an oxygen-free medium really make -it difficult to suppose that narcosis is the result of an acute -suppression of the processes of oxydation? On closer view, it will be -found that this difficulty is merely apparent. In reality it is quite -possible to bring these facts into harmony with the assumption that -narcosis consists in a suppression of these processes. If one proceeds -from the supposition that living substance possesses a certain, even -though merely a small supply of oxygen in its interior, then it is at -once evident that a more or less complete recovery of irritability -from narcosis depression is possible, even in an oxygen-free medium. -It can take place at the cost of the oxygen still present in the -living substance and which during the narcosis, on account of the -suppression of the oxydation processes, could not be consumed. If -the presence of a certain oxygen reserve in living substance is -entirely set aside and a different explanation sought for the primary -continuance of irritability after a complete withdrawal of the oxygen -supply from without, the great difference of time in the setting in -of the depression in narcosis and that of the complete elimination -of the oxygen supply from without would make it necessary to assume -the processes occurring in narcosis are entirely different in nature. -The explanation that narcosis is the result of suppression of the -oxydative processes would indeed be out of the question in such a view. - -The assumption, however, that in a living system at the same moment -when oxygen is removed from the neighborhood, let us say by a stream -of nitrogen, no oxygen would be present and that in consequence -every oxydative process must cease, contains so little probability -that I have rejected it on various occasions.[218] The way in which -irritability is lost in asphyxiation of the nerve likewise very clearly -demonstrates the untenability of this view. The recent investigations -of _Lodholz_[219] have shown that decrease of irritability takes -place after a sudden displacement of all oxygen from the surrounding -medium uniformly and gradually in the form of a logarithmic curve. If -at the moment of oxygen withdrawal from the outer medium, metabolism -became entirely anoxydative, the curve of irritability must under -all circumstances show a sudden _steep decline_ at this point, -and subsequent to this a further _slower_ decrease. For, as the -oxydative processes constitute by far the _chief_ part in the energy -production of living substance, the production of energy, and with -this irritability, would undergo considerable loss at the same moment -in which oxydative was replaced by anoxydative disintegration. The -curve of decrease of irritability during the transition period from -oxygen supply to oxygen withdrawal shows, on the contrary, a completely -uniform course and it is not until later that a very slow decline takes -place, which only after a prolonged time assumes increasing rapidity. -But the assumption that at the moment when the supply of oxygen ceases, -anoxydative breaking down could acquire such enormous dimensions that -it furnishes just exactly the same amount of energy as was before -supplied oxydatively, is a view which no one will seriously entertain. -In connection with this I wish to call attention to the experiments of -_Fröhlich_[220] in which he compared the time required for asphyxiation -to take place in the nerves, when, on the one hand, the frogs had -been kept several days previous to the experiment in temperature of -14–40° C., and on the other, in one merely a few degrees above zero. -He found that the nerves of the cooled frogs required on an average -twice or three times as long for their irritability to sink to the same -degree as those of the heated frog, although during the experiment -the same temperature was present in both. It was also shown that the -asphyxiation period was prolonged up to a certain limit, depending -upon the length of time the animals were kept at a low temperature. It -would seem to me that these facts admit of no other explanation than -that in a low temperature a greater amount of oxygen is stored in the -nerve than in high temperatures. From the standpoint that from the -moment of withdrawal of oxygen from without, disintegration likewise -takes place exclusively anoxydatively, these facts would be completely -incomprehensible. When, however, the assumption is made, and this -would appear to me as inevitable, that living substance contains in -itself a certain even though a very slight quantity of oxygen, which in -low temperature is greater, in a high temperature less, the recovery -from narcosis, when oxygen is withheld, is not at all surprising. The -comparatively rapid setting in of depression in narcosis finds a simple -explanation in the _violent_ manner in which the oxydative breaking -down, notwithstanding the presence of oxygen, is suddenly suppressed by -the flooding by the narcotic. Finally, this view receives unlooked-for -support by a group of facts which at the first glance would appear to -bear no relation whatever to the process of narcosis. - - [218] Compare lecture V; lecture VII. - - [219] The investigations have not yet been published. - - [220] _Fr. W. Frölich_: “Das Sauerstoffbedürfniss des Nerven.” - Zeitschr. f. allgem. Physiol. Bd. III, 1904. - -In a series of investigations on the mechanism of movement in naked -protoplasm,[221] I have pointed out the rôle played by oxygen in the -genesis of the amœboid protoplasm movement. We can distinguish two -antagonistic phases in the movement of amœboid cells, the expansion -phase and the contraction phase. The first consists in an increase, -the latter in a diminution of the surface, the mass remaining the -same. The expansion phase is manifested in the stretching out of the -pseudopods by a centrifugal outflowing of the protoplasm into the -surrounding medium, the contraction phase by the indrawing of the -pseudopods by the centripetal inflowing of the protoplasm to the cell -body. In total contraction, such as occurs, for instance, in strong -excitation following stimuli, the cell body becomes ball shaped. -In local contraction of the long thread or net-shaped outstretched -pseudopods of the sea rhizopoda, the protoplasm of the retracting -pseudopod forms balls and spindles. Considered from a physical point -of view the expansion phase of amœboid movement is an expression of -decrease, the contraction phase an increase of the surface tension. -I have shown that the factor which under physiological conditions -decreases the surface pressure and thereby brings about the expansion -phase is the introduction of oxygen into the living substance. With -removal of oxygen the stretching out of the pseudopods ceases. The cell -gradually draws in all pseudopods and assumes the shape of a ball. -On the reintroduction of oxygen the outflow of the pseudopods begins -anew. This fact can be observed in all amœboid cells. When, therefore, -consumption of oxygen and oxydative changes is suppressed during -narcosis it is to be expected that all naked protoplasm masses by being -narcotized lose their capability of assuming the expansion phase of -movement and contract into the shape of balls. Experimentation confirms -this deduction in the most striking manner. When amœbæ are placed in -a drop of water under the microscope in a gas cell through which air -and a little ether are allowed to flow, the pseudopod formation of the -amœbæ ceases within a few minutes and they all assume the shape of a -ball. (Figure 62.) In asphyxiation in pure nitrogen, the changes in the -amœbæ take place in exactly the same manner with the exception that in -this case a longer period ensues according to the size and activity of -the animals. About 20 to 60 minutes elapse before depression becomes -complete. If larger sea rhizopoda are narcotized in the same manner -all pseudopods are more or less retracted and the contained protoplasm -flows centripetally and contracts in the characteristic manner into -balls and spindles. (Figure 63.) If the narcosis is removed by -displacing the ether by pure air, the stretching out of the pseudopods -then begins anew, provided the narcosis has not been too deep or too -prolonged. - - [221] _Max Verworn_: “Die physiologische Bedeutung des Zellkerns.” - Pflügers Arch. Bd. 51, 1891. - - The same: “Die Bewegung der lebendigen Substanz. - Eine vergleichend-physiologische Untersuchung der - Contractionserscheinungen.” Jena 1892. - - The same: “Allgemeine Physiologie.” V Auflage. Jena 1909. In the last - place the same theory of the contraction movements with some new - corrections is described. - -[Illustration: _A_ - -_B_ - -Fig. 62. - -Amoeba limax. _A_--In normal state. _B_--Narcotized by ether.] - -[Illustration: Fig. 63. - -Rhizoplasma Kaiseri. Effect of chloroform.] - -In the face of all this evidence there can be indeed no further -barrier to the assumption that the symptoms in narcosis are a result -of a suppression of the oxydative processes. Nevertheless, I would -not at present venture to maintain that the entrance of the narcotic -into living substance produces no alterations whatever, except just -this oxydative suppression. For the present it seems to me that the -possibility is in no way precluded that the same process, which -is expressed in the oxydative suppression, is connected with other -alterations in the living substance, of which we are as yet ignorant. -As far as the effects of larger doses of narcotics are concerned, the -assumption that other alterations take place in the living substance -can in any case hardly be avoided. An application of larger quantities -of narcotics brings about destruction of the living system with great -rapidity. Here the alterations in the optical properties of the cell -are of such magnitude that the changes are directly perceptible under -the microscope. _Binz_[222] has observed such alterations in the nerve -cell and looked upon them as coagulation. In unicellular organisms -these optical alterations can readily be followed. If amœbæ, sea -rhizopods or infusoria are narcotized with stronger doses of ether or -chloroform, the protoplasm becomes opaque and granulated, it appears -darker than formerly and in many cases displays a yellowish brown color -in transmitted light. Cells altered in this way no longer recover -after removal of the narcotic. These intense and rapidly appearing -alterations of protoplasm resulting from the application of stronger -doses of the narcotic can scarcely be explained as simply the result of -a mere decrease of the oxydative processes. They would seem to consist -rather, as suggested by _Binz_, as coagulation, in an alteration of -the state of certain components of living substance. Whether these -alterations are already present in a correspondingly slight amount in -those degrees of narcosis after which complete recovery can take place -and further whether in this case they are in any way concerned in -bringing about the individual symptoms of the former, are questions the -decision of which must be left to future investigations. _Höber_[223] -indeed makes such an alteration of the colloidal state of the lipoid -the basis of a theory of narcosis. But such assumptions are scarcely -more than speculations. This is one of the points in which our present -knowledge is lacking. - - [222] _Binz_: “Vorlesungen über Pharmakologie für Aerzte und - Studierende.” II Aufl. Berlin 1891. - - [223] _Höber_: “Beiträge zur physikalischen Chemie der Erregung - und der Narkose.” Pflügers Arch. Bd. 120, 1907. The same: “Die - physikalisch-chemischen Vorgänge der Erregung.” Sammelreferat. - Zeitschr. f. allgem. Physiol. Bd. X, 1910. - -Even if we restrict ourselves to the actually established alterations -produced by the narcotic in living substance, new problems present -themselves, the investigation of which requires further effort. Above -all, the question arises as to the finer mechanism of oxydative -depression. In what manner does the narcotic molecule, entering into -the living substance, suppress the oxydative processes? Here there are -very different possibilities to be taken into consideration and up to -the present in our investigations of a suppression of the oxydative -processes resulting from narcosis, we have stood on the firm ground -of assured facts. However, the discussion of the nature of this -suppression leads us into the domain of _hypothesis_. But without -hypothesis there can be no progress in knowledge. In all branches of -scientific research, working hypotheses are required for the obtainment -of new facts. - -On closer reflection, there are chiefly _three_ possibilities, which, -considered from the standpoint of our present knowledge of the -processes in living substance, offer an explanation of the oxydative -suppression as a result of narcosis. - -One of these possibilities is, that the _narcotic itself consumes -the oxygen which activates living substance_ and uses it for its -_individual_ oxydation, so that the specific oxydable material of -living substance receives less oxygen from the oxygen carriers. Based -on a series of interesting experiments this view has been recently -maintained by _Bürker_.[224] He observed that with the electrolysis -of acidulated water, to which a small per cent. of ether was added, a -much less amount of oxygen was at the anode than in one used as means -of control, containing acidulated water without ether. The oxygen was -replaced at the anode by oxydation products of the ether, such as -carbonic oxide, carbon dioxide, acetate aldehyde and acetic acid. In -experiments with various narcotics he likewise found that the stronger -the effect produced by narcosis, the greater the oxygen amount required -for the oxydation taking place of electrolysis. _Bürker_ applies these -results obtained for electrolysis to the processes in living substance -and takes the view that the narcotic seizes on the active oxygen, and -so withdraws it from the masses of living substance possessing a great -oxygen requirement. It cannot be denied that this conception of the -nature of certain narcotics deserves careful investigation. It seems -to me, however, that before considering it in the light of a serious -probability a grave difficulty would first have to be removed. In -living substance the narcotic would occur under conditions essentially -different from those existing during the experiment in the voltameter. -In the former case there would be the struggle for oxygen of the -specific oxydable cell masses to be met with. Considering the small -amount of chemical activity of the greater number of narcotics it would -appear at least doubtful if in this battle for supremacy the latter -would achieve a victory. For some narcotics, as, for instance, carbon -dioxide, this method of a depression of the oxydative processes would -have no bearing whatever. This is rather to be looked for in the -effects of oxydative suppression of the aldehydes, which _Warburg_[225] -has recently observed and investigated. Here, however, it is not a true -narcosis which is concerned. - - [224] _Bürker_: “Eine neue Theorie der Narkose.” Münchener Med. - Wochenschrift, 1910. - - [225] _Warburg_: “Ueber Beeinflussung der Sauerstoffathmung. II - Mitteilung. Eine Beziehung zur Constitution.” Zeitschr. f. physiolog. - Chemie Bd. 71, 1911. - -A second possibility of a suppression of oxydation would be the -_fixation of the molecules of the oxydable substances by chemical or -physical combinations_ in that they would lose their capability of -oxydative disintegration. Such a supposition would, however, likewise -contain but few elements of probability. As has been shown, an -anoxydative breaking down continues during narcosis, which, and this we -may assume with certainty, furnishes very different products in great -variety. These anoxydative disintegration products, as recovery on the -cessation of narcosis shows, are removed during recovery by oxydation. -If the effect of the narcotic consisted in the prevention in spite of -the presence of oxygen of the oxydation by combination, it would be -necessary to assume that the narcotic was bound to a mass of completely -heterogeneous substances, a conclusion we should find difficult to -entertain. - -If, however, depression of the oxydative processes is founded neither -on the seizure of oxygen by the narcotic nor the fixation of oxydable -substances by the former, there remains the possibility _that the -narcotic suppresses the transmission of oxygen to these points -of consumption_. We assume that the oxygen transmission to those -points where its consumption takes place is carried out by special -substances, the existence of which has been established in the most -varied vegetable and animal cell forms. Unfortunately we only know -these oxygen-carrying substances by their effects. Of their chemical -constitution we have no knowledge, but we usually assume that the -transmission of oxygen occurs in the same manner as in catalytic -processes. On another occasion I have previously expressed the -suggestion,[226] that the narcotic suppresses oxydation by producing -incapability of the groups acting as oxygen carriers to carry out this -function. If we assume that the substances possessing the character -of oxygen carriers, which activate the molecular oxygen and so render -it capable of attacking the oxydable substances, lose this capability -under the influence of narcotics, this supposition would not only -make all of the facts of suppression of oxygen exchange in narcosis -comprehensible, considered from one point, but likewise, as careful -investigation has shown, be in complete harmony with all knowledge -obtained up to the present of the process of narcosis. - - [226] _Max Verworn_: “Ueber Narkose.” Deutsche med-Wochenschrift, - 1909. - -Here is the point where the interesting observations of _Hans -Meyers_[227] and _Overton_[228] on the relations of the depressing -influence of narcotics to their solubility of fat and water may be -connected with the facts of the suppression of oxydation. _Meyer_ -and _Overton_ have quite independently of each other made the same -observation, that the depressing effect of a narcotic is the greater, -the larger the coefficient of distribution between substances of a -fatty nature and water. Those narcotics produce the strongest effects -which are readily soluble in substances of a fatty nature, but not -easily so in water, that is, in which the coefficient distribution -between fat and water is very great. This law, which has been -demonstrated by _Meyer_ and _Overton_ for a large number of narcotic -processes, is in itself not a theory of narcosis, as has been often -erroneously assumed. It shows us, however, an important condition, -which must be considered in every theory of narcosis. It demonstrates -that it is the ease with which transmission in the lipoid occurs which -allows a substance to develop narcotic effects. These facts would seem -to indicate that the lipoids of the cell are connected in some way -or other with the exchange of oxygen. If we assume that the oxygen -carriers, the chemical constitution of which is so far not known, bear -the character of lipoids and belong, say, to the generally extended -group of phosphatides, there results at once an apparent connection -of the law established by _Meyer_ and _Overton_ with the nature of -narcosis. - - [227] _Hans Meyer_: “Welche Eigenschaft der Anaesthetica bedingt ihre - narkotische Wirkung?” Arch. experimentelle Pathol. u. Pharmacol. - Bd. 42, 1899. Further: _Fritz Baum_: “Ein physiologisch-chemischer - Beitrag zur Theorie der Narkotica.” _Ibidem._ - - [228] _Overton_: The first communication of the results obtained - by _Overton_ were made by _Rost_: “Zur Theorie der Narkose” in the - Naturwiss. Rundschau Jarhrg. 1899. _Overton_ has treated the subject - in detail in his work, “Studien über die Narkose zugleich ein Beitrag - zur allgemeinen Pharmakologie.” Jena 1901. - -The depressing effect of the narcotic would then consist in producing -incapability of the lipoids transmitting oxygen to act as carriers of -the same, and it is, therefore, self-evident that the effect of the -narcotic would be the stronger the more readily it found entrance into -the lipoids. It is perhaps not without interest that in similar manner -_Mansfeld_[229] has attempted to establish a connection between the -facts which _Meyer_ and _Overton_ have found and those ascertained -by my coworkers and myself. He expressed the view that the lipoids -of the cells represent the channels followed by the oxygen on its -entrance, and that in consequence of their accumulation in the lipoids, -the narcotics bring about asphyxiation by physically obstructing the -transmission of the oxygen from the outer medium through the surface -layer of the lipoid into the protoplasm. The divergence in our views -is not essential in their nature, and I attach the less importance to -them as we find ourselves here, as I must again emphasize, on purely -hypothetical ground. - - [229] _Mansfeld_: “Narkose und Sauerstoffmangel.” Pflügers Arch. Bd. - 129, 1909. - -In consideration of these observations we may perhaps establish the -following hypothesis of the effect of the oxydative suppression of -narcotics: The narcotics obstruct, either by absorption or loose -chemical combination the oxygen carriers of the cell and render them -incapable to activate the molecular oxygen. In consequence, oxydation -of the oxydable substances cannot take place and disintegration occurs -of an _an_oxydative form. The cell asphyxiates. - -In conclusion I wish to warn against erroneous assumption that _all_ -oxydative depressions by chemical substances are _narcosis_ and that -the mechanism is the same. It is true that a number of chemical -substances depress the processes of oxydation. But the latter can be -brought about in very varying ways. I would like to mention the effect -of oxydative depression of aldehydes. To this _Warburg_[230] has added -hydrocyanic acid, arsenic acid, ammonia and substitution compounds -of ammonia. These substances do not follow the _Meyer-Overton_ law of -the coefficient of distribution. We cannot consider them, therefore, -as narcotics. Future investigation will establish the existence of a -large number of substances belonging to this great group of oxydation -suppressing poisons, which are not narcotics. And it is likewise -certain that depressing substances will be found, the depressing -effects of which will not have their point of attack in the oxygen -exchange, but will be shown to exist in other constituents of the -metabolic chain. Our research in these fields, as already said, is -still in the first beginnings and its perspective reaches into infinite -space. - - [230] _Warburg_: “Ueber Beeinflussung der Sauerstoffatmung. II - Mitteilung: Eine Beziehung zur Constitution.” Zeitschrift f. physiol. - Chemie Bd. 71, 1911. - - - - -Spelling errors: - - possibilites → possibilities - deliminated → delimitated - equilibrum → equilibrium - fur → für - künstliche Immunisirungsprocesse → künstlichen Immunisierungsprozesse - methan → methane - aldehyd → aldehyde - Rüchenmarks → Rückenmarks - metronom → metronome - irrritability → irritability - tranverse → transverse - the the → the - Mittleilung → Mitteilung - whereever → wherever - oxdyative → oxydative - anoxdyative → anoxydative - -Spelling inconsistencies: - - ae/æ/e (inconsistent ligatures) - cannot/can not - cell-pathology/cell pathology (inconsistent hyphenation) - æthyl/ethyl - - -*** END OF THE PROJECT GUTENBERG EBOOK IRRITABILITY *** - -Updated editions will replace the previous one--the old editions will -be renamed. - -Creating the works from print editions not protected by U.S. copyright -law means that no one owns a United States copyright in these works, -so the Foundation (and you!) can copy and distribute it in the -United States without permission and without paying copyright -royalties. 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font-size:1.2em; font-weight:bold'>The Project Gutenberg eBook of Irritability, by Max Verworn</p> -<div style='display:block; margin:1em 0'> -This eBook is for the use of anyone anywhere in the United States and -most other parts of the world at no cost and with almost no restrictions -whatsoever. You may copy it, give it away or re-use it under the terms -of the Project Gutenberg License included with this eBook or online -at <a href="https://www.gutenberg.org">www.gutenberg.org</a>. If you -are not located in the United States, you will have to check the laws of the -country where you are located before using this eBook. -</div> - -<p style='display:block; margin-top:1em; margin-bottom:0; margin-left:2em; text-indent:-2em'>Title: Irritability</p> -<p style='display:block; margin-left:2em; text-indent:0; margin-top:0; margin-bottom:1em;'>A Physiological Analysis of the General Effect of Stimuli in Living Substance</p> - <p style='display:block; margin-top:1em; margin-bottom:0; margin-left:2em; text-indent:-2em'>Author: Max Verworn</p> -<p style='display:block; text-indent:0; margin:1em 0'>Release Date: November 19, 2021 [eBook #66767]</p> -<p style='display:block; text-indent:0; margin:1em 0'>Language: English</p> - <p style='display:block; margin-top:1em; margin-bottom:0; margin-left:2em; text-indent:-2em; text-align:left'>Produced by: Thiers Halliwell, Tim Lindell, Bryan Ness and the Online Distributed Proofreading Team at https://www.pgdp.net (This file was produced from images generously made available by The Internet Archive/American Libraries.)</p> -<div style='margin-top:2em; margin-bottom:4em'>*** START OF THE PROJECT GUTENBERG EBOOK IRRITABILITY ***</div> - -<div class="transnote"> -<p><b><a id="Transcribers_notes"></a>Transcriber’s notes</b>:</p> - -<p>The text of this e-book has largely been preserved in its original -form. However, some <a href="#Spelling_corrections">spelling -errors</a> have been corrected and some missing punctuation -items inserted (hyphen, space, parenthesis, quotation mark). <a -href="#Spelling_corrections">Inconsistent spellings</a> have not -been changed. Missing footnote markers on pages 96 and 136 have been -inserted at what seemed to be likely locations. A few long paragraphs -have been split to allow repositioning of diagrams closer to the -relevant text. Two diagrams have the same number (Fig. 24.).</p> - -<p>Hyperlinks are indicated by a black underline and coloured -highlighting when the mouse pointer hovers over them. <span -class="htmlonly">Page numbers are shown in the right margin. Footnotes -have been numbered consecutively and are located at the end.</span> <span -class="epubonly">Footnotes have been numbered consecutively and are -listed at the end.</span></p> - -<p class="epubonly">The cover image of the book was created by the -transcriber and is placed in the public domain.</p> -</div> - - - -<p class="tac fs110 ws04em">YALE UNIVERSITY</p> - -<p class="tac fs110 ws04em">MRS. HEPSA ELY SILLIMAN MEMORIAL LECTURES</p> - -<hr class="r10" /> - -<p class="tac fs110">IRRITABILITY</p> - - -<hr class="chap x-ebookmaker-drop" /> - -<p class="tac ws04em">SILLIMAN MEMORIAL LECTURES</p> - -<p class="tac ws04em">PUBLISHED BY YALE UNIVERSITY PRESS</p> - -<hr class="r10" /> - -<p>ELECTRICITY AND MATTER. <i>By</i> <span class="smcap">Joseph John Thomson, D.Sc., -LL.D., Ph.D., F.R.S.</span>, <i>Fellow of Trinity College, Cambridge, Cavendish -Professor of Experimental Physics, Cambridge</i>.<br/> - -<i>Price $1.25 net; postage 10 cents extra.</i></p> - - -<p>THE INTEGRATIVE ACTION OF THE NERVOUS SYSTEM. <i>By</i> -<span class="smcap">Charles S. Sherrington, D.Sc., M.D., Hon. LL.D., Tor., F.R.S.</span>, <i>Holt -Professor of Physiology in the University of Liverpool</i>.<br/> - -<i>Price $3.50 net; postage 25 cents extra.</i></p> - - -<p>RADIOACTIVE TRANSFORMATIONS. <i>By</i> <span class="smcap">Ernest Rutherford, -D.Sc., LL.D., F.R.S.</span>, <i>Macdonald Professor of Physics, McGill University</i>.<br/> - -<i>Price $3.50 net; postage 22 cents.</i></p> - - -<p>EXPERIMENTAL AND THEORETICAL APPLICATION OF -THERMODYNAMICS TO CHEMISTRY. <i>By</i> <span class="smcap">Walther Nernst</span>, -<i>Professor and Director of the Institute of Physical Chemistry in the -University of Berlin</i>.<br/> - -<i>Price $1.25 net; postage 10 cents extra.</i></p> - - -<p>PROBLEMS OF GENETICS. <i>By</i> <span class="smcap">William Bateson, M.A., F.R.S.</span>, -<i>Director of the John Innes Horticultural Institution, Merton Park, Surrey, -England</i>.<br/> - -<i>Price $4.00 net; postage 25 cents extra.</i></p> - - -<p>STELLAR MOTIONS, WITH SPECIAL REFERENCE TO -MOTIONS DETERMINED BY MEANS OF THE SPECTROGRAPH. -<i>By</i> <span class="smcap">William Wallace Campbell, Sc.D., LL.D.</span>, <i>Director of the -Lick Observatory, University of California</i>.<br/> - -<i>Price $4.00 net; postage 25 cents extra.</i></p> - - -<p>THEORIES OF SOLUTION. <i>By</i> <span class="smcap">Svante August Arrhenius, Ph.D., -Sc.D., M.D.</span>, <i>Director of the Physico-Chemical Department of the Nobel -Institute, Stockholm, Sweden</i>.<br/> - -<i>Price $2.25 net; postage 14 cents extra.</i></p> - - -<p>IRRITABILITY, A PHYSIOLOGICAL ANALYSIS OF THE GENERAL -EFFECT OF STIMULI IN LIVING SUBSTANCE. <i>By</i> <span class="smcap">Max -Verworn, M.D., Ph.D.</span>, <i>Professor at Bonn Physiological Institute</i>.</p> - -<p><i>Price $3.50 net; postage 20 cents extra.</i></p> - - -<hr class="chap x-ebookmaker-drop" /> - -<div class="titlepage"> -<h1> -<span class="t1">IRRITABILITY</span><br /> - -<span class="t2 ws04em">A PHYSIOLOGICAL ANALYSIS OF THE GENERAL<br /> -EFFECT OF STIMULI IN LIVING SUBSTANCE</span></h1> - -<div class="tp1">BY</div> - -<div class="tp2">MAX VERWORN, M.D., <span class="smcap">Ph.D.</span></div> - -<div class="tp3"><i>Professor at Bonn Physiological Institute</i></div> - -<div class="tp4">WITH DIAGRAMS AND ILLUSTRATIONS</div> - -<div class="figcenter illowe8_125" id="colophon"> - <img class="w100" src="images/colophon.jpg" alt="" /> -</div> - -<div class="tp5"><span class="smcap">New Haven: Yale University Press</span><br /> -<span class="smcap">London: Henry Frowde</span><br /> -<span class="smcap">Oxford University Press</span><br /> -<span class="fs110">MCMXIII</span></div> -</div> - -<hr class="chap x-ebookmaker-drop" /> - -<p class="tac"> -<span class="fs80 ws04em">COPYRIGHT, 1913</span><br /> -<span class="fs80 ws04em"><span class="smcap">By</span> YALE UNIVERSITY PRESS</span></p> -<hr class="r5" /> -<p class="tac smcap fs80 ws04em">First Printed May, 1913, 600 Copies</p> - -<hr class="chap x-ebookmaker-drop" /> - -<h2 id="SILLIMAN_FOUNDATION"><span class="title">THE SILLIMAN FOUNDATION.</span></h2> - - -<p>In the year 1883 a legacy of eighty thousand dollars was left -to the President and Fellows of Yale College in the city of New -Haven, to be held in trust, as a gift from her children, in memory -of their beloved and honored mother, Mrs. Hepsa Ely Silliman.</p> - -<p>On this foundation Yale College was requested and directed to -establish an annual course of lectures designed to illustrate the -presence and providence, the wisdom and goodness of God, as -manifested in the natural and moral world. These were to be -designated as the Mrs. Hepsa Ely Silliman Lectures. It is the -belief of the testator that any orderly presentation of the facts -of nature or history contributed to the end of this foundation -more effectively than any attempt to emphasize the elements of -doctrine or creed; and he therefore provided that lectures on -dogmatic or polemical theology should be excluded from the scope -of this foundation, and that the subjects should be selected rather -from the domains of natural science and history, giving special -prominence to astronomy, chemistry, geology, and anatomy.</p> - -<p>It was further directed that each annual course should be made -the basis of a volume to form part of a series constituting a -memorial to Mrs. Silliman. The memorial fund came into the -possession of the corporation of Yale University in the year 1901; -and the present volume constitutes the ninth of the series of -memorial lectures.</p> - - -<hr class="chap x-ebookmaker-drop" /> - -<h2 id="PREFACE"><span class="title">PREFACE</span></h2> - - -<p>The lectures on irritability here published were held at the -University of Yale in October, 1911. When the authorities of -that University honored me by an invitation to give a course of -Silliman memorial lectures, I accepted with the more pleasure as -it furnished me with the opportunity of summarizing the results of -numerous experimental researches carried out with the assistance -of my co-workers during the course of more than two -decades in the physiological laboratories of Jena, Göttingen and -Bonn, to unite therewith the results obtained by other investigators -and thus present a uniform exposition of the general effects -and laws of stimulation in the living substance. I have long -entertained this plan and this for the following reason:</p> - -<p>The physiologist, the zoölogist, the botanist, the psychologist, -the pathologist, have to deal, day in, day out, with the effects of -stimulation on the living substance. No living substance exists -without stimulation. In the vital manifestations of all organisms -the interplay of the most varied stimuli produces an enormous -and manifold variety of effects. Experimental biological science -employs artificial stimulation as the most important aid in the -methodic production of certain effects of stimulation. The number -of researches in which special effects of stimulation are -treated is endless. Nevertheless the systematic investigation of -the effects of stimulation have, curiously enough, been strangely -neglected. Although countless results of individual effects of -stimulation have been studied, the attempt has never been made -to establish a general physiology of the laws of stimulation and -consider it as an independent problem. This circumstance induced -me to systematically investigate the general laws of the effect of -stimulation. In the fifth and sixth chapters of my book on -general physiology the results of these studies are recorded for -the first time. Since then, especially during our own researches -on the general physiology of the nervous system, a great number<span class="pagenum" id="Page_viii">viii</span> -of new facts of importance for the general physiology of the -effects of stimulation have been obtained. All these results I -have endeavored to combine and elucidate in the following -lectures.</p> - -<p>The text of the lectures in its present form was written in -German in 1911. The English translation was made by my wife, -with the help of our friend, Dr. Lodholz of the University of -Pennsylvania, who also undertook the reading of the proofs. -We wish here to thank him once again and express our deep -appreciation of the great sacrifice of time and labor involved in -this task. I am likewise much indebted to Dr. Julius Vészi for -his assistance unstintingly given, especially in obtaining a number -of curves. Finally, I wish to take this opportunity to render -warmest thanks to the authorities of Yale University, and especially -to President Hadley and Professor Chittenden, as well as -to my special colleagues, for the hospitality and cordial reception -extended to me in New Haven and for the pleasant hours I was -privileged to spend in their midst.</p> - -<p class="tar pr1"> -<span class="smcap">Max Verworn.</span></p> - -<p class="pl2hi1">Bonn.<br /> -Physiological Laboratory of the University.</p> - -<hr class="chap x-ebookmaker-drop" /> - -<div class="chapter"> -<p><span class="pagenum" id="Page_ix">ix</span></p> - -<h2 id="CONTENTS"><span class="title">CONTENTS </span></h2> -</div> - -<div class="center"> -<table width="550" summary="table of contents"> -<tr><td class="tac ptb12"><div>I</div></td></tr> -<tr> -<td class="taj pl2hi2 pr1"><i>Contents</i>: Introductory. Earliest period. <i>Francis Glisson</i> as founder -of the doctrine of irritability. <i>Albrecht von Haller.</i> The vitalists. -<i>Bordeu</i> and <i>Barthez</i>. <i>John Brown’s</i> system. <i>Johannes Müller</i> -and the specific energy of living substance. <i>Rudolf Virchow’s</i> -doctrine of the irritability of the cell. Discovery of the inhibitory -effects of stimulation. <i>Weber</i>, <i>Schiff</i>, <i>Goltz</i>, <i>Setschenow</i>, <i>Sherrington</i>. -<i>Claude Bernard</i> studies on narcosis. Tropisms. <i>Ehrenberg</i>, -<i>Engelmann</i>, <i>Pfeffer</i>, <i>Strassburger</i>, <i>Stahl</i>. <i>Semon’s</i> speculations -on mneme.</td><td class="tar vab"><div><a href="#Page_1">1</a></div></td> -</tr> - - -<tr><td class="tac ptb12"><div>II</div></td></tr> -<tr> -<td class="taj pl2hi2 pr1"><i>Contents</i>: Principles of scientific knowledge and research. Origin -and meaning of the conception of cause. Cause and condition. -Criticism of the conception of cause. The conditional point of -view. Conception of cause. The conditional point of view applied -to the investigation of life. Conception of vital conditions. Definition -of the conception of stimulation.</td><td class="tar vab"><div><a href="#Page_18">18</a></div></td> -</tr> - - -<tr><td class="tac ptb12"><div>III</div></td></tr> -<tr> -<td class="taj pl2hi2 pr1"><i>Contents</i>: The quality of the stimulus. Positive and negative alterations -of the factors which act as vital conditions. Extent of the -alteration in vital conditions or intensity of the stimulus. Threshold -stimuli, sub-threshold, submaximal, maximal and supermaximal -intensities of stimulus. Relations between the intensity of -stimulus and the amount of response. The <i>Weber</i> and <i>Fechner</i> -law. All or none law. Time relations of the course of the -stimulus. Form of individual stimulus. Absolute and relative -rapidity in the course of the stimulus. Duration of the stimulus -after reaching its highest point. Adaptation to persistent stimuli. -Series of individual stimuli. Rhythmical stimuli. The <i>Nernst</i> -law.</td><td class="tar vab"><div><a href="#Page_39">39</a></div><span class="pagenum" id="Page_x">x</span></td> -</tr> - - -<tr><td class="tac ptb12"><div>IV</div></td></tr> -<tr> -<td class="taj pl2hi2 pr1"><i>Contents</i>: Various examples of the effects of stimulation. Metabolism -of rest and metabolism of stimulation. Metabolic equilibrium, -Disturbances of equilibrium by stimuli. Quantitative and -qualitative alterations of the metabolism of rest under the influence -of stimuli. Excitation and depression. Specific energy of -living substance. Qualitative alterations of the specific metabolism -and their relations to pathology. Functional and cytoplastic -stimuli. Relations of the cytoplastic effects of stimuli to the functional. -Hypertrophy of activity and atrophy of inactivity. Metabolic -alterations during growth of the cell. Primary and secondary -effects of stimulation. Scheme of effects of stimulation.</td><td class="tar vab"><div><a href="#Page_65">65</a></div></td> -</tr> - - -<tr><td class="tac ptb12"><div>V</div></td></tr> -<tr> -<td class="taj pl2hi2 pr1"><i>Contents</i>: Indicators for the investigation of the process of excitation. -Latent period. The question of the existence of assimilatory excitations. -Dissimilatory excitations. Excitations of the partial -components of functional metabolism. Production of energy in -the chemical splitting up processes. Oxydative and anoxydative -disintegration. Theory of oxydative disintegration. Dependence -of irritability on oxygen. Experiments on unicellular organisms, -nerve centers and nerve fibers. Restitution after disintegration by -metabolic self-regulation. Organic reserve supplies of the cell. -The question of a reserve supply of oxygen of the cell. Metabolic -self-regulation as a form of the law of mass effect, and metabolic -equilibrium as a condition of chemical equilibrium. Functional -hypertrophy.</td><td class="tar vab"><div><a href="#Page_87">87</a></div></td> -</tr> - - -<tr><td class="tac ptb12"><div>VI</div></td></tr> -<tr> -<td class="taj pl2hi2 pr1"><i>Contents</i>: Only processes of excitation are conducted, not processes of -depression. Conduction of excitation in its two extreme instances. -Conduction in undifferentiated pseudopod protoplasm of rhizopoda. -Conduction of excitation with decrement of intensity and rapidity. -Conduction of excitation in the nerve. Rapidity of conduction. -Conduction of excitation without decrement. Relation between -irritability and conductivity. Conduction of excitation with decrement -of the nerve after artificial depression of irritability by narcosis. -Theory of the decrementless conduction of the normal -nerve. Proof of the validity of the “all or none law” in the -medullated nerve. Theory of the process of the conductivity of -excitation. Theory of core model (Kernleiter). Electrochemical -theory of conduction based on the properties of semi-permeable -surfaces.</td><td class="tar vab"><div><a href="#Page_118">118</a></div><span class="pagenum" id="Page_xi">xi</span></td> -</tr> - - -<tr><td class="tac ptb12"><div>VII</div></td></tr> -<tr> -<td class="taj pl2hi2 pr1"><i>Contents</i>: Conception of specific irritability. Alteration of specific -irritability during and after excitation. Refractory period in -various forms of living substance. Absolute and relative refractory -period. Curve of irritability during refractory period. -Dependence of the duration of the refractory period on the -rapidity of the course of the metabolic processes in the living -substance. Dependence on temperature. Dependence on supply -of oxygen. Theory of refractory period. Refractory period as -basis of fatigue. Fatigue as a form of asphyxiation. Alterations -of irritability and the course of excitation in fatigue. Recovery -from fatigue. The rôle played by oxygen in recovery. Fatigue -as an expression of the prolongation of the refractory period -conditioned by the relative want of oxygen. Fatigue of the nerve.</td><td class="tar vab"><div><a href="#Page_154">154</a></div></td> -</tr> - - -<tr><td class="tac ptb12"><div>VIII</div></td></tr> -<tr> -<td class="taj pl2hi2 pr1"><i>Contents</i>: Examples of effects of interference of stimuli in unicellular -organisms. Interference of galvanic and thermic stimuli in Paramecia. -Interference of galvanic and thermic stimuli and narcotics. -Interference of galvanic and mechanical stimuli. Interference of -galvanotaxis and thigmotaxis in Paramecia and hypotin infusoria. -Real or homotop interference, apparent or heterotop interference. -The two effects of homotop interference of excitations: Summation -and inhibition of excitations. Theory of the processes of -inhibition. <i>Hering-Gaskell</i> Theory. Inhibition as an expression -of the refractory period. Individual possibilities of interference -of two stimuli. Interference of an excitating and a depressing -stimulus. Interference of two depressing stimuli. Interference -of two excitating stimuli. Analysis of the interference of two -excitations. Interference of two single stimuli. Conditions upon -which the result of interference is dependent. Heterobole and -isobole living systems. Intensity of the two stimuli. Interval -between the stimuli. Specific irritability and rapidity of reaction -of the living system. Latent period. Interference of single stimuli -in a series. General scheme of the development of the effect -of interference. Summation and inhibition. Apparent increase of -irritability. Conditions of summation. Tonic excitations. Conditions -of inhibitions. Various types of inhibition. Interference of -two series of stimuli. Relations in the nervous system. Peculiarities -of the nerve fibers. Conversion of the nerve by relative -fatigue from an isobolic into a heterobolic system.</td><td class="tar vab"><div><a href="#Page_189">189</a></div><span class="pagenum" id="Page_xii">xii</span></td> -</tr> - - -<tr><td class="tac ptb12"><div>IX</div></td></tr> -<tr> -<td class="taj pl2hi2 pr1"><i>Contents</i>: Necessity of cellular physiological analysis of toxic depressions -by pharmacology. Apparent variety of processes of depression. -Depression of oxydative disintegration as the most extended -principle in the processes of depression. Asphyxiation, fatigue, -heat depression, as a consequence of restriction of oxydative disintegration. -Narcosis. Theories of narcosis. The alteration of -specific irritability and conductivity in narcosis. Depression of -oxydative processes in narcosis. Asphyxiation of living substance -when oxygen is present during narcosis. Persistence of anoxydative -disintegration in narcosis. Increase of the same by stimuli. -Depression by narcosis as a form of acute asphyxiation. Hypothesis -on the mechanism of depression of oxygen exchange by narcotics. -Possibility of combining the facts with the observations of -<i>Meyer</i> and <i>Overton</i>.</td><td class="tar vab"><div><a href="#Page_235">235</a></div></td> -</tr> -</table> -</div> - -<p><span class="pagenum" id="Page_1">1</span></p> - -<hr class="chap x-ebookmaker-drop" /> - -<p class="tac fs120">IRRITABILITY</p> - - -<hr class="chap x-ebookmaker-drop" /> - -<div class="chapter"> -<h2 class="nobreak" id="CHAPTER_I">CHAPTER I<br /> -<span class="title">THE HISTORY OF THE SUBJECT</span></h2> -</div> - - -<div class="blockquot"> - -<p class="pl2hi2"><i>Contents</i>: Introductory. Earliest period. <i>Francis Glisson</i> as founder of -the doctrine of irritability. <i>Albrecht von Haller.</i> The vitalists. <i>Bordeu</i> -and <i>Barthez</i>. <i>John Brown’s</i> system. <i>Johannes Müller</i> and the -specific energy of living substance. <i>Rudolf Virchow’s</i> doctrine of the -irritability of the cell. Discovery of the inhibitory effects of stimulation. -<i>Weber</i>, <i>Schiff</i>, <i>Goltz</i>, <i>Setschenow</i>, <i>Sherrington</i>. <i>Claude Bernard</i> -studies on narcosis. Tropisms. <i>Ehrenberg</i>, <i>Engelmann</i>, <i>Pfeffer</i>, -<i>Strassburger</i>, <i>Stahl</i>. <i>Semon’s</i> speculations on mneme.</p> -</div> - - -<p>Irritability is a <i>general</i> property of living substance but not -exclusively so. Irritable systems also exist in inanimate nature. -What characterizes living substances is not irritability as <i>such</i>, -but an irritability of a specific type. The irritability of the living -system can, therefore, not be studied alone, but as the properties -of a living system are dependent upon each other, so this property -must be considered with the others possessed by a living substance. -In this sense irritability presents a problem of fundamental -physiological importance. For if we could analyze the -irritability of living substance to its essence, then the nature of -life itself would be fathomed. The analysis of irritability of -living substance offers us, therefore, a path to the investigation -of life and herein lies the importance of the study of irritability.</p> - -<p>I wish to follow this path toward the knowledge of the vital -processes and to endeavor to show in these lectures what information -the analysis of irritability and that of the effect of stimuli -can give us of the mechanism of the processes in living substance. -Before doing so, however, I wish to consider somewhat more in -detail the question as to how we have arrived at the conception -of the nature of irritability.</p> - -<p><span class="pagenum" id="Page_2">2</span></p> - -<p>To the thinkers both in the field of physiology and medicine of -ancient and mediæval times the conception of irritability was -quite foreign. Even a comprehension of the nature of stimuli -had not yet begun to crystallize from vague impressions of the -various influences of different agents on the human being. -Nevertheless they knew of such influences of the most varying -kinds upon the human body. The ancients already possessed -a materia medica, founded on the real or supposed influence of -various mineral, vegetable and animal substances upon the organism. -It was also known that heat and cold, light and darkness -had an effect upon disease. They likewise believed in the influence -of certain factors upon the health of man, which in reality -have no effect whatsoever, as the stars and the magnet. But -neither in ancient nor in mediæval times was the state of knowledge -reached wherein generalizations were made from these -agents, which had a real or supposed action upon the organism, -and to combine these to a general conception of stimulation.</p> - -<p>The conception of stimulation and irritability cannot however -be separated.</p> - -<p>The founder of the doctrine of the irritability of living substance -is <i>Francis Glisson</i> (1597–1677), member of the <i>Collegium -Medicum</i> in London and at the same time Professor in Cambridge. -It is a fact also not altogether without interest, that -<i>Glisson</i> at the same time was in a certain sense a forerunner of -those who interpreted nature from a physical standpoint. <i>Glisson</i> -as an anatomist and physiologist was an excellent observer and -experimenter, but the most prominent trait of his character -was his inclination to philosophic observation and analysis of -nature. His “<i>Tractatus de natura substantiæ energetica</i><span class="nowrap">”<a id="FNanchor_1" href="#Footnote_1" class="fnanchor">1</a></span> must, -therefore, be considered as the chief work of his life. In this -voluminous book <i>Glisson</i> develops an entire system of natural -philosophy, which in accord with the character of the philosophy -of that time is unfortunately of an absolutely speculative nature -and which had hardly emancipated itself from the scholasticism<span class="pagenum" id="Page_3">3</span> -of the preceding period of thought. When the ideas of <i>Glisson</i> -are isolated from the wilderness of scholastic phraseology, the -system is somewhat as follows. The basis of all existence, -“<i>substance</i>,” has according to him two general properties, its -“<i>fundamental subsistence</i>,” that is, the essence of its being, and -its “<i>energetic subsistence</i>,” that is, the essence of its activity. To -these are added the properties possessed in specific cases, that is, -its “<i>additional subsistence</i>.” The energetic subsistence forms the -basis of all life. Life is therefore present not only in organic -nature, but in all nature which is characterized by the union of -the general energetic subsistence with the special additional subsistence -of an animal and vegetable nature. In other forms of -life in nature the energetic subsistence is combined with other -special forms of the additional subsistence. The universal -essence of all life, that is the energetic subsistence, has only three -fundamental faculties: the “<i>appetitiva</i>,” the “<i>perceptiva</i>” and the -“<i>motiva</i>.” The <i>modus</i> is the result of a “<i>perceptio</i>,” but the -“<i>perceptio</i>” is not thinkable unless the object has the “<i>appetitus</i>” -to receive the external influence. <i>Glisson’s</i> doctrine of irritability -is based on this conception, which he develops in a second work -already begun before the “<i>Tractatus de natura substantiæ</i>,” but -not finished until later and only published after his death. In -this “<i>Tractatus de ventriculo et intestinis</i>,<span class="nowrap">”<a id="FNanchor_2" href="#Footnote_2" class="fnanchor">2</a></span> <i>Glisson</i> dwells in -detail on the physiological properties of animal structures and -develops for the first time his conception of irritability in the -chapter “<i>De irritabilitate fibrarum</i>.” The “irritability” manifests -itself in the appearance of the alteration of movement, which is -brought about by external influences on the animal structure, for: -“<i>Motiva fibrarum facultas nisi irritabilis foret, vel, perpetuo -quiesceret, vel perpetuo idem ageret.</i>” The fundamental factor of -this irritability <i>Glisson</i> attributes to the “<i>perceptio</i>,” which he distinguishes -as a “<i>perceptio naturalis</i>, <i>sensitiva</i> and <i>animalis</i>.” -The want of clearness produced here by <i>Glisson’s</i> artificial distinctions -and mode of expression is in part removed if we endeavor<span class="pagenum" id="Page_4">4</span> -to transfer his meaning into our present methods of thought. -This distinction would then simply point out the different means -by which the stimuli can reach the irritable structures. The “<i>Perceptio -naturalis</i>” is that which today we should call “direct -response” to stimulation, that is, the excitation of the fiber by -artificial stimuli applied directly to the tissue. <i>Glisson</i> shows -here, that the intestines and muscles in the body immediately -after death and even when removed from the body can be -stimulated to movement by means of corrosive fluids or cold. -The “<i>Perceptio sensitiva</i>” is, according to <i>Glisson</i>, the excitation -of the fibers by external stimuli which act on the intact body as -a whole by way of the sensory nerves. The “<i>Perceptio ab appetitu -animali regulata</i>” finally is the excitation by inner stimuli -proceeding from the brain. The <i>Perceptio naturalis</i> is possessed -by all parts of the body, even the fluids, the bones and the fat. -All of them are irritable. But a “vitale” and a special “animal” -irritability they do not possess to a perceptible degree. These -forms of irritability belong only to the special parts of the body. -Here, however, the distinctions made by <i>Glisson</i>, are quite vague -and contradictory. In his “<i>Tractatus de ventriculo et intestinis</i>” -<i>Glisson</i> sharply distinguishes the “<i>sensatio</i>” from the “<i>perceptio</i>.” -The perceptio in itself is not a sensation, for although individual -organs of the body are irritable, as they all possess a “perceptio,” -they are not in themselves sensitive. The “<i>sensatio</i>,” the sensation, -only arises when the external “<i>perceptio</i>” of the individual -organs combine through the nerves with the internal “perceptio” -of the brain. “<i>Nisi enim percepto externa ab interna simul percipiatur, -non est cognitio sensitiva completa.</i>” Sensitivity is, -therefore, a special faculty, that is only based upon irritability.</p> - -<p>I have treated the views of <i>Glisson</i> somewhat in detail for -on the one hand this seemed to me to be only due to the founder -of the doctrine of irritability, and on the other we have -here for the first time, although in somewhat vague and little -worked out form, the discovery of a general property of all -living substance, and its fundamental importance for the life -of the organisms. One might, therefore, in a <i>certain</i> sense, date -from <i>Glisson</i> the beginning of general physiology, and all the<span class="pagenum" id="Page_5">5</span> -more so, because <i>Glisson</i> from the very first connected the irritability -of the living substance through its possessing universal -energy with the phenomena in nature generally, just as we do -today two hundred years after, on the basis of the modern teachings -of energy.</p> - -<p>It might appear strange that a teaching of such fundamental -importance as that of <i>Glisson’s</i> theory of irritability was not at -once accepted on all sides and further developed. There were -two reasons, however, which prevented this. Firstly, <i>Glisson</i> did -not devote himself to his post of teacher at the University of -Cambridge with any particular zeal and so consequently did not -establish a school of his own, to further work out and develop -his ideas. Secondly, his doctrines were so speculative and difficult -to understand, his differentiations and definitions so artificial -and labored, that it required the greatest effort to penetrate to -his fundamental conceptions and so it happened that <i>Glisson’s</i> -theory of irritability received attention only at a comparatively -late date. Even then, of his speculative theories hardly more than -the name “doctrine of irritability” was adopted. Since the middle -of the eighteenth century this name, however, was destined to lead -to excited controversies.</p> - -<p>The first attempt to give <i>Glisson’s</i> expression “irritability” a -more concrete meaning was made by <i>Haller</i> (1708–1777<span class="nowrap">)<a id="FNanchor_3" href="#Footnote_3" class="fnanchor">3</a></span>. -Unfortunately, though, he confined this conception solely to -muscles, in that he understood by the term irritability “the capability -of the muscles to contract, when stimulated, as the result -of vital force (<i>vi viva</i>).” He, therefore, applied the term “irritability” -to that which we today refer to as “contractility.” -On the other hand he applied the term contractility solely to a -property possessed by other living and dead animal as well as -vegetable matter, elasticity, that is, the capability to resume its -original form after distortion. He makes a sharp distinction -between “irritability,” which manifests itself by a contraction of -the muscles after stimulation by its own vital force (<i>vi viva</i>), -and the “sensitivity,” which is possessed only by the nervous<span class="pagenum" id="Page_6">6</span> -system. “<i>Sola fibra muscularis contrahitur vi viva; sentit solus -nervus et quæ nervos acciperunt animales partes.</i>” By confining -the conception of irritability to a single living substance, the -muscle, <i>Haller’s</i> theory represents a great regression in comparison -to the correct fundamental thoughts of <i>Glisson</i>. This unfortunate -use of the term of “irritability,” “contractility” and -“sensitivity” has opened wide the gates to confusion and misunderstanding. -This confusion was still further augmented by -the fact that the vitalistic school of Montpelier confused the idea -of vital force with that of irritability. In the works of <i>Bordeu</i> -(1722–1776) these views are comparatively clear, if one bears -in mind that he substitutes <i>Glisson’s</i> term of “<i>irritability</i>” with -that of “<i>sensitivity</i>.” He assumes a “<i>sensibilité générale</i>” or a -common property of all living structures, both solid and fluid. -Besides this, each different part has according to him its “<i>sensibilité -propre</i>.” Here in place of the clear conception of irritability -we find one of more or less mythical nature possessing -traces of <i>Stahl’s</i> “anima.” Nevertheless we observe here the -idea that all living organisms possess in common a capability to -respond to stimuli. Even though <i>Bordeu’s</i> differentiation of the -“sensibilité propre” and the “sensibilité générale” is too artificial -and the coexistence of both not justifiable, his discussion of the -“sensibilité propre” shows that he is already on the track of the -characteristics of the effect of stimuli which only later under the -name of “specific energy” was clearly recognized as a fundamental -property of all living substance. On the other hand the -celebrated pupil of <i>Bordeu</i>, <i>Barthez</i> (1734–1806), accepted the -existence of a meaningless vital principle, the “<i>principe vitale</i>,” -governing all vital manifestations. The two forms of vital force -of all living substances, the “<i>forces sensitives</i>” and the “<i>forces -motrices</i>,” were according to his views manifestations of this -vital principle. He differentiates the “<i>force sensitive</i>” into a -“<i>sensibilité avec perception</i>” and “<i>sensibilité sans perception</i>,” -using the term sensibility in the sense adopted by <i>Bordeu</i> and -which today we, with <i>Glisson</i>, call irritability.</p> - -<p>In this way serious thinkers of that time trifled with the words -irritability, sensitivity, contractility, perception. This led to<span class="pagenum" id="Page_7">7</span> -futile conceptions, which equalled the phantasies of the worst -period of speculative philosophy and which in no way led to -progress. Hence it is easy to understand that numerous attempts -were made in those days to reconcile in some way these different -conceptions. An explanation, which was the beginning of further -development, came from England in the works of <i>John -Brown</i> (1735–1788)<span class="nowrap">,<a id="FNanchor_4" href="#Footnote_4" class="fnanchor">4</a></span> a man who was as talented as he was dissolute. -<i>Brown</i> was an independent thinker, not without genius, -whose knowledge in practice and theory, however, was limited. -This combination in his mentality enabled him to observe the -problems somewhat differently than through the glasses of the -usual conceptions of that time. In direct opposition to his teacher -<i>Cullen</i> (1712–1790), one of the leading minds in the medical -school of Edinburgh, who considered irritability only as an -effect of sensibility and pronounced the latter a specific property -of the nervous system, <i>Brown</i> took the standpoint that all living -substance, vegetable as well as animal, in contrast to lifeless -matter, possessed a fundamental property which he designated -as excitability, that is to say, the capability of being stimulated -to specific vital manifestations through external factors or -“stimuli,” in which sensitivity and indeed all mental processes as -well as movement are interpreted as specific effects, which the -“stimuli” produce on the irritable organs. This was an important -advance and from a wilderness of trifling conceptions his observations -led to a clearer knowledge of this subject. But <i>Brown</i> -went even further. In his so-called “theory of irritation,” he -has presented a whole system of responsivity to stimulation, which -in the first chapters of his chief work he expounds with wonderful -clearness. The fundamental principles here established must -be accepted even today. The essential basis of this “theory of -irritability” which he worked out especially for his doctrine of -disease, and which has also played an important part in pathology, -is the following: Every living, that is, excitable system, is continually -influenced by stimuli. The stimuli consist of either external -factors, such as heat, food, foreign matter, poisons, etc., -or inner factors which result from the influence of the activity<span class="pagenum" id="Page_8">8</span> -of one organ upon another. Only as a result of the continual -action of stimuli is life maintained, in that the stimuli produce -continual “excitement” in the irritable substance. The degree of -irritability differs in various plants, animals, in different structures -of the body, and even in the same individual at different -times under different circumstances. The strength of the -“excitement” depends on the one hand upon the degree of irritability, -and on the other upon the strength of the stimulus. The -irritability itself is influenced and changed by the action of the -stimuli. If the stimuli are too strong and are of prolonged duration, -the irritability diminishes as a result of exhaustion; if weak -stimuli act during a prolonged time, the irritability increases. -The healthy organism has a mean degree of irritability. Disease -occurs when this state is altered by <i>strong</i> stimuli or by an -<i>absence</i> of stimulation. Disease and health, therefore, differ not -qualitatively but only quantitatively. It is here seen that we have -the first attempt at a systematic interpretation of the effects of -stimulation, and it is astonishing how sharply and successfully -<i>Brown</i> has pointed out the foundations of this important field. -He has in this way not only amply compensated for the great setback -in the history of the teaching of irritability produced by the -confusions of conceptions created by <i>Haller</i> and the vitalists, but -also placed the whole of the physiology of stimulation on a firm -foundation upon which it is possible to build further. Though it -is true that many of his special theories, in particular those on -nature and the origin of disease, are quite erroneous, still a just -critic must judge work in relation to the period in which it was -written, and I question if at the present day the science of medicine -does <i>not</i> contain teachings which in a hundred years will -also prove untenable.</p> - -<p><i>Johannes Müller</i> (1801–1858) then added an important stone -to the building up of our knowledge of irritability. This was the -clear recognition of the <i>specific energy</i> of living substances. We -have already found the germ in <i>Bordeu’s</i> term “<i>sensibilité propre</i>” -or “<i>sensibilité particulière</i>.” <i>Brown</i> was also of the opinion that -different living objects possessed different types of irritability -and that excitation of their special functions was not dependent<span class="pagenum" id="Page_9">9</span> -upon the <i>kind</i> of stimulus acting upon them. <i>Johannes Müller</i>, -grasping the idea hidden in this presentation, transformed it into -a clear and fundamental conception. Already in the work written -in his early years treating of optical illusions he says<span class="nowrap">:<a id="FNanchor_5" href="#Footnote_5" class="fnanchor">5</a></span> “It is -immaterial by which means the muscle is stimulated, whether -by galvanism, chemical agents, mechanical irritation, inner organic -stimuli or sympathetic response from quite different organs; -to every means by which it is stimulated and an effect produced, -it responds by movement. Movement is, therefore, the -<i>effect</i> and the <i>energy</i> of the muscle at the same time.” “Thus -it is throughout with all reactions in the organisms.” “The sensory -nerve, responding to any stimulus of whatever kind, has its -specific energy; pressure, friction, galvanism and inner organic -stimuli produce in nerves of sight that which is peculiar to them, -light sensation; in the nerves of hearing, that which is peculiar -to them, sound sensation; and in the nerves of touch, touch -sensations. On the other hand, everything which affects a secretory -organ produces change of the secretion; that which affects -the muscle, movement. Galvanism is not superior to any other -methods, of whatever kind, which can bring about stimulation.” -And in his handbook of physiology <span class="nowrap"><i>Johannes Müller</i><a id="FNanchor_6" href="#Footnote_6" class="fnanchor">6</a></span> formulates -the law of specific energy for the sensory structures briefly in the -following words: “The same external factor produces different -sensations in the different senses according to the nature of each -sense, namely, the sensation of the particular sensory nerves; -and the reverse: the characteristic sensations peculiar to every -sensory nerve can be produced by several internal and external -influences.” This doctrine of the specific energy of the sense -substance possesses an importance which extends far beyond the -domain of the physiology of stimulation, for it forms the basis -on which the whole theory of human knowledge must be built -up, no matter how it may be constructed in detail.</p> - -<p>As <i>Johannes Müller</i> already clearly emphasizes, it is here not<span class="pagenum" id="Page_10">10</span> -the question of a law confined to the sense substance, but one -that applies to all living substances. Every living substance has -its “specific energy,” that is, its characteristic vital phenomena -and this is produced by stimuli of the most varied kind. This -doctrine received an extension of inestimable value for its future -development by the great discovery of <i>Schleiden</i>, that the cell is -the elementary building stone of the plant organism. Subsequently -<i>Schwann</i> at the instigation of <i>Schleiden</i> made further -investigations and found that this discovery applied also to the -animal organism. Irritability having been recognized as a general -property of living substance, it followed that, after the foundation -of the cell doctrine, every cell must possess irritability and -have its own specific energy. It now became necessary to study -the manifestations of irritability of the cells in their specific form. -Strange to say, this was done at an earlier date in pathology than -in physiology. Indeed, since the time of <i>Brown</i> the study of irritability -was furthered far more by pathology than by physiology. -The chief reason for this is probably the great practical interest -that the investigation of disease possesses, <i>Brown</i> having already -quite correctly ascribed the existence of disease to the relations -of the organism or its parts to stimuli. <i>Rudolph Virchow</i> then, -after the establishment of the cell doctrine, arrived at the momentous -conclusion, that disease must be considered as reactions of -the body cells to stimuli. In his epoch-making “Cellular pathologie,<span class="nowrap">”<a id="FNanchor_7" href="#Footnote_7" class="fnanchor">7</a></span> -he has carried out this idea in a classical manner. By irritability -<i>Virchow</i> understands “a property of the cells, by virtue -of which they are set into activity, when affected by external -influences.” There are, however, <i>various</i> kinds of actions which -can be brought about by external influences. But essentially there -are three kinds. The effects produced are functional, nutritive, -formative. The result of excitation, or if one will, of stimulation -of a living part, can, therefore, according to circumstances, be -either merely a functional process, or there can be a more or less -intense nutritive activity produced without the function being -necessarily at the same time activated, or finally, it is possible<span class="pagenum" id="Page_11">11</span> -that a process of formative change may occur which produces -new elements in greater or less numbers. <i>Virchow</i> touches here -for the first time upon a question of extraordinary moment, the -important bearings of which have only now begun to be recognized -and seriously considered. We now know, for example, -that the functional excitation can be separated to a certain degree -from the cytoplastic excitation of the muscle. If the muscle is -acted upon by functional stimuli, the excitation takes place mainly -in the form of functional metabolism, nitrogen-free substances -are broken down in increased quantities, whereas cytoplastic -metabolism, which produces more profound alteration in the living -substance, and which goes so far as to bring about a breaking -down and building up of the nitrogen containing atom groups, is -hardly at all increased. It would be an error, however, to look -upon these different kinds of metabolism as quite independent. -Considering the close correlation which all the phases of metabolism -bear to each other, this idea cannot well be entertained. -If, however, we question in what manner, for instance, the -functional and the cytoplastic metabolism are linked together, -we have a problem before us which does not belong to the past, -but to the present and future. Indeed, <i>Virchow</i> seems already to -have felt that a sharp division between the different phases -and parts of functional metabolism in the cell does not exist, for -he says: “It is true that it cannot be denied that, especially between -the nutritive and formative processes and likewise between -the functional and nutritive, intermediate gradations occur.” Still -they differ essentially in their characteristic action and in the -internal alterations which the stimulated part undergoes, depending -on whether it functionates, nourishes itself, or is the seat of -special growth. Disease consists of the influence of stimuli upon -these physiological processes. The law of the specific energy of -living substance is as clearly expressed in functional disease as it -is in the physiological effects of stimuli. The pathological disturbance -of function is purely quantitative, “nowhere is there a -qualitative divergence.” The function exists or it does <i>not</i> exist. -If it is present, it is either strengthened or weakened. This gives -the three fundamental forms of disturbance: absence, weakening<span class="pagenum" id="Page_12">12</span> -and strengthening of the function. No function other than the -physiological, even under the greatest pathological alterations, -exists in any <i>structure</i> of the body. “The muscle does <i>not</i> perceive, -the nerve moves no bone, the cartilage does not think.” -In this way <i>Virchow</i> rediscovered in the domain of pathology -the law that his great teacher, <i>Johannes Müller</i>, had already -clearly established in the field of physiology. But this law can -no longer be applied to all pathological disturbances of the nutritive -and formative activities of the cell. Here processes occur -which do not consist of a quantitative change of the normal -phenomena, but in the appearance of wholly foreign states, as -in the case of amyloid degeneration or heteroplastic tumors. -The question today and for the future arises, therefore, as to -where the limits of the validity of the law of the specific energy -of living substances are to be placed, a question closely connected -with the other before mentioned, of the relations between -functional and cytoplastic metabolism.</p> - -<p>By means of cell pathology <i>Virchow</i> has laid the foundations -upon which our modern medical attitude is built and which must -remain essentially forever the basis of all future medical thought. -Certain critics, lacking in appreciation of the interrelations -between things and ignoring the safer and established knowledge, -have considered, in view of the unfoldings of the researches on -immunity and of serum therapy, that the time of cell-pathology -was <i>passed</i> and must be replaced by the humoral-pathological -teaching. These ultramodern critics, however, have here completely -ignored the fact that, on the one hand, the life of our -body is built up from the life of all of the contained cells, for -life in our body exists only in the cells; and on the other, a fact -not considered by them is that the components of the body fluids -originate from vital activity of the cells either directly or indirectly. -No result, indeed, of present serology can alter in the -least degree the fact that every disease represents only a disturbance -of the physiological processes of cell life of the organism -and the harmony in their combined workings. Indeed the more -recent observations of serology and chemotherapy are so little -opposed to cell-pathology that they are in fact only possible when<span class="pagenum" id="Page_13">13</span> -based on the latter. They are only comprehensible then from -the unfoldings of cellular pathology.</p> - -<p>Until quite recently all those effects of external factors on the -living substance which consist in excitation, that is, in an increase -of their specific vital processes, have always stood in the foreground -of all researches and observations on irritability. It was -gradually, however, more and more recognized that the depressing -influence of stimuli played a great rôle in the vital process of -the organism. <i>Brown</i> was acquainted with exhaustion produced -by stimuli, and the discussion of “asthenic” diseases, in which the -irritability was reduced, occupied an important place in his pathology. -That, however, in the normal activities of the organism -such depression or lessening of vital manifestation could result -from the influence of stimulation, first became clear after the -brothers <span class="nowrap"><i>Weber</i><a id="FNanchor_8" href="#Footnote_8" class="fnanchor">8</a></span> in 1846 discovered the inhibitory effects of the -galvanic stimulation of the vagus upon the heart.</p> - -<p>Since then the inhibitory processes in nerves have been frequently -investigated by <i>Schiff</i> (1823–1896), <i>Goltz</i> (1834–1901) -and others, who gave us a theory concerning the same. Only -a small number of inhibitory processes were known at that -time, as for instance the inhibition of the croak reflex of the -frog, or the inhibition of the grasp reflex during copulation -of these animals through skin stimuli, and a few other cases. -They regarded the inhibitory nervous processes as a special state, -of which the inhibition of the heart through the vagus was the -best illustration. Further, the Russian physiologist <i>Setschenow</i> -succeeded by directly stimulating certain parts of the central -nervous system, especially the optic lobes of the frog, in producing -inhibition. It was, therefore, frequently assumed, as <i>Setschenow</i> -did, that in the brain there exist special inhibitory centers, just -as there are motor centers. This view was later shown to be -untenable. It is only quite recently, and especially since <i>Sherrington</i> -has shown that inhibition plays a part in all antagonistic -muscle movements, that we have obtained a broad and more -thorough understanding of the inhibitory processes in the life<span class="pagenum" id="Page_14">14</span> -of the organism, and a physiological explanation of this important -group of activities of the central nervous system. This inhibitory -effect of stimulation, brought about by the involvement of the -central nervous system in the normal organism, was studied side -by side with the depressing effects of stimulation. <i>Claude Bernard</i> -(1813–1878<span class="nowrap">)<a id="FNanchor_9" href="#Footnote_9" class="fnanchor">9</a></span> first discovered that the excitation of all living -substance could be depressed or totally suspended through the -influence of certain anæsthetics, such as ether or chloroform. -By a series of experiments, as simple as they were convincing, -the French scientist showed that irritability could be depressed -in mimosa leaves, the growth of germinating plant seeds and the -ferment action of yeast cells stopped, likewise the disintegration -of the carbon dioxide in the cells of the green leaf, as well as the -development of the egg cells, and also the movements of the -animal organism and the sensations of man. By this means he -recognized that not only does all living protoplasm possess irritability, -but that it can also by means of certain substances be put -into the condition of “anæsthesia,” a state dependent upon a -change of the protoplasm, which he termed “semi-coagulation.” -Finally, besides the more apparent processes of excitation and -those less so, belonging to the group of inhibition and depression, -in the last century the knowledge of the subject was greatly increased -by the addition of another group, which recently in consequence -of various reasons has met with particular interest. These -being effects of stimuli on the direction of movements of motile -organisms, it became more and more recognized that these curious -manifestations of irritability, which appeared to have such a surprising -likeness to the mysterious attraction and repulsion in the -sphere of electricity and magnetism, occur universally in the vegetable -as well as in the animal world. These movements are of -the greatest biological importance for the obtaining of food, -propagation, protection against disease, etc. Botanists have long -known of the geotaxis of the roots and stems of plants, the -heliotaxis of their leaves and flowers and of the thigmotaxis -of their tendrils. Likewise the phototaxis of freely moving<span class="pagenum" id="Page_15">15</span> -protistæ had been often observed, especially by <span class="nowrap"><i>Ehrenberg</i><a id="FNanchor_10" href="#Footnote_10" class="fnanchor">10</a></span> of -Berlin, well known for his researches on infusoria. Then -<i>Engelmann</i>, <i>Pfeffer</i>, <i>Strassburger</i>, <i>Stahl</i>, and many others -discovered and studied more carefully the facts concerning -chemotaxis, thigmotaxis, rheotaxis, geotaxis, phototaxis, etc., -of bacteria, motile spores, rhizopoda, and so on. The question -arose if one should regard this singular behavior of the unicellular -organisms as an expression of conscious sensations, discrimination -or will. This view was as determinedly denied on the one hand -as it was accepted on the other. Whilst even today certain -scientists still consider the reactions of the unicellular organisms -as a manifestation of conscious sensation, discrimination or -will, others look upon them as unconscious reflex reactions of -cell organism, taking place as purely mechanically as the spinal -cord reflexes of vertebrates. This divergence of opinion would -have practically no value for the development of our knowledge -of irritability had not here, as in the case of the relations between -the mental and physical processes in man, the view been entertained -with more or less fervor, that at some stage or other in -the chain of the purely physiological processes of responsivity, -an intangible factor had been introduced which was considered -as the essential “cause” of the peculiar reactions to stimuli. It -is not here the place to enter into the question if, and in what -degree, animal psychology may be a field of scientific research. -Even if one looks upon conscious processes as effects of stimulation, -in both lower animals and in man, in no case should one -assume them to be factors of an essentially different nature, -interrupting the chain of the mechanical reactions; neither should -one consider the particular characteristic responses observed in -unicellular organisms as effects of non-mechanical “causes.” As -a result, a mysticism, in reality quite foreign to it, would be introduced -into physiology. As a matter of fact the physiological -investigations for the tropic reactions of stimuli, which have -been carried out in great number since the end of the eighties, -have shown more and more clearly that this peculiar behavior -of unicellular organisms towards unilateral stimuli is produced<span class="pagenum" id="Page_16">16</span> -by a comparatively simple mechanism. The analysis of this -shows a difference in the intensity of the exciting or depressing -effect produced by the stimulus. The stimulus exerts its influence -unequally upon the specific activity of the motor elements of -different parts of the surface of the cell body. This difference -in response causes the axis of the freely moving organism to -assume a different direction in which to move. It is <i>compelled</i> -to move in a definite direction and so, in this field, the apparently -mysterious attraction and repulsion of living organisms toward -stimuli has, by means of the most simple analysis, been robbed -of its mystical character.</p> - -<p>Finally, I should like to touch briefly upon a view of the irritability -of living substance which has recently been brought forward -by <i>Semon</i><span class="nowrap">.<a id="FNanchor_11" href="#Footnote_11" class="fnanchor">11</a></span> It assumes the proportions of a whole system -and is proclaimed as a basis for the comprehension of organic -phenomena. It originated with an idea which <span class="nowrap"><i>Hering</i><a id="FNanchor_12" href="#Footnote_12" class="fnanchor">12</a></span> developed -many years ago and which later was accepted by <i>Haeckel</i><span class="nowrap">,<a id="FNanchor_13" href="#Footnote_13" class="fnanchor">13</a></span> -namely that heredity is a species of memory of the living substance. -<i>Semon</i> attributes to living substance, in contrast to non-living, -a “<i>Mneme</i>.” By “<i>Mneme</i>” he understands the capability -of living substance to assume, through the influence of a stimulus, -a permanently altered condition. The latent alteration resulting -from the stimulus he terms “<i>Engramm</i>.” These “<i>Engramms</i>” -can later, however, not only be activated by the reapplication of -the original stimulus, but also by other stimuli, so that the state -of excitation once brought about by the original stimulus reappears. -<i>Semon</i> calls the reproduction of the state of primary -excitation by a later stimulus “<i>Ekphorie</i>.” A great number of -other new word formations, such as “<i>chronogene Engramme</i>,” -“<i>phasogene Ekphorie</i>,” “<i>mnemische Homophonie</i>,” “<i>mnemisches -Protomer</i>” and countless others are supposed to serve for the -better understanding of a series of special facts, chiefly in the<span class="pagenum" id="Page_17">17</span> -domain of the processes of heredity. That which is termed -“<i>Mneme</i>” and “<i>Engramm</i>” is not further analyzed. <i>Semon</i> -expressly declines to discuss the kind of alterations in which -the physical or chemical nature of an “<i>Engramm</i>” consists. -Hence physiological analysis has not been advanced in any -way by <i>Semon’s</i> new formation of words applied to long-known -facts. With a series of new expressions the originator -of the “<i>Mneme doctrine</i>” deceives himself, as well as a number of -his readers not endowed with the critical faculty, into supposing -that he has achieved a serious analysis. Of such, however, there -is not a trace. As can be conceived, this way of treating the -manifestations of life has met with no further attention from the -physiological side. For indeed, what physiologist would consider -that the fact of muscle responding by a contraction to an -induction shock, or to any other stimulus, is sufficiently analyzed -by the explanation that we have the “<i>Ekphorie</i>” of a state of -excitation that was once previously produced by an original -stimulus of some unknown kind, and of which the living substance -of the muscle, in consequence of its “<i>Mneme</i>,” has retained -a latent “<i>Engramm</i>”? Here the deep gulf is apparent which -exists between the demands of a physiological analysis and the -futile explanation of the mneme doctrine. Physiological investigation -must reject such a manner of treating its problems.</p> - -<p>With this the history of the doctrine of irritability enters into -its present phase of development. To future research remains -then the problem of further analyzing irritability, this common -property of living substance, and finally rendering it into its simplest -chemical and physical components. This last goal can only -be approached very gradually, step by step. With the analysis of -irritability we shall investigate life itself. In the following lectures -it will be my endeavor to show how far, with our present -knowledge, we can penetrate by this path into the great secret.</p> -<hr class="chap x-ebookmaker-drop" /> - -<div class="chapter"> -<p><span class="pagenum" id="Page_18">18</span></p> - -<h2 class="nobreak" id="CHAPTER_II">CHAPTER II<br /> -<span class="title">THE NATURE OF STIMULATION</span></h2> -</div> - -<div class="blockquot"> - -<p class="pl2hi2"><i>Contents</i>: Principles of scientific knowledge and research. Origin and -meaning of the conception of cause. Cause and condition. Criticism -of the conception of cause. The conditional point of view. Conception -of cause. The conditional point of view applied to the investigation -of life. Conception of vital conditions. Definition of the -conception of stimulation.</p> -</div> - - -<p>The common problem of all scientific research is the investigation -and formulation of natural laws. The assumption of a -unity in the happenings and of existence in the world, in accordance -with definite laws, forms the indispensable foundation of all -scientific study and is fully justified by experience. Experience -has taught us, as a result of innumerable individual observations, -the existence of such an accordance, whereas in not a single -instance has it been shown that this is not the case. We are thus -justified in assuming without further discussion that every scientific -research, every new problem which we approach, is likewise -founded on this unity of occurrences in accordance with natural -laws. Only on the firm basis of this assumption has scientific -investigation a purpose, and every success is a new proof of this. -There is an unanimity of opinion concerning this among scientific -investigators in all fields.</p> - -<p>Not such complete agreement, however, exists in regard to the -question by what symbols of human thought and speech these -laws can be described in part as well as <i>in toto</i>, so that existing -laws can not only be <i>fully</i> and conclusively defined, but at the -same time without the use of <i>superfluous</i> terms. According to -<i>Ernst Mach</i>, thought is an adaptation to facts. Our speech is<span class="pagenum" id="Page_19">19</span> -simply a method of expression of our thoughts and indeed the -most satisfactory form we have. We must, therefore, use those -symbols which are most closely adapted to facts as the most -precise expression of these existing laws. What forms of -expression have we?</p> - -<p>It might appear that a discussion of this fundamental question -has not a close connection with our special subject of physiology -of stimulation. This, however, is not the case. Indeed, it is an -irremissibly previous requirement not only for the elucidation, -but also for the understanding itself in this particular field. We -<i>could not</i> come to a clear understanding in this field without -such analysis. The interpretation of the unity of being and happenings -in accordance with natural laws, which today is widely -accepted in the scientific world as the only exact one, implies the -assumption of a “<i>causation</i>” according to which things are explained -by the law of “<i>cause</i>” and “<i>effect</i>.” <span class="nowrap">I<a id="FNanchor_14" href="#Footnote_14" class="fnanchor">14</a></span> have already on -various occasions taken the opportunity to criticise this view and -to show the error and confusion to which it leads. I should like -here to enter somewhat more in detail into the reason for this -criticism. It is particularly directed against the scientific use of -the term “<i>cause</i>” on the basis of our best-known theoretical principles. -It is clear that all scientific observations and explanations -are founded on experience. Can it be said that the conception -of “cause” originates from experience?</p> - -<p>We can say with absolute certainty that the conception of -cause dates from prehistoric times. Its beginning reaches back -to the stone age, at least to neolithic, possibly to palæolithic culture. -This is demonstrated by the careful reconstruction of these -prehistoric races based on a critical comparison of the remains -of their culture with that of primitive races living today. The -ideas of these primitive races show an inclination to an extraordinary<span class="pagenum" id="Page_20">20</span> -degree to explain all happenings in the world anthropomorphously. -All happenings in surrounding nature are given -the same origin as the activities of man himself. To man, on -this plane of phantastic religious speculation, all events in nature -appear as acts of the will of invisible powers, which, having -originally proceeded from the souls of dead human beings, think, -feel and act exactly as <i>he does</i>. This anthropomorphic conception -of the occurrences in the surrounding world is one of the many -conclusions which ensue from the supposition of an invisible -soul, which can be separated from the body. It was this conception -which gave the impetus for the transition of human -thought from the era of the naïvely practical to the era of the -theoretical spirit in that far removed age. In this anthropomorphic -transference of personal subjective impulses of will to -the objectively observed events of the surrounding world, lies -the origin of causal conception, which since then has been generally -used as the explanation of the happenings in the world. -One cannot assert that the formation of the conception of cause is -purely a product of <i>experience</i>, but rather a result of <i>naïve speculation</i>. -Even if a later evolution of human thought shows a continued -endeavor to dismantle the conception of cause of its primitive -trappings and to modernize, as it were, its outer appearance, -we still find today many inner components clinging to it, which -do not agree with the strict demands of critical scientific exactness, -demands which must particularly be made concerning a -conception which has been given such fundamental importance -in theoretical knowledge.</p> - -<p>I wish to observe here, however, that the conception of cause, -even though more or less unconsciously so, is still the remains of -a part of the old anthropomorphic mysticism carried over into -our own times. This shows itself especially in the conception -of <i>force</i>, which is nothing more than a form of the conception -of cause. Force is the cause of movement. One has here in -anthropomorphic manner transferred the action of the <i>will</i> of -man, which produces movement of the muscles, into lifeless -nature. The force of the sun attracts the earth, that of the magnet -attracts iron, etc. In short, one has introduced a mysterious<span class="pagenum" id="Page_21">21</span> -unknown factor instead of being content with the simple description -of facts, such as <span class="nowrap"><i>Kirchhoff</i><a id="FNanchor_15" href="#Footnote_15" class="fnanchor">15</a></span> has advanced in the field of -mechanics. Although of late natural science has also dispensed -more and more with conception of force as a means of explanation, -it is still today not wholly done away with. That which -applies to the conception of force is likewise true of the conception -of cause.</p> - -<p>Another point concerning the application of the conception of -cause seems to me, however, to be of much more importance, -namely that a single cause is held responsible for the taking -place of a process. One endeavors to explain a process in general -by seeking for its “cause.” The cause being found, the -process is considered as fully accounted for. This idea is not -only widely spread in everyday life, but is even found frequently -in natural science, especially in biology, although here, it should -be known, the processes are decidedly more complicated. The -search for the “cause” of development, for the “cause” of heredity, -for the “cause” of death, for the “cause” of the respiration, -for the “cause” of the heart beat, for the “cause” of sleep, for -the “cause” of disease, etc., was for a long time and frequently -even today a characteristic of biological investigation. As if -such a complicated process as development, death or disease -could be explained by a single factor! In reality, one has -obtained very little as a result of the analysis of a process by -discovering its cause; and in addition the false impression arises -that through the finding of this one factor the process has been -definitely explained. It has been generally recognized in the -natural sciences in recent times that no process in the world -is dependent upon one single factor and attempts have been made -to give this fact more consideration.</p> - -<p>It is the custom at the present time to hold the view that every -process or state is brought about by its <i>cause</i>, but that a series of -<i>conditions</i> are also necessary to the production of the process. -Such a view, however, which considers that two different factors -existing at the same time are necessary to the accomplishment of<span class="pagenum" id="Page_22">22</span> -every happening or state, namely, the cause and the conditions, -leads to new difficulties, for then, upon a more exact analysis -arises the question: Which is the cause and what are the conditions? -It is very soon found, however, that this does not permit -of any strict differentiation, as the two conceptions can not be -sharply separated. This difficulty was brought to my notice with -particular force during an animated discussion with a friend -and colleague about twenty years ago, which I have always -remembered. I had observed at that time the dependence of -pseudopod formation of amœboid cells on the oxygen of the -medium, and had found that the expansion phase of protoplasmic -movement, that is, the extension of pseudopods, the -centrifugal flowing of the protoplasm into the surrounding -medium and with this the enlargement of the surface of the cell -body, only takes place when oxygen is contained in the surrounding -medium and never occurs in its absence. Being at that -time wholly under the influence of the conception of cause, I -believed that oxygen was the cause of the formation of the -pseudopods. To this my friend made the objection: “Yes, I -quite acknowledge the fact of the dependence of the formation -of pseudopods on oxygen, but what informs me that the oxygen -is really the <i>cause</i>? It might be simply a necessary <i>condition</i>.” -This objection led to a long debate, which ended, however, without -our being able to agree. We were not in a position to distinguish -between the conception of cause and that of condition, -and at that time the idea <i>did not occur</i> to us to emancipate -ourselves from the conception of cause deeply implanted in us -as a result of our training. In fact, one is greatly embarrassed -if one attempts to sharply distinguish by a definition the conception -of cause and that of condition. A condition is a factor on -which a state or a process is dependent for its existence or its -taking place. To the conception of condition belongs, besides -the factor of <i>relation</i>, that of <i>necessity</i>. Every condition is necessary -to the existence or taking place of this state or process. -Without the condition in question the state or process does not -occur. The same must be demanded for the conception of cause. -No state exists, no process takes place, without its cause. The<span class="pagenum" id="Page_23">23</span> -cause then has itself the specific character of a condition, it is -itself a condition. Has it perhaps then some specific peculiarity -in contrast to the other conditions, which would give it a prominent -place? Experience teaches us that nothing, that is to say, -no state or process in the world, is dependent upon a single factor -alone. There are always numerous factors which bring about -the state or process. Would it be possible to distinguish which -of these particular conditions is of the greatest importance?</p> - -<p>First of all, it must here be taken into consideration that the -importance of a condition is not one which is capable of increase -or decrease, for the simple reason that necessity, which forms -an essential component of the conception of cause cannot be -varied. A factor cannot be <i>more</i> than necessary for the existence -of a state or the taking place of a process. If, however, -it is less than necessary, then it is not necessary at all, and -the state or process exists also without it, that is to say, the -factor is not a condition. In other words: <i>all conditions for a -state or process are of equal value for its existence, as they are -all necessary</i>.</p> - -<p>If one attempts to prove by means of concrete examples this -statement obtained by purely logical deduction—a control which, -considering the experimental nature of modern thought, never -should be neglected even in the simplest of reasoning—it might -appear that an objection could still be made against its general -validity. From various instances it might be concluded that -there are conditions, which as such are not absolutely necessary -for a state or process, but can be replaced by other factors. An -example may serve to make this clear. I pour diluted hydrochloric -acid on powdered carbonate of sodium, and carbon dioxide -is set free. The addition of hydrochloric acid is here a condition -for the liberation of the carbon dioxide. Without the presence of -the hydrochloric acid the process does not occur. Nevertheless -I can substitute diluted sulphuric acid for the hydrochloric acid. -Here it would appear that one condition can be replaced by -another. But one must not be deceived. A closer observation -soon shows that the process has not been sufficiently analyzed -if we look upon the addition of hydrochloric acid as a condition<span class="pagenum" id="Page_24">24</span> -for the liberation of carbon dioxide. It is not the presence of -hydrochloric acid or sulphuric acid, as such, which is a condition -for the process, but rather the separation of the sodium atoms -from their combinations with the oxygen in the molecule of the -carbonate. This reaction can occur as a partial component in -very different complexes of processes. Or to quote another -example, taken from the subject with which we are especially here -concerned. I allow an induction shock to act on the nerve of -a nerve muscle preparation of the frog. The muscle contracts. -The electric stimulus is the condition for the muscle contraction. -But I can substitute for the induction shock a mechanical -stimulus by sudden pressure of the nerve. The muscle again -contracts. The analysis again shows that the induction shock as -such was not the condition for the muscle contraction, but the -excitation of the nerve which it produced and which is conducted -as a specific impulse to the muscle. This excitation of the nerve -can, however, be induced by very different kinds of processes, -namely, by all processes which possess in common the condition -that they suddenly increase certain disintegration processes in the -living nerve substance. Indeed, the further analysis of the whole -process shows in addition that the nerve impulse as such likewise -does not form a condition for the contraction of the muscle, but -it first of all produces the necessary condition for the muscle -contraction by suddenly greatly increasing certain chemical processes, -which take place in the living substance of the resting -muscle. The nerve impulse can, therefore, also be replaced by -other processes, if only these contain the condition for an increase -of disintegration of the muscle substance, as in the case of the -direct stimulation of the curarized muscle, where the influence -of nervous impulses is totally eliminated. In a further analysis -of this process we should penetrate even more deeply into the -differentiation of the individual constituent processes and the -isolating of the special conditions on which each link in the chain -is dependent.</p> - -<p>Such an analysis then shows us the following: Every thing, -every state or process, is a complex of numerous components, of -which <i>one</i> always conditions the other in the manner that the<span class="pagenum" id="Page_25">25</span> -individual conditioning components are themselves in their turn -contained as constituents of other complexes and are conditioned -here again by other factors. These factors in themselves -as such are not directly necessary to the taking place or existing -of the special component and can, therefore, be replaced by -others. Closer observation shows that there is a constant interdependence -between all things in the world. <i>Every</i> thing in the -world is <i>indirectly</i> dependent upon <i>every other</i>, although often so -remotely that we are not able to trace the connection. Absolute -things, completely isolated and independent of others, <i>do not</i> exist -in the world. In observing and studying complexes individually, -we must not forget that we only <i>think</i> of them as isolated from -the great eternal coherence, from which they are in reality not -separated. The conception of condition, however, only then has -meaning, if we refer to it in connection with the direct dependence -of one factor upon another. Nevertheless if we understand -by conditions those which are connected by multitudinous intermediate -components, then we would render the conception of -conditions useless. For if every thing in the world were the -condition for every other, the conception of relation would lose -its value in special states or processes. Should the conception of -condition have a meaning in regard to a <i>certain</i> state or process, -then we should only look upon <i>that</i> part of a complex upon which -the other is <i>directly</i> dependent as a condition. When, however, -we meet with a factor for a process or state, which can apparently -be replaced by another factor, we have not carried the -analysis far enough. Upon deeper penetration into the subject, -it is found that the essential condition for the process, which -exists, is a component common to both factors, one of which in -consequence can replace the other.</p> - -<p>It is the task of all scientific research to penetrate deeper and -deeper into these relations, these connections and the order of -succession of states and processes and to separate them into -their individual components, and in this way gain a more thorough -knowledge of the constancy of existence and happenings in -the world.</p> - -<p>This analytical process, it is true, only advances very gradually,<span class="pagenum" id="Page_26">26</span> -and we must accept for the present, especially in the complex -biological processes, that a whole complexity of members -appear conditioned, and that a complex aggregate is a condition -of the whole process. We are not yet in the position to -define the special components of the constituent processes. It -is only step by step that we are able to differentiate the necessary -from the accessory parts in these complexes. However, we are -here only concerned for the present with a purely theoretical -question and we may be permitted to say: If we maintain that -the conception of condition has as an integral part the element -of necessity and of relation to a special thing, then there are no -substituting conditions. For then every condition for a state or -process is of equal value. There is no justification to give more -prominence to one condition and place it in the position of being -the “<i>cause</i>.”</p> - -<p>If the cause is elevated, then it is done from some superficial -motive. This is confirmed by a glance at the practical use of the -term cause. The cases in which the cause is always at once -clearly recognized and named without doubt or hesitation are -those where a new factor is added to an already existing system -of conditions, which bring about a process. When such a process -is produced, the last added condition is considered as “cause.” -A shock acts on an explosive body, the body explodes: the shock -is considered the cause. An induction shock acts on a muscle, the -muscle contracts; the induction shock is looked upon as the cause -of the muscle contraction. To regard only the last added condition -as being of especial importance to the taking place and the -explanation for a process is, however, a standpoint which could -satisfy only the most superficial of observers.</p> - -<p>In a scientific investigation such methods should play no rôle. -For to every careful observer it must appear quite clear from the -beginning, that the previously existing conditions have as great -a value for the taking place of the process and its explanation as -that last added.</p> - -<p>The induction shock would not have produced the characteristic -effect had not the other conditions been already previously -combined, had not certain special atoms in the molecule of the<span class="pagenum" id="Page_27">27</span> -explosive combination in consequence of former processes -assumed quite a peculiar labile position, had not in the evolution -of the muscle in the growth and metabolism certain combinations -been formed, and certain chemical processes taken place.</p> - -<p>Therefore if I do not analyze these previously existing processes -and the conditions brought about by them in the system -of the explosive substances or the muscle, and simply know the -condition added last, then I have learned nothing of the process -itself, have <i>explained</i> nothing. The time of application of a new -condition does not justify in any degree the assignment of a dominant -position to a factor. But more: in many cases there is not -a question at all of the <i>addition</i> of a process to an existing state, -but rather of the <i>simultaneous</i> interference of two or more processes. -Several conditions can appear at the <i>same</i> time. In other -cases the sequence of the combination can be reversed. Which -then is the cause? Has the process several causes, or has it no -cause? Here one sees plainly to what absurd results it leads if -time alone is used as a basis of the conception of cause. To -illustrate this I return to the case of the liberation of carbon -dioxide from carbonate of sodium. I place anhydrous carbonate -of sodium in a beaker and add hydrochloric acid. The carbon -dioxide escapes. Here the addition of hydrochloric acid would -be assumed to be the cause of the freeing of the gas. Then I put -hydrochloric acid in a beaker and add carbonate of sodium. The -same process takes place, but now the addition of <i>carbonate of -sodium</i> would be considered the cause for the formation of gas. -Now I put both simultaneously into a beaker. Again the same -process. Which was now the cause? Has the process now <i>two</i> -or has it <i>no</i> cause at all? Finally I put anhydrous carbonate of -sodium and hydrochloric acid in ether solution into the beaker. -The formation of gas does not take place, and <i>yet</i> both causes for -this formation of gas are present, the carbonate of sodium and the -hydrochloric acid. Only when I add water to the mixture does the -formation of carbon dioxide take place. Here water would be -considered the cause. Hence every condition would be in succession -the cause for one and the same process. Under some -circumstances the same process would have <i>several</i> and in others<span class="pagenum" id="Page_28">28</span> -<i>no</i> cause at all. It is scarcely necessary for further comments -upon the value of the conception of cause for the scientific explanation -of a state or process. If we do not seek to introduce -into exact science the antiquated symbols which have become useless -and belong to a primitive phase of development of human -thought, there cannot be a moment’s doubt that a strict scientific -analysis in whatever field of investigation it may be carried on can -consist only in the study of all the conditions concerned in a state -or process. If this is done, then the work of exact research is -accomplished. Further problems do not exist. The use of superfluous -terms or symbols for the definition of things would be in -opposition to the fundamental principle, already brought forward -by <i>Kirchhoff</i>, especially for mechanics, namely, that of formulating -comprehensively and in the simplest manner the processes -which take place in nature.</p> - -<p>At first glance one might be tempted to find an incompleteness -in the observation and description, when a conditional standpoint -is adopted. It might be thought that conditionalism were a -purely <i>formal</i> method of observation, and only considered the -<i>interdependence</i> of things, but not the <i>properties</i>, the <i>nature</i> of -the objects themselves. Regarded more closely, however, it is -seen that this objection does not hold good. For what is a -condition?</p> - -<p>A condition is in itself a <i>thing</i> of quite distinct <i>properties</i>. -The properties of a thing are, however, determined by the specific -combination of conditions which characterize the thing. The -conditions by which a thing, that is to say, a state or process, is -determined, are <i>identical</i> with its being and nature; in other -words, they are the thing itself. Purely formal relations without -essence would be altogether an absurd fiction <i>not</i> in accord with -reality, and which even the science of mathematics does not -acknowledge, for we cannot have a conception without concrete -content, just as in nature we do not find a form existing independently -of a thing. Every thing is equal to the sum of all its -conditions and depending upon the uniform constancy in accordance -with natural laws is solely determined by its conditions.<span class="pagenum" id="Page_29">29</span> -The problem of all scientific research consists wholly in the -ascertaining of the conditional interdependency.</p> - -<p><i>A state or process is solely determined by the sum total of its -conditions. A state or process is identical with all of its conditions -in totality.</i> From this it follows that equal states or processes -are always the expression of equal conditions and wherever -unequal conditions exist, unequal states or processes will -result; and further, a state or process is completely investigated -when the entire number of its conditions is ascertained.</p> - -<p>This fundamental statement of conditionism should be engraved -over the portals to the entrance of every scientific investigation.</p> - -<p>That there is not the least difficulty in presenting scientific -observations strictly according to these principles of conditionism, -and that one can perfectly well do without the causal conception -in a scientific description, I have shown by a concrete example, -namely, in the fifth edition of my “General Physiology.” In the -whole volume the conception of cause is only mentioned in one -place, where its theoretical value is criticised, elsewhere not at -all, and yet I do not think that any one will miss this conception, -and indeed, if their attention is not especially called to the fact, -even notice the omission.</p> - -<p>These principles of an exact conditional investigation must also -guide us in the analysis of the processes of stimulation. The -process of stimulation is especially apt to tempt one to employ -the old conception of cause, for it belongs to that group of processes -which originate from an already existing system by the -addition of a new factor. An electric stimulus acts on the muscle. -The muscle contracts. The stimulus is considered the cause of -the contraction. But what would I explain if I were to prove -that the stimulation is the cause of the contraction?</p> - -<p>The history of physiology shows us that this subject has advanced -long since far beyond the stage of being satisfied with -such an explanation. Today the process would only then be -fully investigated if we knew the entire number of its conditions -and had traced the dependency of the individual partial constituents -of the whole complex process upon one another. For<span class="pagenum" id="Page_30">30</span> -this, however, it is essential that we study the conditions already -existent in the entire system previous to the action of the -stimulus.</p> - -<p>That which we describe with the word life is an exceedingly -complex process. If we analyze life, it is found to be composed -of an immense number of separate constituent processes, each -one being conditioned by the others. These constituent processes -are the vital conditions. A vital process occurs, and must -occur, where and when the whole sum of vital conditions is -realized. It is identical with the sum total of the vital conditions. -If only one condition is absent, then life does not exist. -It is then expedient to reserve the expression “life” for the -<i>entire sum</i> of the vital conditions. When we speak of the individual -constituent processes as “<i>vital processes</i>” in the plural, -we must bear in mind that in reality each is not in itself life. -Only the whole complex “lives,” not an individual constituent -of the same. Living substance is rather the <i>whole</i> system, and -not a constituent part of the same, not a piece of protoplasm, not -a nucleus and not a specific protein combination in the cell.</p> - -<p>A property of this system should receive our consideration at -this point. It is a characteristic of every system in the world, -namely, the fact that a system <i>is not isolated</i> from its surroundings. -It is a deception resulting from the selective action of our -sensory organs, if we consider the bodies as separated and isolated -from their environment. This deception disappears upon -further analysis and when we assist our organs of sense, which -only respond to certain parts of the whole process, by experimental -methods of investigation. Our experience then shows -us that an isolated system does not exist, but that there are -instead everywhere connections which extend further and further -into the infinity of the world. An organism is consequently -no delimitated system and the vital process cannot, therefore, be -sharply separated from the processes in the medium. We cannot -draw a sharp line between vital processes and say: on the -right we have factors which are necessary for the maintenance -of life, and on the left factors which are not necessary. The -conditional connection between individual processes extends to<span class="pagenum" id="Page_31">31</span> -the entire world, and likewise a great series of constituents, each -influencing the others, extend from the medium into the organism. -The nature of our sense perception, and consequently the knowledge -derived therefrom, is such that we are obliged to arbitrarily -take into consideration merely <i>fragments</i> from the endless interdependence -of all things in the world, and so we separate the -vital conditions of the organisms from their surrounding factors, -as though they were independent. A conscientious theoretical -analysis requires that we should never forget that in reality such -an isolation does not exist. Only with the recognition of this -can we distinguish for practical purposes between <i>internal</i> and -<i>external</i> vital conditions. In such a differentiation the <i>internal -vital conditions</i> which compose the living system conceived to be -isolated, are the organs, the tissues, the cells, the protoplasm and -the cell nucleus, and within the protoplasm and the nucleus the -arrangement and quantitative relations of certain substances, -such as proteins, salts, water and the thousands of special components -with their interactions and continued alterations. On -the other hand, the <i>external vital conditions</i>, which act on the -periphery, are the conditions of the surrounding medium, as -foodstuffs, water, oxygen, static and osmotic pressure, temperature, -light, etc. But this distinction has only a <i>practical</i> value -for the study of the organism as an <i>independent</i> system. Theoretically -it is as impossible to make a sharp distinction between -internal and external vital conditions, as to distinguish between -the vital conditions generally and the more remote conditions of -the environment. All these conditions form a widely branching -system of factors of which one is conditioned by the other reaching -continually from the interior of the vital system into the -surrounding medium, so that on the periphery of the system it -cannot always be said whether or not a component still belongs -to life. Considering these circumstances we can roughly for the -present define the conception of stimulus as follows:</p> - -<p><i>A stimulus is every change in the vital conditions.</i></p> - -<p>The most essential point in this definition is the relation of -the conception of stimulus to that of vital conditions. These -relations, however, call for a brief explanation. Here again the<span class="pagenum" id="Page_32">32</span> -conditional method of observation saves us from error, for it -would be wrong to place the conception of stimulus and vital -conditions in contrast to one another, one excluding the other. -On the other hand, this method of observation shows that the -stimuli are likewise only conditions, but conditions producing -certain changes in the vital system. If a stimulus acts, that is, -if there is any change whatever in the vital conditions, the whole -complex of life in consequence of the dependency of the constituent -parts upon each other is also changed, and a new state -of living substance occurs. Stimuli are, therefore, also only -vital conditions, but vital conditions for new vital manifestations. -The <i>relation</i> of <i>one</i> given state to <i>another</i>, forms an indispensable -point in the understanding of vital conditions as well as that of -the stimulus. The stimulus becomes a vital condition for the -new state which it produces. It is only a stimulus <i>relatively</i> to -the original state, which <i>previously</i> existed. The essential point, -therefore, in the conception of the stimulus is that of alteration. -An example will serve to make this clearer. If <i>Amœba limax</i> are -bred in a hay infusion they appear in countless masses. Observed -in water in a watch glass they show at first the well-known form -of <i>Amœba proteus</i> with short, broad, lobate pseudopods. (Figure <a href="#i_033">1</a>, A.) -After a period of rest, however, they gradually assume the -characteristic elongated <i>limax</i> form. (Figure <a href="#i_033">1</a>, B.) In this shape -they constantly move about. But if I add to the water only a -faint trace of diluted solution of caustic potash, the amœbæ first -assume the shape of a ball (Figure <a href="#i_033">1</a>, C), and then after a time, -stretch out long, pointed pseudopods, which give them the characteristic -form of <i>Amœba radiosa</i>. I have observed them for several -hours at a time. (Figure <a href="#i_033">1</a>, D and E.) They -remain <span class="nowrap">permanently<a id="FNanchor_16" href="#Footnote_16" class="fnanchor">16</a></span> in this form. They move in the same manner as <i>Amœba -radiosa</i>. They draw in one pseudopod, stretch out another and -float freely in the water in contrast to their <i>limax</i> state, in which -they are always attached to some support. The long, pointed, -often threadlike pseudopods, yield to every movement of the -water, bending in consequence like whipcords. In this example<span class="pagenum" id="Page_34">34</span> -the amœbæ under the vital conditions existing in tap water have -<i>limax</i> form. The vital conditions undergo a change by the addition -of a solution of caustic potash, which acts as a stimulus. The -consequence is a reaction, in which the animal assumes <i>radiosa</i> -form. By the action of the stimulus a new state of the living -substance is produced, and remains as long as the solution of -caustic potash is contained in the medium. The solution of -caustic potash is, therefore, a stimulus for the state of the vital -system, which is manifested in the <i>limax</i> form, whilst for the -state of the system which shows itself in the <i>radiosa</i> form, it is a -vital condition. If I place the amœbæ of the <i>radiosa</i> form once -again in tap water, they assume the <i>proteus</i> and then the <i>limax</i> -form. The withdrawal of the solution of caustic potash, the presence -of which is a vital condition for the <i>radiosa</i> state, acts as a -stimulus, which results in a transition of the vital system to -another state. By altering the medium I can at will bring about -this change of form in the same individuals. In this way one and -the same factor can figure as stimulus and vital condition, according -to the state of the vital system on which it acts. Whilst its -addition acts as stimulus in the one state, its withdrawal acts as a -stimulus in the other state, which it has produced. The same -fact is shown by the well-known example of <i>Artemia salina</i>, which -on being placed in fresh water changes into <i>Branchipus stagnalis</i> -and, when again introduced into sea water, becomes once more -<i>Artemia salina</i>.</p> - -<div class="figcenter illowe30_625" id="i_033"> - <img class="w100" src="images/i_033.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 1.</p></div> -</div> - -<p>These facts show clearly that some stimuli can also be considered -as vital conditions. In the absence of certain stimuli, -life could not exist for any length of time. In the highly differentiated -cell community of the animal organism, for instance, -as a result of the coexistence of the cells and the tissues, many -parts have forfeited in a measure their independence. An -example of this is the skeletal muscle, which, in the absence of -impulses from the nervous system, reaches a low level of chemical -change and energy transformation. Here the nervous impulses -which act as momentary stimuli, are also in the course of time -indispensable vital conditions. Without them the muscle would -gradually become atrophied from inactivity. The same applies<span class="pagenum" id="Page_35">35</span> -to all other tissues of our bodies. The functional stimuli are for -them at the same time vital conditions. These vital conditions -undergo fluctuations and interruptions but at each alteration -from a given state they act as stimuli.</p> - -<p><i>Stimulus is every change in the vital conditions.</i> But is this -definition complete? Are we really justified in regarding <i>every</i> -alteration in the vital conditions as a stimulus?</p> - -<p>In considering this question, one point must not be omitted. -This is the fact that one of the chief characteristics of the vital -process is, that it undergoes continuous change. A vital process -involves not simply an alteration in metabolism or transformation -of energy in the sense that the same chemical processes continuously -reoccur in the same manner. Such a view could only -be admissible for the observation of living substance during a -limited period. An investigation over a long period of time -shows rather that every living system alters as long as it exists, -although this alteration is very gradual. The constituent processes, -in short, continuously undergo metabolic change both -quantitative and qualitative in nature.</p> - -<p>If we observe the occurrences in a living system at various -moments of the cycle of life, we will find that the condition -differs qualitatively at each period. The progressive alteration -of the system is such that every state of living substance conditions -another, by which it is followed. No state can permanently -exist as such. Every state is the product of the preceding, -as it in turn conditions its successor. Consequently the -relations of the system to the surrounding medium also undergo -alteration, even when the external factors themselves in no -way alter. That which today is still a vital condition, is not -in consequence necessarily one tomorrow. These progressive -changes exist continuously until the death of the system takes -place. They characterize life. It is development, and life -cannot exist without development. Death is only the last phase -of development. The individual constituent processes of metabolism -gradually change to such a degree that they can no longer -work harmoniously together. Then the chain of processes is -interrupted at one point or another. The system develops into<span class="pagenum" id="Page_36">36</span> -death or, on the other hand—and this, as <i>Weissman</i> especially -emphasizes, is realized in the case of unicellular organisms—a -corrective process takes place, a process of cell division by which -the original state of the cell is restored and development begins -anew and in a similar manner.</p> - -<p>Ought we to designate these constant alterations in the inner -vital conditions as “stimuli”? Usage in this connection has -already answered in the negative, by applying to them the word -“<i>development</i>.” And this use is in a certain sense justified. -Let us imagine an organism or any other object for the purpose -of investigation as isolated from its surroundings. This conception, -which we have already stated, proves untenable on closer -analysis, but it, however, is based on the nature of the methods -of human observation and is indispensable for practical use -within certain limits. Then the inner vital conditions belong to -the organism, the external to the medium. They differ in so far -that the external vital conditions can exist permanently without -alteration, that is, independently of the development of living -systems, whilst the inner vital conditions of every living organism -continuously and progressively undergo alteration. In this sense, -but only in this, there is evidently a difference between the inner -and outer vital conditions, which permits a separation of the two -groups. But we should always bear in mind that this separation -cannot be sharply defined. On the same basis we assume that -the organism for purposes of study is separated from its surroundings -as an independent system, which leads us in consequence -to contrast the alterations in the internal with those in -the external vital conditions, in which we designate the first as -processes of <i>development</i>, the latter as stimuli. This distinction, -as all differentiations and separations in nature, gives us only a -practical working basis.</p> - -<p>In this way we confine the conception of the stimulus to all -alterations in the external vital conditions of a living system, -considered as isolated. This view does not exclude the fact -that stimuli can also occur and act within an organism. If a nervous -impulse is conducted from the cerebral cortex through the -pyramidal tract to a skeletal muscle, this impulse acts upon the<span class="pagenum" id="Page_37">37</span> -muscle cells as a stimulus. Although the explosion of the impulse -is an alteration within the body, nevertheless, as far as the -muscle is concerned, it may be looked upon as an external vital -condition, therefore as a stimulus. As the conception of stimulus -involves the relation to a given state, it likewise involves at the -same time the relation to a given living system, upon which it acts -from the exterior.</p> - -<p>What is the value then of all this theoretical discussion?</p> - -<p>In presenting the conception of stimulation from a conditional -standpoint, I desired to show what difficulties stand in the way -of a theoretical isolation of a fundamental conception in the field -of physiology, which indeed is used in our practical research -work at every step. “<i>Natura non facit saltus.</i>” I wished to -demonstrate that the sharp separation of the conception of stimulation, -like all artificial divisions which we make in nature, must -always contain an arbitrary note, as in reality isolated systems -do not exist in the world. I wished to show that, for this reason, -the conception of vital system, the conception of life, the conception -of vital conditions are not sharply defined. I wished -likewise to show that as a necessary consequence of this fact -a sharp separation of the conception of stimulation, which can -only be made in relation to that of vital conditions, cannot be -maintained theoretically. I wished to show further that there -is no sharp line of division between inner and outer vital conditions, -and that we cannot, therefore, make a strictly theoretical -distinction between the conception of stimulation and that of -the processes of development. I wished to show that, for these -reasons, we must not expect from the conception of stimulation, -as we understand it, anything beyond its possibilities. But finally -I wished also to show that, whilst fully conscious of and with -due consideration of all these difficulties, it is possible to work -out a definition of stimulation which is of great <i>practical</i> working -value. The definition in short is: “<i>Stimulus is every alteration -in the external vital conditions.</i>”</p> - -<p>This definition gives to the conception of stimulation its most -complete, that is to say, its generally applicable and simplest -form. The great importance from a methodical standpoint of<span class="pagenum" id="Page_38">38</span> -this definition of stimulation for the research of life is evident. -Our whole experimental natural science always employs for -investigation of any state or process the same method: the state -or process to be observed is studied under systematically altered -conditions. By stimulating the living substance it is brought -under changed external conditions. A systematic employment -of stimulus is, therefore, the experimental means for the research -of life.</p> -<hr class="chap x-ebookmaker-drop" /> - -<div class="chapter"> -<p><span class="pagenum" id="Page_39">39</span></p> - -<h2 class="nobreak" id="CHAPTER_III">CHAPTER III<br /> -<span class="title">THE CHARACTERISTICS OF STIMULI</span></h2> -</div> - - -<div class="blockquot"> - -<p class="pl2hi2"><i>Contents</i>: The quality of the stimulus. Positive and negative alterations -of the factors which act as vital conditions. Extent of the alteration -in vital conditions or intensity of the stimulus. Threshold stimuli, -sub-threshold, submaximal, maximal and supermaximal intensities of -stimulus. Relations between the intensity of stimulus and the amount -of response. The <i>Weber</i> and <i>Fechner</i> law. All or none law. Time -relations of the course of the stimulus. Form of individual stimulus. -Absolute and relative rapidity in the course of the stimulus. Duration -of the stimulus after reaching its highest point. Adaptation to persistent -stimuli. Series of individual stimuli. Rhythmical stimuli. -The <i>Nernst</i> law.</p> -</div> - - -<p>We have found that stimuli are alterations in the external vital -conditions and that the irritability of living substance consists in -the capability to respond to stimuli by changes of the vital processes. -It now behooves us in the interest of experimental -research to investigate the relations between the nature of the -alterations in the external vital conditions on the one hand, and -that of the alterations of the vital process on the other; that is to -say, to systematically study the effects of stimulation on the living -organism. For this purpose it is above all necessary to become -acquainted with the almost countless numbers of alterations -which take place in the external vital conditions of an organism, -and to create a systematic scheme of stimulation which differentiates -and presents in comprehensive order those various elementary -factors which, among the innumerable varieties of stimuli, -would prove effectual. For this purpose it is necessary to -select the various factors which are involved in an alteration of -the external vital conditions.</p> - -<p>The first of these factors is the <i>quality of the stimulus</i>. The -external vital conditions are, in short, a series of chemical factors, -such as foodstuffs, water and oxygen; the presence of a certain<span class="pagenum" id="Page_40">40</span> -temperature; the existence of a certain light intensity; the -existence of a definite static pressure; and finally the presence of -an equal osmotic pressure. The stimulus according to its quality -can be differentiated into chemical, thermal, photic, mechanical -and osmotic varieties. To these must be added other forms of -stimuli not ordinarily operative, for instance, many uncommon -chemicals, and certain kinds of rays. The form of stimulation, -par excellence, which has acquired the greatest importance for the -<i>experimental</i> investigation of life, is electricity. In its manifold -forms it permits, as no other, of such fine gradations of intensity -and duration that it has become in the hand of the physiologist -an invaluable means of research.</p> - -<p>Alterations in those factors which act as vital conditions compose -the great mass of physiological stimuli which act continuously -on every living organism. The first point to be considered -in every alteration is its <i>direction</i>. The alterations produced by -stimuli may be of two different kinds, either positive or negative. -The quantity of foodstuffs, water or oxygen, in the surrounding -medium, can undergo an increase or diminution; as may the -temperature, intensity of light, the atmospheric and osmotic pressure. -The strength of the electric current, which may be applied, -can also be regulated. In accordance with the definition of stimulation -already referred to, we must consider these alterations, -whether negative or positive, as forms of <i>stimulation</i>. Now the -question arises: Is this point of view justifiable? Should one -also consider, for example, the lessening or total removal of a -vital condition as a stimulus? Should one consider the removal -of water or oxygen, cooling or darkening, as a stimulus? It has, -in point of fact, been occasionally attempted <i>not</i> to regard these -negative deviations as forms of stimuli. These observers permitted -themselves to be led by the dogma, that only that which -produces an excitation, that is, an increase of the processes in the -living substance, should be regarded as a stimulus. Such a limitation -of the conception of stimuli would only result from the -one-sided consideration of an all too limited circle of facts. Considered -from the point of view which results from a broader -range of experience, this narrow view becomes untenable.</p> - -<p><span class="pagenum" id="Page_41">41</span></p> - -<p>In the first place it does not follow that only <i>positive</i> fluctuations -of a factor, acting as a vital condition, result in <i>excitation</i> -in the existing vital processes. The <i>withdrawal</i> of water produces -a diametrically opposite effect. A muscle, from which -water has been removed, if exposed to dry air or placed in a -hypertonic salt solution, shows violent <i>excitation</i>, which manifests -itself in great increase of irritability and development of fibrillary -contractions. The breaking of a constant current which has for -a long time flowed through a nerve or muscle also elicits a -momentary excitation. Further, the abrupt removal of light -may also bring about stimulation. To cite an example from -the physiology of the single cell, I should like to call to your -attention the interesting observations of <span class="nowrap"><i>Engelmann</i><a id="FNanchor_17" href="#Footnote_17" class="fnanchor">17</a></span> on the -<i>Bacterium photometricum</i>, of which he was the discoverer. -When the field containing these organisms is suddenly darkened, -all the individuals contained in the drop immediately dart forward -for some distance, at the same time, as is usually the case, quickly -rotating around their own axis, and then after a moment of -immobility, swim on quickly in another direction. An analogous -responsivity has also been shown by other single cell organisms, -as has been pointed out by several observers and especially by -<i>Jennings</i><span class="nowrap">.<a id="FNanchor_18" href="#Footnote_18" class="fnanchor">18</a></span> In all these cases the excitation was produced by a -lessening or total withdrawal of the factors which act as vital -conditions; and even those who take the standpoint that only such -factors are to be considered as stimuli which produce an <i>exciting</i> -effect, are compelled to regard these alterations as stimuli, in -spite of the fact that they are <i>negative</i> variations of external -vital conditions.</p> - -<p>But further, the restriction of the term stimulation to those -alterations which increase the course of the changes in the living -substance involves the observer in still greater contradictions. -It can easily be shown that one and the same factor in one and -the same form of living substance has now an exciting, now a -depressing effect on the vital processes. This fact can be readily<span class="pagenum" id="Page_42">42</span> -<span class="nowrap">demonstrated<a id="FNanchor_19" href="#Footnote_19" class="fnanchor">19</a></span> by means of the infusoria <i>Colpidium colpoda</i>, -which can be grown without difficulty in a hay infusion. A -number of individuals in a drop of fluid may be placed in a -warm stage and observed under the microscope; one then sees -that at room temperature they swim about by moving their ciliary -processes at a definite rate. Now if the temperature is raised to -about 35° C., the ciliary movement becomes enormously increased. -The infusoria swim madly through the field of vision. They are -in a state of violent excitement. The increase has, therefore, -acted as a strong, exciting stimulus. But if one allows the temperature -to further increase only a few degrees the ciliary movements -are suddenly greatly retarded. The infusoria now swim -sluggishly through the field of vision and finally remain stationary. -In this case the increase in the temperature has had a depressing -effect. If the infusoria are not quickly removed, the depression -is followed by death. Should the increase in temperature be -regarded in the <i>first</i> instance as a stimulus, and <i>not as such</i> in the -<i>second</i>, in which the temperature rises only a few degrees higher? -Here the change in the vital conditions concerned is in both -instances positive. In all cases of overstimulation we are confronted -by the same question. Nevertheless it is not at all necessary -to refer to such strong or even life-endangering stimuli for -the observation of these conditions. In this connection I would -like to cite an even more striking instance and which is of special -interest for the understanding of the phenomena in nerve centers. -If the posterior spinal roots of a <i>Rana temporara</i> are severed, and -the eighth root stimulated with a faradic current, whilst the <i>musculus -Gastrocnemius</i> of the same side is connected with a writing -lever, one obtains, as <span class="nowrap"><i>Vészi</i><a id="FNanchor_20" href="#Footnote_20" class="fnanchor">20</a></span> has found, at the moment of the -beginning of stimulation a contraction of the muscle. The faradic -stimulus has, therefore, produced an excitation reflexly. If instead -of the <i>eighth</i> the <i>ninth</i> posterior root is stimulated, the result -obtained is also an excitation of the muscle. In this case, however, -the excitation in the form of a tetanic contraction lasts for<span class="pagenum" id="Page_43">43</span> -some time, provided that the stimulation is not at once stopped. If -now during tetanic stimulation of the ninth root the eighth is at -the same time stimulated, with a strength of current equal to -that which previously brought about contraction of the muscle, -instead of an <i>increase</i> and a <i>strengthening</i> of contraction there -is, on the contrary, an <i>inhibition</i> which continues throughout the -time during the stimulation of the eighth root. If the stimulation -of the eighth root is discontinued, the tetanic response of the -ninth root reappears. If, on the other hand, the faradic stimulation -of the ninth root is interrupted and the eighth root now -again stimulated, one obtains once more, as in the beginning, with -each stimulation a contraction of the muscle. This fact is illustrated -by the accompanying tracings. (Figure <a href="#i_043">2</a>.) In this investigation -undertaken in the Göttingen laboratory it was further -shown that a faradic current of the same strength and the same -frequency had at one time an augmenting, at another an inhibitory -effect, and these effects could be produced alternately at will. -Should the faradic current at one time be called a stimulus, at -another not? It is here clearly shown to what absurd consequences -it leads if the conception of stimulation is limited solely -to the cases in which an external factor has an exciting effect;<span class="pagenum" id="Page_44">44</span> -and yet an immense number of instances of a like nature could -be cited to show the untenability of this view.</p> - -<div class="figcenter illowe30_625" id="i_043"> - <img class="w100" src="images/i_043.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 2.</p> - -<p class="tac">Lower thick line shows duration of stimulation of 9th root; upper thick line that of -8th root.</p></div> -</div> - -<p>It follows from this, that it is altogether impracticable to define -the stimulus itself in relation to the nature of the effects which -the stimulus has upon the substances in the living system. One -can only appreciate the nature of stimulation in relation to the -vital conditions and without considering the nature of the action -of the stimuli on the living substance. It is true that every -stimulus is followed by an alteration in living processes, but this -is to be expected when one clearly understands the nature of -vital conditions. A stimulus is in all cases an alteration in vital -conditions and, in that each of the vital conditions is necessary for -the continuance of life, it follows of necessity that every alteration -in the vital conditions, so intimately connected with the -living processes, will also be followed by an alteration in the -processes occurring in the living system. In short, response is -produced. Nevertheless, a definite alteration of an external vital -condition, depending upon the state of other vital conditions, -that is, according to the state of living substance at the moment, -can produce quite opposite effects. Although it may appear -expedient to include in the conception of stimulation in given -instances, distinctions between stimuli according to the nature -of their effects upon the living substance, in all cases the conception -must under all circumstances be so formulated that it -comprises <i>all</i> alterations in the external vital conditions, either -positive or negative, that is to say, an increase or decrease, an -augmentation or diminution in those factors, acting as vital -conditions.</p> - -<p>Besides the quality there is another highly important factor -to be considered in the study of every alteration in the living -process, namely, its <i>amount</i>. The chemical concentration of the -medium, temperature, amount of light, the static and osmotic -pressure may undergo more or less variation. The electric -stimulus can rise from zero to great intensity and from great -intensity can fall to zero. The extent of the alteration determines -the intensity of the stimulus. In relation to the intensity, -a differentiation of stimulation has been introduced, which is not<span class="pagenum" id="Page_45">45</span> -dependent upon the absolute intensity of the stimulus, that is, -upon the extent of the alterations in the external vital conditions, -but the intensity of the response that can be observed. One -refers frequently to threshold stimulation, to stimulation beneath -the threshold, to submaximal, maximal and supermaximal stimulation. -Such a classification is in many ways very valuable. It -is not only of practical value for the establishment of definite -intensities of stimulation, but also for the study of the state of -irritability in the living organisms.</p> - -<p><i>The threshold of stimulation</i> furnishes roughly a standard for -the degree of irritability of a living system. The threshold value -of a stimulus is then that degree of intensity which is just sufficient -to bring about a perceptible response. The threshold of -stimulation is low, that is, the irritability is great, when the intensity -of the threshold stimulus is small; the threshold is high, -that is, the irritability of a system is small, if the intensity of the -threshold stimulus is great. All intensities of stimuli beneath the -threshold are sub-threshold stimuli. Here a point must not be -overlooked, which in older physiology did not generally meet -with sufficient attention. From the fact that the sub-threshold -stimuli produce no apparent effects, the wrong deduction must -not be made, that they have no effect whatsoever. The conception -of the threshold of stimulation originated in the field of -muscle physiology and that of the special senses. Here the indicator -of the response is, on the one hand, contraction of the -muscles, and on the other, conscious sensation. There was a -great temptation to consider the stimulus altogether ineffectual, -if it produced no conscious sensation or no contraction of the -muscle. Today with our finer and more sensitive indicators for -the study of the alterations in the living substance, we know in -reality that sub-threshold stimuli, which produce no apparent -effect in the living substance, can have an effect in reality.</p> - -<p>I will call your attention later to the fact that these sub-threshold -stimuli play a very important rôle under certain conditions -in the activities of the central nervous system. It only -depends upon the sensitivity of our special senses, or the indicators -used for this purpose, as to whether the alterations can<span class="pagenum" id="Page_46">46</span> -be observed or not. The conception of the threshold of stimulation, -therefore, has meaning only when used in relation to -a certain indicator. The threshold of the same living system -may be different for different indicators. When we use the -term threshold we must necessarily know the indicator employed -in its determination. The threshold stimulus produces only -barely perceptible effects. The amount of response in most -living substances increases with the intensity to a certain limit. -If this limit is reached, that is, if the response is maximal, the -stimulus of the weakest strength necessary to produce this result -is termed the <i>maximal stimulus</i>, whereas all intensities lying -between the threshold and the maximal stimulus are termed -<i>submaximal stimuli</i>. If the intensity of the stimulus is increased -<i>above</i> that of the maximal, the response, as in the case of the -muscle, does not increase, and therefore one could say that all -intensities above the maximal could also be called maximal -stimuli.</p> - -<p>In realty, however, the response to stimuli of different intensities -is never equal, even though it may appear so, when measured -by an indicator, as for instance, the height of the maximal -muscle contractions. This is clearly shown, for example, when -the electrical stimulus is increased far beyond that intensity which -is necessary to produce maximal effect. Injury is thereby produced, -which is manifested, for instance, in the muscle contraction -by the nature of its course and also by its height. One is, -therefore, justified in a certain sense in calling the intensities of -the stimulus, which are above the value which barely produces -maximal contraction, “<i>supermaximal stimuli</i>,” notwithstanding -this is logically far from being a happy expression. The term -“maximal stimulus,” then, is limited to the intensity of the stimulus -which just produces a maximal effect. I wish to point out this -distinction between maximal and supermaximal stimulus, as there -is often a lack of clearness in the use of these terms.</p> - -<p>In that the nomenclature of intensity of stimulation is based -upon the intensity of response, the question arises as to the <i>relation -between the intensity of stimulus and the amount of response</i>. -It is well known that this question has met in one special field<span class="pagenum" id="Page_47">47</span> -of physiology with a very detailed and comprehensive treatment. -I allude to the teaching concerning sensation. <i>Ernst Heinrich</i> -<span class="nowrap"><i>Weber</i><a id="FNanchor_21" href="#Footnote_21" class="fnanchor">21</a></span> first called attention to the relation between increase in -sensation and that of the stimulus in the case of the sense of -touch. His observations, which have been formulated into -“<i>Weber’s law</i>,” have been the object of animated discussion. A -presentation of this law is the following: “The amount of pressure -necessary to produce a perceptible increase of sensation -always bears the same ratio to the amount of the stimulus already -applied.”</p> - -<p>If in accordance with <span class="nowrap"><i>Ziehen</i><a id="FNanchor_22" href="#Footnote_22" class="fnanchor">22</a></span> we designate the relative -increase in pressure to that already applied, which is necessary -to produce a perceptible increase in sensation, as the <i>threshold of -relative differentiation</i>, we can formulate the law in the simplest -way thus: The <i>relative threshold of differentiation is constant</i>. -<i>Fechner</i><span class="nowrap">,<a id="FNanchor_23" href="#Footnote_23" class="fnanchor">23</a></span> who indeed attempted to apply this law, applicable to -the sense of pressure, to all the other special senses, has given -us a mathematical formula, based on the assumption that the just -perceptible increase of sensation has the same value at all levels. -By this assumption he was able to establish for the first time a -relation between the intensity of sensation and that of stimulus, -for it follows that “<i>the sensation increases in intensity in arithmetical -progression, whereas the intensity of the stimulus increases -in geometrical progression</i>.” From this <i>Fechner has</i> -worked out a psychophysical formula, which today is generally -termed the <i>Fechner law</i>. This is the law: <i>The intensity of sensation -varies with the logarithm of the intensity of the stimulus.</i></p> - -<p>Soon the <i>Weber</i> as well as the <i>Fechner</i> law had been extended -over the whole field of sensation and stimulation. In this connection -<span class="nowrap"><i>Preyer</i><a id="FNanchor_24" href="#Footnote_24" class="fnanchor">24</a></span> has formulated his “myophysical law,” which -states that there is the same relation between strength of stimulus -and the intensity of response of the muscle as is laid down by the<span class="pagenum" id="Page_48">48</span> -<i>Fechner</i> law for stimulation and sensation. <span class="nowrap"><i>Pfeffer</i><a id="FNanchor_25" href="#Footnote_25" class="fnanchor">25</a></span> has found -that <i>Weber’s</i> law applied also to the relations of the chemotaxis -of bacteria, to the intensity of the chemical stimulus, and likewise -the attempt has been made to show that all living substances -respond in the manner laid down by the <i>Weber-Fechner law</i>. -Unfortunately the innumerable investigations in this field have -shown more and more clearly that it is not possible to formulate -a general mathematical law, which strictly fixes the relations of -the intensity of the stimulus and the intensity of response. Even -in the field of the physiology of the special senses many voices -have opposed the general application of the <i>Weber</i> and the -<i>Fechner law</i>. <i>Lotze</i>, <i>G. Meissner</i>, <i>Dohrn</i>, <i>Hering</i>, <i>Biedermann</i> -and <i>Löwitt</i>, <i>Funke</i> and numerous other investigators have already -demonstrated for some decades, partly by means of critical -inquiry, partly by experimentation, that these laws are not strictly -valid. Above all these experiments have shown that logarithmic -relations are not tenable and likewise are not applicable to very -strong stimuli. The assumption made by <i>Fechner</i>, that is, the -acceptance that all barely perceptible increases of sensation have -an equal value, has been set aside as incorrect, and with this his -mathematical formulation within those boundaries of intensity -of the stimulus, in which the <i>Weber</i> law has proven itself valid, -must also be abandoned. That which we can say today with certainty -concerning the relation between the intensity of stimulus -and the amount of response is as follows: A law generally applicable -to the relation between the strength of the stimulus and -the amount of response cannot be mathematically formulated. -For a great number of living systems the rule which holds for -the intensity of stimulation within certain boundaries is the following: -With increase of the intensity of stimulation the <i>response</i> -at first increases rapidly and later more and more slowly.</p> - -<p>This rule of course only applies within the boundaries of the -intensity between the threshold of stimulation and maximal -stimulus. The interval, however, between these intensities varies<span class="pagenum" id="Page_49">49</span> -considerably in different living substances. In this connection -there are several forms of living substance which call for our -special attention. In these the surprising condition seems to exist, -that the interval between the threshold and the maximal stimulus -is zero; that is, every stimulus which acts at all always produces -a maximal response. <span class="nowrap"><i>Bowditch</i><a id="FNanchor_26" href="#Footnote_26" class="fnanchor">26</a></span> first observed this behavior in -the frog’s heart and this has also been confirmed by <i>Kronecker</i><span class="nowrap">.<a id="FNanchor_27" href="#Footnote_27" class="fnanchor">27</a></span> -The induction current produces, as <i>Bowditch</i> says, either a contraction -or nothing. If the former, it is the strongest contraction -which can be produced by an induction shock at the given -time. Here for the first time a constancy of response was discovered -which has been termed the <i>all or none law</i>. <span class="nowrap"><i>McWilliams</i><a id="FNanchor_28" href="#Footnote_28" class="fnanchor">28</a></span> -has later verified the same fact for the mammalian heart. -<span class="nowrap"><i>Gotch</i><a id="FNanchor_29" href="#Footnote_29" class="fnanchor">29</a></span> has also arrived at the same conclusion in connection with -the nerve. He states that “the comparison of submaximal with -maximal responses shows that although there is an obvious difference -in the amount of E. M. F., there is little or no difference -between such time relations as the moment of commencement, the -moment of culmination of E. M. F. and the rate at which E. M. F. -disappears.” Further: “the rate of propagation of the excitatory -wave is the same whether this is maximal or submaximal.” He -likewise assumes that the “all or none law” is applicable to the -constituent fibers, and that the variations in the strength of -response with weak and strong stimulation are brought about -in the first instance by stimulation of a few, in the latter by -a greater number of fibers in the nerve trunk. The same conclusion -has been reached by <span class="nowrap"><i>Keith Lucas</i><a id="FNanchor_30" href="#Footnote_30" class="fnanchor">30</a></span> for the single cross-striated -fiber of the skeletal muscle, founded on the fact that<span class="pagenum" id="Page_50">50</span> -by direct stimulation of a bundle of curarized muscle fibers, -the contraction only increases inconstantly and not regularly -with the increasing intensity of the stimulus. This is only -comprehensible if one takes into consideration that, with the -increasing intensity of the stimulus, a greater and greater number -of fibers are stimulated. <span class="nowrap"><i>Keith Lucas</i><a id="FNanchor_31" href="#Footnote_31" class="fnanchor">31</a></span> came to the same conclusion -in the case of the muscle stimulated indirectly through -the nerve. He, therefore, sees, because of the nature of the -response of the single muscle cell, no difference between heart -muscle and skeletal muscle. The “<i>all or none law</i>” applies to the -individual muscle cells of both kinds. The difference between -the heart and skeletal muscle, according to him, lies in the fact -that in the heart the individual muscle cells in their totality stand -together as conductors of excitation, whereas in the skeletal -muscle the individual muscle fibers are separated, as far as conduction -of excitation is concerned, by the sarcolemma. Finally, -the recent investigations of <span class="nowrap"><i>Vészi</i><a id="FNanchor_32" href="#Footnote_32" class="fnanchor">32</a></span> with strychnine poisoned ganglia -cells of the posterior horns of the spinal cord, have made it -appear probable that “the all or none law” can be applied likewise -to the individual ganglion cell. He draws this conclusion -not only from the fact that all reflex contractions of a muscle -of a strychninized frog are maximal, whether they are produced -by weak or strong stimuli, but also especially because of the -loss in the strychninized spinal cord of the capacity of the summation -of irritability. The normal spinal cord does not reflexly -respond at all to weak single stimuli, but responds to equally -weak faradic stimulation very readily. Therefore, the threshold -lies very high for the individual induction shock and very low -for faradic shocks. But these differences are equalized in the -strychninized frog. This seems intelligible, when we assume -that the strychninized cell responds to every stimulus, to which -it responds at all, to the maximal extent which is permitted at -that moment by its stored up energy, otherwise the excitation -would necessarily be summated by faradic stimulation.</p> - -<p><span class="pagenum" id="Page_51">51</span></p> - -<p>Such are the instances to which one has up to the present -applied the “all or none law.” The question if, as a matter of -fact, such a condition has ever been realized in any living substance -has until now found no final answer. Most authors, who -accept the validity of the “all or none law” for certain living substances, -do so with a certain reserve and speak only of the possibility -or probability of such behavior. The subject has, however, -as will be shown later, a great and even vital interest in -another direction. For this reason I should prefer to postpone the -treatment of the same to a later occasion. Here I wish simply to -say, that <i>if</i> the “all or none law” is valid in a strict sense for -certain structures, then there exists no general constancy of the -relations of the intensity of the stimulation and the amount of -response, applicable to all living organisms.</p> - -<p>We will now return from this digression concerning the relations -between the intensity of the stimulus and the response, to -the further characterization of the properties of the stimulus. -Besides the quality, the direction and the intensity of every alteration -in vital conditions, an equally important factor is the duration -of the alteration. The time relations, under which a deviation -of the external vital conditions takes place, present immense -and manifold variations in nature. In many cases the change -is very complicated, as for instance, the alteration of the static -pressure or the temperature under the influence of air or -water currents, the osmotic pressure or chemical factors in -diffusion currents, and the light intensity produced by the movement -of clouds. These very irregular alterations have practically -little interest for us. Here we are concerned rather with the -differentiation of the time alterations of the processes of the -simplest fundamental types, which are of importance in studying -the course of the reaction. For it is of such simple elements -that the complicated and irregular alterations of the above-mentioned -kinds are composed.</p> - -<p>The simplest form of an individual change in the external -vital conditions would be a regular and constant alteration of -intensity which can be graphically represented as a straight line, -wherein the intensities are the ordinates and the time the abscissa.<span class="pagenum" id="Page_52">52</span> -(Figure <a href="#i_052">3</a>, A.) A regularly rising pressure would, for instance, -represent a stimulus in its simplest form. But such forms of -stimuli are only very rare in nature and are also experimentally -very difficult to produce. It is, for example, not easy to give the -<i>electrical</i> stimulus, so much used for experimental purposes, this -form. <i>Fleichl</i> and <i>v. Kries</i> have only accomplished this by means -of complicated apparatus. The usual <i>form of the individual -stimulus</i> is not a straight line, but a logarithmic curve. (Figure -<a href="#i_052">3</a>, B.) The alteration hardly ever progresses with equal rapidity -from its beginning until it reaches its highest point, but as a rule, -with decreasing rapidity. This is the usual course of alterations -of concentration, also of chemical and osmotic stimuli, of changes -of temperature and of electric stimulation.</p> - -<div class="figcenter illowe30_625" id="i_052"> - <img class="w100" src="images/i_052.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 3.</p></div> -</div> - -<p>The <i>rapidity of alterations</i> in vital conditions has quite an -important influence on the development of the response to stimulation. -It is well known that if a constant current, which reaches -its highest intensity rapidly, is permitted to act upon a muscle, -the effect differs from that following the application of a current -of the same intensity but in which this is reached very slowly. In -the first case there is a sudden strong twitch, in the second none -at all. In spite of this there can be no doubt whatever of the -current in the last case being effective. That the muscle is also -excited when the current is slowly increased is shown by the -contracture, which grows more and more plainly perceptible with -the increasing intensity of the current and in higher intensities -by the so-called <i>Porret’s</i> phenomenon, which consists in a curious -wave-like movement of the muscle-substance. In reference to<span class="pagenum" id="Page_53">53</span> -the rapidity of the alterations in the factors which act as stimuli, -the behavior varies greatly. Many stimuli because of their nature -never have a steep ascent or descent of intensity, as, for instance, -alterations in the concentrations of soluble substances, that is, -chemical or osmotic stimuli; likewise temperature variations may -be mentioned. They always act relatively slowly. On the contrary -there are forms of stimuli which have now a rapid, now a -slow, ascent or descent of their intensity, such as the photic and -mechanical stimuli. Finally, there are other stimuli that nearly -always show a very abrupt change of intensity, such as the -electrical form.</p> - -<p>The most important factor to be considered in producing the -response to variations of intensity, is not the <i>absolute rapidity</i>, but -rather the <i>relative rapidity</i>; that is, the rapidity in relation to the -characteristic rapidity of reaction of the particular living substance -concerned. The rapidity of the reaction to stimuli is very -different in various forms of living substance. On the one -hand, we have forms reacting very quickly, as the nerve and the -striated muscle; on the other, those which respond very slowly, -such as a great number of unicellular organisms. Between these -are a great number of living substances which, as far as the -rapidity of the reaction is concerned, occupy intermediate positions -of every varying degree. It is clear that the adequate -stimuli for slowly reacting substances must be those having also -a slow change of intensity; for quickly reacting, those having a -rapid change of intensity<span class="nowrap">.<a id="FNanchor_33" href="#Footnote_33" class="fnanchor">33</a></span> If a nerve muscle preparation is -simulated with the single induction shock, the “break” as well as -the “make” shock has effect. But even here a difference is -noticeable. The “make” shock has a weaker effect than the -“break” shock. This difference is due to the difference of -abruptness in its course, which when the current is made is less -than that of opening, for, when the current is made, the ascent -of the primary current is retarded by the extra current flowing -in the opposite direction, whereas, when broken, with the fall -of the intensity of the primary current, the extra current in the<span class="pagenum" id="Page_54">54</span> -primary coil flows in the same direction. In consequence of this -there is a perceptible difference in the rapidity of the alteration -of the “make” and “break” shocks. (Figure <a href="#i_054">4.</a>)</p> - -<div class="figcenter illowe27_5" id="i_054"> - <img class="w100" src="images/i_054.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 4.</p> - -<p class="tac">Course of induction shocks. 1 and 2 make and break of the primary current. -1<sub>1</sub> and 2<sub>1</sub> make and break induction shocks. (After <i>Hermann</i>.)</p></div> -</div> - -<p>Now slowly reacting forms of living substance, such as certain -foraminifera, in which the extended pseudopods are stimulated -with single induction shocks, the break as well as the make -shocks are wholly without effect, as both take place far too quickly -for the slow responsivity of these organisms. I have made such -observations on various forms of foraminifera of the Red Sea, on -<i>Orbitolites</i>, <i>Amphistegina</i> and others. The movement of granules -in the pseudopods is not influenced by the induction shocks in the -least. It also continues without interruption when the pseudopods -are extended. Even with the strongest induction shocks at my -disposal I could <i>not</i> induce them to contract; the faradic current,<span class="pagenum" id="Page_56">56</span> -also, the intensity of which I found quite unbearable, remained -utterly without effect<span class="nowrap">.<a id="FNanchor_34" href="#Footnote_34" class="fnanchor">34</a></span> These two extreme cases, the nerve and -the foraminifera, show plainly that the effect of a stimulus is not -produced by the absolute rapidity of the increase of intensity, but -is solely influenced by the relative rapidity of the same.</p> - -<div class="figcenter illowe49_5" id="i_055"> - <img class="w100" src="images/i_055.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 5.</p></div> -</div> - -<p>A further point for consideration in the duration of an alteration -in a vital condition in producing a stimulant action is the -<i>length of time the stimulus remains after reaching its highest -point</i>. In the forms of stimuli occurring in nature the duration -of the alteration after reaching its highest level can vary considerably. -The stimulus may remain indefinitely at a certain level, -when this is once reached. (Figure <a href="#i_055">5</a>, A.) The alteration likewise -persists. This would be the case, for instance, with the -changes of concentration in the transfer of an organism from -fresh into sea water. The alteration can also, however, immediately -after attaining its highest level, return, so that the original -state is at once reestablished. (Figure <a href="#i_055">5</a>, B and C.) -Here it is a case of a quick deviation in the external vital conditions. A -<i>sudden jar</i> would be a case in point. Between these two extremes -we have all variations in the duration of all natural and experimental -forms of single stimuli.</p> - -<p>Now we arrive at the question: Has a prolonged stimulation -really a prolonged effect? This question might seem superfluous, -as from a conditional standpoint it is self-evident that every -alteration in any one of the conditions of a system is followed -by an alteration in the system. But this very question played an -important rôle in older physiology and led to prolonged discussions -for the reason that a special case was taken into consideration -in this connection, which at that time was not clearly understood. -<i>Du Bois-Reymond</i><span class="nowrap">,<a id="FNanchor_35" href="#Footnote_35" class="fnanchor">35</a></span> as a result of his investigations on -the nerve muscle preparation of the frog, formulated a law of -nerve excitation, according to which it is not the <i>absolute value</i> -of the intensity of the constant current which produces an excitation -of the nerve and contraction of its muscle, but an alteration<span class="pagenum" id="Page_57">57</span> -of the intensity from one moment to another. The more rapidly -these changes are produced, the greater is the excitation. His -arguments were based upon the fact that a contraction can only -take place on the “making” or “breaking,” or by rapidly strengthening -or weakening the constant current; it is possible to subject -a nerve muscle preparation to a current of considerable strength -without a muscle contraction resulting, provided it is slowly -increased. One might be disposed to conclude from this that -the constant current, when showing no fluctuations, has no stimulating -effect whatsoever. Should this observation be carried -even further and the attempt made to extend it into a general law -of excitation by assuming that the effects of stimulation are only -produced by variations in the intensity, not by its continued -duration, one would commit the error of judging the occurrence -of a stimulus only by the unsatisfactory criterion of an abrupt -muscle contraction. Today we know with positiveness that a -continued effect also exists during the uninterrupted flowing of -a constant current in nerve or muscle, though much weaker, however, -than in the case of the excitations produced by sudden -fluctuations of the intensity. This is shown in the nerve by an -altered excitability, which continues at the poles during the whole -duration of the current. In the region of the anode the excitability -is diminished, in that of the cathode it is increased. An -excitation can also be demonstrated which extends from the -cathode through the nerve, which can easily be detected by -sufficiently delicate methods. Among other effects of prolonged -stimulation is that of cathodal contracture, which remains localized -in the region of the cathode and which excitation persists as -long as the current continues. This permanent excitation can be -particularly well observed in the single cells of the rhizopods. -If a constant current is allowed to flow through an <i>Actinosphærium</i><span class="nowrap">,<a id="FNanchor_36" href="#Footnote_36" class="fnanchor">36</a></span> -the straight, smooth, ray-shaped pseudopods of the -cell body at the moment of “making,” show evidence of contraction -by being drawn <i>in</i>, particularly those directed towards<span class="pagenum" id="Page_58">58</span> -the anodic and in less degree also those towards the cathodic -pole. This excitation, greatest at the time of “making” of the -current, though diminishing rapidly in intensity during its continuance, -remains, however, to a less degree, and leads to a -progressive disintegration of the protoplasm on the side towards -the anode, which lasts until the current is again broken. (Figure -<a href="#i_058">6</a>.) Thus even though there can be no doubt, on the one hand, -that the effect of stimulation, which appears at the moment of -the entrance, is to produce alterations, which develop very rapidly, -and that by a continuation of this state there is a more or less -rapid fall to a low level; on the other hand, it is just as certain -that the alterations in the living system persist throughout the -duration of the changed external conditions, or to put it more<span class="pagenum" id="Page_59">59</span> -concisely: the effect of the stimulus never wholly disappears -unless the changes in the external vital conditions return to their -original state.</p> - -<div class="figcenter illowe25" id="i_058"> - <img class="w100" src="images/i_058.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 6.</p> - -<p class="tac"><i>Actinosphaerium eichhornii.</i> Four stages showing the progressive influence -of a constant current. Protoplasmic disintegration at -the side toward the anode.</p></div> -</div> - -<p>But more, an effect of the stimulus cannot indeed take place -<i>without</i> a certain duration of stimulation, which is related in <i>its</i> -turn to the rapidity of reaction of particular living system. This -can be much more readily observed in more slowly reacting substances. -<span class="nowrap"><i>Fick</i><a id="FNanchor_37" href="#Footnote_37" class="fnanchor">37</a></span> first proved this fact on the muscle of the <i>Anodonta</i>. -I have also been able to demonstrate the same fact in the -slowly reacting sea <span class="nowrap">rhizopods<a id="FNanchor_38" href="#Footnote_38" class="fnanchor">38</a></span> by the use of the constant current. -When <i>Orbitolites</i> is stimulated with a constant current lasting -approximately the tenth of a second, no response is seen in its -extended pseudopods, which are directed towards the poles. -The same is the case if the induction current is employed. Only -when the constant current of the uniform strength lasts -approximately .05 seconds, a barely perceptible response occurs, -manifested by the sudden stoppage of the centrifugal flowing of -granules in the anodic pseudopods, which, however, after the -lapse of one to three seconds continues again unaltered. Should -the duration of the constant current be still further prolonged, -typical symptoms of contraction are seen being manifested by a -heaping up of the protoplasm in the pseudopods in the form of -spindles and balls, whilst the protoplasm flows in a centripetal -direction towards the central cell body. (Figure <a href="#i_060">7</a>.)</p> - -<p>Two effects can be realized by the alteration in the living -system as the result of prolonged stimulation. Either a new -state of equilibrium is established by the prolonged action, or -sooner or later death develops. In considering both results, however, -we will ignore for the present the fact that every living -system in the absence of such prolonged stimulation is always in -a state of change, i.e., development. Only with this restriction -can an equilibrium of the living system be spoken of.</p> - -<p><span class="pagenum" id="Page_60">60</span></p> - -<div class="figcenter illowe36_25" id="i_060"> - <img class="w100" src="images/i_060.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 7.</p> - -<p class="tac"><i>Orbitolites complanatus.</i> A—Before stimulation. B—Under influence of a constant current.</p></div> -</div> - -<p><span class="pagenum" id="Page_61">61</span></p> - -<p>It is sometimes the case that under the influence of a stimulus -a new equilibrium is developed, which may remain as long as -the stimulus persists. This most frequently occurs as a result -of <i>weak</i> stimuli. That which is usually termed “individual -adaptation” belongs in this category. Likewise some of the natural -and artificial immunizations may also be included. The continued -stimulation in such cases of adaptation as we learned -before in the example of <i>Amœba limax</i> and <i>radiosa</i> or <i>Branchipus -stagnalis</i> and <i>Artemia salina</i> becomes a vital condition for the -living substance in its new state.</p> - -<p>The other result, namely, that of death ensuing sooner or -later, is most frequently produced by stronger stimulation. -Through the effect of the prolonged stimulation, the change in -the living system is so great that all harmonious interaction of -the various processes of life become after a time impossible. -The disturbance of this equilibrium after a longer or shorter time -becomes so great that life ceases. By far the greater number of -all diseases furnish examples of this kind. Disease is nothing -else but reaction to stimulation. Should a constant stimulus persist -and if the development of a new equilibrium of this system -is not established, the result is premature death.</p> - -<p>In most cases, as, for instance, the nerve impulses which move -toward an organ, or better still the electrical stimuli as used for -experimental purposes, it is not a question of a permanent but -of a temporary alteration in the external vital conditions. The -stimulus starts, then ceases after a longer or shorter period. In -this way there is added to the deviation at the start also the alteration -at its termination. The latter takes place with different -degrees of rapidity, in a manner analogous to that of the initial -alteration, and can bring about response. With this the curve -of the duration of the course of the stimulus becomes somewhat -more complicated and in consequence a like effect is observed in -the response. The “making,” duration and “breaking” of the -constant current furnishes the example of this type. The -“making” of the current being a quick alteration calls forth a -strong and sudden excitation (in the muscle contraction); the -continuation of the current maintains weak excitation of equal<span class="pagenum" id="Page_62">62</span> -intensity (in the muscle a continued contraction) and the -“breaking,” being a sudden alteration, is followed again by a -stronger excitation (in the muscle a contraction). The duration -of the change can, however, be so short that its intensity does -not remain at two periods of time at the same height, but instead -the ascent of the intensity is immediately followed by its descent -to zero. Induction shocks of short duration, the duration of -which have been observed more in detail especially by <i>Grützner</i><span class="nowrap">,<a id="FNanchor_39" href="#Footnote_39" class="fnanchor">39</a></span> -offer typical examples. Here a single effect of the stimulus results -from the rise and fall of the intensity curve. Hence the induction -shocks as momentary stimuli are universally used for experimental -purposes.</p> - -<p>In contrast to the single stimuli, which find their ideal in -induction shocks, another form of stimulation should receive our -attention, namely, the series of stimuli which produce a rhythmical -alteration of vital conditions. These show among their -complex combination of simultaneous and successive actions of -their single stimuli relatively the simplest and most easily understood -regularity in their effects. They are of particular interest, -because they develop in the normal physiological happenings of -the animal body in the form of rhythmical intermittent impulses -of the nervous system.</p> - -<p>Here again it is self-evident that with regard to the course of -response, we must first consider the character of the single -stimulus of the series, and this must be done from all those standpoints -already here discussed. However, a new factor is met -with here, that is, the frequency of the single stimuli of the series, -or that which has the same meaning, the duration of the intervals -between them. This is a feature upon which the result of stimulation -depends in a very high degree. But here, too, however, -it is not a case of the absolute frequency of the single stimulus, -but simply of the relative frequency in regard to the rapidity of -reaction of the particular living system. I should like to remark -here that it is of greatest importance whether the interval between -the two single stimuli of the series is sufficiently long or not to<span class="pagenum" id="Page_63">63</span> -allow the living system time to completely recover from the effect -of the <i>preceding</i> stimulus. In the cases, for instance, where we -have recovery, we have the same rhythm of stimulation as that -of response. When recovery <i>does not</i> occur, interferences of the -response are developed, which are of great physiological importance, -with the analysis of which we shall later on find occasion -to occupy ourselves in detail. The physiological example for these -stimuli is the rhythmical discharge of impulses of the nerve -centers; the physical method, which is most widely used for -experiments, is the faradic current.</p> - -<p>It is apparent that the question of frequency must again be -combined with all those factors previously discussed in connection -with the <i>single</i> stimulus. In consequence another complication -arises and with this another point must be taken into -consideration, namely, the fact that the duration of the single -stimulus in a series undergoes alteration by increasing frequency -beyond a certain limit. Beyond this limit the duration of the -single stimulus must become less and less. As the result of the -fact that stimulation is, as we have seen, dependent on the duration -of stimulus, it is evident that, depending upon the rapidity -of response of the living system, sooner or later the rhythmical -stimulation must become ineffectual. Nevertheless, this effect -of shortening the duration of the single stimulus can be compensated -by a corresponding increase of its intensity. In this connection -<span class="nowrap"><i>Nernst</i><a id="FNanchor_40" href="#Footnote_40" class="fnanchor">40</a></span> showed a very simple relation for induction currents -of higher frequency of interruption, which furnishes a law -according to which such a compensation takes place. In conjunction -with <i>Barratt</i> he found, namely, that the intensity must increase -proportionately to the square root of the number of single -stimuli if the threshold value of the stimulus is to be maintained, -that is, I : √m = const., in which <i>I</i> is the intensity of the current -and <i>m</i> the frequency of interruptions. The limits of the validity -of this law cannot at present be conclusively established.</p> - -<p>This exhausts the small number of elementary factors concerned -in the course of the stimulation, and which are of importance<span class="pagenum" id="Page_64">64</span> -in considering its effect. The combination of the different -varieties of these single factors, that is, the nature, the direction, -the intensity, the rapidity, the duration and number of alterations -in the external vital conditions of the organism produce -the enormous variety of effects of stimulation which we observe -in the living world.</p> -<hr class="chap x-ebookmaker-drop" /> - -<div class="chapter"> -<p><span class="pagenum" id="Page_65">65</span></p> - -<h2 class="nobreak" id="CHAPTER_IV">CHAPTER IV<br /> -<span class="title">THE GENERAL EFFECT OF STIMULATION</span></h2> -</div> - - -<div class="blockquot"> - -<p class="pl2hi2"><i>Contents</i>: Various examples of the effects of stimulation. Metabolism -of rest and metabolism of stimulation. Metabolic equilibrium. Disturbances -of equilibrium by stimuli. Quantitative and qualitative -alterations of the metabolism of rest under the influence of stimuli. -Excitation and depression. Specific energy of living substance. -Qualitative alterations of the specific metabolism and their relations -to pathology. Functional and cytoplastic stimuli. Relations of the -cytoplastic effects of stimuli to the functional. Hypertrophy of -activity and atrophy of inactivity. Metabolic alterations during -growth of the cell. Primary and secondary effects of stimulation. -Scheme of effects of stimulation.</p> -</div> - - -<p>In the foregoing lectures we have had occasion to touch more -or less often on the subject of the effects of the stimuli. This -was the case, however, only when it appeared necessary to obtain -a systematic knowledge of the stimuli and the differentiation of -the individual factors. We will now proceed to consider the -effect of stimulation in a more systematic manner. The conditional -method of observation, however, will remain our guide.</p> - -<p>We have already pointed out the relations between the conception -of stimulation and that of vital conditions, now we will -consider that of the effect of stimulation with that of vital processes. -Nevertheless, the <i>effect</i> of stimulation being a manifestation -of the vital process is not, therefore, in opposition to the latter -as such. Hence the question presents itself as to the connections -between vital process and the effect of stimulation.</p> - -<p>When we study the motile flagellate infusorium <i>Peranema</i> -swimming undisturbed in water, we observe that the swimming -movements are absolutely regular in character. The elongated -cell body remains unaltered in shape. The long flagellum is -extended in a perfectly straight line in the axis of the body and<span class="pagenum" id="Page_66">66</span> -only the extreme end lashes with regularity through the water -(Figure <a href="#i_066">8</a>, A). There is majestic grace in this perfect uniformity -of motion. The picture suddenly alters the moment the <i>Peranema</i> -is influenced by the slightest jar. The whole flagellum at once -executes a few violent movements (Figure <a href="#i_066">8</a>, B), the body draws -together, soon stretches itself again and swims immediately after, -in another direction, with the same majestic calm as before.</p> - -<div class="figcenter illowe12" id="i_066"> - <img class="w100" src="images/i_066.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 8.</p> - -<p class="tac"><i>Peranema.</i> A—Swimming in non-stimulated condition. -B—Mechanically stimulated at the end of the flagellum.</p></div> -</div> - -<p>Another instance. A number of fertilized eggs of the sea -urchin are placed in a watch glass in sea water. The temperature -of the water should correspond with the mean temperature in -which the animals live in the sea, averaging about 15° C. The -eggs begin to form grooves and to develop slowly by progressive -division. In another glass we observe a second sample of fertilized -eggs of the same kind and under the same conditions, but -in this case we increase the temperature to 25° C. The increased -temperature brings about a decided increase of segmentation and -the same stage of development is reached in less than half the -time. The increased temperature, therefore, increases the development. -Further we take a third sample of the same urchin -eggs in a watch glass with sea water of 15° C. and add a little<span class="pagenum" id="Page_67">67</span> -sea water mixed with ether. The development of the eggs now -comes to a standstill. The narcotic has produced an inhibition -of development.</p> - -<p>To quote another instance. <i>Bacterium phosphorescens</i> having -been bred upon a putrid fish are exposed in the culture fluid to -the air. In the dark the bacteria give forth a phosphorescent -light. Then the culture fluid containing the bacteria is put into -a glass receptacle, which can be rendered air-tight and all oxygen -excluded. After a short time the light formation ceases completely. -The absence of oxygen has here had a depressing effect -and it is only after air has been again introduced that light is once -more produced.</p> - -<p>Lastly, an example from the group of mammals may be cited. -The metabolism of a dog in complete rest is examined for a prolonged -length of time and we ascertain the values of the oxygen -consumption, the carbon dioxide production, and the nitrogen -elimination in the urine. Under the same nutritive conditions -the animal is then allowed to work from time to time in a treadmill. -During these working periods impulses of excitation are -continually conducted to the muscles from the nervous system. -It is now found that under the influence of the constantly recurring -stimuli the quantity of nitrogen in the urine has only -very slightly augmented, whereas the consumption of oxygen and -the production of carbon dioxide has markedly increased.</p> - -<p>What conclusions can be drawn from these instances of response -to stimuli, of which any number could still be quoted? -They show us, first of all, that a state or process existing under -given conditions, is altered by the influence of the stimulus. This -is a fact, however, which could be expected from the beginning -and is self-evident, for stimuli are alterations in the vital conditions, -and when these are altered the state of the system or the -happenings thereof must also alter. The question with which -we are here more closely concerned, however, is a somewhat -more detailed characterization of the state or process itself, as -well as that of alterations produced by the influence of the stimulus. -The instances of response to stimuli already cited furnish -us with information in both kinds.</p> - -<p><span class="pagenum" id="Page_68">68</span></p> - -<p>In all these examples, the living processes occur with equal -constancy and unaltered rapidity, provided a stimulus is not -operative. Here, however, the gradual alterations, the result of -development, must not be overlooked. An excellent example of -this is seen in the eggs of sea urchin, where the development is -readily perceptible. In all these instances, however, the condition -is immediately changed by the influence of the stimulus. -The previous state of constancy in the vital process is disturbed. -The rapidity of its course is changed, being either increased or -decreased, and the specific vital manifestations concerned are, -therefore, augmented or diminished. We will now study the -vital process with the methods of chemical investigation and consider -the problem from the standpoint of metabolism. It may -be noted here, that other methods, such as the transformation of -energy or changes of form of the living system, would serve -equally well as indicators for this purpose. In every instance -there is a uniformity of the processes; the difference, however, -is in the nature of the indicators and the terms used. The methods -and the terms used in chemical investigation and description -reach proportionately much deeper than those employed when -the transformation, energy or the variations of form of the -organisms are studied, and permit of the finest differentiation of -the processes. The atomistic terminology is, for this reason, -preëminently fitted for the description of vital processes. When -we study the vital process metabolically, we can, as shown in the -above-mentioned instance, divide the processes into a <i>metabolism -of stimulation</i> in contradistinction to a <i>metabolism of rest</i>.</p> - -<p>The comprehension of <i>the metabolism of rest</i> demands a closer -consideration. On closer observation we must say that this -much-used conception is merely an abstraction nowhere realized -in a strict sense. In truth, there is nowhere in nature a metabolism -of rest. No cell exists which in a mathematical sense -remains for even two successive moments under absolutely the -same external conditions. If we imagine a single living cell of -the simplest kind living in a fluid nutritive medium, and if we -suppose its body and surroundings so magnified that the single -molecules and atoms were respectively of the size of cannon and<span class="pagenum" id="Page_69">69</span> -rifle balls, the boundary between cell and medium would represent -a battlefield, on which a heavy bombardment is constantly -taking place. The rain of shot of food and oxygen molecules -penetrating into the cell from the medium, would produce an -explosion in the existing ammunition depots, now at one point, -now at another, creating great breaches through which new -masses of shot would reach the interior. The fragments of these -exploding molecules would be flung out here and there into the -medium and would stem, now at this, now at that point the -besieging masses of shot. In this wild confusion on the whole -boundary line between cell and medium there can be no question -of rest or even equilibrium at any point. The human mind, -superior to the material world as we may deem it, is yet always -dependent upon the results of experience, and even in its highest -flights cannot become wholly emancipated from the concrete -objects. For this reason it is of great purport to conceive processes -whose dimensions cannot be observed even microscopically, -as enlarged and transformed to that method of expression most -familiar to the human mind, namely, in the field of optical presentation. -This method is of great help in aiding our understanding, -and likewise here, even in the resting state, the cell is -constantly exposed to local effects of stimulation, now at one -point, now at the other. The conception of the metabolism of -rest is, therefore, in a strict sense fiction.</p> - -<p>Nevertheless, the conception of the metabolism of rest as an -abstraction can be of value provided always that it is strictly -and definitely limited. It must, for instance, not be applied to -short periods of time. The continued local and temporary responses -to stimulation constitute a mean value which, although -composed of numberless small sub-threshold responses, we can -still call a metabolism of rest. Weak stimuli have, however, as -already seen, the property, provided their influence is constant, -of effecting an adaptation to the stimulus on the part of the living -organism, so that the stimulus becomes a vital condition for this -state of the organism. Hence the continued existence of a vital -process resulting from the constant action of stimulation is made -possible. That which we are in the habit of calling metabolism<span class="pagenum" id="Page_70">70</span> -of rest, would, therefore, be metabolism of stimulation, but one -that is characterized by a constantly existing metabolic equilibrium.</p> - -<p>This “<i>equilibrium of metabolism</i>” distinguishes the metabolism -of rest from that form which is developed in response to temporary -stimulation, in that every temporary stimulation has the -effect that it disturbs the existing metabolic equilibrium for a -longer or shorter time. This disturbance of the equilibrium of -metabolism can in contrast to the metabolism of rest be termed -“<i>metabolism of stimulation</i>.” In this, but only in this sense, can -these two conceptions be placed in opposition and used to characterize -the processes in the living organism. The conception -of the metabolism of stimulation must always stand in relation -to that of an equilibrium of metabolism characterized by a constantly -existing metabolism of rest, just as the conception of -stimulus can likewise only be defined relatively to that of vital -conditions.</p> - -<p>Nevertheless, the conception of the equilibrium of metabolism -requires a somewhat more accurate definition before we can feel -justified in using this term. Definitions are always trite, nevertheless -they are the basis of all our thinking and a definite understanding -is impossible unless we first clearly fix their contents. -The history of theology and philosophy even to the most recent -times furnishes a long line of instances in which the most eminent -minds, for the want of fixed definitions of the conceptions which -they made use of, failed to find a mutual basis for their ideas. -Without a sharp definition every conception is a mere word, -which each individual, according to his personal experiences and -views, endows with a different meaning. To such conceptions -we may apply Mephisto’s ironical comment to his pupil:</p> - -<p class="tac fs90"> -“Mit Worten lässt sich trefflich streiten,<br /> -Mit Worten ein System bereiten.”<br /> -</p> - -<p>The natural sciences, if they are to retain their reputation for -exactness and precision, require the strictest and clearest definitions -of all conceptions. If we seek to penetrate more deeply -into the varied happenings in concrete conditions, we must reconcile<span class="pagenum" id="Page_71">71</span> -ourselves to dry pedantic definitions. In the case of that -of the equilibrium of metabolism indeed we have before us one -of the most important conceptions in physiology.</p> - -<p>The justification to speak of an equilibrium of metabolism -arises from investigations of metabolism in mammals. The classical -experiments of the previous century, as is well known, have -shown that in the adult mammal receiving a necessary quantity -of nourishment and in a state of rest, the intake and outgo of -the constituent elements are the same. The carbon, hydrogen, -nitrogen, oxygen, sulphur, phosphorus, etc., taken in during -a lengthened period in the form of food and respired air, -appear again in equal quantity, in other combinations, in the -products of excretion of the organisms. Calorimetric experiments -likewise show an equilibrium of the consumption and elimination -of energy. If there thus exists an equilibrium of metabolism for -the whole cell community, it is clear that the same must also apply -to the individual cell, that is, for all living substance. The quantitative -relations of the foodstuffs taken <i>in</i>, and the excreted metabolic -products given <i>off</i>, are, however, merely a standard of the -metabolism. We know that the former are used to build up new -living substance and that the latter represent the result of disintegration -of that previously existing living substance; for we -find, as in the case of the plant, complicated protein combinations, -which are built up from comparatively simple constituents of the -food and are again broken down into comparatively simple substances. -And so the building up and breaking down processes -form the two great processes of metabolism, which with <span class="nowrap"><i>Hering</i><a id="FNanchor_41" href="#Footnote_41" class="fnanchor">41</a></span> -we can briefly call “<i>assimilation</i>” and “<i>dissimilation</i>.” In the -terms assimilation and dissimilation are comprised the sum of <i>all</i> -processes of construction and disintegration in the living organism. -It is apparent that equilibrium of metabolism occurs when -assimilation and dissimilation are equal. The formula A : D, that -is, the relation of the sum of all assimilation to the sum of that of -all dissimilative processes, is a factor of fundamental importance -in the study of the course of the vital processes, for upon its<span class="pagenum" id="Page_72">72</span> -value depends individual vital manifestation, and, in fact, the continuation -of life. I have, therefore, designated the formula -A = D “<i>Biotonus</i>.” The equilibrium of metabolism would then -be characterized by the <span class="nowrap">biotonus<a id="FNanchor_42" href="#Footnote_42" class="fnanchor">42</a></span> of a living organism being -equal to <i>one</i>. This would be the metabolism of rest of a system, -whilst its metabolism of stimulation would consist in an alteration -of the <i>biotonus</i>. But is this state of living substance strictly -speaking ever realized?</p> - -<p>In considering the nature of the equilibrium of metabolism -one factor has been disregarded which must be taken into account -at every point; this is growth. Growth changes, although -varying more or less, are never absent during the life of the -organism. An equilibrium of metabolism never exists in a -strictly mathematical sense, and here again we are working with -a conception which is faulty, because it is an abstraction, originating -from experience with rather too restricted boundaries. -But an error of which one is aware is not dangerous. In mathematics -we also consciously reckon with errors, without the result -being altered. In the before mentioned cases the equilibrium of -metabolism was maintained, because the investigations involved -only a short time in an adult mammal. In the adult mammal the -growth processes occur very slowly, so that alterations within -a relatively short time are not demonstrated.</p> - -<p>If it were possible to subject the adult mammal to metabolic -or calorimetric experiments, extending for years, it would be -found that the intake would be qualitatively and quantitatively -different at the end of the investigation and that the same would -apply to the outgo. In the growing egg cell this takes place with -much more rapidity. In the organism which rapidly grows, it -can be seen at once that the quantity of the outgo of the products -of disintegration cannot be equal to that of the intake of foodstuffs. -If biotonus were equal to one, the organism could not -grow. Equilibrium of metabolism can only be understood when -we take into consideration a period of time in which the alterations -in growth take place with such imperceptible slowness that<span class="pagenum" id="Page_73">73</span> -the resultant error is inconsiderably minute. This period of time -is of greatly varying length in different living organisms and this -fact must be taken into account in every living form. Only with -this restriction can we justify the use of the term “equilibrium -of metabolism.” Then, however, its use is of great value.</p> - -<p>The <i>metabolism of stimulation</i> is then a disturbance of the -metabolism of rest, that is, a disturbance of the equilibrium of -metabolism through the effect of stimuli.</p> - -<p>The question here follows: Is there a <i>constancy of this interruption -of the equilibrium of rest produced by the stimulus</i> which -can be formulated into a general law? To begin with, the number -of possible responses are greater than the variety of forms of -living substance, for every living organism with its specific properties -can undergo alteration in its metabolism in various directions. -Thereby results an infinite number of manifold reactions -to stimuli. However, in answer to the question, in which direction -the change in the specific metabolism of rest in response to a -stimulus takes place, we find a comparatively simple scheme of -general reaction. All phenomena can change in their rapidity as -well as in their nature. That is quantitatively and qualitatively. -In this way the specific vital process of an organism can be altered -by the stimulus, on the one hand, in its rapidity; on the other, in -the manner of its action.</p> - -<p>The majority of all temporary responses to stimuli consist in -<i>alterations of rapidity of the vital process</i>, and form either a -quickening or retardation of its course. The former is manifested -in a strengthening or an increase, the latter in a decrease -or repression of the specific action of the living organism. The -stimuli have the same effect as in the case of the catalysers in -chemical processes. According to <span class="nowrap"><i>Ostwald’s</i><a id="FNanchor_43" href="#Footnote_43" class="fnanchor">43</a></span> well-known definition -of catalysis a catalyser is a substance which, without -appearing in the final product of a chemical reaction, alters its -rapidity. This group of reactions can, therefore, be referred to -as “<i>catalytic stimulation and response</i>.” When the response -consists in <i>increase</i>, we speak, in a physiological sense, of an<span class="pagenum" id="Page_74">74</span> -excitation, and when there is decrease in the vital processes, we -speak of a depression.</p> - -<p>The conception of <i>excitation</i> and <i>depression</i> are purely empirical. -They are terms for real things, referring, in fact, simply to -alterations in rapidity of life process, which can be as readily -observed as the process itself. I wish to lay particular stress on -this fact, for the reason that <span class="nowrap"><i>Cremer</i><a id="FNanchor_44" href="#Footnote_44" class="fnanchor">44</a></span> has recently made the -extraordinary statement that I have introduced hypothetical processes -into the definition of the conception of excitation. I have -always considered excitation as merely an increase or change of -intensity of the specific actions of a living system, and as such is -an established process without a <i>trace</i> of the hypothetical element<span class="nowrap">.<a id="FNanchor_45" href="#Footnote_45" class="fnanchor">45</a></span> -If, however, the excitation process is to be regarded as something -<i>absolute</i>, as a mysterious state <i>sui generis</i>, which is entirely independent -and totally unlike the metabolism of rest, then, of course, -it would appear utterly incomprehensible and would be without -purpose. As an <i>absolute</i> process excitation is merely a meaningless -word. Excitation and depression are <i>relative</i> conceptions -and can only acquire meaning when the process which is excitated -or depressed is more closely defined. This is the specific -vital process of a given organism, and the two conceptions only -have meaning in relation to it. The conception of the vital process, -however, is one directly gained from experience. However -complex or difficult to analyze the process may be, it still is as -little hypothetical as that of the combustion of carbon into carbon -dioxide, or the revolving of the earth around the sun. It can be -looked upon as something positive and real. Quite another -question is the manner in which we are to consider the mechanism -of the vital process. In analyzing this mechanism we cannot, at -least in the present state of our knowledge, entirely dispense with -hypothesis. But these hypotheses are in no way involved in the -<i>definition</i> of the process of excitation. If we look upon every<span class="pagenum" id="Page_75">75</span> -excitation or depression produced by a stimulus as an alteration -in rapidity in the specific vital process of a given organism, we -are thereby expressing the same fact which <i>Johannes Müller</i> has -termed “<i>specific energy</i>.” We give, however, the doctrine of -specific energy a more general application in so far as it comprehends -not only the increase but likewise the decrease of activity -in response to stimuli. <i>Johannes Müller’s</i> doctrine of specific -energy of the living substance at all times has been the subject -of most animated discussion. When I refer here to the specific -energy of living substance, it is with the knowledge that <i>Johannes -Müller</i> did not use this expression of “living substance” in this -connection. He was already acquainted, however, as we have -seen, with the fact of the existence of the specific energy of all -living structures. For appertaining to the muscle he says: “This -is universal in all organic reaction.” The reason why the doctrine -of <i>sense energy</i> has become of importance in the discussion -of the specific energy of the living substance, is in consequence of -the theoretical interest, resulting from its connection with the -nature of the specific energy of our <i>sense substances</i>. The controversies -on this subject are still far from settled<span class="nowrap">.<a id="FNanchor_46" href="#Footnote_46" class="fnanchor">46</a></span> Indeed, -according to the special philosophical standpoint taken by an -observer, the existence of a specific energy of the senses is -acknowledged or disputed. For any one acquainted with the -general physiological reaction to stimuli, such a discussion is -wholly without purport. The sense substances have as a matter -of course in common with all living substances their specific -energy, that is, the influence of stimuli can produce an increase -or decrease of their specific vital processes. “Specific energy” of -“sense substance” in this sense is like that of all other living substances, -a fact. In that the psychical capability of these sense -substances, in which we include not only the peripheral, but also -the central portion, are dependent upon their specific vital processes, -it must be self-evident that the excitation and the suppression -of sense sensation can be brought about by adequate and<span class="pagenum" id="Page_76">76</span> -inadequate stimuli, no matter what one may think of the relations -between physical and psychical phenomena.</p> - -<p>The only debatable question is that concerning the limits of the -validity of the doctrine of the specific energy of living substances. -This question will involve our attention when we have analyzed -somewhat more closely the happenings in the living substance -taking place under the influence of stimuli. We will, therefore, -return later on to a more detailed consideration of the last question. -Nevertheless, we will here refer to a fact which, upon a -superficial observation, seems to restrict the validity of the conception -of the specific energy of living substance.</p> - -<p>In contrast to those reactions to stimuli, which consist merely -in the changes of a rapidity of the specific vital process, are -another group of reactions in which the influence of stimuli leads -to qualitative alterations in the specific vital process. In these -instances, the influence of the stimulus directs the metabolism of -rest into new channels, so that chemical processes occur in the -cell, which under ordinary circumstances do not take place. This -group of reactions, which I wish to term “metamorphic stimulation -and response,” are chiefly observed where weak stimuli act -continuously upon the living substance. These are essentially -weak chemical stimuli, which last for a prolonged period or frequently -reoccur in the life of the cell community. Examples of -this are found in the continual ingestion of alcohol and other -poisons by the human being, or in the formation of metabolic -products of bacteria, etc. The majority of <i>chronic</i> diseases -belong to this group of reactions; disease being simply response -to stimulation. Disease is life under altered vital conditions and -altered vital conditions are stimuli. This simple and self-evident -fact shows the immense importance which the knowledge of the -general laws of the physiology of stimulation has for pathology. -The pathologist, who does not wish to confine his observations -to a purely superficial symptomatology or a merely histological -morphology, must seek above all to penetrate as deeply as possible -into the nature of the general reactions to stimulation in the living -organism. It is the essential point which meets him everywhere. -In spite of their great interest for pathology, however, it is just<span class="pagenum" id="Page_77">77</span> -these qualitative alterations of the normal vital process produced -by continuous stimulation which have up to now been least analyzed. -In this field we expect much from pathological investigation -which alone has the immense amount of material at its -command. This will take place only when pathology adds to the -almost exclusively histological direction of investigation, that also -of experimental physiology. It is true that the problems of the -qualitative alterations of a vital process by chronic stimulation -are much more complicated than those of the rapid responses to -temporary stimuli, consisting simply in mere alterations of -rapidity of the specific vital process. An understanding of the -nature of the former can only be expected when a deeper knowledge -of the latter is gained, for, as will be seen presently, there is -the closest relation between the two groups.</p> - -<p>The reactions to catalytic stimuli of short duration, which produce -merely an alteration of rapidity in the specific phenomena -of a living organism, show on a closer analysis the interesting -fact, that it is not always the <i>entire</i> metabolic processes of the -cell which are perceptibly quickened, but that only certain constituent -processes of the same are affected by the action of excitation. -This is the <i>more</i> noticeable, as, considering the close correlation -which all the individual links of the chain of metabolism -bear to each other, it is to be expected that the alteration in rapidity -of <i>one</i> would be followed at once by a corresponding change -in all the others. An example of the case in question, in which -a special constituent process may be predominately affected, is -that of the specific activity of a muscle which is repeatedly stimulated -by nervous impulses. Since the classical investigation of -<i>Fick</i> and <span class="nowrap"><i>Wislicenus</i><a id="FNanchor_47" href="#Footnote_47" class="fnanchor">47</a></span> on themselves, and of <span class="nowrap"><i>Voit</i><a id="FNanchor_48" href="#Footnote_48" class="fnanchor">48</a></span> on the dog, we -know that the nitrogen metabolism is practically unaltered by -the functional use of the muscle and there is a remarkable -increase only in the breaking down of the nitrogen-free groups<span class="pagenum" id="Page_78">78</span> -of the living substance. Sufficient importance has not as yet been -attached to this knowledge. This fact not only has a particular -interest for the much-discussed question of the source of muscle -energy, but also affords a deeper insight into the metabolic activity -of the living substance. It shows us that we must not imagine -a purely linear linking of the individual constituent metabolic -processes, but rather, at least at certain points, a branching formation, -the individual members spreading in various directions. An -alteration in an individual member can occur without an immediate -change in the other branches. This <i>would not</i> be the case -if there were only a linear connection of the constituent processes, -for the breaking of a single member of the chain would be -followed by a change in all the following members.</p> - -<p>It shows us, further, that certain branches are more labile than -others. In the case referred to here, the branches of this system, -which bring about the nitrogen metabolism, are relatively <i>firm</i> -and <i>stable</i>, the branches, which are disturbed by the stimulus producing -functional activity of the muscle, are particularly <i>labile</i>. -I should like in passing to call here your attention to the fact that -as is well known, <i>Ehrlich</i><span class="nowrap">,<a id="FNanchor_49" href="#Footnote_49" class="fnanchor">49</a></span> in another field involving other conditions -and other experiences and considerations, has arrived in -analogous manner at his “side chain theory.” In order to have -an expression for those stimuli which involve rapid alteration of -the labile constituent processes and which are connected with the -specific action of the particular organism, I have called them -“<i>functional stimuli</i>,” and contrasted with them the “<i>cytoplastic -stimuli</i>.” In the latter the alterations produced include all the -constituent processes extending even to the stable processes of -nitrogen changes, and sometimes extend to complete disintegration -and rebuilding of living substance<span class="nowrap">.<a id="FNanchor_50" href="#Footnote_50" class="fnanchor">50</a></span> To the first group belong -all adequate stimuli within certain limits of duration and intensity, -and the greater part of inadequate stimuli of brief duration so<span class="pagenum" id="Page_79">79</span> -long as they do not exceed a certain intensity. To the latter -group belong in general all the stronger adequate and inadequate -stimuli of prolonged duration; such as extreme temperature, the -stronger electric currents, constant alteration in the supply of -food, water, oxygen, the prolonged or stronger influence of -extraneous chemical matter, etc.</p> - -<p>Considering the close correlation of the individual part processes -it would appear very strange, however, if a single one of -these could undergo an alteration of its rapidity without the -course of the rest of the processes being in the least influenced. -One cannot comprehend such <i>absolute</i> independence of a process -brought about by functional stimulation from all the other constituent -processes, particularly when this is of prolonged duration -and involves to a considerable extent the alterations in rapidity, -for the individual constituent processes are dependent in a -high degree upon the quantity of the particular chemical substances -of which the living system is composed. The cycle of -the individual constituent processes of this system is determined -in the most delicate manner in its rapidity and extent, by the -relative quantities of the individual substances. Associated with -an alteration in the rapidity of an individual constituent process, -there would also be a relative alteration quantitatively of the -substances. And with the increase in the <i>quantity</i> of the disintegration -products, and also the increase of the substances for -their replacement, there would result, during this time, an alteration -in the amount of interaction of the molecules of the other -constituent processes, so that these processes secondarily suffer -an alteration in rapidity which is perceptible after long continued -involvement of the functional part of metabolism.</p> - -<p>In fact, in the previously mentioned case of the functional -stimulation of the muscle, the proof has been furnished that a -long-continued increase of the functional metabolism is followed, -although to a less extent, by an increase in the entire -cytoplastic metabolism. <i>Argutinski</i> showed this on himself in -1890 in <i>Pflüger’s</i> laboratory. He found, namely, that after the -exertion of a long walk in a hilly district, a considerable increase -of nitrogen excretion in the urine took place, which extended<span class="pagenum" id="Page_80">80</span> -over the succeeding two or three days. This increase of the -nitrogen metabolism in its totality is not nearly as great as that -of the breaking down of nitrogen-free substances, but it is, -nevertheless, present and shows us that functional metabolism -cannot experience a lasting excitation without being followed by -secondary results in the entire cytoplastic metabolism. This -fact is even more strikingly illustrated in the alteration of the -entire volume of a living organism as produced by the lengthened -duration of functional stimulation. It has been long known, that -the muscle as the result of frequent functional excitation by -means of adequate nerve impulses, that is, prolonged activity, is -considerably increased in size, whereas in the absence of such -it loses more and more in volume. A hypertrophy of activity, -produced by functional stimuli, and the atrophy of inactivity, the -result of the discontinuance of the functional excitation, is universal -and can be observed in the various tissues of our body. -We see it, for example, in the glands; we see it in the skin and -we see it in the elements of the nervous system. <i>Berger</i><span class="nowrap">,<a id="FNanchor_51" href="#Footnote_51" class="fnanchor">51</a></span> for -instance, established the fact that the ganglion cells of the optic -lobe in the cerebrum of newborn dogs only reach their full -development when functionally excitated by adequate light stimuli -(Figure <a href="#i_081">9</a>, B), coming from the eye, whereas they remain in -the embryonic state when these light stimuli are eliminated. (Figure -<a href="#i_081">9</a>, A.) The cytoplastic increase of volume of the neurons -under the influence of functional stimuli is a fact of fundamental -importance for the entire happenings of the nervous system and -forms the physiological basis for reinforcement of reflexes, which, -in its turn, is essential for all acts of memory and intelligence. -For the increase in volume of the ganglion cell body is, when -functionally activated, accompanied at the same time by an -increase of specific capabilities and the intensity of discharge. -Its excitation impulses can, therefore, be conducted through a -greater number of neurons, with which it is connected, than would -be the case if development of the volume of the ganglion cell -increased to a less extent.</p> -<p><span class="pagenum" id="Page_81">81</span></p> - -<div class="figcenter illowe29_375" id="i_081"> - <img class="w100" src="images/i_081.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 9.</p> - -<p class="tac">A—Undeveloped ganglia cells in the optic lobe of a dog, the eyes of which have been -sewn up immediately after birth. B—Fully developed ganglia cells in the same -region of a normal dog of the same age. (After <i>Berger</i>.)</p></div> -</div> - -<p><span class="pagenum" id="Page_82">82</span></p> - -<p>The increase in volume under the influence of stimuli further -shows the relation between the group of those solely catalytic -effects of stimulation consisting in mere alterations of rapidity of -the specific vital process, and that of the metamorphotic effects -of stimulation, which manifest themselves in qualitative alterations -of the vital process. Simple observation shows us that a -qualitative change of individual constituent processes must necessarily -result from the increase of volume of a cell, and that considering -the close correlation of all the individual processes a -profound alteration of the entire metabolism must be produced. -I have already at another <span class="nowrap">place<a id="FNanchor_52" href="#Footnote_52" class="fnanchor">52,</a> <a id="FNanchor_53" href="#Footnote_53" class="fnanchor">53</a></span> treated these conditions more in -detail and will, therefore, only briefly refer to them here. If we -study the growth of a ball-shaped cell, we find that the surface -then increases as a square, and the volume as the cube. It therefore -follows that, by progressive volume increase, the conditions -for the interchange of substance with the surrounding medium -must become more and more unfavorable for those cell portions -situated in the interior, whereas those at the exterior are at much -greater advantage. This must lead to a constantly increasing -difference of the rapidity of the metabolic processes between the -peripheral and central portions. Accordingly, the intricate interworkings -of the individual constituent processes, the rapidity of -action of all which is intimately connected, are, therefore, followed -by corresponding alterations in the entire metabolism. -Sooner or later a stage is reached in which the individual constituent -processes become so limited that certain metabolic products, -which previously were broken down as soon as formed, can be -no longer eliminated and remain in the cell acting as foreign -bodies. In this way the relative quantity of the individual cell -substances become more and more altered, and as the course of -chemical processes occurs in accordance with the law of mass -action, the whole metabolism is directed into another channel, -so that finally new constituent processes take place, which were -formerly not possible. These in their turn produce deep-seated<span class="pagenum" id="Page_83">83</span> -alterations of the relations of the cell to its surrounding medium, -etc. Hence this mere increase of volume of the cell in growth -forms the source of an infinite mass of alterations in the activities -of cell metabolism, which we briefly term its “<i>development</i>,” and -which by constant progression, leads either to a process of cell -division, and with this to a correction of existing disorder, or -finally to irreparable disturbances ending in death. In this way -an inseparable relation exists between increase of volume and -the development of living substance. We have seen, however, -that the catalytic reactions of stimulation, which at first only -produce an alteration of rapidity of the individual constituent -processes, if of prolonged duration or of frequent recurrence, -secondarily effect a change of volume of the entire living organism. -One can, therefore, hardly reject the conclusion that seeing -the close interworkings of the individual part process of metabolism, -every change of rapidity of a single member, if of prolonged -duration or of frequent occurrence, must finally lead to -qualitative alterations of the entire metabolism. In consequence -there results an important dependence between catalytic stimulation -and metamorphic reaction. Indeed, it is not unlikely that -the metamorphic reactions, which are especially seen in the continued -effect of weak stimuli, result from alterations of rapidity, -which the individual members of the vital processes have -primarily undergone from this influence.</p> - -<p>It is perhaps expedient to cite a concrete instance in illustration. -A simple example is furnished by asphyxiation. If oxygen is -withdrawn from any living organism, the result is a depression -of its oxydation processes. Here there is primarily only a change -in rapidity, especially a retardation of oxydation processes. The -metabolism, however, proceeds, the disintegration of living substance -continues, although at a slower rate, but produces an -accumulation of other products. Whereas formerly during the -existence of a sufficient supply of oxygen an oxydative disintegration -of nitrogen-free groups into carbon dioxide and water took -place, both of which could easily be eliminated from the cell, the -anaërobic disintegration furnishes only complex products, having -a higher carbon content, such as lactic acid, fatty acids, aceton,<span class="pagenum" id="Page_84">84</span> -etc. These, being more difficult to excrete from the cell, accumulate. -These asphyxiation products have in their turn a depressing -effect and so on. In this way the whole metabolism is forced into -a wrong course. The accumulation of fat in those tissue-cells -with an insufficient blood supply, as we have seen in the case of -the fat metamorphosis, is doubtless brought about in the same -manner by relative oxygen insufficiency. The fatty acids accumulate -as products of an incomplete combustion and combine with -glycerine to form neutral fats. In like manner it may be that the -accumulation of amyloid substance in amyloid metamorphosis, of -lime salts in arteriosclerosis, etc., is produced by a primary -depression of the individual constituent processes of the particular -cells.</p> - -<p>The relation here described, of the catalytic stimuli to the production -of the metamorphic processes, leads us to the distinctions -between primary and secondary effects of stimulation. -Should the general fact be established, which has up to now only -been pointed out in individual cases, that all the metamorphic -processes are merely secondary results of primary alterations in -rapidity of individual metabolic constituent processes, <i>then the -primary reactions of every stimulus would consist purely in the -excitation or depression of the directly concerned constituent</i>. -Whether or not, as may be assumed, this primary effect of stimulation -applies to <i>all</i> stimuli, is a question which only the future -can answer.</p> - -<p>The metamorphic processes are not, however, the only secondary -effects of stimulation. The influence of long-continued -excitation of the functional constituent processes upon the entire -cytoplastic metabolism can be looked upon as a secondary response. -Therefore, they may be considered as a <i>secondary</i> effect -of stimulation which, in contrast to this <i>primary excitation</i>, may -be called the <i>secondary excitation</i>.</p> - -<p>Further: While the secondary excitation and metamorphic -processes are generally produced by the continued existing effects -of weak stimulation, we also observe as the result of a stimulus -of short duration or frequently repeated at brief intervals, but -otherwise not exceeding the physiological limits of intensity, a<span class="pagenum" id="Page_85">85</span> -secondary effect, which plays a very important part in the activity -of the organism. I refer to fatigue. Here a secondary depression -is developed in connection with the primary excitation, for -fatigue of a living organism must be characterized as a depression -of activity. This case shows that we have to distinguish between -a <i>primary depression</i>, as for example, produced by temperature -reduction, withdrawal of food, deficiency of oxygen, etc., which -occurs as a direct effect of stimulation, and <i>secondary depression</i>, -which as in fatigue is an <i>indirect</i> result of primary excitation.</p> - -<p>After the cessation of a briefly catalytic stimulus, not exceeding -the physiological limit of intensity, another secondary result -is observed, which is of the greatest importance for the continued -existence of the living substance. The catalytic stimulus -brings about a disturbance of the equilibrium of metabolism, -which after cessation of the stimulus is reestablished by the living -substance. In other words: recovery takes place. This fundamental -principle has been known for a long time as the result -of observation. If a skeletal muscle of our body has been activated -for a prolonged period by nerve impulses, until it has -become completely fatigued and incapable of work, a recovery -takes place on the cessation of these impulses and the muscle is -again capable of action. Likewise, as the result of strong mental -activity during the day, we are mentally fatigued in the evening; -recovery, however, occurs during the night, which results from -the removal of the source of activity. The next morning finds -us refreshed. This restitution occurs in every cell, and the return -of its former capability of action, which had disappeared under -the influence of stimulation, shows that compensation has taken -place of the metabolism of rest, disturbed by the effects of the -stimulus. <span class="nowrap"><i>Hering</i><a id="FNanchor_54" href="#Footnote_54" class="fnanchor">54</a></span> has aptly termed this restitution as “<i>the internal -self-regulation of metabolism</i>.” All recovery after disease is -based on this self-regulation. The physician simply provides, by -means of therapy, for the possibility of its taking place. Healing -itself is brought about by the organism. “<i>Natura sanat, medicus -curat.</i>”</p> -<p><span class="pagenum" id="Page_86">86</span></p> - -<p>Finally, a third kind of secondary effect of stimulation claims -our interest. This is the <i>secondary extension of the result of -stimulation</i> from the part of a living organism directly and primarily -affected by the stimulus, to the surrounding structures. -All living substance has the capability of conducting an excitation, -which is produced locally through a catalytic stimulus, to a neighboring -part, not directly affected by the stimulus. It finds its -highest development in the nerve, but in no living structure is it -completely absent. This capability has been frequently termed -“<i>conductivity of stimulation</i>.” It is more precise, however, to -speak of conductivity of excitation, for it is not the primary -influencing external stimulus which is conducted in the living -substance, but the excitation which it has produced. I have intentionally -considered only the excitating effects of stimulation, and -not those of the depressing reactions, as only excitations, not -depressions, are conducted by the living substance. These questions, -however, demand a closer analysis. Here we were concerned -only with a survey of the general effects of stimulation. -If I, therefore, once more summarize the results which have been -gained, this is most clearly demonstrated by the following scheme:</p> - -<p class="tac pt1b02"> -<span class="smcap">Primary Effects of Stimulation</span></p> - -<p class="tac fs90">Excitation  Depression<br /> -Functional  Cytoplastic  Functional</p> - -<p class="tac ptlb02"><span class="smcap">Secondary Effects of Stimulation</span></p> - -<p class="tac fs90">Secondary excitation  Secondary depression<br /> -Conduction of excitation, Metamorphic processes, Self-regulation of metabolism</p> - -<p>This, however, is simply a scheme, like all other schemes, having -for its purpose a superficial survey of the subject.</p> - -<p>It brings to some extent order into the overwhelming mass of -manifold effects of stimulation but tells us nothing of the mechanism -and genesis. Our further task must, therefore, be a more -thorough analysis of this field.</p> - -<hr class="chap x-ebookmaker-drop" /> - -<div class="chapter"> -<p><span class="pagenum" id="Page_87">87</span></p> - -<h2 class="nobreak" id="CHAPTER_V">CHAPTER V<br /> -<span class="title">THE ANALYSIS OF THE PROCESS OF EXCITATION</span></h2> -</div> - - -<div class="blockquot"> - -<p class="pl2hi2"><i>Contents</i>: Indicators for the investigation of the process of excitation. -Latent period. The question of the existence of assimilatory excitations. -Dissimilatory excitations. Excitations of the partial components -of functional metabolism. Production of energy in the chemical -splitting up processes. Oxydative and anoxydative disintegration. -Theory of oxydative disintegration. Dependence of irritability on -oxygen. Experiments on unicellular organisms, nerve centers and -nerve fibers. Restitution after disintegration by metabolic self-regulation. -Organic reserve supplies of the cell. The question of a -reserve supply of oxygen of the cell. Metabolic self-regulation as a -form of the law of mass effect, and metabolic equilibrium as a condition -of chemical equilibrium. Functional hypertrophy.</p> -</div> - - -<p>If it is true that all primary effects of stimulation consist either -in an excitation or depression of the metabolism, and that all other -effects of stimulation secondarily follow this primary alteration -of the metabolism of rest, then every thorough analysis of the -mechanics of reaction must have its beginning in the investigation -of these primary processes. I desire to adopt this method -here and will analyze somewhat further the <i>primary process of -excitation</i> and its immediate and remote sequences. This will be -followed later by the analysis of the process of primary depression -and its results.</p> - -<p>The investigation of the more obscure processes in the living -substance places us in a difficult position, for their details cannot -be observed by the unaided senses. That which we can perceive -is merely the grosser vital action, consisting of a complex combination -of the individual processes, the total result of a multitude -of different components. For this reason the conception of excitation -can only be established by observations based upon the -combined vital actions, which are produced by the effect of stimulation<span class="pagenum" id="Page_88">88</span> -upon the complex system. In the beginning, the process -of excitation was studied exclusively on the muscle and nervous -system. A physical factor served as indicator, such as muscle -contraction or production of electricity. These showed, besides -the direct and primary effect of stimulation, the secondary process -of conductivity. Even graphic registration is merely an -expression of the phenomena composed of a great mass of individual -elements. The visible course of the phenomena, as shown, -for instance, by the latent period by the ascent and descent of the -curve of contraction, represents as it were a reflected picture of -the actual excitation processes similar to an object seen in a distorting -mirror; the first and the last parts of the process are not -even perceptible. Later, when organ physiology was extended -into a cell physiology the processes of excitation were studied in -numerous simple organisms, such as the plant cell, the rhizopoda, -the infusoria, etc. Later, in this way, by the use of comparative -methods many essential facts were discovered. However, -even the single cell, in spite of its minuteness, is, compared with -the size of a molecule, a gigantic system, and it would be a grave -error if we should consider this system even in its simplest aspect -as homogeneous. In order, therefore, to analyze the vital activities -in the cell, cell physiology must endeavor to penetrate into -molecular conditions. For this purpose the indicators employed -must be essentially of a chemical nature, capable of magnifying -the processes of molecular dimension to such a degree that we -are enabled to base conclusions upon these not otherwise directly -perceptible phenomena. To obtain a sufficient magnification we -must necessarily place somewhat larger quantities of living substance -under observation and apply a stimulus of such frequency -or length of duration that the chemical alterations as a result of -excitation are so increased as to be plainly perceptible with the -aid of our chemical indicators. Unfortunately, we do not possess -specific chemical indicators for every individual molecular -constituent process of the cell and so cannot dispose with the help -of indicators of the combined happenings in a greater quantity of -living substance. It remains for us to obtain data concerning the -cycle of excitation processes in the living substances by the aid<span class="pagenum" id="Page_89">89</span> -of the combined employment of the most varied kinds of physical -as well as chemical indicators. If we use the most varied types of -living substance of widely differing properties, showing us the -greatest variety of vital manifestations, we may hope by the use -of comparative physiological methods, even though with difficulty, -to separate more and more the essential details of the general -processes of excitation. At present we are still at the very -beginning of this task and vast fields of unexplored regions are -yet before us. But it is the unknown which has a particular fascination, -especially if we succeed from time to time in making new -advances.</p> - -<p>If we suppose a living system in a state of metabolism of rest -influenced by an instantaneously excitating stimulus, the entire -course of excitation extends from the first alteration produced -by the stimulation until the complete restitution of the metabolic -equilibrium, and we will, therefore, differentiate individually the -successive stages of this whole process.</p> - -<p>The very beginning of the chain of alterations produced by the -excitating stimulus cannot be studied by any indicator. The -changes must first reach a certain dimension by conduction from -the point of stimulation before they influence even the most delicate -indicators. The application of the stimulus is, therefore, -followed at first by a measurable “<i>latent period</i>,” in which the -living substance remains apparently at rest. This latent period -has been particularly studied in muscle. After its discovery by -<span class="nowrap"><i>Helmholtz</i><a id="FNanchor_55" href="#Footnote_55" class="fnanchor">55</a></span> it was made the object of innumerable investigations -and met with an interest which can only be explained by the exactness -of the methods employed. Among others <span class="nowrap"><i>Tigerstedt</i><a id="FNanchor_56" href="#Footnote_56" class="fnanchor">56</a></span> has -made the most thorough study of the influence of various factors -on the duration of the latent period. These experiments have -established the fact that the duration of the latent period varies -according to the intensity of the stimulus, temperature, loading<span class="pagenum" id="Page_90">90</span> -or fatigue. This is apparent when it is understood that the -amount of the alterations produced by the stimulus must ascend -from the value zero to a certain height before the changes are -perceptible, and that under various conditions this amount is, on -the one hand, attained in different lengths of time and, on the -other, must reach a varying amount before it is perceptible by -means of the indicator.</p> - -<p>The facts concerning the whole latent period and its dependence -on various factors would be incomprehensible if it were -assumed that no alterations whatever take place during the latent -period although the stimulus is already operative. In reality, the -alterations following a stimulus occur with imperceptible rapidity -in the form of a molecular interchange, and the latent period is -simply an expression of the fact that the primary alterations, -being limited in nature, are not registered by our indicators.</p> - -<p>The question first arises, In what do these first imperceptible -alterations consist? <span class="nowrap"><i>Nernst</i><a id="FNanchor_57" href="#Footnote_57" class="fnanchor">57</a></span> has evolved the theory for electric -stimulus, that the primary effect produced by the electric current -is an alteration in the ion concentration on the surface of the -living substance. In fact, we know that the surfaces of all protoplasm -possess the property of semi-permeable membranes and that -changes in the concentration of ions invariably occur when an -electric current flows through two electrolytes separated by a -semi-permeable membrane, in which the anions and cations have -a different rapidity of movement. It is apparent, therefore, that -such an alteration in the ion concentration must be followed by -further chemical processes in the living substance. According -to the theory of <i>Nernst</i> the first impetus for all further alterations, -which the electrical stimulus brings about in the metabolism -of rest, is the alteration in the concentration of the ions on both -sides of the semi-permeable membrane, which represents the surface -of the protoplasm. In view of the present findings of physical -chemistry, objections can hardly be made to this theory of -<i>Nernst’s</i>. It is a question, however, in how far this theory, especially -established for the <i>electric</i> stimuli, can be applied to other<span class="pagenum" id="Page_91">91</span> -forms of stimuli and their action. It cannot be denied that the -degree of dissociation of an electrolyte can be altered by very -different factors, such as heat, light, chemical processes, etc., -and in that the surfaces of the protoplasm, acting as semi-permeable -membranes, bring about a selective action on the passage -of the ions, there arises the opportunity for the development -of difference of electrical potential on both sides, and for further -chemical alterations in the protoplasm. These observations, however, -require further experimental investigations in many fields, -before we are justified in extending the <i>Nernst</i> theory of the -manner of action of the electric stimuli to a general explanation -of the primary alterations produced by all stimuli in the living -substance. For the present we must confine our observations to -<i>those</i> alterations which are known to be responses to an excitating -stimulus; these are the chemical alterations in the metabolism -of rest in the living substance.</p> - -<p>If it is asked, which members of the entire metabolic chain -are increased primarily by the stimulating excitation of a vital -system, we should not be able to answer this question generally -for <i>all</i> living systems. To begin with, it appears highly -probable that the various forms of vital substances in this respect -act quite differently. It is to be regretted that, up to the present, -this question has not been treated from a comparative standpoint. -This inquiry should be extended to the greatest possible -number of organisms. Still there is enough material at hand, -obtained from the muscles, glands, ganglion cells, nerve fibers -and plants, to show that the complexity is by no means so great -as one might at first assume.</p> - -<p>In considering the two stages of metabolism, assimilation and -dissimilation, in their entirety, it appears as a very remarkable -fact, that nearly all stimuli produce primarily a <i>dissimilative</i> -excitation. We are only acquainted with a primary <i>assimilative</i> -excitation, that is, an augmentation of the building up -processes, in short, the <i>formation</i> of living substance, occurring -as a primary result of stimulation, following increased introduction -of <i>foodstuffs</i> extending over a prolonged length of time. -With this exception it cannot be proved that <i>any</i> other stimuli,<span class="pagenum" id="Page_92">92</span> -either especially those operative in the activity of the animal -organism or any of the physiological nerve impulses which regulate -the actions of the different organs and tissues, bring about -primarily an assimilative excitation, which leads to an increase -of new formation of living substance. The much-discussed -teaching of the existence of the trophic nerves has not given us -a single case in which there was positive proof that a nerve -impulse brought about a primarily assimilative excitation. I have -endeavored for nearly fifteen years to discover such a case. -My efforts have been, however, without avail. In the most recent -critical review by <span class="nowrap"><i>Jensen</i><a id="FNanchor_58" href="#Footnote_58" class="fnanchor">58</a></span> on the subject of the trophic nerves, the -same conclusion is reached although certain facts, as, for instance, -the excitation of assimilative processes in the green plant cell, -produced by light, seems at the first glance to clearly demonstrate -a primary excitation of the building up processes resulting from -a stimulation. Nevertheless closer observation invariably shows -that these conditions are much more complicated and that primarily -assimilative excitating reaction of the stimulus cannot be -conclusively shown. There remains, therefore, as a primary -assimilative excitating stimulus only the increased introduction -of nutrition in a living organism. This excitating effect on the -assimilative portion of metabolism is, as we shall see later, a -simple manifestation of the law of mass action.</p> - -<p>As a result manifold effects of excitating stimulation, which -seemed possible at a first glance, are already considerably restricted. -The great mass of excitating stimuli produce an acceleration -of the dissimilative processes of the metabolic chain. But -here our former observations have already shown that certain -constituent processes are especially responsive and very readily -increase as a result of the most varied adequate and inadequate -stimuli. These are the “<i>functional</i>” members of metabolism. -These members are particularly labile, so that they are always -affected by every influence to which the system is subjected in -the form of a stimulus. The functional portion of metabolism -of the muscle, which is particularly labile and is always primarily<span class="pagenum" id="Page_93">93</span> -affected by stimulation, consists as demonstrated in increase -of formation of carbon dioxide and water, and in the disintegration -of the nitrogen-free groups. The innumerable observations -on metabolism during the stage of the activity of the muscle, as -those of <i>Hermann</i>, <i>v. Frey</i>, <i>Fletcher</i>, <i>Johannson</i>, <i>Thunberg</i>, -and many others on the individual muscle, and those by <i>Voit</i>, -<i>Fick</i> and <i>Wislicenus</i>, <i>Pflüger</i>, <i>Rubner</i>, <i>Zuntz</i>, <i>Lehmann</i> and -<i>Hagemann</i>, <i>Bernstein</i> and <i>Löwy</i> and others on the muscle of the -entire organisms, have sufficiently proved this fact. However, we -should not apply in detail the conditions existing in the <i>muscle</i> -to <i>all</i> living substance. Comparative methods show us, rather, -that the functional portion of metabolism is very differently -involved in various forms of living substance. The formation of -carbon dioxide and water is constant in nearly all forms of living -substance. We must, however, exclude certain micro-organisms, -which have adapted themselves to unusual vital conditions. -Further, there appear in some forms manifold special constituent -processes consisting in a disintegration of living substance -which are in part converted into very complex combinations. In -the gland cells this type is represented in an especially high degree. -Here the functional disintegration leads to excretion of proteins, -glycoproteins, nucleoproteins, cholic acid, enzymes of various -kinds, all of which are complex and at the same time nitrogenous -organic combinations. This fact must not be lost sight of. The -origin of these special members, however, for the present is completely -unknown, while on the other hand, it is self-evident that -the general and constant constituents of the process of excitation -must claim a first place in our interest. It is just at this point, -therefore, that we must endeavor to penetrate somewhat more -deeply into the mechanism of the excitation process and analyze -in greater detail the acceleration of the functional constituent -parts of metabolism produced by the stimulus bringing about the -formation of carbon dioxide and water.</p> - -<p>The question arises: <i>By what means is the particular labile state -of just this constituent part of functional metabolism conditioned?</i> -The lability of the functional portion of metabolism, excitated -by the stimulus, resembles the processes in the disintegration of<span class="pagenum" id="Page_94">94</span> -explosive combinations. Iodide of nitrogen, for instance, in a -manner similar to the living substance in the state of the metabolism -of rest, constantly disintegrates even without the influence -of an impact. The disintegration is suddenly enormously increased -by the result of a jar. An explosion follows. In a like -manner the functional metabolism of rest is explosively excitated -by the stimulus, the transformation of the energy involved -likewise bears a similar relation.</p> - -<p>In both instances the transformation of energy, <i>constant</i> in the -resting state, is by the impact of the stimulus suddenly increased. -The dynamic method of investigation of the excitation process -with its physical indicators, forms, therefore, in many respects -an excellent addition to the chemical analysis. A development, -that is, exothermic formation, of energy can only occur in a -chemical process when the chemical affinities which are to be -combined are stronger than those which have been separated. -When this process is brought about by a simple impact, the energy -value of which bears no relation to that of the quantity of energy -in the process itself and which occurs with explosive rapidity, -then it can be simply a question of a liberation process, that is, -a process by which the impact brought about a conversion of -latent chemical energy into that of kinetic energy. The comparison -of the functional excitation process with that of an explosion -does not, therefore, consist in a merely superficial analogy, but is -founded on the same dynamic principles.</p> - -<p>When we study the chemical process which occurs in the explosive -transformation of potential into kinetic energy we find two -types of chemical processes. The first type includes the synthetic -processes. For this, the synthesis of water from explosive gas -may serve as a simple example. Here the weaker affinities in -comparatively simple molecules (H + H and O + O) are separated -and stronger affinities are combined in the formation of -more complicated molecules (H + O + H). The second type -represents the process of cleavage. As example for the latter, the -explosive disintegration of nitroglycerine may be quoted. Here -the atoms, held together in a complex molecule by weaker affinities, -are changed by transposition of nitroglycerine. For instance,<span class="pagenum" id="Page_95">95</span> -the hydrogen atoms loosely combined with carbon enter -into strong combinations with oxygen and the oxygen loosely -combined with the nitrogen enters into strong combination with -carbon, so that water and carbon dioxide are formed and nitrogen -and oxygen set free.</p> - -<div class="figcenter illowe15_165" id="i_095"> - <img class="w100" src="images/i_095.jpg" alt="" /> -</div> - -<p>In the functional disintegration of living substance, the last -type is realized. Living substance contains loose complex combinations, -and we know that functional disintegration is accompanied -by the consumption of these organic combinations. In -the functional disintegration of muscle substance the nitrogen-free -groups are concerned, and we must, consequently, first consider -the carbohydrates. However, without further study we -should not generalize from that which is true in the case of -muscle. There are other forms of living substances which contain -different combinations, which disintegrate as a result of the -contact of a stimulus and yield carbon dioxide. A clue as to -which combinations in individual cases undergo disintegration -as a result of excitating stimulation, is furnished by the metabolism -of rest in the particular substance. Plants and micro-organisms -have been investigated more thoroughly in this connection -than animals. Plant physiology has demonstrated that<span class="pagenum" id="Page_96">96</span> -the material employed for the CO<sub>2</sub> formation and with it the -production of energy is carbohydrate, but that, on the other hand, -various plant organisms and protistæ also use a quantity of other -substances, such as fats and protein, indeed even such comparatively -simple organic combinations as alcohol, formic acid and -methane. It may be accepted that in all these various instances -of excitation of the functional metabolism as a result of stimulation, -the specific respiratory material of the substance concerned -is used in greater amount in the decomposition and likewise -invariably yields carbon dioxide.</p> - -<p>The point of most essential interest for the analysis of the -excitation processes is, above all, the <i>mechanism</i> of the organic -combustion and the associated energy production. Here we may -base our observations on the disintegration of carbohydrates, -which is most extensive in the animal as well as in the vegetable -kingdom. We may now ask how dextrose, for instance, disintegrates -in the living system into carbon dioxide, for it is this, -or a sugar of similar chemical nature, which is generally concerned. -Plant physiology, which here, as in many other respects, -is in advance of animal physiology, has indicated two ways by -which this can be accomplished in the living substance. One is -oxydative, the other, <i>an</i>oxydative disintegration.</p> - -<p>In the <i>oxydative disintegration</i> of dextrose, taking place in -aërobic organisms, if sufficient quantities of oxygen are present, -there occurs a splitting up of the carbohydrate molecule, as a -result of the introduction of oxygen, into simpler substances and -finally into carbon dioxide and water, just as the dextrose molecule, -when subjected to oxydative processes, is split up into simpler -molecules. In the living substance the oxydases play the -important rôle of oxygen carriers. It cannot be denied, however, -that up to now no carbohydrate splitting oxydases have been -obtained from living substance. This, of course, does not prove -its nonexistence. But this deserves consideration in connection -with an assumption very widely spread among plant physiologists -in regard to the aërobic disintegration of the carbohydrate molecule, -which I shall touch upon presently. If we suppose that -oxydases exist, which bring about primarily the oxydative disintegration<span class="pagenum" id="Page_97">97</span> -of the dextrose molecule, its first point of attack must -obviously be sought in the aldehyde group. Here would be situated -the activator, as it were, for the whole carbon chain, from -which, as by a spark, the entire series of links would be ignited.</p> - -<p>In an <i>anoxydative disintegration</i> of dextrose as observed in -anaërobic as well as in aërobic organisms, provided the latter have -an insufficient supply of oxygen, the dextrose molecule, by -enzymic action as a result of the splitting off of carbon dioxide, -is converted into substances having a comparatively large carbon -content. The best-known example of this anoxydative disintegration -is the formation of alcohol by fermentation in which -the dextrose molecule is split up by the yeast into alcohol and -carbon dioxide. (C<sub>6</sub>H<sub>12</sub>O<sub>6</sub> = 2C<sub>2</sub>H<sub>5</sub>OH + 2CO<sub>2</sub>.) Instead of -the production of alcohol and CO<sub>2</sub> we may have other enzymic -actions with the formation of other carbon-containing disintegration -products, such as lactic acid, fatty acids, hydrogen, etc. Of -course in such an anoxydative disintegration, which does not lead -to the formation of such simple combinations as carbon dioxide -and water, the <i>quantity</i> of energy set free is much less in amount -than in complete <i>oxydative</i> decomposition, the energy production -of the alcohol fermentation being only 11 per cent of the latter. -In order to produce the same amount of energy as in the former, -a much greater number of molecules is required. We find, therefore, -that the anoxydative type of disintegration develops either -only where the respiratory substances are present in sufficient -amounts, as for instance, in the case of yeast cells, existing in -nutritive solutions rich in sugar; or where the chemical and -energy transformations occur only to a limited extent, as, for -example, in the presence of low temperature. In this respect -<span class="nowrap"><i>Pütter</i><a id="FNanchor_59" href="#Footnote_59" class="fnanchor">59</a></span> has demonstrated in the leech that at a higher temperature, -the oxydative, at a lower, the anoxydative, decomposition -predominates. These are important facts in that they show us -the superiority of oxydative to that of the anoxydative disintegration -in the cell economy. This is of particular interest when -we consider those organisms in which great demands are made<span class="pagenum" id="Page_98">98</span> -upon the capability of movement, above all, in homothermous -forms, the metabolism of which takes place on a continuously -high level. For this reason, in homothermous animals the respiration -of oxygen is the almost exclusive source of energy -production.</p> - -<p>The previously mentioned facts make it clear that in one and -the same form of living substance both oxydative and anoxydative -decomposition processes are found, depending upon the conditions. -This does not apply merely to the individual organic -forms, such as the facultative anaërobic organisms, but generally -to all aërobic living substance. If oxygen is withdrawn from an -aërobic organism the disintegration does not cease in consequence. -In place of the oxydative we have anoxydative decomposition. -The various aërobic organisms are, however, adapted -in very different degrees to the possibility of an anaërobic existence. -While the facultative anaërobic organisms can continue to -exist without oxygen, the homothermous animals become asphyxiated -in a very short time in the absence of oxygen, in that they -are poisoned by the products of the anoxydative decomposition, -which are eliminated with much more difficulty than carbon -dioxide and water. The fact, however, that disintegration also -continues in an anoxydative form, if oxygen is withdrawn, has -given rise to the thought, which has been accepted especially by -plant physiologists with great readiness, that the decomposition -of organic respiratory substances of the aërobic organisms invariably -takes place in two stages; in that the dextrose molecule—to -again use this as an example—is split up first by an enzyme into -larger fragments, which then in the second stage of the process -undergo combustion to the formation of carbon dioxide and -water. Such a possibility cannot be repudiated. I wish, however, -to state that one should be very reluctant in generalization -of this assumption for all aërobic organisms. The types of metabolism -in the different organisms are so manifold and of such -immense variety that we should be very careful in our generalizations -before being in possession of material extending over a -great number of groups of organisms. Above all, it does not -seem justifiable to also accept this type for life existing at higher<span class="pagenum" id="Page_99">99</span> -temperatures, and still less to apply it to those instances in which -the production of energy following stimulation is suddenly increased -to great amounts. Let us suppose that the disintegration -process occurs in two phases, the first of which after the type of -the fermentation of dextrose separates the molecule into larger -fragments, while in the second phase these fragments are split -up through oxydation into the formation of carbon dioxide and -water. We can then say with certainty that in the first stage only -a comparatively <i>small</i> amount of energy production occurs, for -energy production by enzymic processes of this kind is never -great; the second phase, on the other hand, must be associated -with a very considerable energy production, for by the addition -of oxygen and the formation of carbon dioxide and water the -strongest affinities possible are combined. With this assumption -in certain cases, as, for instance, in the sudden production of -energy in muscle contraction, which necessarily occurs in the -purely oxydative phase of the whole process, the view is forced -upon us, that, in these cases, the entrance of oxygen into the -molecule from the very beginning, even the first impact, produces -oxydative decomposition of the whole molecule. The view that, -in the reactions of warm-blooded animals, which occur with great -rapidity and considerable energy production, the oxygen primarily -explosively breaks up the whole carbon chain, certainly -presents no more difficulties than the supposition that the simpler -substances are attacked secondarily, provided sufficient oxygen -be present. This method would be obviously the simplest. -This is, however, mere speculation and a definite decision between -the two possibilities cannot be made at present. However, -whether the process takes place in two phases, an anoxydative -and an oxydative, or simply in an oxydative phase, in <i>any case, -the sudden discharge of energy in the aërobic organism set free -by the stimulus, is brought about by the addition of oxygen</i>.</p> - -<p>This is a highly important fact and as such requires the most -thorough confirmation, and is best accomplished by the investigation -of the state of excitation of aërobic substances on the -withdrawal of oxygen. Experience gained by observation in this -respect on a great number of living substances shows that excitability<span class="pagenum" id="Page_101">101</span><span class="pagenum" id="Page_100">100</span> -decreases upon the withdrawal of oxygen. In this connection -I should like to cite some particularly significant instances.</p> - -<div class="figcenter illowe30_625" id="i_100"> - <img class="w100" src="images/i_100.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 10.</p> - -<p class="tac"><i>Rhizoplasma kaiseri.</i> A—Under normal conditions. -B—In an atmosphere of pure hydrogen.</p></div> -</div> - -<p>During a sojourn at the Red Sea in 1894–95 I was able to -establish this dependence in the single-celled organism, the <i>Rhizoplasma -Kaiseri</i>, a large naked orange-colored rhizopod. (Figure <a href="#i_100">10</a>, A.) -Mechanical stimulation, which under normal vital conditions -of these organisms brings about contraction in the long-branched -pseudopods, becomes ineffective with a cessation of the -movement of protoplasm, when oxygen is removed and is replaced -by a stream of hydrogen. (Figure <a href="#i_100">10</a>, B.) With renewed introduction -of oxygen there is a return of the protoplasmic movement -and entire recovery takes place.</p> - -<p>This dependence of irritability upon oxygen is most clearly -demonstrated in the <i>nerve centers</i>. For this purpose I have -employed the spinal cord of the frog<span class="nowrap">.<a id="FNanchor_60" href="#Footnote_60" class="fnanchor">60</a></span> A canula is introduced -and fixed into the aorta of the animal and the blood is replaced -by a current of oxygen-free saline solution. The centers of the -spinal cord are thereby wholly isolated from the supply of oxygen. -The indicator for the irritability here used is reflex excitation -from the skin to the gastrocnemius, or better, stimulation -of the central stump of the sciatic nerve with single induction -shocks, bringing about reflex response of the triceps. The reflex -may be considerably augmented by increasing the reflex excitability -of the spinal cord by poisoning the animal with strychnine. -On testing the reflex excitability at the beginning of the experiment -it will be found that the reaction to each individual stimulus -consists, in consequence of the strychnine poisoning, of a long-continued -maximal tetanus. The longer the deficiency of oxygen -continues, the briefer become the tetanic reflex contractions following -a single stimulus. Soon reflex tetanic responses are -merely short single contractions, which decrease more and more -with the continuance of oxygen deficiency. Finally, the same -stimuli which previously produced strong tetanic contractions -of long duration are altogether without effect. Although by<span class="pagenum" id="Page_102">102</span> -increasing the intensity of stimulation brief contractions can -again be brought about, irritability decreases more and more, -until at last even the strongest stimuli remain without result. -If the oxygen-free saline solution is now replaced by one saturated -with oxygen, or blood of the ox, rendered arterial, the -excitability returns within a few minutes and soon reaches the -maximal height which it possessed under the influence of the -strychnine poison. Even the weakest single stimuli now again -produce tetanus. The same process reoccurs, if the fluid used -for transfusion containing oxygen is again replaced by an oxygen-free -saline solution. In this way, by repeated change of the perfusing -fluid, we can demonstrate in the most positive manner this -alteration in irritability, the result of the alternate presence and -removal of oxygen. This is perhaps the best example of the -close dependence of irritability on oxygen.</p> - -<p>This same fact can be observed with equal clearness in the -nerve. At my suggestion <span class="nowrap"><i>H. v. Baeyer</i><a id="FNanchor_61" href="#Footnote_61" class="fnanchor">61</a></span> showed as the result of -investigations made in the Göttingen laboratory the dependence -of irritability of the nerve upon oxygen for the first time. By -employing as the method the ascertainment of the threshold of -stimulation I then made a closer study of the alterations in irritability -during asphyxiation. These observations were soon after -continued by <i>Fröhlich</i><span class="nowrap">.<a id="FNanchor_62" href="#Footnote_62" class="fnanchor">62</a></span> The method is as follows: the nerve of -a nerve-muscle preparation of the frog is drawn through a glass -chamber which is made completely air-tight and containing platinum -electrodes. The air in the chamber is then displaced by a -stream of pure nitrogen. (Figure <a href="#i_103">11</a>.) On testing that part -of the nerve situated within the glass chamber with single break -induction shocks it can be observed that its irritability, measured -by the threshold of stimulation for muscle contraction, decreases -more and more, until after the lapse of some hours, the stimulation -required is so strong as to reach the region of the “Stromschleifengrenze.” -If in place of the stream of nitrogen, air or -pure oxygen is now allowed to flow through the chamber, the<span class="pagenum" id="Page_103">103</span> -nerve recovers almost instantaneously. Within the space of a -minute its irritability has risen again to its full height and the -same experiment, with the same result, can be repeated. Finally, -as <span class="nowrap"><i>Fillié</i><a id="FNanchor_63" href="#Footnote_63" class="fnanchor">63</a></span> has shown, the like result is obtained when the nerve is -asphyxiated in a fluid medium.</p> - -<div class="figcenter illowe35" id="i_103"> - <img class="w100" src="images/i_103.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 11.</p> - -<p class="taj pl1hi15">Arrangement for asphyxiating the nerve. A—Gasometer containing pure nitrogen. B and B<sub>1</sub>—Vessels for -washing the gas. C—Ether chamber for eventual experiments with narcosis. D, D<sub>1</sub> and E—Glass -faucets. F—Moist chamber. G—Asphyxiation chamber. H and H<sub>1</sub>—Two pairs of electrodes over -which the nerve is laid. I—Nerve muscle preparation. -</p></div> -</div> - -<p>All these facts, the number of which indeed could be increased -greatly for other aërobic forms, suffice to establish the fundamental<span class="pagenum" id="Page_104">104</span> -importance of oxygen to the maintenance of irritability of -living substance. <i>Oxygen is of greatest importance for a high -degree of irritability in all aërobic organisms.</i> All living systems -which are characterized by a great capability of activity and -evince strong responses under the influence of stimulation, such -as the vertebrates and insects, are necessarily aërobic, whereas -the living organisms of pronounced anaërobic character, as some -bacteria, yeast cells, parasitic organisms, etc., manifest on the -average much less capability of activity.</p> - -<p>Finally, to briefly summarize the foregoing, the following -picture presents itself of disintegration produced by a momentarily -acting stimulus. It is immaterial how the stimulus produces -an excitating effect in the given case, whether through -changes in the ion concentration of the living system, by increase -of intramolecular atomic movement or in any other manner, it -invariably accelerates the disintegration of the complex molecules -concerned in functional metabolism, the nature of which -varies in the special cases. In the great majority of instances -nitrogen-free organic combinations serve as material for the -functional constituent members of metabolic processes. In the -anaërobic organisms this decomposition takes place anoxydatively -with the coöperation of enzymic processes, and as larger -fragments generally result from the disintegration of the complex -molecule, the production of energy is accordingly smaller. -The disintegration of aërobic organisms, on the other hand, occurs -in the form of an oxydative splitting up of the complex molecules -into carbon dioxide and water so that the production of -energy attains a high value. The details concerning the manner -in which the individual stages of this decomposition take place -and the interactions by which its end products are reached is -at present beyond our knowledge. It would be a mistake to generalize -in this connection from the behavior of certain groups of -organisms. The assumption that under certain conditions the -disintegration occurs in two phases, the splitting up resulting -from enzymic action of the complex molecule into larger fragments, -followed by an oxydative splitting up of these into carbon -dioxide and water, can in no case as yet be justifiably applied to<span class="pagenum" id="Page_105">105</span> -all conditions and all aërobic organisms. This is more or less the -impression which we derive of the functional excitation process -as seen today.</p> - -<p>Under normal conditions the functional excitation is at once -followed by a succession of secondary processes, the “<i>self-regulation -of metabolism</i>.” Self-regulation after a functional -excitation is a fact demonstrated by experience. But in what -manner does it take place in detail?</p> - -<p>As the functional constituent members of metabolism involve -a disintegration of the nitrogen-free atom groups, the functional -self-regulation must necessarily furnish in sufficient quantity and -in proper form the carbon, hydrogen and oxygen atoms, which -have been removed in the production of carbon dioxide and water. -This is accomplished, as is well known, by the food and the intake -of oxygen. It is of importance to the maintenance of living substance -that after every functional activity it is as soon as possible -again capable of reaction. Therefore, it is absolutely necessary -that this material is in the proper place, where building up is -essential, and is at the same time constantly in proper form. -Indeed, the restitution of the original state follows under favorable -conditions with lightning rapidity, although varying in different -forms of living substance. This occurs in the nerve in -an extremely short time. From this it might be supposed that -the living system by accumulating a store of the necessary compensation -substances in suitable form, had made itself independent -to a certain degree of the frequently varying supply of -material obtained from the medium.</p> - -<p>This may be held as the proper view, first with regard to compensation -substances. The fact that living organisms can under -some conditions remain for a lengthened period in a state of -starvation, without losing their capability of activity, can only -be explained by the presence of a great quantity of reserve supplies -of compensation substances. In the course of work in the -laboratory every physiologist has become acquainted with the -fact that frogs which have been kept without food for a year, -although much reduced in weight, are still capable of some -muscular activity.</p> - -<p><span class="pagenum" id="Page_106">106</span></p> - -<div class="figcenter illowe26_25" id="i_106"> - <img class="w100" src="images/i_106.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 12.</p> - -<p class="tac">Motor ganglia cells from the spinal cord of the frog. A—In normal state. -B—After an asphyxiation lasting 8 to 9 hours. (After <i>Gordon Holmes</i>.)</p></div> -</div> - -<div class="figcenter illowe15_165" id="i_107"> - <img class="w100" src="images/i_107.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 13</p> - -<p class="tac"><i>Paramecium aurelia.</i> A—In normal state. B—In a state of starvation.</p></div> -</div> - -<p>Organs and tissue, which are cut off from all food supply -through the blood and lymph, may remain active for many hours. -<span class="nowrap"><i>H. v. Baeyer</i><a id="FNanchor_64" href="#Footnote_64" class="fnanchor">64</a></span> has shown that the ganglion cells in the frog, in -which saline solution was transfused at room temperature and -containing no trace of organic substances and where irritability -has been increased to the maximal by means of strychnine, were -capable of strenuous work for nine or ten hours before losing<span class="pagenum" id="Page_107">107</span> -responsivity. The nerves and muscles of the animal retain their -excitability for even a longer period under the same conditions. -Indeed, we have histological evidence of the existence of organic -reserve material in the various cells in the form of embedded -bodies in the protoplasm. As for instance the disappearance of -the <i>Nissl</i> granules in the ganglion cells following great activity<span class="nowrap">,<a id="FNanchor_65" href="#Footnote_65" class="fnanchor">65</a></span> -(Figure <a href="#i_106">12</a>), or that of the granules in infusoria cells during -starvation<span class="nowrap">.<a id="FNanchor_66" href="#Footnote_66" class="fnanchor">66</a></span> (Figure <a href="#i_107">13</a>.) We assume that a certain amount of -organic foodstuffs in a state properly prepared is present in the -cell. As the amount of these prepared substances is consumed, -new quantities of stores, having undergone various preparatory -processes, among which the enzymic actions may be considered -to play a chief rôle, are brought into that form in which they -appear suited to fill the gap produced by disintegration. Plant -physiologists in particular have here again furnished us with some<span class="pagenum" id="Page_108">108</span> -essential data for the assumption of the existence of such processes -which regulate the transformation of reserve substances -as well as its extent. <span class="nowrap"><i>Pfeffer</i><a id="FNanchor_67" href="#Footnote_67" class="fnanchor">67</a></span> has found in several fungi and -bacteria that there exists a compensation between the diastatic -breaking down of the carbohydrates stored as reserve material -and the quantity of dextrose introduced. He further found that -the more the reserve substance is split up into dextrose the less -of the latter is introduced from without and <i>vice versa</i>. <span class="nowrap"><i>De Bary</i><a id="FNanchor_68" href="#Footnote_68" class="fnanchor">68</a></span> -some time ago also observed in the <i>bacillus amylobacter</i> an analogous -relation between the enzymatic cellular digestion and the -quantity of dextrose introduced with the food. An equilibrium, -therefore, exists between the required amount of dextrose and -the extent of enzymic splitting up processes of the reserve material. -A great number of similar processes have been observed. -Even though the details of the whole preparatory assimilative -processes are beyond our knowledge we can still say with certainty -that, on the one hand, everywhere great quantities of organic -reserve substances are always present in the cell, and on the other, -that these substances are subjected to a transformation into suitable -material for building-up processes, the extent of which is -controlled according to need, by the processes of self-regulation.</p> - -<p>Entirely different is the question if the cell also possesses a -reserve store of oxygen. In this respect views have widely -differed, and even today no conformity of opinions has been -arrived at. The fact that many purely aërobic organisms and tissues -can exist under complete exclusion of oxygen for a longer -or shorter period, retaining their excitability and producing carbon -dioxide, has for a long time led a great number of investigators, -such as <i>Liebig</i>, <i>Matteucci</i>, <i>Engelmann</i>, <i>Pettenkofer</i> and -<i>Voit</i>, <i>Claude Bernard</i>, <i>Verworn</i>, <i>H. v. Baeyer</i> and others, to the -supposition that a reserve store of oxygen must exist in the living -substance which maintains its excitability for a time. More -recent information, however, of the transition of the oxydative -to the anoxydative disintegration under a deficiency of oxygen,<span class="pagenum" id="Page_109">109</span> -as can be observed in plants and certain invertebrate animals, -indicates that here also there is the possibility of another explanation -of these facts. Various attempts have been made to solve -the problem if reserve oxygen is present in the cell or not. The -experiments of <i>Rosenthal</i><span class="nowrap">,<a id="FNanchor_69" href="#Footnote_69" class="fnanchor">69</a></span> carried out with his respiration calorimeter, -seemed to point directly to an oxygen reserve in the -organism of the mammal. He observed that during respiration in -an atmosphere rich in oxygen the respiratory quotient (CO<sub>2</sub> : O<sub>2</sub>) -became lower than in ordinary air, that is, that oxygen, and that -indeed in considerable quantity, must be retained in the organism. -Nevertheless <span class="nowrap"><i>Falloise</i><a id="FNanchor_70" href="#Footnote_70" class="fnanchor">70</a></span> found that when rabbits, which had been -kept in an atmosphere containing 80 per cent of oxygen, were -asphyxiated, the time necessary to produce death was no longer -than in animals which had been kept previously in ordinary air. -The correctness of the observations of <i>Rosenthal</i> have been disputed -by <i>Durig</i>.<a id="FNanchor_71" href="#Footnote_71" class="fnanchor">71</a> <span class="nowrap"><i>Winterstein</i><a id="FNanchor_72" href="#Footnote_72" class="fnanchor">72</a></span> also, employing the microrespiration -methods of <i>Thunberg</i> upon the spinal cord of the frog, -believed that he had found proof that an oxygen reserve cannot -take place. He reasoned thus: If the cells of the spinal cord -contain reserve oxygen, which is used up when pure nitrogen only -is breathed, then it necessarily follows that after reintroduction -of oxygen, following asphyxiation, a definite quantity must be -stored up again as reserve. In consequence, the respiratory -quotient following the intake of oxygen after asphyxiation should -be smaller than when the animal is in air. He found, however, -that the respiratory quotient does not essentially change and concluded -from this that storage of oxygen does not take place. -In these experiments, however, there exists no certain indicator -as to the state of the spinal cord during asphyxiation and recovery -in the given case. The spinal cord may be severely injured and<span class="pagenum" id="Page_110">110</span> -even undergo degeneration during asphyxiation, and the recovery -following the reintroduction of oxygen may be either incomplete -or nil, without there being a method for its determination. Apart -from this, <span class="nowrap"><i>Lesser</i><a id="FNanchor_73" href="#Footnote_73" class="fnanchor">73</a></span> has already emphasized, in opposition to these -experiments, that the respiratory quotient in recovery is no criterion -to guide us. It is immaterial whether during asphyxiation -oxygen respiration occurs following a reserve supply, or that -an anoxydative formation of carbon dioxide has taken place, -for in both instances the respiratory quotient would be less <i>after</i> -asphyxiation when there is again an oxygen supply. It is, therefore, -quite impossible to decide the question by the employment -of this method. For this reason <i>Lesser</i> has attempted to solve -the problem by means of quite another method, and was convinced -that he had refuted finally the belief in the existence of -reserve oxygen. His method consists in the employment of the -<i>Bunsen</i> ice calorimeter, by which he determines the heat production -of frogs, kept first in air, then in nitrogen, and at the -end of each experiment ascertaining the amount of output of -carbon dioxide, respectively in air and nitrogen. He found that -the quantity of heat, calculated in terms of 100 grms. body -weight per hour, produced in nitrogen was considerably less than -that under corresponding conditions in air, but that the production -of carbon dioxide, on the other hand, during the first hours in -nitrogen was doubled in amount, as compared to that in air. -From this he concludes that the carbon dioxide formation in -nitrogen must be different from that in air, as it is associated -with a reduced heat production. In other words, carbon dioxide -formation, while the animal is in a nitrogen atmosphere, does not -have its origin in oxydative processes at the cost of stored up -oxygen. I regret that I am unable to accept these arguments as -conclusive evidence against the assumption of an oxygen reserve, -as this question cannot be decided by the use of such -methods. <i>Lesser</i> does not measure the amount of carbon dioxide -until the end of his experiments, that is, he learns merely the<span class="pagenum" id="Page_111">111</span> -entire carbon dioxide production during a period of many hours. -No conclusions can be drawn from this as to the conditions -existing in the first period of time, directly after the animals -have been subjected to an atmosphere of nitrogen. It is quite -possible that subsequent to the change to nitrogen an oxydative -carbon dioxide formation may have continued in decreasing -degree, without this being shown in the final result. The problem -of the existence of a reserve supply of oxygen is in no way -solved by these experiments.</p> - -<p>In assuming the presence of a reserve supply of oxygen in the -cell we must above all entertain no false conception as to its -amount. This must be, as I have often had occasion to emphasize, -exceedingly small and in no way comparable with the great -masses of organic reserve substances contained in the cell. The -assumption, especially for the <i>nerve centers</i> of the frog, that the -excitability remains after complete exclusion of oxygen must be -looked upon as demonstrating a reserve supply of oxygen, would -oblige one to suppose the presence of such a small store of oxygen -that it would be completely exhausted by continued activity in -room temperature within ten to twenty-five minutes. Strychninized -frogs, in which the blood has been replaced by an oxygen-free -saline solution, lose, as I have shown<span class="nowrap">,<a id="FNanchor_74" href="#Footnote_74" class="fnanchor">74</a></span> their excitability completely -within ten to twenty-five minutes after the blood has -been displaced. Nevertheless the assumption of the existence of -a small oxygen supply in the cell can hardly be evaded. It must -not be imagined that the moment the blood of the frog has been -replaced with an oxygen-free solution, there is not a trace of -oxygen left in the organism. Were such the case, the irritability, -if measured by the extent of the response, would sink <i>momentarily</i> -to a very low level, for the anoxydative disintegration processes -are associated with an incomparably smaller production of -energy than those of oxydative disintegration. We see, however, -that the irritability in the muscles, nerves and nerve centers of the -frog even after the complete withdrawal of oxygen at first remains -practically at the former height and only very gradually<span class="pagenum" id="Page_112">112</span> -decreases. Above all it would seem to me to be in the interest -of the preservation of the organism and especially of those parts -in which there is a high energy production and particularly those -substances in which energy production predominates, that the -material necessary for its formation is always at its disposal in -sufficient quantity. Otherwise the capability of action of the -organism would be impaired at every moment or at least suffer -great fluctuations.</p> - -<p>In accordance with this we must suppose that under physiological -conditions all those substances required to replace the disintegrated -molecules are always present in the cell in sufficient -quantity and suitable form to replace at once those lost by excitation. -Further, without doubt, in the organism which is always -aërobic, oxygen must be present in certain quantities to assure at -any moment oxygen replacement following oxydative disintegration, -to guarantee sufficient amount for succeeding stimulation.</p> - -<p>A further question arises: How is it that the material lost -in disintegration is always replaced in just sufficient quantity -to establish the metabolic equilibrium? In short, how are we -to understand in a mechanical sense the self-regulation of -metabolism?</p> - -<p>In the preservation of metabolic equilibrium, we have a process -before us, the principle of which is nowadays restricted to -living substance. In my “Biogen hypothesis,<span class="nowrap">”<a id="FNanchor_75" href="#Footnote_75" class="fnanchor">75</a></span> I have associated -the self-regulation of metabolism with the chemical equilibrium -in interreacting masses. I have considered the metabolic self-regulation -as the expression of the formation of a mass equilibrium -between the quantity of foodstuffs and the quantity of a -hypothetical combination of living substance, the <i>biogen</i>, which -continuously disintegrates and builds up again of its own accord. -In fact, however, we have in the chemical equilibrium of reacting -mixtures in the non-living world, a principle which is completely -analogous to the self-regulation in living substance. The chemical -facts are, indeed, well known. If we take the classical example -of the formation of ethylacetat from acetic acid and alcohol,<span class="pagenum" id="Page_113">113</span> -we have a case of an inanimate system, in which the amounts of -the reacting substances are in constant equilibrium. The reaction -following the mixture of equal amounts of alcohol and acetic acid -is as follows:</p> - -<p class="tac fs110"> -<span class="nowrap"><sup>1</sup>⁄<sub>3</sub></span> Mol. C<sub>2</sub>H<sub>5</sub>OH + <span class="nowrap"><sup>1</sup>⁄<sub>3</sub></span> Mol. CH<sub>3</sub>COOH<br /> -= <span class="nowrap"><sup>2</sup>⁄<sub>3</sub></span> Mol. CH<sub>3</sub>COOC<sub>2</sub>H<sub>5</sub> + <span class="nowrap"><sup>2</sup>⁄<sub>3</sub></span> Mol. H<sub>2</sub>O. -</p> - -<p>In this reaction there is an alteration only in the absolute -quantity of the individual constituents but never in the relative -amount. In the living system we have a completely analogous -instance, which apart from its course differs from the inanimate -example merely in the following points: In the first place, certain -quantities of substances reacting on each other are continually -introduced into and certain reaction products continually removed -from the living system. Secondly, the reacting mixture -of the living substance is not homogeneous, and at the same -time is more complicated than that of the inanimate example. -Thirdly, the sum total of the reaction is not reversible in its entirety. -The question arises, should any essential difference -between metabolic self-regulation and the maintenance of chemical -equilibrium be assumed upon this statement? I must confess -that this does not appear to me to be the case. The fact -that organisms exist in a stream of substances by which their -nutrition is introduced and the metabolic products removed, -cannot have any influence on the state of equilibrium so long as -the conditions are again and again replaced in the same manner. -The equilibrium can only be influenced when the introduction of -foodstuffs or the output of metabolic products is changed in value. -Then they occur as the inanimate example, when various amounts -of material are brought together. A new equilibrium takes place, -having a higher or a lower mass level. This is also true in the -living substance, in growth and in atrophy. The equilibrium is -disturbed as happens in the inanimate reacting mixture, where -different quantities of reacting substances are brought together. -In both instances we have in principle a conformity of behavior -of the inanimate and the living system. Secondly, as far as the -greater complexity and inhomogeneity of the living reacting mixture<span class="pagenum" id="Page_114">114</span> -is concerned, it is self-evident that this likewise does not -constitute an essential difference, for we are acquainted with conditions -of equilibrium in chemical reactions possessing a number -of members and in inhomogeneous mixtures. Finally, the fact -that the reaction in the living system is not totally reversible, -forms no barrier to the assumption in principle of metabolic self-regulation -as a chemical equilibrium. It is quite possible to conceive -of a chemical equilibrium in a reacting mixture, of which -only certain constituent processes are reversible, without the -totality of the reactions as a whole being necessarily so. Let us -assume, by way of example, that the assimilative processes of -the metabolic chain are reversible, then under constant quantitative -relations of foodstuffs, following every disintegration of -assimilative products with removal of the decomposition products, -the same amount of assimilatory processes is required for building -up. And this is just that which we observe in metabolic -equilibrium. Accordingly, we may look upon the metabolic equilibrium -as a special, although a very highly complicated, instance -of chemical equilibrium, and we may explain the metabolic self-regulation -following a dissimilative excitation of the same, by -those principles on which the rebuilding of chemical equilibrium -is founded. It is true that the special details of this process can -be differentiated in only that degree in which it is possible to -penetrate at all into the details of metabolism of the given cell -form. In this, as is well known, the advance is extremely slow.</p> - -<p>The rebuilding process following decomposition of living substance -in response to an excitating stimulus consists not merely -in compensation for the decomposed atom groups but also in the -removal of disintegration products. This removal can be accomplished, -in so far as simple chemical substances such as carbon -dioxide and water are concerned, by diffusion. Observations -have shown that the semi-permeable protoplasm surface is pervious -to water and carbon dioxide. The latter can, therefore, -depending upon the amount of concentration, be eliminated from -the living substance. Output of water likewise takes place in so -far as the specific water content of the living substance is exceeded -and which is osmotically regulated by its amount of salt<span class="pagenum" id="Page_115">115</span> -content. When, finally, osmotic pressure within the living cell -and in the surrounding medium is equal, the interchange of water -ceases. All these processes are explained by diffusion. Self-regulation -takes place in this regard simply by osmotic means. -The conditions in respect to those decomposition products consisting -in more complicated organic combinations, such as lactic -acid, fatty acids and nitrogen derivatives of protein disintegration, -are somewhat different in that the protoplasm surface possesses -the property of hindering the passage of these substances into the -medium. These are, as is well known, first transformed by secondary -chemical processes into transfusable substances. In this -transference the oxydative decomposition with the formation of -simpler substances plays the most important rôle, so that the substances -thereby formed, namely, carbon dioxide, water and -ammonia, are osmotically eliminated as the result of the selective -permeability of the surface of the protoplasm. In this way the -living cell rids itself of the useless products of metabolism.</p> - -<p>Finally, the question remains, is the original state, as it existed -before the influence of the stimulus, really completely recovered -by metabolic self-regulation, or does even individual excitation of -brief duration produce a continued change in the protoplasm? It -is quite impossible to prove that such an effect follows the momentarily -acting single stimulus, if stimulation has not exceeded the -physiological limits of intensity. Should it exist, it must be -imperceptible. Nevertheless, it ought to be possible by frequently -repeated application of the stimulus to increase this which is -imperceptible to an extent in which it is perceptible. This is, -indeed, the case and is manifested as we have already seen in -the increase of the volume of living substance by frequently -recurring functional excitation. We can, therefore, assume with -great probability that even the momentarily acting individual -stimulus produces, although not perceptible <i>per se</i>, lasting effect -in the cell. The functional excitation must be followed secondarily -by an increase of the assimilative phase of the entire -cytoplastic metabolism. Otherwise the taking place of the increase -of volume of the living system following frequent excitation -of the functional constituent members of metabolism, is<span class="pagenum" id="Page_116">116</span> -unintelligible. But how are we to interpret these secondary -results from a physical standpoint? First of all, it must be stated -that we do not know of such hypertrophy following activity in -unicellular organisms, but only in the tissues and organs of multi-cellular -forms, in muscles, nerve cells, glands, etc. In the cell -community of the vertebrates, however, the studies on the relations -between activity and the blood supply of the particular -tissue or organ furnish a physical interpretation for the existence -of the functional hypertrophy. The active portions show -a dilation of the blood vessels, therefore an increased supply of -blood and consequently an increase in the circulation of lymph. -In other words: the supply of nourishment to the individual cell -and the removal of the metabolic products in a unit of time is -increased. The preceding discussion of the dependence of the -conditions of equilibrium upon the quantitative relations of the -reacting substances makes it clear that under these conditions a -metabolic equilibrium on a higher quantitative level must occur; -that is, the living substance must increase in amount just as in -the inanimate example the absolute amount of the æthylacetat -increases if more alcohol and acetic acid are introduced to an -equal degree. Some time <span class="nowrap">ago<a id="FNanchor_76" href="#Footnote_76" class="fnanchor">76</a></span> I expressed the opinion that the -increase of the blood supply in a functionally active organ must -be based on a physical self-regulation, which takes place as a -result of the fact that metabolic products of the tissue cells -influence the cells of the vessel walls in that part, so that the -vessels dilate and more lymph is formed. In the meantime this -has been proved to be indeed the case. <span class="nowrap"><i>Schwarz und Lemberger</i><a id="FNanchor_77" href="#Footnote_77" class="fnanchor">77</a></span> -and <span class="nowrap"><i>Ishikawa</i><a id="FNanchor_78" href="#Footnote_78" class="fnanchor">78</a></span> have shown that especially the weak acids, which -are produced in larger amount as a result of strong activity of the -cells, bring about vessels’ dilation. By the demonstration of this -highly important process of self-regulation the last link has been -added for the physical understanding of the hypertrophy of -activity of the tissue cells by continued functional excitation.<span class="pagenum" id="Page_117">117</span> -Whether or not the same applies to the single living cell, if the -unicellular organism likewise undergoes a quantitative increase -by a continuous functional excitation, and if the single cell possesses -in itself a corresponding mechanism of self-regulation -similar to the cell community in the vertebrates, cannot be -answered, for concerning all these problems information is lacking -for the present.</p> - - -<hr class="chap x-ebookmaker-drop" /> - -<div class="chapter"> -<p><span class="pagenum" id="Page_118">118</span></p> - -<h2 class="nobreak" id="CHAPTER_VI">CHAPTER VI<br /> -<span class="title">CONDUCTIVITY</span></h2> -</div> - - -<div class="blockquot"> - -<p class="pl2hi2"><i>Contents</i>: Only processes of excitation are conducted, not processes of -depression. Conduction of excitation in its two extreme instances. -Conduction in undifferentiated pseudopod protoplasm of rhizopoda. -Conduction of excitation with decrement of intensity and rapidity. -Conduction of excitation in the nerve. Rapidity of conduction of -excitation without decrement. Relation between irritability and conductivity. -Conduction of excitation with decrement of the nerve after -artificial depression of irritability by narcosis. Theory of the decrementless -conduction of the normal nerve. Proof of the validity of -the “all or none law” in the medullated nerve. Theory of the process -of the conductivity of excitation. Theory of core model (Kernleiter). -Electrochemical theory of conduction based on the properties of semi-permeable -surfaces.</p> -</div> - - -<p>When the response to a stimulus is studied in a living system, -whether it be a single cell, a tissue, or a complex organism, the -indicator used, either that of movement, current of action, production -of certain substances, the development of light, of heat -or the alteration of form, is the result of two distinct processes. -The first of these is primary excitation, brought about by the -stimulus at a local point, and the second is an extension of the -excitation to the surrounding tissue. We are not in a position -to experimentally bring about a response to stimulation, in which -the primary excitation occurs and not the secondary process, -that of conductivity. All living substance contains this property, -although to a very different degree, as all living substance possesses -irritability, and this presents the condition not only for -the taking place of the process of excitation but also that of its -conduction.</p> - -<p>If I here speak only specifically of the conduction of excitation -instead of the conductivity of response to stimulation this is not<span class="pagenum" id="Page_119">119</span> -only primarily for the reason that we intend especially to analyze -the conductivity of excitation on this occasion, but also because -no other effects of stimulation except those of excitation can be -conducted from the part affected by the stimulus to the surroundings.</p> - -<p>Although considered on theoretical grounds it appears more -or less improbable that depression is extended from the place of -its origin, it is very easy to convince one’s self experimentally of -the fact that depression following a stimulus is invariably localized -to that portion directly affected by the stimulus. The nerve -furnishes a very favorable object for this purpose. If a nerve -muscle preparation of the frog is made and introduced in the -glass chamber previously described containing platinum electrodes, -and another pair is applied to the nerve between the chamber -and the muscle, it is possible to subject the stretch of nerve in -the chamber to various agents, producing a paralyzing effect. In -this way it may be exposed to an atmosphere of pure nitrogen -for example, or to narcosis as by ether, chloroform, carbon dioxide -and other gases, to an increase in temperature or to other -agents, without these in any way affecting the irritability of the -nerve stretch situated over the electrode between the chamber -and the muscle. The contractions of the muscle, which are produced -by stimulation of the periphery region of the nerve with -stimuli of a definite strength, remain unaltered, even when the -asphyxiated stretch of nerve in the chamber is already completely -degenerated. The central depression of a ganglion cell of a -motory neuron is likewise wholly without influence on the degree -of excitability of its nerve fiber, as I was able to <span class="nowrap">demonstrate<a id="FNanchor_79" href="#Footnote_79" class="fnanchor">79</a></span> -in the reflex inhibition of the motor neurons of the spinal cord -of the dog. (Figure <a href="#i_120">14</a>.) That which is conducted by the -nerves is solely the process of excitation.</p> - -<p>It is our task to analyze in detail the conditions involved in the -conduction of excitation in order to obtain a deeper insight into -the physics of this process. A comparative survey of a series of -various types of living substance shows us that they differ in<span class="pagenum" id="Page_120">120</span> -respect to the conduction of excitation in the following points: -In regard to the rapidity with which the excitation is conducted, -the extent of the area over which it spreads, and the intensity -with which it extends. These conditions may be best illustrated -by citing two extreme examples. The one is formed by the -rhizopods, the other by the nerve fibers. Between these two -extremes we have manifold gradations in the conditions of conductivity. -Not all cell forms are suitable objects for the study of -conductivity. There are forms of rhizopods which are as favorable -to investigation as the nerve; this is due to the fact that,<span class="pagenum" id="Page_121">121</span> -although they are often of microscopic dimensions, they possess -elongated fingerlike or threadlike pseudopods.</p> - -<div class="figcenter illowe35" id="i_120"> - <img class="w100" src="images/i_120.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 14.</p> - -<p class="taj pl1hi15">Contractions of the musculus extensor digitorum communis longus of the dog, brought about by rhythmic -stimulation of the nervus peroneus. The muscle is in the condition of tonic excitation which -proceeds from the center. The arrows indicate the point where reflex inhibition of the central tonus -is produced. The height of the single contraction undergoes no diminution. -</p></div> -</div> - -<p>Indeed, a rhizopod cell, with its straight, elongated pseudopods, -is preëminently fitted as an object of comparison with a neuron. -Although the difference in respect to the individual points is so -far-reaching, still, based on their outward morphological similarity -various physiological parallels in both are forced on our observation. -A comparison of the rhizopod cell with the neuron can -consequently guard us from many erroneous generalizations -which we might be inclined to deduce from a one-sided investigation -of the nerve. This is especially the case in regard to the -conductivity of excitation, which was formerly studied almost -exclusively on the nerve and only occasionally on the muscle, -which offers similar conditions. The nerve, in which the function -of the conductivity of excitation is particularly highly developed, -was considered at the same time as the type in which this -process could be most readily analyzed, and from which it was -believed general information of the process of the conductivity of -excitation could first be gained. This view has led to serious -errors, as the nerve, resulting from the high development of its -conductive capability, shows quite one-sided specialized conditions, -which can by no means be transferred to other forms of living -substance.</p> - -<p>A very suitable object among rhizopods for the study of conductivity, -and which is everywhere easily procured, is <i>Difflugia</i>. -This species living in small pools has a delicate urn-shaped, pear-shaped -or flask-shaped capsule built up of sand grains, diatomes -or material produced by the organism itself. From the opening -the protoplasm extends often to a considerable length its finger-shaped -hyaline pseudopods. When <i>Difflugia</i> is placed in a flat -dish in water and observed under the microscope, it is frequently -seen to extend from the opening long pseudopods in exactly opposite -directions, which reach for a considerable distance on the -bottom. These offer particularly favorable conditions for the -study of the conduction of excitation. When this animal is -placed under a microscope, the pseudopods are very readily stimulated -at any position to a desired extent by means of a sharp<span class="pagenum" id="Page_122">122</span> -needle, to which fat has been previously applied and subsequently -the excess removed. The extension of the response -from one point toward the other can then be followed with -great ease. The pseudopod of the rhizopod has the great advantage -over the nerve that its excitation can be directly observed. -The excitation following weaker stimulation is manifested by -a wrinkling of the previously completely smooth surface; stronger -stimulation produces differentiation of the hyaline protoplasm to -a strongly refractive strand in the axis and a turbid myelinlike -mass at the periphery, the pseudopod at the same time retracting -toward the central cell body. In spite of all these occurrences -being of microscopic dimensions, still with some practice it is -quite possible to experiment on them under the microscope. In -this way I found it comparatively simple to study the fundamental -principles of conductivity<span class="nowrap">.<a id="FNanchor_80" href="#Footnote_80" class="fnanchor">80</a></span></p> - -<div class="figcenter illowe31_25" id="i_123"> - <img class="w100" src="images/i_123.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 15.</p> - -<p class="taj pl1hi15"><i>Difflugia urceolata.</i> A—Weak local stimulation at the end of a long extended pseudopod. -B—Stronger local stimulation applied to the end of a long pseudopod.</p></div> -</div> - -<div class="figcenter illowe31_25" id="i_124"> - <img class="w100" src="images/i_124.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 16.</p> - -<p class="taj pl1hi15"><i>Difflugia urceolata.</i> A—In non-stimulated condition. B—The same individual -locally stimulated in the middle of a long extended pseudopod. The excitation -spreads in both directions, centripetal as well as centrifugal. -</p></div> -</div> - -<p>All these factors, the intensity with which the excitation -extends from the point of stimulation, the rapidity of the extension, -and finally the area over which conduction takes place, are -manifestations of the intensity of stimulus, and as such alter -with these in corresponding manner. If the end of a pseudopod -is barely touched and thereby weakly stimulated, the response is -restricted to a slight wrinkling of the surface, which slowly extends -to the immediate neighborhood, whilst the more distant -parts of the pseudopod are not affected at all by the excitation. -(Figure <a href="#i_123">15</a>, A.) On a stronger stimulation of the pseudopod by -slight pressure, the response is likewise stronger, and the characteristic -differentiation of the protoplasm, consisting in the -strongly refractive strand in the axis and the turbid myelinlike -outer mass, appears at the point of stimulation. From here a -peculiar alteration spreads gradually further over the pseudopod, -in that first upon its smooth surface a few myelinlike droplets -are seen, which become larger and with the development of the -strand in the axis, dissolve into a wrinkled mass on the surface. -The further this process extends from the point of stimulation, -the weaker it becomes and the more slowly it proceeds, until at<span class="pagenum" id="Page_123">123</span> -last there is complete disappearance. (Figure <a href="#i_123">15</a>, B.) The -pseudopod has at the same time retracted to a considerable -degree. If a still stronger stimulus is applied by firm pressure -at the end of the pseudopod the process takes place with much -greater violence. The differentiation of the protoplasm spreads -centripetally from the point of stimulation over the whole -pseudopod with great rapidity, and produces a quick retraction -in the same, then involves the oppositely directed pseudopod, -in which it then extends more and more slowly, until, proceeding -in a centrifugal direction, it is at last gradually completely obliterated. -When strong stimulation is applied, the process occurs -with such rapidity that the contraction of the pseudopod is -almost twitchlike. As the rapidity of the conduction alters<span class="pagenum" id="Page_124">124</span> -within a wide limit according to the strength of the stimulus -and the distance from the point of stimulation, it is self-evident -that no constant figure can be stated. To give a general idea of -the rapidity, they might be estimated according to observations -I have made with second watch and ocular-micrometer as from -within a slight fraction to that of a millimeter in the second. -When a very long extended pseudopod is locally stimulated in -the middle, the response spreads from the point affected in both -directions diminishing in intensity and rapidity. The excitation -extends equally in all directions. (Figure <a href="#i_124">16</a>.) These facts<span class="pagenum" id="Page_125">125</span> -show very clearly that in <i>Difflugia</i> the excitation following a -localized stimulus is dependent on the intensity of the stimulus, -and that according to the degree of this, the wave progresses -in either stronger, more rapid and extended, or weaker, -slower and more limited manner. With the greater distance -from the point of stimulation the excitation undergoes an increasing -decrement of its intensity and rapidity of conduction. Different -species of <i>Difflugia</i> which I have investigated, <i>Difflugia -lobostoma</i>, <i>urceolata</i>, <i>pyriformis</i>, have shown a complete conformity<span class="pagenum" id="Page_126">126</span> -in this respect. A great number of other fresh water and -marine rhizopods, the pseudopods of which I have used for analogous -experiments, although differing in the manner of reaction -in regard to the extent and rapidity of the course of excitation, -manifest exactly the same fundamental principles. A very -favorable form is, for instance, the much smaller <i>Cyphoderia -margaritacea</i>, which is distinguished by a somewhat higher degree -of excitability and rapidity of reaction<span class="nowrap">.<a id="FNanchor_81" href="#Footnote_81" class="fnanchor">81</a></span> The long straightly -extended pseudopods are thinner and more threadlike than those<span class="pagenum" id="Page_127">127</span> -of <i>Difflugia</i> and show upon stimulation as a result of their local -excitation a simple contraction into clumps of the stimulated -protoplasm without the characteristic differentiation of that of -<i>Difflugia</i>. (Figure <a href="#i_125">17</a>.) In the case of the marine rhizopods, -<i>Orbitolites</i> (Figure <a href="#i_127">19</a>), <i>Amphistegina</i>, etc., which I investigated -at the Red Sea, the conduction of excitation takes place also as -in <i>Difflugia</i> with a decrement of intensity and rapidity becoming -larger with the distance from the point of stimulation until the -wave of excitation is obliterated.</p> - -<div class="figcenter illowe25" id="i_125"> - <img class="w100" src="images/i_125.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 17.</p> - -<p class="tac"><i>Cyphoderia margaritacea.</i> Result of localized mechanical stimulation at the end -of a long extended pseudopod. A, B, C—three successive stages.</p></div> -</div> - -<div class="figcenter illowe25" id="i_126"> - <img class="w100" src="images/i_126.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 18.</p> - -<p class="tac"><i>Cyphoderia margaritacea.</i> Result of localized mechanical -stimulation in the middle of a long extended pseudopod.</p></div> -</div> - -<div class="figcenter illowe25" id="i_127"> - <img class="w100" src="images/i_127.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 19.</p> - -<p class="taj pl1hi15">A pseudopod of Orbitolites complanatus (cf. Fig. <a href="#i_060">7</a>). <i>a</i>—In normal condition. -<i>b</i>—Severed by a cross section near the end. <i>b-f</i>—Five successive stages -of the effect. <i>b-d</i>—The pseudopod retracts by centripetal flowing of the -protoplasm contracted in the shape of microscopic balls and spindles. <i>e</i> -and <i>f</i>—The pseudopod begins to extend again. The centripetal flowing -balls and spindles begin to disappear. -</p></div> -</div> - -<p><span class="pagenum" id="Page_128">128</span></p> - -<p>A sharp contrast to this type is formed by the other extreme -as represented by that of the medullated nerve. As an indicator -of the course of excitation we will take the action current in -an isolated nerve of the frog. If this is stimulated at one end, -we can test the intensity of the conducted excitation by leading -off the action current from two points at varying distances from -the one influenced by the stimulus. Since the classical discovery -of <i>Du Bois-Reymond</i> of the action current of the nerve, we know -that in the fresh medullated nerve, if observed under favorable -experimental conditions, no decrement of intensity of excitation -during its course from the point of stimulation along the length -of the nerve can be demonstrated<span class="nowrap">.<a id="FNanchor_82" href="#Footnote_82" class="fnanchor">82</a></span> If unpolarizable electrodes -are applied to a nerve in such a position that they are equidistant -from the cross section and are connected with apparatus for -testing the current, it will be found that there exists an “unwirksame -Ableitung” in the sense of <i>Du Bois-Reymond</i>, that is, in -which there is no demarcation current. When a tetanizing current -is applied to one end of the nerve, no difference of potential -between the two nonpolarizable electrodes is observed, which -indeed would be the case if excitation with its current of -action would have a decrement on its way from one to the other -point of leading <i>off</i> the current. <i>This fact, which has been repeatedly -confirmed, shows us that the medullated nerve, under normal -conditions, conducts excitation without a perceptible decrement -of the intensity.</i></p> - -<p>This specific property of a medullated nerve is in conformity -with the conditions in connection with the rapidity of conductivity. -Since <span class="nowrap"><i>Helmholtz</i><a id="FNanchor_83" href="#Footnote_83" class="fnanchor">83</a></span> has devised the method for measuring -the rapidity of conduction in the nerve, this investigator himself -and numerous others have studied the rate in different nerves<span class="nowrap">.<a id="FNanchor_84" href="#Footnote_84" class="fnanchor">84</a></span> -<i>Helmholtz</i> found the rate for motor nerves of the frog to be -27 meters per second, for the sensory nerves of man 60 meters,<span class="pagenum" id="Page_129">129</span> -and the motor nerves of man 34 meters. Other investigators -have obtained quite different results; <i>Hirsch</i>, for the sensory -nerves of man, 34 meters; <i>Schelske</i>, for the same, 25–33 meters; -<i>De Jaager</i>, 26 meters; <i>v. Wittich</i>, 34–44 meters, and <i>Kohlrausch</i>, -56–225 meters; <i>v. Wittich</i> for the motor nerves of man, 30 meters; -<span class="nowrap"><i>Piper</i><a id="FNanchor_85" href="#Footnote_85" class="fnanchor">85</a></span> finally in the most recent investigations about 120 meters -in the second.</p> - -<p>These differences may be explained in a <i>large</i> measure by the -variety of the methods used, in part also by the difference in the -structures. The methods employed for the study of the velocity -have also been used to solve the question, whether the velocity of -the excitation wave in its course over the nerve meets with a -decrement as it moves further and further away from the point -of stimulation. Here the endeavor was made to study the difference -in time of the latent period, which is observed by the indicator, -when the nerve is stimulated at two points at different distances -from the muscle, used as an indicator, or from the wires -leading the current to the indicator. The more recent investigators, -as <i>René Du Bois-Reymond</i><span class="nowrap">,<a id="FNanchor_86" href="#Footnote_86" class="fnanchor">86</a></span> -<i>Engelmann</i><span class="nowrap">,<a id="FNanchor_87" href="#Footnote_87" class="fnanchor">87</a></span> -<i>G. Weiss</i><span class="nowrap">,<a id="FNanchor_88" href="#Footnote_88" class="fnanchor">88</a></span> have -arrived at the same conclusion, that the rate of conductivity in -the medullated nerve under normal conditions is the same at all -distances from the point of stimulation. (Figure <a href="#i_130">20</a>.)</p> - -<p>The medullated nerve shows, therefore, under normal conditions -neither a decrement of its conductivity, nor of its <i>irritability</i>, -as the distance of the wave of excitation increases from that of -the position of stimulation; this means, in other words, that excitation -is conducted with the same intensity with which it is started, -and with a constant rate throughout the entire course of the -nerve.</p> - -<div class="figcenter illowe26_25" id="i_130"> - <img class="w100" src="images/i_130.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 20.</p> - -<p class="taj pl1hi15">Curves of muscle contraction obtained by stimulation of 3 and 4 points situated -at equal distances from each other on the sciatic nerve of the frog. The -increase of length of the nerve stretch corresponds with an equal increase of -the latent period of contraction. From this follows, that the rapidity of the -wave of excitation is the same at all points of the entire length of the nerve. -(After <i>Engelmann</i>.) -</p></div> -</div> - -<p>There is, nevertheless, a third point of considerable difference<span class="pagenum" id="Page_130">130</span> -between the types of conduction of excitation in the rhizopods -and in the nerve. Whereas in the rhizopods the rapidity of conduction -is dependent upon the <i>intensity</i> of the stimulus, it has -been long known as the result of investigation by <i>Rosenthal</i>, -<i>Brücke</i> and <i>Lautenbach</i> and at a more recent date by <span class="nowrap"><i>Gotch</i><a id="FNanchor_89" href="#Footnote_89" class="fnanchor">89</a></span> and -<i>Piper</i><span class="nowrap">,<a id="FNanchor_90" href="#Footnote_90" class="fnanchor">90</a></span> that in the nerve of the frog, as well as in man, the velocity -is <i>not</i> dependent upon the intensity of stimulation. (Figure <a href="#i_131">21</a>.) -Contrary results have been obtained by a few early observers -wherein the latent period was shorter when the stimulation was -strong. <span class="nowrap"><i>Nicolai</i><a id="FNanchor_91" href="#Footnote_91" class="fnanchor">91</a></span> explains this shortening of the latent period,<span class="pagenum" id="Page_131">131</span> -resulting from the application of strong electrical stimuli, to a -spreading out of the “Stromschleifen” from the point of application -and consequently there is a shortening of the stretch of -nerve between the point of stimulation and the indicator.</p> - -<div class="figcenter illowe30" id="i_131"> - <img class="w100" src="images/i_131.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 21.</p> - -<p class="taj pl1hi15">Course of the action current of the nerve. The thin line indicates the action current -produced by a weak, the thick line the action current produced by a strong stimulus. -The duration of the action current is the same in both cases. (After <i>Gotch</i>.) -</p></div> -</div> - -<p>This conspicuous difference in the conduction of the two -extreme types of living substance, which we have already observed, -arouses the question as to what properties of living substance -bring about these differences. In order to answer this -question, it is necessary, first of all, to make some general statements -concerning the processes of conductivity.</p> - -<p>As already emphasized, all living substance possesses the capability -of conducting excitations to a definite degree. We may, -therefore, assume that the same fundamental <i>property</i> of conductivity -exists in all substances. A fact to be considered in the -conduction of excitation, is that the primary breaking down of -the complex molecules at the position of stimulation act in turn -as exciting stimuli upon the neighboring portion of the living -substance, which in turn undergoes a similar decomposition. And -so this process continues. This fact is evident from the observations -on the process of excitation. But the nature of the stimulus<span class="pagenum" id="Page_132">132</span> -which produces the breaking down of the complex molecules -upon the surrounding molecules is a problem which can only be -studied later. Here only one point will be mentioned in advance -concerning the intensity of the stimulus. It is apparent from the -experiments on the rhizopods, that the greater the intensity of the -stimulus the more extensive must be the breaking down of the -living substance. A stronger primary stimulation must also -secondarily produce a stronger stimulus in the neighborhood. In -other words: the <i>conduction of excitation</i> is a function of irritability. -The greater the irritability, that is, the greater the number -of molecules broken down in a unit of time and space by a stimulus -of a certain intensity, the greater also is the conductivity of -the living system, that is, the stronger, the more rapidly and the -further excitation is extended. Conductivity of excitation is, -therefore, unthinkable without irritability. Both are inseparably -connected. The conclusion forced upon us by this chain of -reasoning admits of no argument. Nevertheless the endeavor -has been made, because of certain evidence at hand, to show that -the property of conductivity could exist without irritability. A -number of authors, such as <i>Schiff</i><span class="nowrap">,<a id="FNanchor_92" href="#Footnote_92" class="fnanchor">92</a></span> <i>Erb</i><span class="nowrap">,<a id="FNanchor_93" href="#Footnote_93" class="fnanchor">93</a></span> <i>Grünhagen</i><span class="nowrap">,<a id="FNanchor_94" href="#Footnote_94" class="fnanchor">94</a></span> <i>Effron</i><span class="nowrap">,<a id="FNanchor_95" href="#Footnote_95" class="fnanchor">95</a></span> -<span class="nowrap"><i>Hirschberg</i><a id="FNanchor_96" href="#Footnote_96" class="fnanchor">96</a></span> and <i>G. Weiss</i><span class="nowrap">,<a id="FNanchor_97" href="#Footnote_97" class="fnanchor">97</a></span> have observed the fact that in spite of -a more or less strong decrease of <i>excitability</i> of a stretch of nerve, -stimuli applied above this stretch can still produce a conduction -of excitation through the affected part. They have concluded -from this that it is possible to separate the conductivity from -irritability. <i>Erb</i> and <i>G. Weiss</i> have even gone so far as to directly -express the opinion that capability of conduction and irritability -involve two different histological elements. In contrast to this,<span class="pagenum" id="Page_133">133</span> -other investigators, such as <i>Hermann</i><span class="nowrap">,<a id="FNanchor_98" href="#Footnote_98" class="fnanchor">98</a></span> <i>Szpilmann</i> and <i>Luchsinger</i><span class="nowrap">,<a id="FNanchor_99" href="#Footnote_99" class="fnanchor">99</a></span> -<i>Gad</i><span class="nowrap">,<a id="FNanchor_100" href="#Footnote_100" class="fnanchor">100</a></span> <span class="nowrap"><i>Piotrowski</i><a id="FNanchor_101" href="#Footnote_101" class="fnanchor">101</a></span> and <i>Wedenski</i><span class="nowrap">,<a id="FNanchor_102" href="#Footnote_102" class="fnanchor">102</a></span> have more or less -decidedly taken the stand that an actual separation of irritability -and of conductivity does not exist. The apparently contradictory -evidence as well as the conflicting theoretical views have been -cleared up by <i>Werigo</i><span class="nowrap">,<a id="FNanchor_103" href="#Footnote_103" class="fnanchor">103</a></span> <i>Dendrinos</i><span class="nowrap">,<a id="FNanchor_104" href="#Footnote_104" class="fnanchor">104</a></span> <span class="nowrap"><i>Noll</i><a id="FNanchor_105" href="#Footnote_105" class="fnanchor">105</a></span> and <i>Fröhlich</i><span class="nowrap">.<a id="FNanchor_106" href="#Footnote_106" class="fnanchor">106</a></span> These -investigators have shown that the length of the narcotized stretch -of the nerve plays an important rôle in the obliteration of conductivity. -It has been found by the application of a stimulus -above the narcotized stretch of nerve, that the longer this stretch -is, the less is the reduction of irritability which obliterates the -excitation wave reaching this area. Further: The shorter -the stretch, the greater must be the reduction in irritability -before this result is brought about. (Figure <a href="#i_134">22</a>.) In other -words, the conductivity in the narcotized nerve is dependent -upon the length and the irritability of the narcotized stretch. -From this observation the important fact is evolved, that -the wave of excitation meets with a decrement of its intensity -in the narcotized area. This decrement becomes larger as -the wave progresses through the involved stretch. Further it -is progressively increased as the amount of the irritability is -reduced. Finally, when the stretch is long enough, the wave<span class="pagenum" id="Page_134">134</span> -of excitation is obliterated. This important fact has been further -established by the experiments of <i>Boruttau</i> and <i>Fröhlich</i><span class="nowrap">,<a id="FNanchor_107" href="#Footnote_107" class="fnanchor">107</a></span> -in which they studied the intensity of the current of action, -produced by a wave of excitation, from two points in the narcotized -stretch. The wave of negative variation, brought about by<span class="pagenum" id="Page_135">135</span> -the excitation, gradually decreases in the narcotized stretch as -the electrode is further removed from the point of entrance. -Beside a decrement of <i>intensity</i>, as the investigations of <span class="nowrap"><i>Fröhlich</i><a id="FNanchor_108" href="#Footnote_108" class="fnanchor">108</a></span> -prove, the wave of excitation shows a decrement of the velocity -in the narcotized stretch. And it is probable that the wave of -excitation extends with <i>progressive</i> reduction in the velocity, -corresponding to the decrement of intensity. The work of <span class="nowrap"><i>Koike</i><a id="FNanchor_109" href="#Footnote_109" class="fnanchor">109</a></span> -under the direction of <i>Garten</i>, in which the conclusion arrived at -is that the reduction in the velocity is the same throughout the -narcotized area, should not be accepted as conclusive in spite -of the delicate method employed. These investigations are extremely -difficult, being in the field of the most delicate of present-day -methods. The decrement, which the wave of excitation -meets with in its progress in the narcotized stretch, makes the -conflicting testimony concerning the apparent separation of irritability -and conductivity intelligible. It depends entirely upon -the length of the narcotized area, and the amount of reduction -in irritability on the one hand, and the strength of the stimulus -used for testing the irritability on the other, whether the conductivity -will disappear <i>before</i> the irritability or <i>vice versa</i>. If -I test the irritability in the narcotized stretch with a weak stimulus, -just slightly <i>above</i> the threshold, then by slight reduction in -the irritability complete absence of response occurs, when the -same stimulus is applied. This occurs at a time when excitation -reaches the narcotized area from above and meets with a -decrement so slight that it can pass through the whole narcotized -stretch, that is, when the narcotized stretch is short enough. -If I test the irritability of the narcotized area with a strong -stimulus, far above that of the threshold, irritability will be -found to be present at a time when the conductivity for the excitation, -coming from above, is already obliterated. This is due -to the fact that the decrement in the narcotized area is already -great enough to bring about the complete disappearance of the<span class="pagenum" id="Page_136">136</span> -wave of excitation coming from above. This, of course, only -occurs provided the length of the narcotized stretch is great -enough. The separation of conductivity and irritability is, therefore, -only an apparent one. In reality, the facts obtained from -experimentation indicate that with the reduction of irritability the -decrement of the wave of excitation increases, whilst the shorter -the stretch, the smaller is the decrement. This shows that <i>conductivity -is a manifestation of irritability</i>.</p> - -<div class="figcenter illowe30" id="i_134"> - <img class="w100" src="images/i_134.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 22.</p> - -<p class="taj pl1hi15">Scheme of the decrement of the excitation wave in the narcotized stretch of a -nerve. A—The narcotized stretch (indicated by the cross section of the -chamber) is 30 mm. long. The ordinates of the dotted lines indicate the -amount of the decrement. If the decrement is slight (upper dotted line), the -excitation wave passes the narcotized stretch and increases again on entering -the normal stretch. If the decrement is great (lower dotted line), the excitation -wave is obliterated towards the end of the narcotized stretch and the -muscle remains at rest. B—The narcotized stretch is 15 mm. long. The -decrement is slight. The excitation wave can therefore pass into the normal -stretch and here increase again. C—The narcotized stretch is 15 mm. long. -The decrement is great. The excitation wave is obliterated, therefore, in the -narcotized stretch, and the muscle remains at rest. -</p></div> -</div> - -<p>The facts just mentioned have, however, a much deeper meaning. -They show us that it is possible by means of narcosis to -convert an extreme type of a living system, with decrementless -conductivity, into another extreme type of living substance, in -which excitation in its progress meets with a strong decrement, -like that seen in the rhizopods. The same results may also be -obtained by asphyxiation and other forms of temporary and permanent -injury of the nerve. We are, therefore, in the fortunate -position in the case of the medullated nerve of having a substance -to study, which, depending upon conditions which are -under our control, may become a type in which conductivity -occurs with or without the presence of a decrement. We can -likewise reduce the irritability to various degrees, producing all -intermediate gradations between the two extremes. This latter -is particularly valuable in that it permits us to study the conditions -in one and the same substance necessary to bring about the -various peculiarities of conductivity. The great differences in -the conductivity of excitation are conditioned by variations in -the degree of irritability. If the irritability of the nerve is at the -normal level the wave of excitation progresses to the end of the -nerve without manifesting a decrement of its intensity or -rapidity.</p> - -<p>If the level of irritability of the intact nerve is artificially -reduced, the wave of excitation meets with a greater decrement -and reduces in velocity, and in fact disappears the more quickly -in the stretch of nerve, as the reduction in irritability is increased. -These three factors, irritability, intensity and velocity of the -progress of the wave of excitation, are inseparable. All living -substances may be grouped according to their capability of conducting<span class="pagenum" id="Page_137">137</span> -excitation into a long series, starting with those possessing -the least irritability, as we found in the rhizopods, then those -having greater irritability, as the smooth muscle and ganglion -cells, then those with still greater irritability, as the striped muscle, -and finally those having the greatest degree of irritability, as the -medullated nerves of the warm-blooded animal. Should the -processes of excitation, as we saw, result from the energy production -following the disintegration of the labile molecules of -the living substance, then the degree of irritability is determined -by the chemical constitution of the disintegrating molecules, by -the number of molecules which are broken down in a definite -space and a given time, and by the nature of the disintegration -itself. All of these individual components, if we observe the -problem from the physical standpoint, are manifested by the -quantity of energy production. The higher the irritability of a -living system, the greater is the amount of energy production in -a given time and space which the stimulus produces. This has -particular interest from the standpoint of the extreme cases of -medullated nerves of the vertebrates with their most highly developed -conductivity, and which will be analyzed in somewhat greater -detail. How are we to explain their decrementless conductivity? -When we study the decrement of the excitation wave in the -series of living substances, before alluded to, we see that this -reduces with a progressive increase of irritability. Consequently -the extreme irritability of the nerve is a manifestation of its -decrementless conductivity. If we study the course of a process -of excitation and its conduction in its molecular details, the fact -of the decrementless conduction indicates that in excitation, produced -by a stimulus, the same number of specific molecules -capable of disintegration are broken down in the same manner -at every following cross section, as at the point of stimulation; -or in other words: an equal amount of energy is set free at every -cross section, which, in its turn, acts as stimulus to the next, -etc. Such a condition presupposes, however, in an elementary -fiber of the nerve, that by the conduction of the wave of excitation -from cross section to cross section, all those molecules -capable of disintegration are broken down. If it is assumed that<span class="pagenum" id="Page_138">138</span> -the entire number of molecules capable of disintegration do not -break down, but only a certain per cent. of the same, then it would -not be possible to conceive of a molecular structure of the nerve -in which this would take place without decrement of the wave of -excitation. With the assumption of a generally homogeneous -molecular structure (Figure <a href="#i_138">23</a>, a) of the elementary fibers it -would be entirely incomprehensible how, with the decrementless -extension of the excitation, individual molecules capable of breaking -down could escape disintegration. If, on the contrary, the -molecular structure is not homogeneous it only is possible to -explain a conduction, on each cross section of which an equal -per cent. of irritable molecules break down, by the hypothesis -that the irritable molecules are in their turn ordered in fiber-shaped -series (Figure <a href="#i_138">23</a>, b) within the elementary fiber and are -thus protected to a certain degree from one another and from -transverse conduction of excitation. This hypothesis would, -therefore, only mean that the elementary fiber is not such in<span class="pagenum" id="Page_139">139</span> -reality and would thus transfer the difficulty to the ultimate -fiber unit, for which a homogeneous molecular structure would -have to be presumed. In short, whatever may be the assumption -on which molecular structure of elementary fibers is based, the -fact of the decrementless conduction peremptorily demands, from -the physical standpoint, that from cross section to cross section -the entire number of irritable molecules are broken down. This -conclusion is highly important, for it indicates very clearly that -the “all or none law” is applicable to the nerve.</p> - -<div class="figcenter illowe23_125" id="i_138"> - <img class="w100" src="images/i_138.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 23.</p></div> -</div> - -<p>This gives us occasion to return to the discussion of the question, -if living systems really exist which respond in accordance -with the “all or none law.” The medullated nerve forms an -object particularly suited to serve as a starting point for the -treatment of this especially important problem. The question -arises in this connection, if the validity of this law for the nerve -can be tested by other means.</p> - -<p>At first it would seem as if the application of the “all or none -law” to the nerve were in contradiction to the well-known fact -that a weak stimulation of the nerve produces a weak, a strong -stimulation, a strong response. In this connection <span class="nowrap"><i>Gotch</i><a id="FNanchor_110" href="#Footnote_110" class="fnanchor">110</a></span> has -pointed out, as the result of experimental studies of the wave -of activity of the nerve, that the difference in response, following -the application of stimuli of varying strengths, is understandable -from the fact that threshold stimuli stimulate only a -few of the fibers of the nerve trunk, whereas progressively increasing -the intensity of the current involves more and more -fibers. There can be no doubt that this factor explains the difference -in the strength of the response. Therefore, in reality we -do not find here a contradiction of the “all or none law.” On -the other hand, the fact that the nerve, in contradistinction to -many other forms of living substance, the ganglion cell, for -example, upon a weak stimulation does not show the phenomena -of summation, even when the stimuli follow each other in a -rapid succession, indicates very strongly that the weakest operable -stimulus produces maximal excitation, so that the response<span class="pagenum" id="Page_140">140</span> -cannot be further increased. But above all, there is a series of -facts, which have been gained in the Göttingen laboratory, which -demonstrate apparently without doubt the validity of the “all -or none law” for the medullated nerve. These observations I -wish now to consider in greater detail.</p> - -<p>If a nerve of a nerve muscle preparation is drawn through a -specially devised glass chamber so that the middle portion can -be narcotized or asphyxiated and the nerve so arranged that it -rests upon a pair of electrodes in the chamber and upon a second -pair without the chamber and centrally located, then the nerve -can be narcotized or asphyxiated and thereby the alterations in -the irritability as well as the conductivity can be followed. In -order to obtain as distinct a picture of this alteration as possible, -I tested continuously the threshold of stimulation, which just produced -minimal contraction in the muscle, and <span class="nowrap"><i>Fröhlich</i><a id="FNanchor_111" href="#Footnote_111" class="fnanchor">111</a></span> continued -these observations. As a result the following very remarkable -conditions were observed. During the increase of the depth -of narcosis or asphyxia the irritability sinks more and more with -regularity. The conductivity remains unaltered for a long time, -as the strength of the threshold stimulus is not changed until -irritability has fallen to a definite point. When this is reached, -conductivity disappears. (Figure <a href="#i_141">24</a>.) The most important point -in this connection, however, is, that the conductivity disappears -simultaneously and practically momentarily for the excitation -produced by both weak and strong stimuli. When the stimulation -at the electrode placed centrally to the chamber does not -bring about response for threshold stimuli, maximal stimuli at -the same time also become inoperative. This is a very interesting -point, the importance of which has not until now been recognized. -This fact is not in harmony with the view held until now, that in -the nerve fiber different strengths of stimuli bring about excitation -of different intensity, and are then conducted. Let us now -clearly comprehend this problem.</p> - -<div class="figcenter illowe33_75" id="i_141"> - <img class="w100" src="images/i_141.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 24.</p> - -<p class="tac">Curves of the changes in irritability (p) and conductivity (c) of a nerve under the influence of -narcosis or asphyxiation. (After <i>Fröhlich</i>.)</p></div> -</div> - -<p>We have already seen that the wave of excitation meets with -a decrement of its intensity in the narcotized stretch, which<span class="pagenum" id="Page_141">141</span> -increases in strength as the irritability diminishes. If the value -of the threshold is learned by stimulating the nerve at the electrodes -centrally placed to the chamber with minimal stimuli, it -would necessarily follow that this weak stimulus would bring -about a corresponding weak excitation of the individual fibers -and the wave of excitation already in the beginning of narcosis -would be obliterated, for it would meet with a decrement, the -result of the reduction in the irritability. A wave of excitation -of minimal strength could under these conditions no longer -reach the muscle, even in the beginning of narcosis. In spite -of this the excitation, even when produced with threshold -stimuli, passes through for a long time, even when the irritability -in the chamber is greatly reduced, as shown by testing -with the electrodes within the chamber. This is not consistent -with the assumption that a threshold stimulus brings about the -minimal excitation, even in the individual nerve fiber. But -further: with a definite decrease of irritability of the narcotized<span class="pagenum" id="Page_142">142</span> -stretch the capability of conductivity disappears, and indeed -simultaneously for the weakest as well as the strongest stimuli. -If it is assumed that weak stimuli bring about weak excitations -in the nerve fiber, it must most certainly be expected that on the -cessation of the response, weak stimuli applied at the central -nerve end would still, by slight increase of the intensity of stimulation, -be followed anew by reaction in the muscle. This is all -the more to be expected, because the irritability of the narcotized -stretch, as shown by stimulation with the electrodes inside the -chamber, very gradually decreases, so that within the chamber -stimuli of moderate strength are still effective. Instead the capability -of conduction is completely obliterated, and even the strongest -stimuli, applied to the end of the nerve, produce no response -in the muscle. This in turn does not agree with the assumption -that the intensity of excitation varies with the strength of the -stimulus in the individual nerve fiber. The facts here alluded to -are, therefore, either not correct, or the intensity of excitation -in the individual nerve fibers is independent of the strength of the -stimulus, and the view which we have entertained up to the -present in this respect is incorrect.</p> - -<div class="figcenter illowe23_125" id="i_142"> - <img class="w100" src="images/i_142.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 24.</p></div> -</div> - -<p>In order to examine these facts once more on an extensive -scale, and at the same time obtain an understanding of the development -of the decrement in the narcotized stretch, I have requested -<i>Dr. Lodholz</i> to register as many accurate curves as possible -in which the positions of the secondary coil of an inductorium -are the ordinates indicating the threshold of stimulation at four -points of a nerve stretch. Of these points three are situated at -prescribed distances from each other in the narcotized or asphyxiated -stretch; the fourth is centrally placed. (Figure <a href="#i_142">24</a>.) As<span class="pagenum" id="Page_143">143</span> -might be expected the result was the same as in former investigations. -They show however even more strikingly the abruptness -of the disappearance of conductivity simultaneously for the weakest -and the strongest stimuli. The curve produced by the centrally -placed electrode remains at the same height for a considerable -period, then suddenly abruptly declines. Those of the electrodes -within the chamber likewise sink, at first slowly, then with increasing -rapidity in successive order corresponding to the distance -which they are situated from the point of exit of the -nerve, so that the curve of the most distant electrode reaches the -abscissa first, that of the electrode nearest the muscle in the -chamber, last. The experiments demonstrate with complete -clearness that in contrast to all those points within the affected -stretch, where the conductivity, though already obliterated for -weaker stimuli, still exists for stronger, that with stimulation -of a point towards the center <i>above</i> the affected stretch, conduction -ceases simultaneously for all different strengths of -stimuli. This last state at the points within the affected stretch -might be ascribed to the diminution of the excitability of this -stretch, and the idea entertained that the weak stimuli no longer -produce excitation capable of further conduction.</p> - -<p>This assumption is contradicted, however, by the fact that -subsequently to the disappearance of the response at a point situated -at the <i>greatest distance</i> from the place of exit, an effect of -stimulation can be obtained at the <i>nearest</i> point to the exit with -the same or even less strength of the current. As the irritability -in the affected stretch is reduced at all points in equal measure, -the fact of a weaker stimulus becoming inoperative whilst a -stronger remains effective can only be attributed to the circumstance -that the wave of excitation set free at some point of the -influenced stretch by a weaker stimulus is sooner obliterated on -its way to the muscle than that produced at the same point by a -stronger stimulus. These experiments, in which the manifestations -of the nerves in response to stimuli applied centrally above -the chamber in the normal stretch are compared to those in -response to a stimulus acting on the affected stretch, clearly -demonstrate the totally different effect in both cases. In stimulation<span class="pagenum" id="Page_144">144</span> -of the centrally situated normal stretch, the wave of excitation, -which enters from here into the influenced stretch, is obliterated -at the same point simultaneously for the weakest as well as -for the strongest stimulus; stimulation of the affected stretch, the -wave of excitation which is set free at one point by a weak stimulus, -is obliterated sooner and after passing through a shorter -stretch than that which is produced by a stronger stimulus. It is -self-evident that in the first instance, in which the stimulus acts on -the centrally situated normal stretch, the wave of excitation, -thereby set free, must in passing through the affected stretch -undergo a decrement of its intensity. If, therefore, the wave -of excitation, coming from above, is obliterated exactly at the -same point, whether brought about by weak or strong stimuli, the -inevitable conclusion must be drawn that, whether either a weak -or a strong stimulus is operative, the wave of excitation must -have entered into the influenced stretch from the normal stretch -with exactly the same intensity. In other words: the weakest -as well as the strongest stimuli produce excitations of equal -intensity in the normal nerve, that is, the “<i>all or none law</i>” is -<i>valid for the nerve</i>.</p> - -<p>This information can no longer be doubted in the presence of -such evidence as was presented above. This indeed is a fact of -far-reaching importance in the understanding of the functional -activity of our nervous system, for it is evident that the difference -of intensity in the conduction of excitation is not, as has -been assumed until now, the result of the conduction of varying -strengths of a single excitation in the same elementary -fibers, but rather the involvement of a various number of fibers, -and that a series of processes which we have to the present -attributed to the varying intensities are now to be explained -by difference in the duration and form of excitation. This gives -us an entirely different but nevertheless a more definite picture -of the physiological character of the processes in the nervous -system. Still, this question belongs to another chapter of physiology. -Here we are interested in the fact that we have in -the nerve a form of living substance, in which irritability has -reached a high degree, and every stimulus which is at all operative<span class="pagenum" id="Page_145">145</span> -brings about disintegration of all the material involved -in excitation, and consequently the property of conductivity -in the nerve reaches the state of highest development of all -living structures, in that the medullated nerve conducts with -the greatest rapidity on the one hand, and on the other, there is -no decrement of the velocity and intensity of excitation. All -these characteristics: the existence of the “all or none law,” the -rapidity of the conduction of excitation, the absence of a decrement -in the velocity, the absence of a decrement of the intensity -of the excitation wave, the want of the capability of summation -of excitation, are all dependent upon one another, for they are -the combined expression of one and the same factor, that of the -high state of irritability. When the irritability is artificially reduced, -then the nerve approaches more and more, depending upon -the amount of reduction, to the series of living substances in -which we found the protoplasm of the rhizopoda to occupy the -other extreme. Between the normal medullary nerve with its -maximal, and the pseudopods of the rhizopods with their minimal -capability of reaction, we find innumerable gradations in groups -of living substances. Whether or not other forms of living substances -follow the type of the nerve, whether for example the -“all or none law” can be applied to the skeletal muscle as the -investigations of <span class="nowrap"><i>Keith Lucas</i><a id="FNanchor_112" href="#Footnote_112" class="fnanchor">112</a></span> seem to show, requires further -investigation.</p> - -<p>Finally, there arises the important question as to the finer -mechanism of conductivity. The progression of excitation from -cross section to cross section in a living system is brought about -by the decomposition of the molecules in one region acting as a -stimulus and producing a disintegration of the molecules in -another region, etc. We have already seen that the intensity is -dependent upon the amount of energy produced by the disintegration -of the molecules following the stimulus, that is, upon the -amount liberated in a definite space in a definite time. The question -which now arises is this: What form of energy is produced<span class="pagenum" id="Page_146">146</span> -by the stimulus at the point of stimulation, which acts upon the -neighboring molecules? The conduction of excitation is a property -of all living substance, and we may presume that this -occurs in all living systems in the same manner. If one examines -the forms of energy which are produced in a living substance by -the breaking down of the molecules, we find that chiefly three -forms of energy may be taken in consideration in the problem -of conductivity: heat, electricity and osmotic energy. Light -cannot be looked upon as a form of energy which is produced -by all living substance, and the other forms of energy, as the -chemical energy and surface tension, remain local. At a first -glance one is inclined to assume that heat is the form of energy -which is liberated by the breaking down of the stimulated molecule -and which spreads to the neighboring molecules and brings -about their decomposition. For we know that heat facilitates -dissociation, and the analogy between living substance and explosive -material is very close. In both instances the decomposition, -which extends over a great mass of molecules, is accomplished by -the heat produced in the breaking down of a few molecules. In -fact, the conduction of excitation of a nerve can in many respects -be compared with the burning of a fuse<span class="nowrap">.<a id="FNanchor_113" href="#Footnote_113" class="fnanchor">113</a></span> Nevertheless, it must -not be forgotten that this analogy, which on first glance seems so -apt, upon closer observation presents serious difficulties. It can -be experimentally shown that an increase in the temperature in -the living substance follows stimulation, but it is also known that -in momentary excitation following a single stimulus, as in the -muscle after the application of an induction shock, the heat production -is extremely small. This difficulty becomes particularly -apparent if we endeavor to gain an approximate idea of the -numerical proportions of the irritable, that is the disintegrating -molecules to the remaining mass of a living system. The -water content above all represents an enormous proportion. -If we calculate this to be for the nerve, for instance, roughly -about 75 per cent., which is a low estimate, only 25 per cent.<span class="pagenum" id="Page_147">147</span> -of dry substances remain. Even of this 25 per cent. by far -the largest part is apportioned to connective tissue, for which 15 -per cent. is certainly not too high a figure. Neither can the remaining -10 per cent. of dry substances be regarded as consisting -entirely of molecules capable of decomposition. For in this is -also included the organic reserve material of the axis cylinder protoplasm, -which is doubtless of very considerable amount. Further, -the salts and products of disintegration, for which the estimate -for the sum total would probably not be too low if we assume the -amount to be equal to that of the group specially concerned in -the process of excitation. As, however, a constant metabolism -of rest takes place, these last molecules or atom groups are certainly -not at the moment of entrance of the stimulus in their -entirety in a condition capable of decomposition. It is quite certain, -therefore, that we are still overestimating the amount of the -molecules capable of disintegration, if we put them down as 5 per -cent. of the entire nerve substance. If we now suppose that this -5 per cent. of irritable molecules are broken down as a result of -stimulation, 95 per cent. of nonirritable substance, separating -these irritable molecules, must become heated to such a degree -by the disintegration of the latter that the amount of heat suffices -to bring about decomposition of the nearest surrounding molecules -or atom groups, for otherwise conduction of disintegration -could not take place in this manner. This condition presents a -serious difficulty for the assumption that heat is the form of -energy responsible for the conduction of disintegration. It is -true that we cannot reject this view at once as being completely -incorrect, as the possibility of conduction does not depend upon -the absolute amount of heat which reaches the next molecule -capable of decomposition, but upon the relative amount of heat -in regard to the degree of lability of the irritable molecules, -of which we cannot even approximately make an estimate. However, -by a comparison with other highly explosive substances, -such as iodide of nitrogen, we find that a slight trace of water -applied to the iodide of nitrogen suffices to prevent the extension -of the disintegration process, and with this the explosion of the -whole mass. Nor does the view of <i>Pflüger</i> remove this difficulty,<span class="pagenum" id="Page_148">148</span> -which assumes that the atom groups capable of breaking down -are joined together by a chemical linking of atoms to long fiber-shaped -giant molecules through the whole nerve fiber, for this -assumption of a firm structure can hardly be reconciled with -the principles concerned of metabolism.</p> - -<p>In consideration of this difficulty it seems easier to assign -the rôle of mediator of disintegration not to heat but to electricity. -Production of electricity is likewise a property of all -living substance. Differences of electrical potential between two -points may be equalized in the stretch by conduction through -the intervening space. Electricity would then fulfil the important -conditions, which must be demanded for the form of energy, -acting as mediator for the conduction of disintegration from -cross section to cross section.</p> - -<p>Physiologists even at an early date, misled by the apparent likeness -in the conduction of excitation, especially in the nerve, to -that of electricity in a metal wire, regarded both processes as -identical. When, however, <i>Helmholtz</i> first demonstrated experimentally -the rapidity of the conduction in the nerve, the thought -that electrical conduction was concerned, such as takes place in -a metal wire, had to be abandoned, as the velocity shows too -great a difference in the two cases.</p> - -<div class="figcenter illowe23_75" id="i_148"> - <img class="w100" src="images/i_148.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 25.</p> - -<p class="taj pl1hi15">Model of a “Kernleiter.” A, B—Glass tube, with a number of side tubes -filled with saline solution, through which a wire is passed. <i>c</i> and <i>d</i>—Side -tubes with electrodes for stimulation. <i>e</i> and <i>f</i>—Tubes for connection -with a galvanometer. (After <i>Hermann</i>.) -</p></div> -</div> - -<p>The observations, on the other hand, on the conductivity in the -so-called “core model,” seemed to offer another possibility of -attributing the conduction of excitation in the nerve to electric<span class="pagenum" id="Page_149">149</span> -processes. <i>Matteucci</i>, later <i>Hermann</i> and finally <span class="nowrap"><i>Boruttau</i><a id="FNanchor_114" href="#Footnote_114" class="fnanchor">114</a></span> have -endeavored to apply the results obtained when electricity is introduced -in a wire covered with a moist envelope (saline solution), -to the explanation of conductivity in the nerve. (Figure <a href="#i_148">25</a>.) -The fact has been shown, that in such a model the application of -electricity to a point, as a result of polarization between the moist -envelope and the metal, produces a weak local current, which in -turn disturbs the electrical potential in the next cross section and -consequently a new local current is produced and so on through -the whole length of the wire. (Figure <a href="#i_149">26</a>.) This fact, in connection -with the apparent similarity in the differentiation of the -axial fibers and peripheral envelope in the nerve, has led <i>Boruttau</i> -to apply the principles of conductivity in the “core model” -to that of the nerve. Then, however, <i>Nernst</i> and <i>Zeyneck</i> brought -forward their theory, according to which the galvanic current is -operative as a stimulus in that it brings about an alteration in -the concentration of the ions at the junction of two different -electrolites which, in turn, produce local currents. <i>Boruttau</i> then -dropped the assumption of the existence of a simple physical -polarization between the wire and the envelope and replaced it -by the assumption of an alteration in the concentration of the -ions at this position. Thereby the “core model explanation” was -already altered in principle, in that only the differentiation of a -central fibrilla and a peripheral enveloping substance was appropriated. -It seems to me that this factor can likewise be considered<span class="pagenum" id="Page_150">150</span> -as completely dispensable and may, therefore, be omitted; -thus nothing remains of the “core model explanation” of the -conduction of excitation in the nerve.</p> - -<div class="figcenter illowe20" id="i_149"> - <img class="w100" src="images/i_149.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 26.</p> - -<p class="tac">Scheme of the conduction by local electric currents -in a “Kernleiter.” (After <i>Hermann</i>.)</p></div> -</div> - -<p>The results of continually increasing numbers of investigation -in recent times make it appear almost as a certainty that the elementary -fibrillæ in the axis cylinder are nothing else but skeletal -substances. <i>Wolff</i><span class="nowrap">,<a id="FNanchor_115" href="#Footnote_115" class="fnanchor">115</a></span> <span class="nowrap"><i>Verworn</i><a id="FNanchor_116" href="#Footnote_116" class="fnanchor">116</a></span> and others have first expressed -the view that the neurofibrillæ must be looked upon as skeletal -fibers for the soft neuroplasm, and more recently <span class="nowrap"><i>Lenhossek</i><a id="FNanchor_117" href="#Footnote_117" class="fnanchor">117</a></span> and -especially <span class="nowrap"><i>Goldschmidt</i><a id="FNanchor_118" href="#Footnote_118" class="fnanchor">118</a></span> have confirmed this assumption in detail. -<i>Goldschmidt</i> has shown by extensive comparative studies of cell -mechanism the rôle played by the neurofibrillæ in a physical connection -as internal skeletal formations, and has proved at the -same time, in complete unanimity with other investigators, their -continuity with other undoubted skeletal fibrillæ. By this the -numerous combinations and speculations of <i>Apathy</i> and <i>Bethe</i> -concerning the part taken by the neurofibrillæ have been rendered -untenable. In no case is there the slightest justification to regard -the apparent “Kernleiterstructur” of the nerve as the principal -condition for the process of conductivity, for should we dispense -completely with this point for the theory of the conduction of -the nerve, we can obtain, solely by the aid of the facts known -today in physical chemistry, the foundations for a theory of the -conductions of excitation which not merely renders the specific -case of the conduction of the nerve intelligible, but contains at the -same time the principles of the process of the conduction of excitation -for all living substance.</p> - -<div class="figcenter illowe21_875" id="i_151"> - <img class="w100" src="images/i_151.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 27.</p> - -<p class="tac">Scheme of the foam structure of living substance. A—In -undifferentiated protoplasm. B—In fibrillae protoplasm.</p></div> -</div> - -<p>On the basis of investigation in the physical chemistry on the -properties of semi-permeable membranes, we know that such -membranes produce an elective effect on the diffusion of dissolved<span class="pagenum" id="Page_151">151</span> -substances. This is in the way that the two different solutions, -separated by a semi-permeable surface, do not follow the known -laws of diffusion, but are altered in that certain substances in -contrast to their rapidity of diffusion pass through the membrane -or are prevented from entering by the latter. This applies likewise -to the two kinds of ions, which are dissociated in diluted -substances. If the surface exercises a selection in the way, -for instance, that the positive kations are allowed to pass through, -whilst the negative anions are held back, a difference of potential -must exist between the two. In this manner, wherever two different -solutions are separated from each other by a semi-permeable -surface, an opportunity occurs for the taking place of galvanic -currents. As we know, living protoplasm by reason of its colloidal -components possesses, in common with all colloidal substances, -on its surface the properties of semi-permeable membranes. -Between the cell and the medium, therefore, there is -always the opportunity for the occurrence of differences of electric -potential. But more. We likewise know that protoplasm itself<span class="pagenum" id="Page_153">153</span> -represents a mixture of colloid substances and actual solutions. -Frequently, if not always, living structure presents a morphological -differentiation of two types, when seen under the microscope, -in the form of a foam structure described by <i>Bütschli</i>. -(Figures <a href="#i_151">27</a> and <a href="#i_152">28</a>.) If we suppose that with the disintegration -of complex molecules, which we must assume as taking place -in the material of the walls of the protoplasm network, substances -are formed which are subjected to electrolytic dissociation, -the anions and kations hereby liberated must be diffused from -the place of their separation into the surroundings. Their diffusion, -however, is restricted by the protoplasmic network. The -positive ions may pass through, but the negative ions may not. -As a result: the reticulated substance is the seat of electric discharge, -which in turn gives the impact to the breaking down of -new molecules and with this to the occurrence of new potential -differences, and so on, consequently the disintegration is extended -further and further through the connected masses of the protoplasmic -framework.</p> - -<div class="figcenter illowe27_5" id="i_152"> - <img class="w100" src="images/i_152.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 28.</p> - -<p class="taj pl1hi15">Protoplasm of different cells, showing foam structures. A—Pseudopod of a marine -rhizopod. The protoplasm only shows foam structure at the point of stimulation. -B—Epidermic cell of lumbricus. C—Nerve fiber. D—Part of the cell -body of a ganglia cell. (A-C after <i>Bütschli</i>, D after <i>Held</i>.) -</p></div> -</div> - -<p>This theory, founded on facts gained entirely from investigation, -would involve those forms of energy which play the rôle of -activator in the extension of the breaking down of the molecule -from cross section to cross section, namely, the osmotic and the -electrical energy. Based on the general properties of physical -chemistry and those of morphology of the living substances, they -would be applicable to all vital systems. It would be premature -to attempt to extend this assumption and further develop its -specific details, above all to make it responsible for the specific -differences in the process of the conduction of excitation in -various forms of living substance. For this our knowledge of -the properties of living substance is still far too incomplete. -Nevertheless, it furnishes us even now with various points of -view for the further analysis of a series of vital manifestations, -as, for instance, the facts concerning the production of electricity, -of galvanotaxis, chemotaxis and so on. This, however, exceeds -the limits of the task we have here mapped out. We are concerned -here solely with the general principle on which the conductivity -of excitation in the living substance is founded.</p> -<hr class="chap x-ebookmaker-drop" /> - -<div class="chapter"> -<p><span class="pagenum" id="Page_154">154</span></p> - -<h2 class="nobreak" id="CHAPTER_VII">CHAPTER VII<br /> -<span class="title">THE REFRACTORY PERIOD AND FATIGUE</span></h2> -</div> - - -<div class="blockquot"> - -<p class="pl2hi2"><i>Contents</i>: Conception of specific irritability. Alteration of specific irritability -during and after excitation. Refractory period in various -forms of living substance. Absolute and relative refractory period. -Curve of irritability during refractory period. Dependence of the -duration of the refractory period on the rapidity of the course of the -metabolic processes in the living substance. Dependence on temperature. -Dependence on supply of oxygen. Theory of refractory period. -Refractory period as basis of fatigue. Fatigue as a form of asphyxiation. -Alterations of irritability and the course of excitation in fatigue. -Recovery from fatigue. The rôle played by oxygen in recovery. -Fatigue as an expression of the prolongation of the refractory period -conditioned by the relative want of oxygen. Fatigue of the nerve.</p> -</div> - - -<p>Every living system possesses, as we know, a peculiar and characteristic -manner of reacting to stimulation. The muscle responds -with a contraction, the salivary cell with production of saliva, the -luminous cell with the emission of light. This is the <i>specific -energy</i> in the sense of <i>Johannes Müller</i>. Every living system is -likewise characterized by a certain degree of irritability, which -can be expressed by the threshold value of the stimulus at which -the specific reaction is just perceptible. This degree of irritability, -by which the system concerned is distinguished, may be -termed its <i>specific irritability</i>.</p> - -<p>From the standpoint of the conditional method of investigation -it is at once apparent that specific energy, as well as specific irritability, -must be solely determined by the specific conditions existing -in the particular system. It follows from this that every alteration -in the conditions of the system, that is, every change of its -state, likewise entails a corresponding alteration of its specific -energy and its specific irritability. It is, therefore, self-evident -that the alteration of the state, which is undergone by the living<span class="pagenum" id="Page_155">155</span> -system in the process of excitation, brings about an alteration of -its specific irritability. Likewise as the original state of the system -is restored by the metabolic self-regulation after the course of an -excitation, the specific irritability of the system must be reestablished. -The specific irritability is, therefore, a property of -the living system, which, like the metabolic equilibrium, undergoes -restitution by the process of self-regulation after variation -produced by a stimulus of any kind. It is scarcely necessary to -repeat each time that this is only applicable within the physiological -variations and for a limited period, during which the alterations -in development need not be considered.</p> - -<p>These alterations of the specific irritability following an excitation -and their compensation through the metabolic self-regulation -will now claim our attention.</p> - -<p>That the specific irritability of a living system undergoes a -diminution as the result of a stimulus of long duration has been -long known through the study of fatigue. This is especially so -with frequently recurring excitating stimuli. It is only within the -last decade, however, that the observation has been made in a few -instances that a single momentary excitation is likewise followed -by such a reduction of the specific irritability. But that this is a -fact of general physiological fundamental importance for the -whole field of response to stimulation in the living substance has -only been recognized within the last few years.</p> - -<div class="figcenter illowe29_375" id="i_156"> - <img class="w100" src="images/i_156.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 29.</p> - -<p class="taj pl1hi15">Eight series of heart contractions. The dotted lines <i>e</i> show the moment of an artificial -stimulus. The artificial stimulus is ineffective if it is applied before the height of a -systole. The artificial stimulus becomes the more effective in producing an extra -systole, followed by a compensatory pause, the later it is applied after the height of -the systolic contraction. (After <i>Marey</i>.) -</p></div> -</div> - -<p>In 1876 <span class="nowrap"><i>Marey</i><a id="FNanchor_119" href="#Footnote_119" class="fnanchor">119</a></span> found that the irritability of the heart in response -to artificial stimulation was greatly reduced during the -systole, and that recovery took place during the following diastole. -(Figure <a href="#i_156">29</a>.) This fact was already apparent from the -observations made by <span class="nowrap"><i>Bowditch</i><a id="FNanchor_120" href="#Footnote_120" class="fnanchor">120</a></span> and <i>Kronecker</i><span class="nowrap">,<a id="FNanchor_121" href="#Footnote_121" class="fnanchor">121</a></span> that by stimulation -of the isolated frog’s heart with single induction shocks, an<span class="pagenum" id="Page_157">157</span> -artificial systole can only be produced with certainty when the -stimuli succeed each other at certain intervals, which must be the -longer as the strength of the stimulation is weaker. <i>Marey</i> calls -this period of reduced irritability “<i>phase réfractaire</i>” of the heart. -The refractory period of the heart has been made the subject of -a great number of investigations, especially by <i>Engelmann</i> and -his pupils. It was <span class="nowrap"><i>Engelmann</i><a id="FNanchor_122" href="#Footnote_122" class="fnanchor">122</a></span> especially who determined more -exactly the duration of the course of the refractory period. He -found, namely, that irritability disappears immediately before -each systole and reappears shortly before the beginning of the -diastole, and again reaches its original height at the end of the -diastole. For a long time, however, this refractory period was -looked upon as a special peculiarity of the heart. It was not until -<i>Broca</i> and <i>Richet</i><span class="nowrap">,<a id="FNanchor_123" href="#Footnote_123" class="fnanchor">123</a></span> twenty years after <i>Marey’s</i> investigations, discovered -an analogous refractory period for the motor centers of -the cerebral cortex of the dog. They first made this observation -on a dog affected with chorea, in which the choreic movements -rhythmically occurred in intervals of one second. They found that -after each movement electrical stimulation of the cortex remained -without result for about .5 seconds. During the next .25 seconds -stimulation was followed by a weak response and it was not until -the last .25 seconds before the next movement that a strong -effect was produced. They also found in the normal dog a refractory -period after every artificial stimulation equal to .1 -second, so that the number of contractions brought about by -rhythmical electrical stimulation were only ten per second. Following -this, numerous other investigations of the refractory period -have been made on the central nervous system. <span class="nowrap"><i>Zwaardemaker</i><a id="FNanchor_124" href="#Footnote_124" class="fnanchor">124</a></span> -and <i>Lans</i> have observed a refractory period in the eyelid reflex -of the human being which, on stimulation of the optic nerve,<span class="pagenum" id="Page_158">158</span> -amounts to about .5–1 second; on the stimulation of the trigeminus -produced by blowing on the cornea on the other hand, -it is somewhat shorter, less than .25 seconds. <span class="nowrap"><i>Zwaardemaker</i><a id="FNanchor_125" href="#Footnote_125" class="fnanchor">125</a></span> -also was able to demonstrate an analogous refractory period for -the swallowing reflex of the cat. Further a refractory period -was found and closely analyzed by <span class="nowrap"><i>Verworn</i><a id="FNanchor_126" href="#Footnote_126" class="fnanchor">126</a></span> for the reflexes in -the spinal cord of the strychninized frog. <span class="nowrap"><i>Dodge</i><a id="FNanchor_127" href="#Footnote_127" class="fnanchor">127</a></span> found a refractory -period in the knee jerk reflex of man. <i>Gotch</i> and <span class="nowrap"><i>Burch</i><a id="FNanchor_128" href="#Footnote_128" class="fnanchor">128</a></span> -showed, by two induction shocks following each other in quick -succession, a refractory period of the nerve, which is characterized -by its extremely brief duration. They found, depending -upon the temperature, a period of nonirritability of .001–.008 -seconds after every stimulus. The investigations of Miss -<span class="nowrap"><i>Buchanan</i><a id="FNanchor_129" href="#Footnote_129" class="fnanchor">129</a></span> lead us to conclude that there is a refractory period -for the cross striated skeletal muscle. Miss <i>Buchanan</i> stimulated -the muscle at times through the nerve, at other times directly -after elimination of the nervous element, with very frequent -electrical stimuli (about 1000 in the second) and found by means -of the capillary electrometer a rhythmical reaction of the muscle -of about 50–100 excitation shocks per second. Likewise the -<i>Ritter</i> tetanus produced by the breaking of an increasing current -proved to be a rhythmical reaction of an analogous nature. In -a more direct manner <span class="nowrap"><i>Keith Lucas</i><a id="FNanchor_130" href="#Footnote_130" class="fnanchor">130</a></span> has determined the refractory -stage for the musculus sartorius of the frog. He allowed two -induction shocks to act successively on the muscle at intervals<span class="pagenum" id="Page_159">159</span> -of varied duration and then registered the action currents by -means of the capillary electrometer. He then found that the -second stimulus was ineffective for about .005 seconds after the -application of the first stimulus. If the second stimulus follows -somewhat later, it produces a contraction which is weaker and -has a longer latent period the nearer the second stimulus approaches -the first in point of time. (Figure <a href="#i_161">30</a>.) <span class="nowrap"><i>Massart</i><a id="FNanchor_131" href="#Footnote_131" class="fnanchor">131</a></span> and -<span class="nowrap"><i>Jennings</i><a id="FNanchor_132" href="#Footnote_132" class="fnanchor">132</a></span> likewise observed the existence of a refractory period -for the myoids of unicellular organisms brought about by mechanical -stimuli. <i>Massart</i> attributes this cessation of reaction to -stimuli following each other at certain intervals, to fatigue, an -explanation which has been disputed by <i>Jennings</i> as the result of -his investigations made on Stentor and Vorticella. <i>Jennings</i> looks -upon the behavior of the infusoria rather as an “adaptation” to -the stimulus. <i>Pütter</i> was the first to see in this the existence of -a refractory period. His experiments on Spirostomun ambiguum -in 1900 showed a refractory period in the reaction to rhythmical -mechanical stimuli. I wish to state, however, that these observations -of <i>Pütter</i> have not as yet been published. Thus the existence -of a refractory period has even today been proved for a -whole series of very different kinds of substances.</p> - -<div class="figcenter illowe23_125" id="i_161"> - <img class="w100" src="images/i_160.jpg" alt="" /> - <img class="w100" src="images/i_161.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 30.</p> - -<p class="taj pl1hi15">Curve of action current of the musculus sartorius excitated by two successive -stimuli (St. 1 and St. 2). The effect of the second stimulus -is the less and the latent period is the longer the more quickly the -first stimulus is followed by the second. (<i>Keith Lucas.</i>) -</p> -</div> -</div> - -<p>We will now examine the alterations of irritability which are -perceptible during the refractory period to complete restitution of -the specific irritability of the particular system, and endeavor by -the analysis of their special conditions to render them comprehensible -from a physical standpoint of view.</p> - -<p>The first fact to take into consideration is, that, as is shown in -the heart, the refractory period begins at the moment of the -appearance of the systolic excitation. The irritability of the -heart is absent and remains so until the excitation has reached -its highest point, that is, shortly before the beginning of the diastole. -From this point the restitution of irritability begins, which -does not reach the maximum until the end of the diastole. In -other words: irritability undergoes the greatest reduction by disintegration<span class="pagenum" id="Page_162">162</span><span class="pagenum" id="Page_161">161</span> -produced by the stimulus and is restored by the metabolic -self-regulation following the decomposition.</p> - -<p>This point of view enables us to interpret this state from a -physical standpoint. In this discussion on the relations between -irritability and the extension of excitation, I have taken the -amount of energy which is produced during the time unit and -space unit in a living system as the general standard for the -degree of irritability, at the same time duly regarding the individual -components involved. This amount of energy is determined -in a given system by the quantity of substance broken down -by a stimulus of a given intensity. It is, therefore, clear that -during the time in which an increased disintegration produced -by a stimulus takes place, the irritability in response to a second -stimulus must be reduced, as during this period the second stimulus -has less of necessary decomposable substances at its disposal, -and at the same time there are more products of disintegration -in a given space. If a living organism is the subject of consideration, -to which the “all or none law” is applicable, as, for instance, -the heart at the moment of the beginning of excitation, irritability -is completely obliterated, as shown by the fact that the -second stimulus of any strength remains without response, for -during the excitation there is a complete breaking down of all -the substances capable of decomposition. If, on the contrary, a -system is the subject of observation, for which the “all or none -law” is not valid, then irritability is merely reduced but not wholly -obliterated during an excitation, and whether or not a response -is obtained to the stimulus depends upon its strength. To impress -the relations between the degree of irritability and the intensity -of the stimulus, I have, therefore, employed the term “<i>relative -refractory period</i>” in contrast to the “<i>absolute refractory period</i>,” -in which irritability is obliterated even for the strongest stimuli. -It is self-evident that irritability must again increase in the same -degree as the restitution of the living system by metabolic self-regulation -takes place, for the more molecules capable of disintegrating -are restored and the more products of disintegration -removed, the more molecules necessary for decomposition in the -unit of space are attacked and broken down by the stimulus. All<span class="pagenum" id="Page_163">163</span> -these are self-evident facts which are in accordance with the conception -we have here developed of the course of the process of -excitation and its physical nature. But another important point -is evolved from the observations we have made of the nature of -the process of self-regulation. The process of self-regulation is -founded on the same principle as that which governs the taking -place of all chemical equilibrium, for metabolic equilibrium is -merely a special kind of a chemical equilibrium. The development -of a chemical equilibrium between reacting substances and -reaction products has, as known, a characteristic course in regard -to its duration. If the rapidity with which the equilibrium is -reached is expressed by a curve in which the abscissa represents -the time, while the ordinates signify the number of contacts of -the interacting molecules, the rapidity of reaction is altered with -the approach to the equilibrium in the form of a logarithmic -curve; that is, the approach to the state of equilibrium, which is -represented by ordinate value zero, takes place at first very rapidly, -then with more and more decreasing speed, for with the -decrease of the number of reacting molecules and the increase -of the amount of products of reaction, the contact of the interacting -molecules and with this the opportunity for the reaction -occurs less and less frequently. Although the self-regulation -of metabolic equilibrium is by no means such a simple process -as, for instance, that of the well-known example of the -forming of ethylester from acetic acid and æthyl alcohol, we have -still in every case to deal with the taking place of a chemical -mass equilibrium. Hence the progress to the metabolic equilibrium -must likewise correspond with a logarithmic curve, i.e., restitution -after a disturbance of the equilibrium must take place at -first rapidly, then at a constantly decreasing rate. For reasons -readily to be understood the special form of this restitution curve -has so far not been accurately ascertained for any kind of living -substance. Even in those cases where the restitution occurs -very slowly we meet with the difficulty that, when the tests are -applied which are necessary to determine the restitution at different -intervals, with each testing stimulus irritability is each -time reduced. Hence the construction of the restitution curve<span class="pagenum" id="Page_164">164</span> -can only be achieved by indirect means, and we must content ourselves -with the ascertainment of a smaller number of its points -from which by interpolation its form can be constructed. Indeed -in this connection a certain number of results have already been -gained quite sufficient to experimentally confirm the correctness -of these types of curves, primarily obtained by purely theoretical -deductions. That irritability very gradually reaches its maximal -height has been already shown, as previously mentioned by -<span class="nowrap"><i>Bowditch</i><a id="FNanchor_133" href="#Footnote_133" class="fnanchor">133</a></span> in his investigations on the influence of rhythmical -induction shocks on the apex of the heart of the frog. He found -that in order to produce response, the weaker the stimuli the -longer must be the intervals between them. It follows from this, -that after a discharge the irritability in response to strong stimuli -reappears more rapidly than for weak, i.e., that they only <i>gradually</i> -regain their maximum. The exact periods of time for the -course of the return of irritability for the heart have unfortunately -not been so far ascertained. On the other hand, the investigations -of <span class="nowrap"><i>Ishikawa</i><a id="FNanchor_134" href="#Footnote_134" class="fnanchor">134</a></span> furnish the material for the construction of -the restitution curve for the centers of the spinal cord of the frog. -<i>Ishikawa</i> did not employ the threshold of stimulation as an indicator -for the course of restitution, but used instead the duration -of the reflex time following on a stimulus of a certain strength. -The reflex time is greatly prolonged after an excitation of extended -duration and only regains its normal value in the same -degree as restitution takes place. By a great number of painstaking -experiments <i>Ishikawa</i> ascertained the duration of the -reflex time at intervals of thirty seconds to one minute, and obtained -figures which show that restitution does actually take -place, at first rapidly and then with constantly decreasing -speed. The detailed study of the course of self-regulation of the -individual forms of living substance will doubtless be more exactly -determined in the near future. But even at the present -we are fully justified in describing the form of restitution -curve as a <i>logarithmic</i> in type. Therefore, a relative refractory<span class="pagenum" id="Page_165">165</span> -period must be present in every metabolic self-regulation after -an excitation, during which stronger stimuli produce response, -while weaker are still without result. This is a fact which, as we -shall see later, is of fundamental importance for the comprehension -of the various kinds of interference responses to stimuli.</p> - -<p>From the information here gained on the nature and origin -of the refractory period the conclusion must inevitably be drawn -that in all living substance there must exist, directly following an -excitation, a period of time in which its irritability is reduced, -that is, under proper conditions a refractory period can be -demonstrated for every living organism. Every living system -possessing irritability undergoes a period of reduced irritability -at the time of and subsequent to every excitation, for every -excitation momentarily decreases the amount of products capable -of disintegration and increases the disintegration products in the -unit of space. As restitution involves time, a stimulus occurring -in the phase preceding complete restitution cannot break down -the same quantity of molecules as would be the case after the -establishment of complete restitution, that is, the response is -weaker, the irritability is decreased. The refractory period during -and subsequent to excitation is as much a general property of the -living substance as irritability and metabolic self-regulation.</p> - -<p>This conclusion appears so self-evident that it would seem -hardly to call for emphasis were it not that even at the present -time the view is still widely held that the refractory period is a -special characteristic of certain forms of living substance. This -assumption is explained on the one hand by the fact that our -information concerning the refractory period is still of comparatively -recent date and that few physiologists are in the habit of -connecting special observations with general physiological conceptions, -but also for the reason that some investigators have -vainly tried to find a refractory period in certain forms of living -substance. <i>Langendorff</i> and <i>Winterstein</i><span class="nowrap">,<a id="FNanchor_135" href="#Footnote_135" class="fnanchor">135</a></span> for instance, have not -succeeded in proving a refractory period for the spinal cord of -the frog. <i>Langendorff</i> stimulated the central sciatic stump<span class="pagenum" id="Page_166">166</span> -with two stimuli in quick succession and used the contractions -of the triceps as indicator of the response. He found that when -the stimuli, if consisting in either single induction shocks or -faradic shocks, followed each other even at intervals of .004 -seconds the second stimulus was still operative, this being perceptible -in an increase of the contraction or with greater intervals -of time in a summation of two contractions. <i>Winterstein</i> -concludes from this that the development of a refractory period -after a stimulation is not a general property of all nerve centers. -If the experiments of <i>Langendorff</i> failed to show the presence -of a refractory period it is not for the reason that this does not -take place in the centers of the spinal cord but rather results from -the fact that the conditions for the investigation were not suited -for its demonstration. In fact, <span class="nowrap"><i>Fröhlich</i><a id="FNanchor_136" href="#Footnote_136" class="fnanchor">136</a></span> and especially <span class="nowrap"><i>Vészi</i><a id="FNanchor_137" href="#Footnote_137" class="fnanchor">137</a></span> -have incontestably proved the existence of relative refractory -periods in the normal spinal cord.</p> - -<p>If the existence of the refractory period is based on the fact -that during the time of and subsequent to an excitation the quantity -of substances necessary for disintegration is decreased and -that of the breaking down products increased, and if it is limited -by the restitution of the substances required for decomposition -and the elimination of the disintegration products, its duration -must be dependent upon the length of these processes. All factors -which lessen the decomposition and hasten the metabolic -self-regulation must, therefore, shorten its duration. This is -completely confirmed by experimental investigations. As can be -understood, the factors of special interest for us are those which -influence the duration of the refractory period in the physiological -occurrences of the organism.</p> - -<p>One of these factors is temperature. As we know, the rapidity -of chemical reactions increases with ascending and decreases with -falling temperature. As in the disintegration as well as in the -restitution, processes are chemical in nature, it is to be expected<span class="pagenum" id="Page_167">167</span> -that the duration of the refractory period is influenced in like -manner by temperature. Indeed, <span class="nowrap"><i>Kronecker</i><a id="FNanchor_138" href="#Footnote_138" class="fnanchor">138</a></span> found some time ago -that in the isolated frog’s heart a much more frequent rhythm of -stimulation is effective at a higher than at a lower temperature. -When the heart is stimulated at a temperature of 11–12° C. with -twelve rhythmical induction shocks in the second, every stimulus -is operative and produces a systole. If a stimulus of the same -frequency is used at a temperature of 5° C., the heart responds -merely to every second stimulus. This shows that the refractory -period is of longer duration at a lower than at a higher temperature.</p> - -<p>A factor of particular interest is the supply of oxygen, for we -know its fundamental importance in all aërobic organisms in the -breaking down of the living substance. The life of these organisms -is primarily dependent upon the supply of oxygen from -without. Organic reserve substances for restitution after disintegration -are contained in ample quantity in the reserve stores in -the living cell substance, whereas oxygen is present in very small -quantities in relation to the former. It is, therefore, self-evident -that the rapidity of the breaking down processes is very closely -dependent upon the amount of available oxygen at hand. Nevertheless -it is not the absolute quantity but the relative amount of -oxygen in relation to the momentary requirement which is of -importance. For instance, the quantity of oxygen present may -completely suffice for the oxydative disintegration in the metabolism -of rest or at lower temperature, whereas the same amount -would be much too small to meet the demand increased by excitation -or at higher temperature. In the latter case “<i>a relative -deficiency of oxygen</i>” occurs. I have introduced the term “<i>relative -deficiency of oxygen</i><span class="nowrap">”<a id="FNanchor_139" href="#Footnote_139" class="fnanchor">139</a></span> for I have found that a number -of authors by neglecting the relations of the available oxygen -to that which is required at the moment have been led to false -conclusions. There is no living object so preëminently fitted -to demonstrate in such a striking manner the dependence of<span class="pagenum" id="Page_169">169</span> -the duration of the refractory period upon the supply of oxygen -as the spinal cord centers of the frog, when their irritability -has been increased to the maximum by strychnine<span class="nowrap">.<a id="FNanchor_140" href="#Footnote_140" class="fnanchor">140</a></span> -Various observers, such as <i>Loven</i>, <i>Buchanan</i>, <i>H. von Baeyer</i> and -others, investigated the action current by the capillary electrometer. -As a means of studying the number of impulses in the -strychnine tetanus, we can upon the basis of their figures roughly -assume the number of impulses to equal ten per second at room -temperature. In short, in the freshly strychninized frog the duration -of the refractory period is about .1 second. By means of the -method of artificial circulation already mentioned a deficiency of -oxygen can readily be brought about. It has been demonstrated -that the rhythmic in contrast to the continuous method of introduction -of circulatory fluid is superior in that the former reproduces -more closely the natural conditions of the circulation of -the blood and renders the smallest capillaries more permeable. -In consequence I have recently constructed a small appliance for -artificial circulation, which accomplishes this in a manner as -simple as it is complete. (Figure <a href="#i_168">31</a>.)</p> - -<div class="figcenter illowe46_25" id="i_168"> - <img class="w100" src="images/i_168.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 31.</p> - -<p class="taj pl1hi15">Arrangement for an artificial circulation in -the frog. A—Accumulator. B—Metronom. C—Mercury key. -D—Electromagnetic apparatus for compressing the rubber tube: 1, -wire spool with magnet; 2, anchor for the magnet; 3, spiral spring -which pulls back the anchor; 4, axis on which the anchor turns; 5, -plate for arresting the anchor. E—Vessel containing saline -solution. F—Slab of cork with frog.</p></div> -</div> - -<p>The fluid flows from a vessel, E, provided with an outlet tube through a thin rubber tube -into a glass canula, which is introduced into the general aorta of -the frog, F. The tube is automatically occluded by the rhythmical -movement of the armative of an electromagnet, D, produced by a -metronome, B. The pressure of the circulating fluid can be readily -changed at will by varying the level of the vessel and the frequency -of the pulse by the rhythm of the metronome, which makes -and breaks the current to the electromagnet<span class="nowrap">.<a id="FNanchor_141" href="#Footnote_141" class="fnanchor">141</a></span> In this way it is -possible to artificially replace the normal circulation with satisfactory -exactitude and substitute for the blood, circulating in the -vessels of the frog, any desired fluid. If the entire quantity of -blood of a frog is displaced by a continuous stream of oxygen-free -saline solution and a weak strychnine solution is injected -with a Pravaz syringe, a violent strychnine tetanus appears after<span class="pagenum" id="Page_170">170</span> -the lapse of a few seconds. (Figure <a href="#i_170">32</a>, A.) If the artificial circulation -with oxygen-free saline solution is now contained in the -rhythm of the natural heart beat, the further reactions can then -be readily observed. The first long-continued tetanic attack, -which can be produced by a slight touch of the skin, is followed -by a whole series of tetanic convulsions of prolonged duration, -which are repeatedly followed by periods of exhaustion. I wish -to emphasize this fact once more, as it appears to me as not without -interest for the understanding of the question of reserve substances.<span class="pagenum" id="Page_171">171</span></p> - -<div class="figcenter illowe36_25" id="i_170"> - <img class="w100" src="images/i_170.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 32.</p> - -<p class="taj pl1hi15">Muscle curve of strychnine tetanus in a frog with artificial oxygen-free circulation. Lower line indicates -seconds. Upper line indicates stimulation by induction shocks. A—A single shock produces a long -tetanic contraction. B—In a more advanced stage each shock produces a tetanus only of short -duration. C—In a still more advanced stage each shock brings about only a single contraction if the -stimuli do not succeed each other too rapidly. If they succeed more rapidly, as, for instance, in a -faradic current, only the first shock is effective. -</p></div> -</div> - -<p>If we assume that at the moment when the entire amount -of blood is removed from the vascular system, no oxygen remains -in the cells of the spinal cord and muscle, then disintegration of -the living substance could from this instant take place exclusively -anoxydatively, and there would be no further oxydative -breaking down into carbon dioxide and water. The energy production -compared in equal number of molecules, taking the -figures of <i>Lesser</i> for the fermentation of sugar, would approximately -amount to about 3.8 per cent. of that of the energy production -in the oxydative disintegration of dextrose into carbon -dioxide and water. In reality, however, the tetanic convulsions -are at first exactly as violent as in the frog with a normal circulation. -There simply remains the assumption, therefore, that -either the disintegration as soon as it becomes <i>an</i>oxydative involves -relatively greater number of molecules than would be the -case if it were oxydative in nature, or to suppose that even -after the complete displacement of the blood a certain, though -relatively small, amount of oxygen is present in the cells which -for a short time suffices for the taking place of oxydative disintegration -and with this an almost maximal production of energy -which naturally decreases as the oxygen is consumed. It seems -to me that the latter supposition contains more probability than -the first. To return, however, from this observation to a further -consideration of the animal we are studying, we see how the -complete tetanic convulsions in the refractory period which we -assumed to be .1 second are gradually transformed into incomplete -tetanus. After a time the tetanic convulsions become shorter -after each stimulus (Figure <a href="#i_170">32</a>, B) and permit us to distinguish -their individual movements, even though the latter at first succeed -each other still very rapidly. Gradually this incomplete tetanic -convulsion assumes the form of a short series of individual contractions, -distinctly separated from each other and soon a stage is -reached in which each reaction to a peripheral stimulus consists -merely in a single contraction. (Figure <a href="#i_170">32</a>, C.) The refractory -period is, however, even now less than a second. Nevertheless, -with a further continuation of the experiment, the refractory -period becomes more and more prolonged, so that stimuli succeeding<span class="pagenum" id="Page_172">172</span> -each other at intervals of less than a second are without effect. -It is possible at this stage, as <span class="nowrap"><i>Tiedemann</i><a id="FNanchor_142" href="#Footnote_142" class="fnanchor">142</a></span> did, to graphically record -the reactions. He severed the sciatic nerve on one side and -stimulated its central stump, at the same time connecting the -triceps with a writing lever. It is then found that when the -single induction shocks follow each other at intervals of a second -or more every stimulus produces a contraction, but that on the -contrary only the first stimulus of a rhythmical series is operative -and all those succeeding ineffectual, if the stimuli follow each -other at shorter intervals. The refractory period becomes, however, -more and more prolonged. The rhythm of the stimulus -must become continually slower if each individual stimulus is -to remain effective. If the rhythm is even slightly too rapid -only the first few stimuli of a rhythmical series are effective -and this with decreasing response and later no contraction at all -is observed. With a further continuance of the experiment, the -stimuli are only effective when following each other at long -intervals. It is necessary that a period of recovery lasting -several seconds must take place before the following stimulus -can meet with response. (Figure <a href="#i_172">33</a>.) The refractory period -can gradually be prolonged for the space of a minute or longer,<span class="pagenum" id="Page_173">173</span> -until finally irritability does not reappear at all, and even the -strongest stimuli fail to produce the least contraction. The -continuous manner in which the refractory period is, in the -absence of oxygen, more and more prolonged until eventually a -prolonged state of nonirritability is developed, can be better -followed by observing the experiment than when described in -words. If at this stage instead of the oxygen-free saline solution, -defibered blood of the ox shaken in air or a saline solution saturated -with oxygen is circulated in the frog, restitution is often -within a few minutes so complete that tetanic attacks are once -more produced by a single stimulus, that is, the refractory period -has from being practically nil returned to the normal. This -experiment can be repeated several times on the same animal. -It is invariably found that the refractory period is prolonged -by the withdrawal of oxygen and shortened with a renewed -supply.</p> - -<div class="figcenter illowe30" id="i_172"> - <img class="w100" src="images/i_172.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 33.</p> - -<p class="taj pl1hi15">Development of the refractory period in the spinal cord of a strychninized frog. Lower -line indicates seconds; upper line stimuli. Of a series of stimuli only the first ones -are operative with decreasing effect. -</p></div> -</div> - -<p>I have described this experiment somewhat in detail as it contains -facts which are the key for the comprehension of a general -physiological process of paramount importance. I refer to -fatigue. The refractory period and fatigue are inseparably connected, -for fatigue is founded on the existence of the refractory -period and is an expression of prolongation of the former, brought -about by want of oxygen. This is shown at once by closer -analysis. It is here necessary to differentiate somewhat more in -detail the factors which bring about the <i>prolongation of the -refractory period in deficiency of oxygen</i>.</p> - -<p>If we first turn our attention to the normal refractory period -which occurs in a system in metabolic equilibrium of rest in -direct connection with dissimilatory excitation, following a -momentary stimulus, we find that reduction of irritability or, -more exactly expressed, the lessening of the response is, as we -have seen, determined by the time involved in the metabolic -decomposition and recovery. Both these processes require time -and until their completion the quantity of substance demanded -for the oxydative disintegration is decreased in a given space, -and every stimulus must consequently be followed by a weaker -response. Our conceptions of the physical details of these processes<span class="pagenum" id="Page_174">174</span> -depend essentially upon the question, if the oxydative disintegration -itself in the given living system occurs in one single -phase, in that the oxygen is the activator for the oxydative splitting -up of the carbon chain, or if this takes place in two periods, -in which the carbon chain is first anoxydatively split up into -larger fragments by the stimulus, which are then seized upon by -the oxygen to be split up into carbon dioxide and water. As we -have seen, this question must remain for the present undecided -as far as the metabolism of rest as well as the excitation produced -by a single momentary stimulus is concerned. It is highly -probable that a uniformity of the process for all living systems -does not exist. We are, therefore, not justified in assuming that -these special chemical processes resulting from single stimuli are -uniform throughout the refractory period.</p> - -<p>On the contrary it is different in the case of oxygen deficiency. -Here we see with increasing want of oxygen a constantly increasing -duration of the refractory period, a prolongation which may -be attributed to the retardation of the oxydative disintegration. -It is necessary, however, that we now study more clearly these -alterations brought about by the deficiency of oxygen.</p> - -<p>If we follow the course of the changes from that of the normal -state of equilibrium of metabolism, wherein oxygen is sufficient -to bring about complete disintegration of the molecules to the -formation of carbon dioxide and water, we must assume in spite -of the great explosive rapidity of this process on the basis of our -chemical knowledge, that first a series of intermediate products -are produced before finally the end products are formed. In -this way the oxydative disintegration produced by a stimulus -becomes more and more prolonged by an increasing want of -oxygen. If, as I have previously suggested, the amount of energy -which is liberated in a given space and time by an excitating stimulus -is taken as a standard of irritability, it is apparent that the -more the oxydative disintegration following a stimulus is retarded, -the greater must be the decrease in irritability. The less oxygen -there is at disposal and the more incomplete the oxydative breaking -down, the smaller is the degree of irritability, the weaker the -response and the slower the return of irritability after every<span class="pagenum" id="Page_175">175</span> -stimulus. In other words, with the increasing deficiency of -oxygen, the response is not merely reduced for every stimulus, -but the duration of the refractory period is likewise progressively -prolonged until finally with an absolute want of oxygen, constant -and complete depression takes place. In the genesis of this process -another factor, however, has the same effect.</p> - -<p>While with a sufficient supply of oxygen disintegration leads -to the formation of carbon dioxide and water, therefore to end -products, which can quickly and easily be removed by diffusion, -the want of oxygen produces complex products of incomplete -combustion and finally of anoxydative decomposition, such as -lactic acid, fatty acids and even more complex substances in constantly -increasing quantities. These products permeate the protoplasmic -surfaces with great difficulty, if at all, and as they cannot -subsequently be oxydatively split up, constantly accumulate. -These asphyxiation substances, as they may be briefly termed, -produce a depressing effect on further disintegration. This can -be experimentally demonstrated.</p> - -<p>For this purpose I have modified the experiment previously -described in the way that after every introduction into the blood -of oxygen-free saline solution and after the injection of strychnine, -the artificial circulation was stopped so that stagnation of -the oxygen-free saline solution took place in the vascular system. -The processes then occurred in exactly the same manner with -the exception that the state of non-irritability appeared somewhat -earlier. If after the beginning of complete depression artificial -circulation with oxygen-free saline solution was again started, a -certain degree of recovery took place within one or more minutes. -The stimuli were once more effective and produced a number -of contractions. At times, several single contractions, following -each other in more or less quick succession, could be brought -about. But complete recovery or the appearance of even incomplete -tetanic convulsions was never again obtained, whereas by -the introduction of oxygen complete recovery could at once be -brought about. If, however, the circulation with oxygen-free -saline solution was continued, irritability gradually decreased. -The refractory periods after the individual stimuli became longer,<span class="pagenum" id="Page_176">176</span> -and in spite of continuous artificial circulation irritability <i>again</i> -disappeared. The experiment shows that by the circulation of -oxygen-free solution irritability can simply be reduced up to a -certain degree. This partial restitution is produced by washing -out the depressing metabolic products. Being desirous to verify -the results of this investigation with greater exactitude I have -requested <span class="nowrap"><i>Dr. Lipschütz</i><a id="FNanchor_143" href="#Footnote_143" class="fnanchor">143</a></span> to repeat the experiments, taking the -utmost possible precaution in respect to the absolute exclusion of -oxygen. <i>Lipschütz</i> has tested the normal saline solution made -oxygen free with the sensitive <i>Winkler</i> method, in which the -slightest trace of oxygen is shown by the oxydation of manganous -chloride to manganic chloride in which the latter in a saline solution -sets free an amount of iodide from iodide of potassium corresponding -to that of the consumed oxygen. These experiments -of <i>Lipschütz</i> have shown that even with the absolute exclusion -of the slightest trace of oxygen a partial recovery can be brought -about by artificial circulation. There can be, therefore, no doubt -that recovery is actually founded on the removal of the depressing -asphyxiation substances by artificial circulation. Moreover -<span class="nowrap"><i>Fillié</i><a id="FNanchor_144" href="#Footnote_144" class="fnanchor">144</a></span> has previously succeeded in the laboratory at Göttingen in -obtaining by the same methods a corresponding result for the -nerve. In both cases the experiments are extremely complicated -and must be carried out with the most painstaking care. -The depressing influence of the asphyxiation products need not -be regarded as a specific effect of poisoning. It can be solely an -expression of mass relations, if we assume that the anoxydative -decomposition is controlled by a chemical equilibrium between -masses capable of disintegrating and products of the disintegration. -It is not possible to give any detailed account as to the part -taken by accumulating asphyxiation substances in the prolongation -of the refractory period. Indeed, we must for the present -relinquish the attempt to delimitate quantitatively the part taken -by the individual constituent processes in the symptoms of depression -resulting from the deficiency of oxygen. We can merely<span class="pagenum" id="Page_177">177</span> -say, the individual alterations produced by the want of oxygen, -that is, the restriction and retardation of the oxydative disintegration, -the corresponding increase of the anoxydative decomposition -and the accumulation of the products of incomplete oxydation -and anoxydative breaking down have the same influence in -that they decrease the strength of the response and retard the -rapidity of the decomposition process. These are the general -effects perceptible in the refractory period by the deficiency of -oxygen.</p> - -<p>The establishment of these facts of the dependence of the refractory -period upon oxygen are of the utmost importance for -the genesis of fatigue, for the state of fatigue in all aërobic organisms -is invariably brought about by deficiency of oxygen. In -other words: <i>fatigue is invariably asphyxiation</i>. A deficiency of -organic reserve substances never occurs in fatigue before the -effect of oxygen deficiency leads to complete depression, for the -quantity of organic reserve substances at the disposal of the cells -is greater comparatively than that of oxygen. This is shown by -transfusion experiments in which the time involved before complete -paralysis was brought about in the frog by the introduction -of an oxygen-free saline solution was ascertained and compared -with the period which elapsed before complete paralysis took -place, when the same solution saturated with oxygen was used.</p> - -<p>Although the previously described experiments on the strychninized -frog show clearly the relations of fatigue to the refractory -period, I should, nevertheless, like to illustrate them somewhat -further.</p> - -<p>The state of fatigue as it is developed in a living system by a -continuous functional activity is characterized by a series of -symptoms which can be best studied in the fatigue of the muscle, -the nervous centers, and the peripheral nerves.</p> - -<p>If the muscle of the frog is isolated and rhythmically stimulated -with single induction shocks and the muscle contractions -graphically recorded, it will be found that the first perceptible -alteration during the course of stimulation is the increasing -height in the curve, which appears directly after the first -contraction and becomes more and more noticeable after every<span class="pagenum" id="Page_178">178</span> -succeeding one. With the isolated apex preparation of the -frog’s heart an effect is produced which <span class="nowrap"><i>Bowditch</i><a id="FNanchor_145" href="#Footnote_145" class="fnanchor">145</a></span> has termed -the “Treppe” and <i>Tiegel</i><span class="nowrap">,<a id="FNanchor_146" href="#Footnote_146" class="fnanchor">146</a></span> <span class="nowrap"><i>Minot</i><a id="FNanchor_147" href="#Footnote_147" class="fnanchor">147</a></span> and others have obtained the -same result for the skeletal muscle. The <i>Treppe</i> has been often -regarded as an expression of increasing of capability of the -muscle following each succeeding stimulus in spite of the fact -that it is physiologically incomprehensible that an isolated muscle -can become more capable by increased demands. <span class="nowrap"><i>Fröhlich</i><a id="FNanchor_148" href="#Footnote_148" class="fnanchor">148</a></span> first -threw light on this seeming contradiction by showing that the -increase in height of the muscle contraction in the <i>Treppe</i> is -in reality the first indication of the beginning of fatigue, and -<span class="nowrap"><i>Fr. Lee</i><a id="FNanchor_149" href="#Footnote_149" class="fnanchor">149</a></span> arrived at the same result. The increase in height of the -contraction curve depends upon the retardation of the course of -contraction. As the contraction extends over the muscle substance -in the form of a wave, a longer stretch of the muscle will -be in a state of contraction when the wave is more extended than -when it is shorter, that is, the shortening of the muscle will be -greater, the contraction curve higher, when the wave is more -extended. With increasing fatigue the retardation in the course -of contraction, as <span class="nowrap"><i>Rollet</i><a id="FNanchor_150" href="#Footnote_150" class="fnanchor">150</a></span> already has shown, becomes continuously -greater. (Figure <a href="#i_179">34</a>.) The consequence of this retardation -in the course of contraction is, therefore, perceptible in the -rhythmically activated muscle in the form of contracture. As -fatigue increases, the muscle requires an increasing length of time -to relax to its full extent and in consequence the period between -the two stimuli is very soon insufficient for this to occur. There<span class="pagenum" id="Page_180">180</span> -remains a certain amount of shortening, when the next contraction -begins. This characteristic extension of the individual contraction -curve of the fatigued muscle is an expression of the retardation -of the oxydative disintegrating processes and of the <i>Treppe</i>. It -shows us that fatigue is perceptible to a slight degree even after -the first excitation. After every succeeding stimulus the oxydative -decomposition in the fatigued muscle is increasingly prolonged. -It is, therefore, self-evident that the capability of action -of the muscle likewise becomes less with increasing fatigue. -Every state of fatigue is, in fact, distinguished by the decrease of -response. This is perceptible in the later stages by the decline of -the height of contraction. Hence all symptoms of fatigue which -we observe form the expression of one single process; it is the -constantly increasing slowness of oxydative disintegration with -increasing fatigue.</p> - -<div class="figcenter illowe36_25" id="i_179"> - <img class="w100" src="images/i_179.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 34.</p> - -<p class="taj pl1hi15">Series of muscle curves graphically recorded one over the other, showing the retardation in the course of contraction with increasing -fatigue. (After <i>Rollet</i>.) -</p></div> -</div> - -<p>Exactly similar conditions as those of the muscle are seen in -the central nervous system. The reflex contraction of the triceps -of the frog produced by stimulation of the central end of the -sciatic nerve with single induction shocks demonstrates clearly -as <span class="nowrap"><i>Ishikawa</i><a id="FNanchor_151" href="#Footnote_151" class="fnanchor">151</a></span> has proved in certain stages of fatigue, an increase -in height and a strong relaxation which does not depend upon the -fatigue of the muscle but on that of the centers. If the fatigue -is greater, the height of the contraction then decreases, whereas -the extension of the course of relaxation increases further. The -possibility of fatigue of the muscle during these experiments was, -of course, precluded by proper precautionary measures. Irritability -and the course of excitation in fatigue of the centers -show exactly the same alterations as developed in fatigue of the -muscle. The processes of oxydative breaking down are retarded -more and more with increasing fatigue, that is, fatigue is characterized -by exactly the same processes as is the prolongation of -the refractory period by the deficiency of oxygen, and likewise -in fatigue this retardation of the oxydative disintegration processes -is conditioned by the relative deficiency of oxygen. This -is shown by the rôle played by oxygen in recovery after fatigue.</p> -<p><span class="pagenum" id="Page_181">181</span></p> -<p>It was found by <span class="nowrap"><i>Hermann</i><a id="FNanchor_152" href="#Footnote_152" class="fnanchor">152</a></span> in 1867 and confirmed by Mademoiselle -<span class="nowrap"><i>Joteyko</i><a id="FNanchor_153" href="#Footnote_153" class="fnanchor">153</a></span> in <i>Richet’s</i> laboratory, that the isolated muscle of -the frog, which was completely nonirritable as the result of -fatigue, does not regain irritability in an oxygen-free medium, -but does so when oxygen is introduced. The previously described -experiments of artificial circulation in the frog show -clearly how dependent the centers are upon the oxygen supply -for the restoration of irritability. In consequence of the strychnine -poisoning the irritability of the centers is so enormously -increased that the “all or none law” is applicable to the centers of -the spinal cord under these conditions<span class="nowrap">.<a id="FNanchor_154" href="#Footnote_154" class="fnanchor">154</a></span> These are the best conditions -for the production of fatigue. One can readily demonstrate -the importance of the oxygen supply for the rapidity with which -irritability returns after fatigue if in the strychninized frog an -artificial circulation is used, at the same time varying on one hand -the amount of oxygen, on the other the activity of the centers. If -a saline solution containing merely a trace of oxygen is circulated, -the centers recover very slowly and incompletely after every -fatigue. Subsequent to every reaction produced by a stimulus, -an increasing length of time is required until irritability is so far -recovered that a new stimulus can meet with response. If, however, -a saline solution is circulated which has been saturated by -being shaken with oxygen and is continuously in a pure atmosphere -of oxygen, recovery takes place in comparison with far -greater rapidity and completeness. If the supply of oxygen is -ample and the stimuli act at longer intervals on the frog, irritability -always is quickly restored in the periods of rest between -the stimuli. With continuous stimulation of quickly succeeding -stimuli, irritability is soon completely obliterated, even though an -abundant oxygen supply be present, and it is not until a pause is -interpolated that oxygen is capable of bringing about a recovery. -By manifold variations of these experiments the connection -between fatigue and the refractory period can be more and more<span class="pagenum" id="Page_182">182</span> -clearly recognized. <i>Fatigue is simply the refractory period prolonged -by deficiency of oxygen.</i> In both cases there is a diminution -of irritability. In both cases this diminution is conditioned -by a retardation of oxydative disintegration following every -stimulation. In both cases it is the relative deficiency of oxygen -which produces this delay. In both cases the oxydative decomposition -can be quickened and irritability restored, that is, the refractory -period lessened and fatigue removed by a sufficient supply of -oxygen. The amount of oxygen which suffices to constantly maintain -the specific irritability of a living system in an undisturbed -metabolism of rest is not sufficient if the system is continuously -functionally activated by stimulation. The refractory period -increases after excitation and merges, although very gradually, -finally into permanent nonirritability, that is, into complete -fatigue.</p> - -<div class="figcenter illowe25" id="i_184"> - <img class="w100" src="images/i_184.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 35.</p> - -<p class="taj pl1hi15">Double glass chamber for comparative experiments on -fatigue of the nerve (<i>n n</i>). A and B—Wires of -the electrodes. (After <i>Thörner</i>.) -</p></div> -</div> - -<p>The knowledge that fatigue represents a prolonged refractory -period resulting from relative deficiency of oxygen has enabled -me with the aid of my coworkers to demonstrate the existence -of fatigue and produce the typical symptoms experimentally for -a living tissue, which up to then was considered indefatigable: -I refer to the medullated nerve. After having found that the -condition necessary for the production of fatigue in the nervous -centers is a deficiency of oxygen, I arrived at the conclusion that -fatigue could only be obtained in the medullated nerve when subjected -to a deficiency of oxygen. Up to that time, however, no -consumption of oxygen was known for the nerve. It was, therefore, -necessary to first ascertain if the nerve possessed an oxydative -metabolism. At my request, <i>H. von Baeyer</i> investigated these -questions. After many vain attempts to obtain absolutely pure -nitrogen, we finally succeeded in finding a method by which it is -possible to gain nitrogen gas, which is, one might almost say, in -a mathematical sense absolutely pure. It was then possible for -<span class="nowrap"><i>H. von Baeyer</i><a id="FNanchor_155" href="#Footnote_155" class="fnanchor">155</a></span> to asphyxiate the nerve and subsequently to bring -about complete restoration by the introduction of oxygen. It -was shown that the nerve requires merely a minute quantity of<span class="pagenum" id="Page_183">183</span> -oxygen and only completely asphyxiates when the last trace of -oxygen is removed, and further that recovery takes place within -a fraction of a minute if the oxygen is again supplied. These -experiments which have been carried further by <span class="nowrap"><i>Fröhlich</i><a id="FNanchor_156" href="#Footnote_156" class="fnanchor">156</a></span> were -afterwards confirmed in other laboratories<span class="nowrap">,<a id="FNanchor_157" href="#Footnote_157" class="fnanchor">157</a></span> and <i>form</i> the basis -for proving the existence of fatigue of the medullated nerve. -Shortly after, <span class="nowrap"><i>Fröhlich</i><a id="FNanchor_158" href="#Footnote_158" class="fnanchor">158</a></span> was able to demonstrate symptoms of -fatigue in the medullated nerve. He found that the refractory -period of the nerve, which, as previously mentioned, <i>Gotch</i> and -<i>Burch</i> fixed at about .005 second duration, was prolonged by -oxygen deficiency to .1 second, so that stimuli following each -other oftener than ten times per minute produced merely single -initial contractions in the muscle concerned, that is, in a series -of stimuli of which the intervals are less than .1 per second, only -the first produces response, whereas the following occur in the -refractory period, brought about by those preceding, and are, -therefore, inoperative. The nerve is fatigued by the quick succession -of stimuli. The normal nerve on the contrary invariably -responds, as known, to an even more rapid succession of stimuli -with a rhythmical excitation corresponding to the number of -stimuli and which is manifest in the muscle by a tetanus. This -again confirmed the identity of fatigue with the prolonged refractory -period, conditioned by the relative want of oxygen. It -likewise explained the conditions of the analogous behavior that -<span class="nowrap"><i>Wedensky</i><a id="FNanchor_159" href="#Footnote_159" class="fnanchor">159</a></span> had observed in the narcotized nerve, but had neither<span class="pagenum" id="Page_184">184</span> -recognized as manifestation of the prolonged refractory period -nor as fatigue. A further advance was made by the investigations -of <i>Thörner</i>. He placed two nerves of the same frog in a double -chamber under completely identical conditions with the exception -that one remained in a state of rest, whilst to the other -tetanic stimuli were applied. (Figure <a href="#i_184">35</a>.) If this took place in -nitrogen, the irritability of the stimulated nerve invariably sank -with much greater velocity than that of the nonstimulated, whereas -after an introduction of oxygen, even when the stimulation was -continuous, both again recovered. In these experiments of<span class="pagenum" id="Page_185">185</span> -<span class="nowrap"><i>Thörner</i><a id="FNanchor_160" href="#Footnote_160" class="fnanchor">160</a></span> the action current and not the muscle contraction served -as indicator. Here the fatigue of the medullated nerve brought -about by the deficiency of oxygen during prolonged stimulation -is demonstrated in the most obvious manner. (Figure <a href="#i_185">36</a>.) -<span class="nowrap"><i>Thörner</i><a id="FNanchor_161" href="#Footnote_161" class="fnanchor">161</a></span> further succeeded by a continuous stimulation of the -nerve in obtaining even in atmospheric air the indications of primary -fatigue. The symptoms were exactly the same as those -characterizing fatigue of the muscle; the extension of the course -of excitation and, as a consequence of this, the appearance of a -summation of excitation produced by tetanic currents and a reduction -of irritability in response to single stimuli. The form of -the curve, resulting from alteration of irritability in fatigue and -recovery, likewise shows complete conformity with that of the -muscle. (Figure <a href="#i_186">37</a>.) Finally <span class="nowrap"><i>Thörner</i><a id="FNanchor_162" href="#Footnote_162" class="fnanchor">162</a></span> proved that the nerve, -when fatigued by continuous tetanic stimulation in nitrogen, -could also partially recover in the latter if the stimulation was<span class="pagenum" id="Page_186">186</span> -interrupted, whereas a complete recovery could not take place -unless a supply of oxygen was introduced. (Figure <a href="#i_187">38</a>.) This -fact is in perfect accordance with the relations found by <i>Verworn</i>, -<i>Lipschütz</i>, in fatigue of the nervous centers. It is the -expression for the accumulation and removal of fatigue substances, -the depressing effect of which <span class="nowrap"><i>Ranke</i><a id="FNanchor_163" href="#Footnote_163" class="fnanchor">163</a></span> first established -for the fatigued muscle. The fact that the nerve could also partially -recover in an atmosphere of nitrogen would seem to likewise -contain the proof that among the fatigue substances products -in the form of gas must be present. It is probable that an escape -of carbon dioxide has taken place.</p> - -<div class="figcenter illowe25" id="i_185"> - <img class="w100" src="images/i_185.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 36.</p> - -<p class="taj pl1hi15">Curve of action current of two nerves, one of which is stimulated -(plain line) whilst the other remains at rest (dotted -line). After decrease of irritability of the stimulated nerve -in nitrogen, oxygen is introduced into the chamber and -irritability increases again. Then the previously resting -nerve is stimulated in nitrogen and the stimulated nerve -remains at rest. (After <i>Thörner</i>.) -</p></div> -</div> - -<div class="figcenter illowe32_5" id="i_186"> - <img class="w100" src="images/i_186a.jpg" alt="" /> - <div class="caption"> - -<p class="taj pl1hi15">Scheme showing course of fatigue (plain line) and recovery (dotted line) of the nerve -as it is manifested on testing the irritability with tetanic stimuli, when fatigue and -recovery alternate at equal intervals. The curve shows at the beginning an apparent -increase of irritability corresponding to the “Treppe” of the muscle. (After <i>Thörner</i>.) -</p></div> - - - <img class="w100" src="images/i_186b.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 37.</p> - -<p class="taj pl1hi15">Scheme showing course of fatigue (plain line) and recovery (dotted line) on testing the -irritability of the nerve by single induction shocks. In fatigue irritability sinks at first -rapidly, then more and more slowly until a state of equilibrium is reached. Recovery -shows the same in reverse succession. (After <i>Thörner</i>.) -</p></div> -</div> - -<p><span class="pagenum" id="Page_187">187</span></p> - -<p>As a result of all these investigations, linked together in a systematic -series, the proof has now been obtained that the nerve -like all other living substances is fatigable. Its fatigue is solely -the manifestation of a prolonged refractory period and the extension -of the latter by continuous stimulation is, as in all aërobic -substances, a result of relative deficiency of oxygen.</p> - -<div class="figcenter illowe25" id="i_187"> - <img class="w100" src="images/i_187.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 38.</p> - -<p class="taj pl1hi15">Curve of irritability as demonstrated by action current of two nerves -in nitrogen, which are alternatively stimulated (plain line) and at -rest (dotted line). Recovery in nitrogen is always merely partial -and relative. It only increases on introduction of oxygen. (After -<i>Thörner</i>.) -</p></div> -</div> - -<p>To briefly summarize in conclusion, I will repeat that just as -all living systems show a refractory period after an excitation, in -which irritability is reduced, all living systems are likewise capable -of fatigue. Both are most intimately connected and are based -fundamentally on the facts of metabolism.</p> - -<p>An excitating stimulus disturbs the metabolic equilibrium of -rest by suddenly bringing about increased decomposition of certain -substances. During and directly after the breaking down, -irritability is reduced in the same degree as the amount of substances -required for disintegration in response to a succeeding -stimulus is decreased and the quantity of the decomposition<span class="pagenum" id="Page_188">188</span> -products is increased. This is the refractory period. By the -metabolic self-regulation in accordance with the principle of -chemical equilibrium, the original metabolic equilibrium is -restored after every excitation. Irritability, therefore, increases -in the same measure as this occurs, that is, in the form of a -logarithmic curve, until it again reaches the specific degree of -irritability of the particular system. The refractory period -diminishes. If the processes of disintegration and self-regulation -are delayed, either by want of substance necessary for breaking -down or the accumulation of decomposition substances, the -refractory period is prolonged and the response to every further -stimulation decreased, that is, the system is fatigued. In all -aërobic organisms the retardation of the course of excitation and -self-regulation under a continuous influence of stimuli is the result -of the relative want of oxygen. The processes of oxydative disintegration -are prolonged and restricted by relative deficiency of -oxygen and merge more and more into anoxydative decomposition. -The products of incomplete oxydative and anoxydative -decomposition accumulate. Both factors decrease the strength -of the response after every stimulation. Thus the want of oxygen -leads to reduced activity. In the anaërobic organisms the refractory -period and symptoms of fatigue are, of course, produced by -the relative deficiency of other substances. Fatigue in the -anaërobic systems has, however, so far not been investigated. We -advance very slowly, step by step, in physiology, and, as in every -science, an acquirement of a new knowledge means a new problem. -In this lies the inexhaustible charm of our scientific -research.</p> -<hr class="chap x-ebookmaker-drop" /> - -<div class="chapter"> -<p><span class="pagenum" id="Page_189">189</span></p> - -<h2 class="nobreak" id="CHAPTER_VIII">CHAPTER VIII<br /> -<span class="title">INTERFERENCE OF EXCITATIONS</span></h2> -</div> - - -<div class="blockquot"> - -<p class="pl2hi2"><i>Contents</i>: Examples of effects of interference of stimuli in unicellular -organisms. Interference of galvanic and thermic stimuli in Paramecia. -Interference of galvanic and thermic stimuli and narcotics. -Interference of galvanic and mechanical stimuli. Interference of galvanotaxis -and thigmotaxis in Paramecia and hypotrii infusoria. Real -or homotop interference, apparent or heterotop interference. The -two effects of homotop interference of excitations: Summation and -inhibition of excitations. Theory of the processes of inhibition. -<i>Hering-Gaskell</i> theory. Inhibition as an expression of the refractory -period. Individual possibilities of interference of two stimuli. Interference -of an excitating and a depressing stimulus. Interference of -two depressing stimuli. Interference of two excitating stimuli. -Analysis of the interference of two excitations. Interference of two -single stimuli. Conditions upon which the result of interference is -dependent. Heterobole and isobole living systems. Intensity of the -two stimuli. Interval between the stimuli. Specific irritability and -rapidity of reaction of the living system. Latent period. Interference -of single stimuli in a series. General scheme of the development of -the effect of interference. Summation and inhibition. Apparent -increase of irritability. Conditions of summation. Tonic excitations. -Conditions of inhibition. Various types of inhibition. Interference -of two series of stimuli. Relations in the nervous system. Peculiarities -of the nerve fibers. Conversion of the nerve by relative fatigue -from an isobolic into a heterobolic system.</p> -</div> - - -<p>Until now the mechanism of the single excitation has received -the major portion of our attention. It was not until we reached -the subject of the origin of fatigue that we became acquainted -with the effects of repeated stimulation. Here we found a case -of interference of individual excitations. But fatigue is simply -a special instance of such interference, for the subject of interference -action occupies a much greater field.</p> - -<p>Every cell of the larger organisms, and more especially the -single celled organisms, is subjected to manifold stimuli. It is<span class="pagenum" id="Page_190">190</span> -indeed, quite common that two stimuli interfere with each other -and manifold effects follow, depending upon the specific reaction -of the cell and the quality, intensity and duration of the interfering -stimuli. Sometimes the interference effect is readily -understandable from a knowledge of the specific effect of the -individual stimuli concerned. At other times, however, the -specific reaction seems entirely different in nature than would -be expected from a study of the effects of the individual stimuli.</p> - -<div class="figcenter illowe30_625" id="i_190"> - <img class="w100" src="images/i_190.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 39.</p> - -<p class="tac">Galvanotaxis of Paramaecium aurelia.</p></div> -</div> - -<p>When I place a drop of Paramecium culture on a slide having -on two sides parallel pieces of baked clay which serve as electrodes -and allow a constant current of about .2 milliampère to -flow through, it will be seen that the infusoria at room temperature -move toward the negative pole at a rate averaging 1–1.4 mm. -per second. (Figure <a href="#i_190">39</a>.) If I increase the temperature, the rate -of movement is increased. Here the galvanic and the thermal -stimuli influence each other in such a manner that the reaction<span class="pagenum" id="Page_191">191</span> -to the galvanic is increased by the thermal stimulation. This -summation of excitation is readily understood on the basis of the -laws concerning the effect of temperature upon the velocity of -chemical change established by <i>van’t Hoff</i>. If, however, the -Paramecia are in a 1 per cent. alcoholic solution, then, as was -shown by <i>Nagai</i><span class="nowrap">,<a id="FNanchor_164" href="#Footnote_164" class="fnanchor">164</a></span> the rapidity of movement following galvanic -stimulation is decidedly reduced. The interference effect between -the galvanic and chemical stimulation is, because of the depressing -effect of the latter, likewise readily understood.</p> - -<div class="figcenter illowe25" id="i_191"> - <img class="w100" src="images/i_191.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 40.</p> - -<p class="tac">Thigmotaxis of Paramaecium aurelia. (After <i>Jennings</i>.)</p></div> -</div> - -<p>Greater difficulty meets us, however, in the following instance. -The forward movements of the Paramecia follow in consequence -of the fact that the individual cilia of the body lash more powerfully -backward than forward. If now the Paramecia, while -moving forward, meet with a resisting body, they withdraw sideways -while executing a sudden strong forward ciliary stroke. The -strong mechanical stimulation brings about retraction of the -organism. Entirely different are the results when the impact is -weak. If Paramecia while slowly swimming touch a resisting -object with the anterior portion of the body, withdrawal does not -occur. The infusoria remain under proper conditions in contact -with the resistance, and the rhythmic activity of the cilia directly -against resistance, as well as those on the other side toward the -posterior portion of the body, are more or less inhibited. (Figure -<a href="#i_191">40</a>.) The degree of inhibition brought about by this weak -mechanical stimulation may vary considerably. At times the cilia<span class="pagenum" id="Page_192">192</span> -of the whole body suddenly cease their movement. (Figure <a href="#i_192">41</a>, A.) -At other times, this cessation is limited to the cilia in the -anterior portion of the body (Figure <a href="#i_192">41</a>, B), while the movements -of those on the posterior portion of the body are of less amplitude -or are irregular and weak. In all cases the infusorium remains -quiescent in the water in contact with the resistance, and it is not -uncommon to find numerous individuals in apposition with -particles of ground, slimy detritus, plant fibers and so forth. -(Figure <a href="#i_192">41</a>, C.) In short, the rhythmic activity of the cilia of -the Paramecia receiving their normal impulses of excitation from -the ectoplasm of the cell body interfere with strong mechanical -stimuli in such a manner that a negative thigmotaxis develops; -following weak mechanical stimuli a positive thigmotaxis results. -Here is an instance of the relation between the intensity of the -stimulus and the manner in which its effects interfere with an -already existing excitation.</p> - -<div class="figcenter illowe35" id="i_192"> - <img class="w100" src="images/i_192.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 41.</p> - -<p class="tac">Thigmotaxis of Paramaecium aurelia.</p></div> -</div> - -<p>However, the strength of the inhibitory effect of a weak contact -stimulus upon another excitation is best appreciated when<span class="pagenum" id="Page_193">193</span> -positive thigmotaxis is interfered with by the effect of a thermal -or galvanic stimulus. <span class="nowrap"><i>Jennings</i><a id="FNanchor_165" href="#Footnote_165" class="fnanchor">165</a></span> and especially <span class="nowrap"><i>Pütter</i><a id="FNanchor_166" href="#Footnote_166" class="fnanchor">166</a></span> have, at -my request, more thoroughly investigated my original observations -and have given us a complete analysis of these interesting -interference effects. If the freely swimming Paramecia are subjected -to a constantly increasing temperature, the movements of -these infusoria become more and more active. At 30° C., the -rapidity is very violent and at about 37° C. they reach their maximal. -If now the same experiment is repeated with Paramecia -which have in consequence of thigmotaxis fixed themselves to -particles of slime, the temperature may be increased to 30° C. -without an observable effect. The infusoria remain throughout -in contact with the resistance. Only when the temperature is -37° C. do they release their contact and move violently through -the water. If a drop containing Paramecia is placed on a slide, -between parallel pieces of fired clay which serve as electrodes, -it will be seen that some freely swim about, whereas others -remain thigmotactically in contact with particles of slime. When -a constant current of about .2 of a milliampère is passed through, -it is observed that the freely swimming individuals hasten -towards the cathode. Those attached to objects, on the contrary, -do not respond in this manner to the electrical current. -(Figure <a href="#i_194">42</a>.) The intensity of the current can be greatly increased -without bringing about detachment of the individuals -from their position of fixation. The typical influence of the -strong current upon the movement of the cilia of the thigmotactically -fixed individuals can be clearly seen. Nevertheless, the -inhibition, brought about by the contact stimulus, predominates -over that of the excitating effect of the current, so that a freeing -of the organisms from their position does not occur. Not until -the current becomes very strong is the excitation thereby produced -sufficient to bring about a separation of the infusoria, -whereupon they immediately swim toward the cathode. In this<span class="pagenum" id="Page_194">194</span> -interference between the contact stimulus, on the one hand, and -the thermal or galvanic on the other, the inhibitory effect of the -former may overpower the strong excitation of the latter.</p> - -<div class="figcenter illowe30" id="i_194"> - <img class="w100" src="images/i_194.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 42.</p> - -<p class="taj pl1hi15">Interference of galvanotaxis and thigmotaxis in Paramaecium aurelia. The -individuals which are thigmotactically attached to slime particles -remain at rest while the freely swimming individuals move toward the -cathodic pole. -</p></div> -</div> - -<div class="figcenter illowe24_375" id="i_195"> - <img class="w100" src="images/i_195.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 43.</p> - -<p class="tac"><i>Hypotrichous infusoria.</i> A—Stylonychia. B—Urostyla.</p></div> -</div> - -<p>Still more complex and striking is finally the following case -of interference between thigmotaxis and galvanotaxis. The -hypotrichous infusoria as <i>Stylonychia</i>, <i>Urostyla</i>, <i>Oxytricha</i>, etc., -have a marked functional and morphological differentiation of -their cilia. They possess a bow-like row of perioral cilia, which -sweep in the food; a number of cilia on the ventral surface used -for locomotion by which they move about upon objects in the -water; a row of border cilia on each side, which, during swimming, -contribute the propelling force. The perioral cilia also<span class="pagenum" id="Page_195">195</span> -form the elements which bring about a screw-like movement on -the axis. They further possess several cilia, which permit a rebounding -of the organism, and finally certain forms have anal cilia, -which probably serve as breaks and to steer the organism. -(Figure <a href="#i_195">43</a>.) Their usual mode of locomotion is that of creeping, -moving by means of the cilia on the ventral surface. These -movements depend upon the positive thigmotaxis of the cilia of -locomotion. At the same time there is inhibition of the cilia on -the sides. When the infusoria are excitated by a new stimulus, -the cilia used for rebounding become active, the body frees itself -from its position of attachment and begins to swim, wherein the -cilia on the sides, as well as the perioral cilia, act in the manner -mentioned above. I have made the striking observation that the -hypotrichous infusoria respond differently to the galvanic current, -depending on whether they are swimming or in a fixed -position. If one places a drop of water with numerous Urostyla -on a slide between parallel pieces of fired clay which serve as -electrodes, it will be seen, upon the closing of a current, that all<span class="pagenum" id="Page_196">196</span> -of the individuals which are freely swimming and turning in -a screw-like manner around their axis, steer immediately toward -the cathode, exactly as in the case of the Paramecia. On the -other hand, those which are fixed to the bottom of the slide as -a result of thigmotaxis, upon closing of the current, make a short -turn and assume a position wherein the long axis is at right -angles to the direction of the current, and the perioral rim is -directed toward the cathode. In this position they move through -the field. (Figure <a href="#i_196">44</a>.) When the current is broken the individuals -draw backwards, distribute themselves and creep and -swim in all directions in the water. If during the course of the -passage of the current, an individual which has been swimming -begins to creep, the axis immediately assumes the position above -described in the case of the organisms which are in contact with -the bottom and <i>vice versa</i>. The thigmotaxis, therefore, influences -galvanotactically swimming organisms in a most characteristic -manner. As a consequence of the interference of thigmotaxis -and galvanotaxis, the organisms move in a direction transversely -to the direction of the current. This most striking reaction has -been cleared up by <i>Pütter</i><span class="nowrap">,<a id="FNanchor_167" href="#Footnote_167" class="fnanchor">167</a></span> the explanation being based upon an<span class="pagenum" id="Page_197">197</span> -accurate investigation of the mechanism of ciliary activity. The -galvanotactic swimming toward the cathode is explained by the -same principle as that applicable to all galvanotaxis<span class="nowrap">.<a id="FNanchor_168" href="#Footnote_168" class="fnanchor">168</a></span> As a result -of the excitation produced by the anode, the cell body must -assume a position wherein the border cilia, which are of greatest -importance in swimming, are equally stimulated on both sides -of that part of the body directed toward the anode. It is only -in this position that forward swimming is possible, for as a result -of unsymmetrical excitation of the border cilia a turning must at -once occur, which automatically brings about a resumption of the -position of the long axis. The perioral cilia bring about the -screw-like movement around the axis during swimming. It follows -that the freely swimming individuals must necessarily move -towards the cathode. In the case of the thigmotactically moving -individuals the activity of the border cilia is inhibited. The -perioral and the locomotion cilia bring about the assumption of -the position of the axis, above described. The perioral cilia during -movement bring about a turning of the body on the vertical -axis toward the side opposite that of the orifice and it follows -that the body can occupy only that axial position wherein the -perioral cilia are least excitated. This is, however, only the -case when the long axis of the body is transverse to the direction -of the current, and the perioral cilia are directed toward the -cathode, for stimulation arises from the anode. The reason why -the infusoria do not turn toward the anode from this transverse -position of the axis is to be found in the fact that the anterior -locomotion cilia are stimulated to a greater extent by the turning -toward the anode, and bring about a movement in the contrary -direction. The transverse position of the axis is thus the result -of an antagonistic action between the perioral and the anterior -locomotion cilia. It therefore follows that the characteristic -position, which is necessarily assumed by the thigmotactically -creeping individuals, is brought about by an interference action -between tactile and galvanic stimulation.</p> - -<div class="figcenter illowe25" id="i_196"> - <img class="w100" src="images/i_196.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 44.</p> - -<p class="taj pl1hi15"><i>Urostyla grandis.</i> Interference of galvanotaxis and thigmotaxis. The -freely swimming individuals move towards the cathode (left side). -The creeping individuals move in transverse direction. -</p></div> -</div> - -<p>These, then, are a few examples of the interference action of -various stimuli on the single cell. They show us in part fairly<span class="pagenum" id="Page_198">198</span> -simple, and in part very complex states. It now behooves us to -obtain a general understanding of interference action, to learn -the fundamental <i>laws</i> in connection with these complex actions, -to shell out, as it were, the general factors involved in the special -conditions. In this connection the examples already referred to -furnish all of the data necessary for our first orientation. In the -simple instance in which the effect of galvanic stimulation was -augmented by increase of temperature and again in the case where -there was a diminution of excitation resulting from the alcohol, -the interference of the two stimuli is consequent upon the -fact that the location of attack is the same. The constant -current acts upon a portion of the infusorium, which also responds -to elevation of temperature. We have a <i>real</i>, or, as I -may term it, “<i>homotopic interference</i>,” for it is an interference -in which the general point of attack is the same for both stimuli.</p> - -<p>In contradistinction to this case, we have the examples of the -interference of thigmotaxis and galvanotaxis in the hypotrichous -infusoria. Here the effect of interference, the characteristic -position of the axis of the cell body, is brought about by the fact -that the galvanic stimulus affects different elements than the -mechanical. The turning of a creeping Stylonychia or Urostyla, -when the current is closed, in which the anterior portion of the -body was previously directed towards the anode, results from -excitation of the perioral cilia from the anodic pole. The mechanical -stimulation, on the contrary, exerts its effect upon the -locomotion and border cilia. Only when there is a turning of -the anterior portion of the body towards the anode, would the -galvanic stimulus affect also the anterior locomotion cilia and -thereby counteract turning towards the anode. Therefore, we -have before us in this case of the assuming of a characteristic -position of the axis of the cell body the expression of an <i>apparent</i>, -or, as I prefer to express it, a “<i>heterotopic interference</i>,” in which -the two stimuli do not actually interfere in their action, but rather -influence the final result, in that the condition for the state of -the system in its totality is dependent upon its individual components. -This heterotopic interference is of particular importance -in the bringing about of the movements of the living system.<span class="pagenum" id="Page_199">199</span> -The locomotion of the animal and especially the direction is -in part a manifestation of heterotopic interference of response. -At the same time, however, especially in the coördinated movements -of nervous origin, the homotopic interference <i>also</i> plays -an important rôle and, not rarely, is combined with heterotopic -interference.</p> - -<p>Although the physical analysis of heterotopic interference is -extremely attractive, we must, however, temporarily set aside its -consideration, for at this point the question arises as to what -happens when there is interference of two stimuli at the same -point. In the heterotopic interference the effect of each stimulus -is the same as if it were applied singly. In the homotopic interference -the interfering effects of stimulation influence each other.</p> - -<p>The above examples of homotopic interference introduce us to -the two principal types of these manifold kinds of interference -effects; the excitation brought about by galvanic stimulation is -summated by the excitation produced by temperature. The other -type consists of an inhibition of one effect of stimulation brought -about by another. The depression produced by alcohol on the -Paramecia weakens the excitation of the galvanic current. These -examples of the two principal types of interference effects are -quite simple; nevertheless, in other cases, the conditions are very -complex. This is especially true in the field of nervous inhibition, -so important in the functionation of the nervous system, -and which has presented the greatest difficulties to physiological -investigators until the last few years. That a stimulus bringing -about excitation in a ganglion cell can be inhibited by another -exciting stimulus, or that the development of excitation in a -ganglion cell may be prevented by another exciting stimulus cannot -be easily understood. The problem as to how two interfering -excitations can bring about inhibition is one that has received -many explanations. An interesting incident in the history of -physiology is that the first explanation of the principles of inhibitory -processes was close on the track of being a correct one, -but was subsequently abandoned by its originator. <span class="nowrap"><i>Schiff</i><a id="FNanchor_169" href="#Footnote_169" class="fnanchor">169</a></span> -(1858) has endeavored to explain this inhibition as a manifestation<span class="pagenum" id="Page_200">200</span> -of fatigue, and this idea he defended with the greatest -tenacity for a long time, until finally, twenty-five years after, in -a treatise which he called “Abschied von der Ershöpfungstheorie,” -he renounced the idea as untenable.</p> - -<p>Among other investigations, which since this time have been -made to explain the mechanism of inhibition, those of <i>Gaskell</i><span class="nowrap">,<a id="FNanchor_170" href="#Footnote_170" class="fnanchor">170</a></span> -<span class="nowrap"><i>Hering</i><a id="FNanchor_171" href="#Footnote_171" class="fnanchor">171</a></span> and <span class="nowrap"><i>Meltzer</i><a id="FNanchor_172" href="#Footnote_172" class="fnanchor">172</a></span> have received widest consideration. These -theories are built upon the existence of the two phases of metabolism, -and assume that inhibition, in contradistinction to dissimilatory -excitation processes, depends upon an increase of the -assimilative processes. The principal evidence which <i>Gaskell</i> -advances is that when the vagus nerve of the tortoise heart, a -typical inhibitory nerve, is stimulated, a positive variation of the -demarcation current of the heart muscle occurs, whereas when a -motor nerve of a skeleton muscle is stimulated the attached muscle -shows a negative variation of the demarcation current. I must -confess that this explanation of inhibitory processes, from the -standpoint of an interpretation of processes in the living substance, -seems very plausible, and I have accepted this even in my -address on excitation and depression before the Frankfurter -Naturforscher Versammlung<span class="nowrap">.<a id="FNanchor_173" href="#Footnote_173" class="fnanchor">173</a></span> I have since then endeavored to -obtain experimental evidence to substantiate this theory, in that -I attempted to prove that increase of the assimilatory processes -brought about by stimulation would be associated with a reduction -of the specific irritability. For this purpose I have sought -for such cases in which a stimulus primarily and momentarily -increases assimilative processes in a system in a state of metabolic -equilibrium. I was disappointed, when, after years of investigation, -I could not find such cases. There is only one kind of -stimulus of which we can say with positiveness that it primarily -increases the assimilative processes, that is, increased supply of<span class="pagenum" id="Page_201">201</span> -food. But here the increase in the processes of assimilation never -occurs momentarily, and indeed this increase is so extremely -slight that it can only be demonstrated over a long course of time. -These totally negative results of my investigation had awakened -strong doubts concerning the assimilation hypothesis of inhibition. -Above all, this explanation seemed to me to be impossible for the -nervous system. I searched, therefore, for another explanation -for the processes of inhibition in the nervous system. If the -increase of energy production resulting from the application of -a stimulus is dependent upon an excitation of a dissimilative -nature, then one is justified to look upon the reduction of functional -energy production as an expression of an antagonistic process -to that of dissimilatory excitation. In this respect the -<i>Gaskell-Hering</i> hypothesis of inhibition rests upon a firm foundation. -When, however, this hypothesis assumes an antagonism -between dissimilatory and assimilatory excitation, then it must -not be overlooked that a second antagonism is possible between -dissimilatory excitation and dissimilatory depression. The antagonism -need not involve the two types of metabolism, it may -depend upon variations of <i>one</i> type. When, therefore, the hypothesis -that inhibition is brought about by assimilatory excitation -meets with insuperable difficulties, the possibility should be -considered if it is not more likely dependent upon dissimilatory -depression. These reflections induced me to investigate if conditions -could not be produced experimentally wherein dissimilatory -depression could bring about inhibitory processes in the -nervous system. The most essential requirement was, that dissimilatory -depression should quickly develop and pass away with -like rapidity, for inhibition of the nervous system sets in momentarily -and disappears again momentarily. Another important -requisite is, that both interference stimuli are individually capable -of producing dissimilatory excitation, for the inhibitory processes -of the nervous type may be assumed to be the result of dissimilatory -excitation which produce by their interference inhibition, -for the nerve fibers, as already stated, are capable of conducting -only dissimilatory excitation to the responding organ. As I -studied the problem in this manner, it became clear to me that all<span class="pagenum" id="Page_202">202</span> -the conditions necessary for the genesis of inhibition are realized -in the existence of the refractory period, and that I had already -produced inhibition by prolonging the refractory period, by -oxygen withdrawal, in the strychninized frog. If we take a -strychninized frog in which the refractory period has been somewhat -prolonged by oxygen withdrawal, so that the reaction is -simply a short reflex contraction, and rhythmically stimulate the -skin, a reaction is only obtained with the first few stimuli, which -reactions rapidly decrease until a stage is reached wherein the -succeeding stimuli are completely inoperative. (Figure <a href="#i_202">45</a>.<span class="nowrap">)<a id="FNanchor_174" href="#Footnote_174" class="fnanchor">174</a></span> -This inhibition is demonstrated even more clearly by the following -experiment. Contractions of the triceps muscle of a strychninized -frog are recorded which reflexly follow from stimulation of the<span class="pagenum" id="Page_203">203</span> -central end of the cut sciatic nerve. Oxygen is withdrawn in the -manner already referred to. At the proper stage of oxygen -deficiency, rhythmic induction shocks applied to the central end -of the nerve, the interval between the individual stimuli of which -being longer than the duration of the refractory period, elicit -reflex contractions of the muscles of the posterior extremity on -the opposite side following each individual stimulus. If, however, -in the same stage the central end of the nerve is stimulated -with induction shocks at intervals briefer than the duration of -the refractory period, a contraction is only observed during the -very beginning, being brought about by the <i>first</i> stimulus, whereas -the subsequent stimuli are ineffective, the muscles remaining at -rest during their entire application. (Figure <a href="#i_203">46</a>.) <span class="nowrap"><i>Tiedemann</i><a id="FNanchor_175" href="#Footnote_175" class="fnanchor">175</a></span> -at a later date continued these observations and analyzed them -more in detail. In all these experiments, therefore, there is an -interference of the frequent stimulus, because each succeeding -stimulus occurs in the refractory period of the proceeding. In<span class="pagenum" id="Page_204">204</span> -consequence there is a strong reduction of irritability and reaction -is absent. That is, the centers during application of the -frequent current are <i>inhibited</i>. If cessation of stimulation by -frequent shocks takes place, stimulation by slowly succeeding -individual shocks becomes effective again in a few seconds. This -is the simplest example of the process of inhibition and by it I -was led to seek in the refractory period the key of the mechanisms -of the process of inhibition. This principle once recognized, -further material for the more detailed working out and extension -of the theory was gathered from the experiences already gained -during the course of the preceding years in the researches on -fatigue and the refractory period in the nerve. Here it became -apparent that the processes resembling inhibition discovered by -<i>Schiff</i> in the nerve preparation and which were studied anew at -a later date by <i>Wedenski</i>, <i>F. B. Hofmann</i> and <i>Amaja</i> and in part -attributed by <i>Hofmann</i> to fatigue of the nerve endings, by -<i>Fröhlich</i> to fatigue of the nerve itself, were in principle of the -same nature as the central inhibitions themselves. <i>Fröhlich</i><span class="nowrap">,<a id="FNanchor_176" href="#Footnote_176" class="fnanchor">176</a></span> by -his analysis of the observations of <i>Richet</i>, <i>Luchsinger</i>, <i>Fick</i>, -<i>Biedermann</i> and <i>Piotrowski</i> on inhibition in the claw of the crab, -then showed that inhibition can be influenced by the alteration of -the intensity of the stimulus as well as its frequency. In a series -of experimental researches he could then demonstrate that the -widely extended antagonistic inhibitions and other special processes -of inhibitions in the centers could on the basis of the same -principle be physiologically explained. Here the supposition was -confirmed that the development of a relative refractory period -plays a very important rôle in the inhibition of the nervous centers. -Thus, the relations of the processes of inhibition to the -refractory period, once established, their entire field, up to then<span class="pagenum" id="Page_205">205</span> -shrouded in darkness, has gradually in the course of years been -completely elucidated.</p> - -<div class="figcenter illowe18_75" id="i_202"> - <img class="w100" src="images/i_202.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 45.</p> - -<p class="tac">Lower line indicates stimuli.</p></div> -</div> - -<div class="figcenter illowe30" id="i_203"> - <img class="w100" src="images/i_203.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 46.</p> - -<p class="taj pl1hi15">Reflex inhibition in the strychninized frog. Lower line indicates seconds, upper line stimuli. -When stimulation with single shocks at longer intervals is applied, each single stimulus -is effective. When faradic stimulation is used, only the first stimulus is operative, -and during the further continuance of stimulation inhibition takes place in the spinal -cord. -</p></div> -</div> - -<p>Before going back to the cases of inhibition and explaining -them by this general principle, it is necessary that we penetrate -more deeply into the details of the characteristic course of the -refractory period. By this means we will find the conditions -which universally determine the interference in the effects of -stimulation.</p> - -<p>First of all, it is self-evident that the occurrence of interference -of stimulation in a living system can only take place when the -succeeding stimulus is applied before the effects of the previous -one have completely disappeared. Within the interval, however, -which is involved from the moment of the beginning of a stimulus -until its effect disappears through the self-regulation of metabolism, -there is the possibility of various interference results from -stimulation.</p> - -<p>If we take into consideration the various instances which can -arise, perhaps we may best start with that type wherein the first -stimulation produces depression, whereas the second has an exciting -effect on disintegration. In this type the response to the -second stimulus is weaker than when the second stimulus alone -is applied. As a concrete example of this type, we may refer to -the interference of an induction shock in a nerve during the -relative want of oxygen. We arrange a nerve of a nerve muscle -preparation of a frog in a glass chamber, as already described, and -determine the threshold of stimulation of the stretch within the -chamber by the weakest induction shocks which produce response. -The oxygen is then removed and the effect on the threshold determined. -As shown by <i>Baeyer</i> it is found that with increasing -asphyxia the threshold of stimulation for induction shocks becomes -continually higher. The irritability is likewise decreased. -This occurs, as the investigations of <i>Lodholz</i> show, at first slowly, -then more and more rapidly. The curve of the decrease of irritability -has a logarithmic form. During the continuation of the -depressing stimulus, i.e., the want of oxygen, the exciting stimulus -has less and less effect. If oxygen is again brought in contact -with the nerve, irritability immediately returns to its original<span class="pagenum" id="Page_206">206</span> -height. The cessation of the depressing stimulus has, therefore, -the effect that the exciting stimulus again brings about its original -response.</p> - -<p>A second type of interference is produced when both stimuli -bring about depression. As an example, we may select the interference -of cold and deficiency of oxygen. If we assume, for -instance, that each of these stimuli of itself brings about only a -partial reduction of living processes and not a <i>complete</i> suppression, -then it would be possible to think of a summation of both -depressions. Nevertheless, the conditions for the summation of -depression have never been carefully analyzed. Quantitative -investigations upon the interference of depressing stimuli are -entirely lacking. One should not, however, in physiology presuppose -what may happen under certain given conditions without -first making the necessary experiments. The strength of -scientific investigation depends upon the fact that every deduction, -no matter how small, must be substantiated by experience -before further progress can be made. So, likewise, we must -await the results of thorough experimentation upon the interference -of depressing stimuli before we can establish a law. The -conditions are not as simple as they appear on first observation, -for the point of attack of the various kinds of the depressing -stimuli upon the chain of metabolic processes may be very different. -In such a case it is not at once possible to understand the -results of the interference.</p> - -<p>There is a third type in which two dissimilatory excitations -interfere with each other. Fortunately there is a great amount -of experimental data at our command so that today we have a -clear understanding of the essential points of the conditions -necessary for the development of summation of excitation on the -one hand, and inhibition on the other. If we take an instance -of a momentary dissimilatory excitation operating upon an -aërobic system in metabolic equilibrium, it is necessary to recall -the two effects thereby produced. The stimulus brings about an -oxydative decomposition of the living substance. Likewise there -is a reduction of irritability. Both of these alterations are the -foundation of interference. Both processes have a specific time<span class="pagenum" id="Page_207">207</span> -of occurrence. The disintegration, determined by energy production, -reaches a maximum suddenly, then diminishes, at first -rapidly, then more and more slowly until the zero point is reached. -In an analogous manner the irritability abruptly reaches a minimum, -then increases rapidly, then more slowly, until it again -reaches its previous value. When we represent these processes -by a curve, they assume the following form. (Figure <a href="#i_207">47</a>.) In -this diagram the abscissa is the time, the ordinate value zero is -the level of the metabolism of rest and the specific irritability. -The points above the abscissa represent disintegration, that is, -energy production, those under the abscissa, the reduction of irritability. -A consideration of the latent period may be omitted. -At the end of the curve the effect of stimulation may be assumed -to have disappeared and the state of metabolic equilibrium reestablished. -If we base our further observations upon this curve -of excitation, we can study in them the factors upon which -responsivity is dependent when a second exciting stimulus is -operative during the course of the first.</p> - -<div class="figcenter illowe18_75" id="i_207"> - <img class="w100" src="images/i_207.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 47.</p></div> -</div> - -<div class="figcenter illowe18_75" id="i_208a"> - <img class="w100" src="images/i_208a.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 48.</p></div> -</div> - -<div class="figcenter illowe18_75" id="i_208b"> - <img class="w100" src="images/i_208b.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 49.</p></div> -</div> - -<div class="figcenter illowe18_75" id="i_209"> - <img class="w100" src="images/i_209.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 50.</p></div> -</div> - -<p>It is from the beginning apparent that the response to the -second stimulus is determined by the intensity of the second -stimulus in relation to the degree of irritability which exists at -the moment when this is effective. This relation is dependent -first upon the absolute intensity of the second stimulus. In the -following diagram the intensity of the existing threshold value is<span class="pagenum" id="Page_208">208</span> -fixed for convenience as ordinates beneath the abscissa. If, for -example, at the time point <i>x</i>, a stimulus of weak intensity R<sub>1</sub> acts, -this stimulus being under the existing threshold, produces no -perceptible effect. (Figure <a href="#i_208a">48</a>.) If now instead of a weak stimulus, -one of stronger intensity acts at the time point <i>x</i>, this stimulus -will produce an appreciable response. (Figure <a href="#i_208b">49</a>.) If the second -stimulus is of the same strength as the first, this second stimulus -will bring about relatively less disintegration, because the -system is then in a state in which irritability is still reduced. -But this lessened disintegration in that it summates the excitation -still existing as the result of the first stimulus can produce -an absolute increase of the height above that of the abscissa.<span class="pagenum" id="Page_209">209</span> -Here then we see the possibility of an increase of response -resulting from summation. Accordingly the increase of disintegration -must occur simultaneously with a diminution of irritability -and this must fall below the level of the reduction of -irritability produced by the first stimulus. This augmentation of -the response through summation above the level of that produced -by the first stimulus acting upon an unexcitated system is, -however, connected with another condition. The above example -refers to systems in which weak stimuli bring about weak response -and strong stimuli strong response, that is, the response -is capable of increase. In systems in which the “all or none -law” is applicable, such an alteration in the absolute height of -excitation, as results in summation, is not possible. In order to -characterize these two types of living systems by a short expression -rather than by a long sentence, we will call the first a -“<i>heterobolic system</i>,” the latter in which the “all or none law” is -operative an “<i>isobolic system</i>.” The former term expresses -various degrees of discharge depending upon the intensity of the -stimulus, the latter term refers to the constancy of discharge -following stimuli of various intensities. Isobolic systems are in -contradistinction to the heterobolic systems not capable of summation. -The response to the second stimulus of equal intensity -cannot be greater than that of the first, it may be equal to the -first (Figure <a href="#i_209">50</a>) or be less in extent, but it can never be greater<span class="pagenum" id="Page_210">210</span> -than that resulting when a single stimulus is applied. These facts -have been known for a long time in the case of the heart muscle. -A word is necessary, however, concerning the effect of stimuli -beneath the threshold in heterobolic systems. We must here -distinguish between the <i>“ideal” threshold</i>, beneath which the -influence of a stimulus is nil, and the <i>threshold of perceptible -effect</i>, beneath which a stimulus apparently has no effect; nevertheless -a weak effect does occur, as is shown by succeeding reactions. -This effect is manifested by a sub-threshold disintegration -and a corresponding slight reduction of irritability. -(Figure <a href="#i_210">51</a>.) The presence of such a sub-threshold effect is -recognized by various facts as, for example, the summation of the -sub-threshold stimuli to production of a perceptible result. Thus -stimulation of a sensory spinal cord root with a single sub-threshold -induction shock will not produce any evidence of a -reflex excitation, whereas, when induction shocks of the same -strength and of sufficient frequency are applied, a strong reflex -contraction results. The fact that sub-threshold stimuli can bring -about sub-threshold effects is also important in consideration of -the result of interference. The relation between the intensity of -the second stimulus and the degree of irritability of the system, -the intensity of the stimulus being absolutely constant, depends,<span class="pagenum" id="Page_211">211</span> -secondly, upon the momentary amount of irritability which exists -just at the time when the second stimulus produces its effects. -It is, therefore, clear that the response produced by interference -must also alter with the momentary degree of irritability in a -manner analogous with variations of the intensity of the second -stimulus. One must, therefore, know the factors which control -the momentary degree of excitation.</p> - -<div class="figcenter illowe18_75" id="i_210"> - <img class="w100" src="images/i_210.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 51.</p> - -<p class="tac">Effect of sub-threshold stimuli. <i>o</i>—Level of the ideal threshold. -<i>s</i>—Level of the threshold of perceptible effect.</p></div> -</div> - -<div class="figcenter illowe19_375" id="i_211"> - <img class="w100" src="images/i_211.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 52.</p></div> -</div> - -<p>The first factor to be considered is the moment of time in which -the second stimulus is applied, that is, the interval between the -first and the second stimulus. If, for example, a weak second -stimulus follows very quickly after the first, the stimulus will -bring about no response, as the system at the time of its application -is in a relative refractory period. (Figure <a href="#i_208a">48</a>.) The -stimulus is, therefore, under the threshold. If, however, a stimulus -of the same strength is applied somewhat later, when the irritability -has already increased to a somewhat greater extent, then -at this moment the stimulus is above that of the threshold and -a response is obtained which, on account of the state of irritability -existing, is summated. (Figure <a href="#i_211">52</a>.) But further, it is not a -question of the <i>absolute</i> interval between the stimuli, but rather -to the <i>relative</i> interval to the <i>specific rapidity of the reaction of -the living substance under consideration</i>. There are living substances, -as we have seen, in which the refractory period is unusually -short, as, for instance, the nerve. There are other substances<span class="pagenum" id="Page_212">212</span> -wherein this period lasts a considerable time after stimulation, -that is, before the irritability returns to the original level, -as, for example, the smooth muscle. Indeed, depending upon -the specific properties of a system, a short or a long interval is -required before a stimulus of a given intensity is again operative. -Finally, in one and the same living system the duration of the -refractory period can be very different, depending upon the -<i>momentary state of the system</i>. Above all we know that the -refractory period is considerably prolonged in fatigue and likewise -after the influence of other agents, as narcotics, lowering of -the temperature, etc. In such states a second stimulus remains -inoperative when it follows at a definite interval from the first, -whereas under normal conditions the same stimulus applied at the -same interval would be operative.</p> - -<p>Finally, there is another factor to be considered, namely, that -the latent period of the second stimulus is more and more prolonged -as the second stimulus approaches more closely to the -absolute refractory period of the first. In the above schemes the -latent period was not taken into consideration because practically -for all the intervals of stimulation considered at that time it could -be assumed to be the same. When, however, a decrease of the -intervals between the individual stimuli takes place, the prolongation -of the latent period can then not be overlooked, as it leads to -a retardation of response. (Figures <a href="#i_156">29</a>, <a href="#i_161">30</a>.) This fact was shown -in the classic investigations of <span class="nowrap"><i>Marey</i><a id="FNanchor_177" href="#Footnote_177" class="fnanchor">177</a></span> upon the refractory period -of the heart, and more recently has been the subject of study -by <i>Samojloff</i><span class="nowrap">,<a id="FNanchor_178" href="#Footnote_178" class="fnanchor">178</a></span> <span class="nowrap"><i>Keith Lucas</i><a id="FNanchor_179" href="#Footnote_179" class="fnanchor">179</a></span> and <span class="nowrap"><i>Gotch</i><a id="FNanchor_180" href="#Footnote_180" class="fnanchor">180</a></span> in the muscle and -nerve. These, then, are the essential factors which bring about -interference, and although there are special details which deserve<span class="pagenum" id="Page_213">213</span> -more close analysis, nevertheless, we are in a position to attribute -to them the origins of summation and inhibitory processes, which -occur in all living systems, especially the nervous system.</p> - -<p>For the analysis of summation and the inhibitory processes -which occur in the physiologically active organisms or which are -experimentally produced, a very important point should be observed, -that is, the fact that the stimuli which bring about these -phenomena are practically always a <i>series</i> of <i>single</i> stimuli. The -nerve impulses, for example, consist of a shorter or a longer -series of single discharges which follow each other in rapid -rhythmic sequence. Here, then, we have the conditions necessary -for the production of interference effects when these single -stimuli follow each other with sufficient frequency and also when -there is the combined action of <i>two</i> series.</p> - -<div class="figcenter illowe30" id="i_213"> - <img class="w100" src="images/i_213.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 53.</p> - -<p class="taj pl1hi15">Curve showing the general development of the effect produced by interference of the -stimuli of the same series in an heterobolic system. The effect is first summation -and then inhibition. <i>R</i> indicates the intensity of the stimuli, <i>S</i> the level of the -threshold of perceptible effect. -</p></div> -</div> - -<p>We will first direct our attention to the simplest case brought -about by an interference between the individual effects of stimuli -in the same series. We will study the effect, which here occurs, -in the accompanying diagram, which shows the facts involved in -the interference of <i>two</i> stimuli of a <i>series</i> of stimuli. (Figure <a href="#i_213">53</a>.) -The curve shows the development of summation and inhibition. -The single stimuli of equal intensity follow at the same -intervals, so that the succeeding stimuli meet with an incomplete<span class="pagenum" id="Page_214">214</span> -recovery of excitation and accordingly a decreased state of irritability. -In spite of the diminution of the relative response to -each stimulus the summation of excitation brings about an -absolute increase of the same. At the same time the irritability -decreases more and more, for after each stimulation the oxydative -disintegration as well as restitution require a progressively greater -time and a relative fatigue must, therefore, necessarily develop. -The summation, consequently, reaches its limit very soon and -then decreases progressively, for, as a result of the increase of -fatigue, the oxydative decomposition which occurs at the instant -of every stimulation reduces and with this the energy production -becomes less and less. The system is relatively refractory for -the given intensity of stimulus. Accordingly the response to stimulation -falls below the threshold of perceptible response (dotted -line S) and finally an equilibrium between disintegration and -restitution occurs, wherein the small amount of material used at -each stimulation by oxydative decomposition is again replaced -before the next stimulus. In other words, the irritability is reduced -at each stimulation to an amount equal to that of the -recovery in the interval. If this all takes place beneath the threshold -of perceptible response, the system during the continuance -of the stimulation seems responseless, that is, inhibited. -The <i>inhibition</i> consists then of a reduction of irritability below -the perceptible threshold of response of the stimulus concerned. -It depends upon a continued lessening of dissimilative excitation -to a low level through the delay of the oxydative decomposition -processes. The inhibition is according to this a relative fatigue, -which is conditioned, as is true of every fatigue, by a lengthening -of the refractory period following a relative deficiency of oxygen. -<i>The processes of inhibition are simply and solely an expression -of a refractory period persisting as a result of dissimilatory -excitating stimuli.</i></p> - -<p>Accordingly the general conditions requisite for summation -on the one side and inhibition on the other may be formulated -as follows:</p> - -<p>A <i>summation</i> may develop in a heterobolic system and by the -use of submaximal stimuli. It always develops when the following<span class="pagenum" id="Page_215">215</span> -stimulus is applied before there is complete recovery of excitation -from the previous stimulus. The absolute increase of -excitation as a result of summation is, however, limited by the -diminution of irritability. By continuation of the series of stimuli -the state of equilibrium between the amount of excitation and -the irritability will be established on a higher or lower level. -There occurs then, depending on whether the feeble persistent -excitation remains above or below the level of perceptible effect, -either a tonus or an inhibition.</p> - -<p>Summation can be transformed into inhibition by the continuance -of stimuli of constant intensity. The principles which underlie -both processes are in no way antagonistic and indeed are not -separated by distinct boundaries. The diagram here shown -(Figure <a href="#i_213">53</a>) illustrates this development of summation and inhibition. -The time required for this development is in manifold -ways influenced by variations of the above-stated factors which -control the occurrence of interference. Thereby results an -immense number of special cases which differentiate themselves -in characteristic manner depending on whether an isobolic or -heterobolic system is involved, depending on whether the irritability -of the system, as measured by the threshold of stimulation, -is high or low, depending on whether fatigability is great or -small, depending upon the intensity and frequency of the stimuli, -etc. Analysis of every instance shows us different combinations -of the interaction of the individual factors. It is, therefore, self-evident -that we cannot here analyze a greater number of these -cases of summation and inhibition. I wish only to refer to a few -typical examples at this time.</p> - -<p>It is known that summation of excitation in the normal nerve -does not occur. As already stated, the nerve is a system in which -the “all or none law” is operative. Such isobolic systems do not -summate, having no power of summation because each individual -stimulus brings about a maximum response. But we have seen -that the nerve, as a result of depressing factors, such as deficiency -of oxygen, narcosis, fatigue, etc., which decrease its irritability, -can be transformed from an isobolic into a heterobolic system. -In this state the nerve possesses the capability of summating<span class="pagenum" id="Page_216">216</span> -excitations. <i>Waller</i><span class="nowrap">,<a id="FNanchor_181" href="#Footnote_181" class="fnanchor">181</a></span> <i>Boruttau</i><span class="nowrap">,<a id="FNanchor_182" href="#Footnote_182" class="fnanchor">182</a></span> <i>Boruttau</i> and <i>Fröhlich</i><span class="nowrap">,<a id="FNanchor_183" href="#Footnote_183" class="fnanchor">183</a></span> -<span class="nowrap"><i>Thörner</i><a id="FNanchor_184" href="#Footnote_184" class="fnanchor">184</a></span> and others have shown that the action current of the -nerve during the application of tetanic stimulation becomes decidedly -greater during a certain stage of narcosis or asphyxiation, -so that the wave of negative variation is higher than when the -nerve is excitated by a single induction shock. <span class="nowrap"><i>Fröhlich</i><a id="FNanchor_185" href="#Footnote_185" class="fnanchor">185</a></span> first -threw light upon this subject in that he made the observation -that here a principle is involved which has far-reaching importance -in the phenomena occurring in the organism. He showed -that as a result of fatigue, cold and narcosis, etc., the course of -excitation brought about by the single stimulation undergoes -retardation. These conditions within certain limits become more -favorable for the production of summation, because each succeeding -stimulus meets with a more incomplete recovery of excitation -than the one previously applied. In consequence of this, the irritability -of the system in the beginning of fatigue, or narcosis, or -immediately after the application of cold, is apparently increased. -This “<i>apparent excitation</i>,” as it was called by <i>Fröhlich</i>, depends, -however, in reality upon a beginning depression which is evident -in that the course of the individual excitations are lengthened by -this means. The irritability is likewise also reduced. <span class="nowrap"><i>Reinecke</i><a id="FNanchor_186" href="#Footnote_186" class="fnanchor">186</a></span> -later studied in further detail the retardation of excitation in the -muscle and attributed to this the characteristic property shown -in muscle in the so-called “reaction of degeneration.” Fatigue, -asphyxia, cold, degeneration, in fact all factors which retard the<span class="pagenum" id="Page_217">217</span> -course of excitation, are favorable to the summation of excitation, -provided their influence does not exceed certain limits.</p> - -<p>Although the nerve as an isobolic system can only be rendered -capable of exhibiting summation when artificially influenced, -there are other forms of living substance which normally are -systems with a slow course of excitation, in which excitation -may be summated, for this type possesses at the same time a -heterobolic character. For example, a single mechanical excitation -elicits a hardly perceptible response in <i>Amœba</i>, <i>Actinosphærium</i>, -<i>Orbitolites</i>. When it is perceptible at all, there occurs -a short interruption of the centrifugal movement of the protoplasm. -After a pause the movement of the protoplasm and the -stretching out of the pseudopods again return. But if the -organism is agitated one or more minutes by rhythmically shaking -the edge of the slide by a special device, as a result of the -summation of weak excitations there occurs a complete drawing -in of the pseudopods and the amœbæ become bell-shaped<span class="nowrap">.<a id="FNanchor_187" href="#Footnote_187" class="fnanchor">187</a></span> The -ganglion cells also possess a great capability for summation. We -have already alluded to the fact that single induction shocks -below that of the threshold produce no evident effect, whereas -when rapidly repeated, summation occurs with reflex reaction.</p> - -<div class="figcenter illowe25" id="i_217"> - <img class="w100" src="images/i_217.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 54.</p> - -<p class="tac">Development of tonus by interference of sub-threshold stimuli. -<i>S</i>—Level of the threshold of perceptible effect.</p></div> -</div> - -<p>The summation of sub-threshold excitation to a certain height -offers very favorable conditions for the development of <i>tonus</i>. -(Figure <a href="#i_217">54</a>.) This fact has been established for many kinds of -centers (cardio-inhibitory center, vasomotor center, etc.). During -the continuance of a series of stimuli, as we have already seen, -an equilibrium between disintegration and replacement soon takes<span class="pagenum" id="Page_218">218</span> -place. The level of this state of equilibrium depends upon the -relative intensity of the stimuli. It is lower in the case of strong -and higher in that of weak stimuli. This fact becomes apparent -from the researches of <span class="nowrap"><i>Thörner</i><a id="FNanchor_188" href="#Footnote_188" class="fnanchor">188</a></span> on the fatigue of medullated -nerves in air. This investigator showed that during continued -tetanic stimulation of the nerve, the irritability fell to a certain -level, at which it remained so long as stimulation persisted. The -irritability decreased to a new level when the strength of the -stimulus was increased. These interesting experiments of <i>Thörner</i> -show that the level reached when stimulation is continued is -higher as the intensity is weaker. It is, therefore, clear that this -level in summation of stimulation beneath the threshold can be -above that of the threshold of perceptible response, that is, a perceptible -tonic excitation may result. In the genesis of tonus in -the muscle, there is another point to be taken into consideration. -Here we have a combination of a heterotopic interference with a -homotopic interference, for the total shortening of the muscle is -brought about in part by several contraction waves which occur -at various points at the same time and which follow each other, -therefore have a heterotopic sequence. If we consider a long -stretch of muscle, to one end of which a stimulus is applied, it will -be found that the contraction wave moves throughout the entire -length. If after a certain interval of time a second stimulus is -applied, the resultant wave moves along the muscle but does not -necessarily homotopically interfere with the first. In short, there -are two waves of contraction occurring coincidently in the muscle, -the muscle is now more strongly contracted. <span class="nowrap"><i>Fröhlich</i><a id="FNanchor_189" href="#Footnote_189" class="fnanchor">189</a></span> has made -the fact intelligible by this means that tetanic shortening of a -muscle is greater than that of maximal shortening which can be -produced by strong single stimulation. This heterotopic interference -dare not be overlooked in the genesis of muscle tonus. -If it is true, as appears from the investigations of <i>Keith Lucas</i><span class="nowrap">,<a id="FNanchor_190" href="#Footnote_190" class="fnanchor">190</a></span><span class="pagenum" id="Page_219">219</span> -that the “all or none law” applies to striated muscle, then an -increase of the contraction from homotopic summation cannot -occur, because an isobolic system cannot show an increase of its -already maximal excitation by summation. Such being the case, -the tonic shortening of striated muscle can only be explained as -an expression of a heterotopic interference.</p> - -<p>If we assume that the summation of sub-threshold stimulation, -by increasing excitation, brings about a state of equilibrium from -below, as it were, so also inhibition may be assumed to be the -reverse, the level of equilibrium being reached from above, as it -were, by decrease of the primary excitation from strong stimulation. -This is expressed in our general scheme of the development -of summation and inhibition resulting from the effect of a -series of stimuli. At the same time the first part of the curve to -the fall of irritation to the level of the sub-threshold equilibrium -can be shortened to a minimum by strong stimulation or greater -frequency of the same, and we have then the type of <i>inhibition -with primary excitation</i>. As example of this I wish to again recall -the strychninized frog which was used in the fundamental experiments -for understanding of the theory of inhibition. If we stimulate -a sensory nerve of a strychninized frog, in which the refractory -period is already lengthened, with rhythmic single induction -shocks of slow frequency, the muscle arranged to make a graphic -record will show reflex contraction following each stimulus. If, -on the other hand, we apply a series of stimuli, consisting of single -stimuli rapidly repeated, contraction is produced only by the first, -or the first few stimuli (Figures <a href="#i_202">45</a> and <a href="#i_203">46</a>, pages 202, 203). For -the succeeding stimuli the centers remain inhibited, because each -succeeding stimulus occurs in the refractory period of the former. -The origin of this inhibition shows us with particular clearness -how excitation produced by each single stimulus depending upon -the frequency of the same, falls rapidly or slowly beneath the -threshold of perceptible response. In this case, the state of equilibrium -is reached which is maintained by the following stimuli. -That a single stimulus is not entirely without effect upon this -state of equilibrium follows from the fact that during the continuation -of the stimulus a recovery to the point of observable<span class="pagenum" id="Page_220">220</span> -response does not occur, whereas such is the case immediately -upon the discontinuation of the stimulus. In inhibition, then, the -dissimilatory excitation produced by a single stimulus falls to a -low level as a result of the reduction of irritability and remains -at this level continuously. <i>Inhibition as well as tonus is based -upon the development of a state of equilibrium between excitation -and recovery, or disintegration and restitution of the living -substance under the continuous effect of a rhythmic series of -stimuli. They differentiate themselves essentially by the height -of this equilibrium, which is dependent upon the intensity of the -stimulus.</i></p> - -<p>We have to the present considered only the <i>simplest</i> conditions -existing as a result of the effect of a <i>single</i> series of stimuli and -also of the interference of its individual members. These elementary -conditions are at the basis of an understanding of complicated -<i>interference effects which arise when two series of stimuli -interact</i>. In that these processes can be readily explained by -the elementary processes previously described, I will, therefore, -dwell but briefly on this subject. From the standpoint already -taken it may be readily presumed what will happen when two -series of stimuli act upon the same system.</p> - -<p>When there is interference of <i>two series of stimuli</i>, there are -two resultant possibilities. In one type the stimuli of the one are -active simultaneously with that of the other. In this instance -both stimuli would act as a single stimulus of greater intensity, -and we have essentially the same condition as exists when a single -series is operative. Nevertheless, such cases are practically hardly -realized in the physiological happenings of the organism. More -often a state exists wherein the single stimuli of one series occur -in the intervals of the stimuli of the other. In these cases there -is an increase in the frequency of the stimuli applied in a given -length of time. We have here, then, in principle the same conditions -as when a series of greater frequency is operative. (Figure <a href="#i_221">55</a>.) -The effect of such alteration in the frequency consists in an -increase of the velocity of the development of summation or inhibition, -as the general scheme (Figure <a href="#i_221">55</a>) has shown us. Depending -upon the special combination of the factors involved in interference,<span class="pagenum" id="Page_221">221</span> -we may have a summation of the exciting effect of each -series of stimuli or an inhibition of one series by the exciting -effects of the other series. If the frequency of both series is -essentially different, we may have here the conditions for periodically -increasing and decreasing excitations. Nevertheless these -conditions have not been systematically analyzed and experimentally -studied.</p> - -<div class="figcenter illowe35" id="i_221"> - <img class="w100" src="images/i_221.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 55.</p> - -<p class="taj pl1hi15">Interference of two series of stimuli. A—Effect of the one series alone. Development of tonus -by summation. The dots below the curve indicate the points of time at which the stimuli -of the second series will operate. B—Effect resulting from the interference of both series. -By the addition of the second series the frequency has been doubled. The result consists -in an inhibition. -</p></div> -</div> - -<p>The greatest number of instances of the interference of two -series of stimuli have been given to us by investigation of the -physiology of the nervous system. In the functionation of the -nervous system the fact that two series of stimuli from different -tracks affect the same ganglia plays a very important rôle. It -is this to which <span class="nowrap"><i>Sherrington</i><a id="FNanchor_191" href="#Footnote_191" class="fnanchor">191</a></span> has alluded as “<i>the principle of -the common path</i>.” Where two nervous excitations involve the -same paths, there arises an interference of the effect of the two -series of stimuli, for the impulses in the nervous system, as -already stated, possess a rhythmic character. This principle has -a broad application in the phenomena of association in the cerebral -cortex. The simpler and, therefore, the most easily understood -cases are, however, in the spinal cord. The motor neurons -of the anterior horns of the spinal cord are the junction of a<span class="pagenum" id="Page_222">222</span> -great number of tracks, for example, the sensory neurons of the -spinal cord at different levels, the neurons of the cerebellum, the -pyramidal tracks from the motor areas of the cerebral cortex, -etc. On the contrary, for example, the sensory neurons of the -spinal cord are strictly “<i>private</i> paths” in the sense of <i>Sherrington</i>, -for excitation can enter by this means only from the special -paths of the spinal ganglia and, therefore, from the periphery. -The motor neurons of the anterior horns offer, therefore, excellent -opportunities for the experimental investigation of the interference -of two series of excitations which enter by different -paths. The spinal cord consequently has become a much-used -object of investigation for this purpose. In fact, we can observe -and produce all types of interference in the spinal cord. These -conditions have been quite thoroughly investigated by <span class="nowrap"><i>Sherrington</i><a id="FNanchor_192" href="#Footnote_192" class="fnanchor">192</a></span> -and his coworkers on the dog, and <i>Fröhlich</i><span class="nowrap">,<a id="FNanchor_193" href="#Footnote_193" class="fnanchor">193</a></span> <i>Vészi</i><span class="nowrap">,<a id="FNanchor_194" href="#Footnote_194" class="fnanchor">194</a></span> <span class="nowrap"><i>Tiedemann</i><a id="FNanchor_195" href="#Footnote_195" class="fnanchor">195</a></span> -and <span class="nowrap"><i>Satake</i><a id="FNanchor_196" href="#Footnote_196" class="fnanchor">196</a></span> on the frog.</p> - -<p>A <i>summation of two excitations</i> was observed already by -<i>Exner</i>. This investigator connected the abductor pollicis of the -rabbit with an apparatus for making graphic records. He then -stimulated first the paw and then the motor areas of the cerebral -cortex with faradic shocks, the intensity of which was just sufficient -to bring about perceptible effect. If both stimuli were -simultaneously operative, an increase in the response was observed. -Even when the stimuli were sub-threshold in type, as a -result of summation there was a perceptible muscle contraction. -(Figure <a href="#i_223">56</a>.) <i>Exner</i> had at that time referred to this increase of -the response as “Bahnung” (reinforcement). However, the word -“Bahnung” has more than one meaning, for processes of various -types are involved in this term. Thus writers have differentiated<span class="pagenum" id="Page_223">223</span> -real and apparent “Bahnungen.” On account of this lack of clearness -in the meaning of the term “Bahnung,” I wish to discard its -use as it is not at all essential. We will speak simply of a <i>summation -of excitation</i>, for here it is simply a question of summation -of two excitations of the motor cells of the spinal cord.</p> - -<div class="figcenter illowe32_5" id="i_223"> - <img class="w100" src="images/i_223.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 56.</p> - -<p class="taj pl1hi15">Summation of two excitations in the rabbit. The one proceeds from the paw, the other from -the motor sphere of the cerebral cortex. <i>S</i>—Time in seconds. <i>Pf</i>—Stimulation of the paw. -<i>H</i>—Stimulation of the motor sphere. <i>M</i>—Contractions of the abductor pollicis. (After -<i>Exner</i>.) -</p></div> -</div> - -<p><i>Fröhlich</i> has shown that summation of two excitations upon a -motor cell of the anterior horn coming by way of different paths -is more readily obtained when the stimuli are somewhat strong, -or when the duration of the excitation processes in the ganglion -cells are somewhat prolonged by fatigue.</p> - -<div class="figcenter illowe30" id="i_224"> - <img class="w100" src="images/i_224.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 57.</p> - -<p class="taj pl1hi15">Summation of two excitations in the spinal cord produced by stimulation of the ninth and -tenth posterior root. Lower line indicates faradic stimulation of the tenth, upper line -of the ninth root. -</p></div> -</div> - -<div class="figcenter illowe29_375" id="i_225"> - <img class="w100" src="images/i_225.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 58.</p></div> -</div> - -<div class="figcenter illowe29_375" id="i_226"> - <img class="w100" src="images/i_226.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 59.</p></div> -</div> - -<p>On the other hand, the conditions for the production of <i>inhibition</i> -are favored when the intensity of the series of stimuli is weak. -Here it is a question of the development of a relative refractory -period for the weak stimuli by increase in their frequency. A -relative fatigue of the motor ganglion cells for weak stimuli -rapidly occurs, and there develops a state of equilibrium beneath -that of the threshold of perceptible effect throughout the continuation -of stimulation. <i>Vészi</i> succeeded in isolating these types -of summation and inhibition in the spinal cord. His method consisted -in cutting the posterior roots of the spinal cord of the frog -and stimulating faradically the central ends, and at the same time -graphically recording the response of the gastrocnemius muscle. -Upon faradic stimulation of the ninth posterior root, one obtains -tetanic reflex contraction of this muscle. When the tenth posterior<span class="pagenum" id="Page_224">224</span> -root is then stimulated, tetanus is also produced but of somewhat -shorter duration. If, while obtaining tetanus reflexly by -stimulation of the ninth root, a faradic current of short duration -and not too weak is applied to the tenth root, then a summation -of excitation occurs, an increase in the reflex contraction. -(Figure <a href="#i_224">57</a>, A and B.) When, on the other hand, the tenth root<span class="pagenum" id="Page_225">225</span> -is stimulated with weak shocks, one can obtain an increase of the -tetanus of short duration followed by inhibition. Here, as the -result of interference, we have an instance of inhibition with primary -tetanus. (Figure <a href="#i_225">58</a>.) When the tenth root is stimulated -with very weak shocks, inhibition of the tetanus produced simultaneously -from the ninth root occurs without primary summation. -(Figure <a href="#i_226">59</a>.) The fact that two series of stimuli, both of which -produce dissimilative excitation, bring about an inhibition by -their combined action, is sufficient to show the untenability of -the <i>Gaskell-Hering</i> hypothesis, that inhibitory processes result -from assimilatory excitation. It would be impossible to understand -how two dissimilatory exciting stimuli, by their simultaneous -action, could bring about assimilatory excitation. When<span class="pagenum" id="Page_226">226</span> -the eighth or the seventh root is stimulated with stronger faradic -shocks during the time when tetanus is produced reflexly by -faradic stimulation of the ninth, an inhibition is practically always -obtained. Indeed, faradic currents that are so weak as to be <i>far</i> -below the threshold of perceptible response bring about when -applied to the seventh or eighth root a decided inhibition of the -tetanus, brought about by simultaneous stimulation of the ninth -root. The inhibitory effect of weak sub-threshold excitations -are here particularly apparent. This inhibition resulting from -excitation far below that of the threshold of perceptible response -is a common occurrence in the functional activities of the central -nervous system. In various parts of the nervous system, the -excitation in its conduction is weakened when passing through -intervening ganglion stations so that it has undergone a strong -decrement before reaching the responding structure, where an -inhibitory effect may be manifested. In this connection it is of -interest that the reciprocal “antagonistic reflexes” discovered by -<i>Sherrington</i><span class="nowrap">,<a id="FNanchor_197" href="#Footnote_197" class="fnanchor">197</a></span> who recognized their importance in the functional -processes of the nervous system, can be explained, as <i>Fröhlich</i> -showed, upon this principle of inhibition resulting from weakened -excitation. On the basis of numerous investigations in the<span class="pagenum" id="Page_227">227</span> -Göttingen laboratory as well as that of <span class="nowrap">Bonn<a id="FNanchor_198" href="#Footnote_198" class="fnanchor">198</a></span> we have come to -look upon the reflex arc in the spinal cord as consisting of the -following elements: a neurone in the spinal ganglion, a neurone -in the posterior horn and a motor neurone in the anterior horn. -This is the most direct route between the point of stimulation -and that of the responding organ of a unilateral reflex. (Figure <a href="#i_227">60</a>.) -It is known that the excitation becomes weaker in passing -from the entrance of the excitation into the spinal cord to the -motor elements of a lower level on the same side or to those on -the opposite side. In order to obtain a response a stronger stimulus<span class="pagenum" id="Page_228">228</span> -is necessary. Here the weakening of the excitation as well as -the prolongation of the reaction time is brought about by the -introduction of intercalated neurones. The reflex arc contains -more stations. (Figure <a href="#i_228">61</a>.) If we accept the most plausible -assumption that the central connection of antagonistic muscles -possesses like relations, then the effects discovered by <i>Sherrington</i> -are self-explanatory. In this case stimulation of the sensory -path, which brings about a strong reflex excitation of the motor -neurons of the anterior horns controlling a muscle, at the same -time stimulates the antagonistic muscle with sub-threshold stimuli. -The result of this as shown by the experiments of <i>Vészi</i> is not a -motor response of the antagonists, but an inhibition if the motor -neurons of the antagonists are at the time in a state of excitation. -It is, therefore, understandable that reflex excitation of a<span class="pagenum" id="Page_229">229</span> -muscle under normal conditions of irritability has an inhibitory -effect on its antagonist.</p> - -<div class="figcenter illowe25" id="i_227"> - <img class="w100" src="images/i_227.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 60.</p> - -<p class="tac">Scheme of the simplest unilateral reflex arc of the spinal cord.</p></div> -</div> - -<div class="figcenter illowe25" id="i_228"> - <img class="w100" src="images/i_228.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 61.</p> - -<p class="tac">Scheme of the simplest reflex arc from one to the other side, and -from a higher to a lower level.</p></div> -</div> - -<p>Finally, I wish to conclude this discussion on the origin of -central inhibition and its dependence upon the strength of the -stimulus by referring to a point which apparently is contradictory. -We have already met with the fact that series of stimuli -by their interference in the nervous system may have different -effects depending upon their intensity; if this is strong, we obtain -summation of excitation, if weak an inhibition. The question -may be asked, how is it possible that a weak stimulus can have -a different effect when it is believed that the nerve as an isobolic -system responds to intensities of all gradations to the same extent, -namely, with maximum excitation? If the “all or none law” is -applicable, then the same intensity of excitation is always carried -to the centers and yet we see that various kinds of responses -follow various intensities of stimulation. Here, indeed, is a -difficulty which has not as yet been explained. Naturally between -the two facts there can be no contradiction. But the question -arises, how are we to bring them into harmony? Two entirely -different possibilities present themselves. If the various intensities -of stimulation always bring about excitation of the same -strength and we see in spite of this that various intensities of -stimulation produce various kinds of effects, then we must think -of the possibility that various intensities of stimulation bring -about some other effect than that of variations in intensity -in the course of the wave of excitation. In this connection -variations in the time involved must be taken into consideration. -One might think that <i>strong</i> stimuli may develop a longer wave -of excitation than such of <i>weak</i> intensity. <span class="nowrap"><i>Gotch</i><a id="FNanchor_199" href="#Footnote_199" class="fnanchor">199</a></span> tested these -questions experimentally with completely negative results. A single -strong stimulus does not result in an excitation differing in its -course from that of a weak stimulus. But there is another possibility -that requires testing. This was brought to light by the -investigation of <span class="nowrap"><i>Thörner</i><a id="FNanchor_200" href="#Footnote_200" class="fnanchor">200</a></span> on the fatigue of the nerve. His investigations<span class="pagenum" id="Page_230">230</span> -showed that in a normal nerve in air the first typical -beginning of fatigue resulting from faradic stimulation can be -demonstrated in the characteristic summation of excitations. -This is shown by the nerve after fifteen minutes of stimulation -with faradic shocks applied for short intervals. The irritability, -when tested with single induction shocks, is at the same time -reduced. Thereby the amount of fatigue of the nerve, that is, -the amount of the reduction of irritability, is dependent upon the -strength and frequency of stimulation producing fatigue. When -the nerve is stimulated with weak faradic shocks of a slow rate -of frequency, there is a slight or a complete absence of the reduction -of irritability. On the other hand, if the nerve is fatigued -with strong faradic shocks of great frequency, the irritability -falls very considerably. This shows that when the nerve is stimulated -for a longer time, even under conditions favorable to the -supply of oxygen, a diminution of irritability occurs and with it -naturally an actual diminution of the wave of excitation, a diminution -the intensity of which becomes greater as the strength of -the stimulus increases. In other words, long-continued faradic -stimulation converts the nerve from a system isobolic in character -to that which is heterobolic in that the intensity of the excitation -which is conducted differs depending upon the intensity of the -stimulus. We have found other cases in the investigation of the -nervous system in which, as in fatigue, an isobolic is converted -into a heterobolic system. <span class="nowrap"><i>Vészi</i><a id="FNanchor_201" href="#Footnote_201" class="fnanchor">201</a></span> has shown that the centers of -the strychninized frog, which are isobolic in character, when -fatigued by <i>weak</i> faradic stimuli can be brought to react again -when the faradic stimulation is increased. According to this and -other experiments of a like nature, it is beyond doubt that an isobolic -system during the refractory period may assume a heterobolic -character, and only after completion of the refractory period -and entire recovery of the equilibrium of metabolism does the isobolic -character return. This permits us to understand the characteristic -properties of an isobolic system more accurately and precisely -than has thus far been possible. The “all or none law”<span class="pagenum" id="Page_231">231</span> -with its associated properties, such as the conductivity without -decrement and the incapability of summating excitations, have -in a system of this character only relative validity. They are -realized only in the state of an equilibrium of metabolism. Only -when the stimuli follow each other at intervals greater than the -duration of the refractory period is there a response of equal -extent to stimuli of all intensities which are above the threshold. -During the refractory period and consequently in fatigue, -asphyxia, cooling and narcosis, etc., in short, in all states in which -the refractory period is prolonged this system loses its isobolic -properties and becomes heterobolic. In order that there may not -be a misunderstanding, we will consider more in detail the capability -in this state of summation of excitations. When we refer -to a summation of excitation of such a system under the influence -of one of these factors, we, of course, at no time mean an increase -of response beyond that of the degree of excitation which exists -in an isobolic system in a normal state consequent upon the application -of a single stimulus, for this degree of excitation is maximal. -We refer rather to a summation which has become reduced -as a result of fatigue.</p> - -<p>On the basis of these facts it is readily understood when a level -of equilibrium of lower intensity has been reached that excitation -produced by weak faradic stimulation must have weaker -effects than when strong stimuli are applied, for when the system -assumes a heterobolic type as the result of relative fatigue weak -stimuli bring about weak, and strong, stronger excitation. Consequently, -during interference induced by a second series of excitations, -in the first case we have the conditions favorable for inhibition, -in the second for those of summation. If we also assume -that this characteristic alteration of the isobolic character of the -elementary nerve fibers which has been shown to occur in fatigue, -as seen when continued faradic stimulation is employed, develops -immediately after the beginning of stimulation then we can -readily understand the various kinds of effects produced by interference -observed in the reflex response following weak and strong -faradic stimulation to the different nerves in spite of the fact that -the nerve in the state of rest is a system isobolic in type. Experimental<span class="pagenum" id="Page_232">232</span> -evidence, therefore, must be brought forward to show -that faradic stimulation of short duration produces the above-mentioned -alteration in the character of the system. <i>Thörner</i> in -his experiments on the nerve stimulated it faradically at least four -minutes and always found after this that excitation was reduced. -After shorter intervals of stimulation <i>Thörner</i> made no test of -the state of excitation. It is, however, highly probable that a -reduction of excitation is much more quickly reached. Indeed, -we are unavoidably compelled to accept the assumption that even -after the first single stimulus of the faradic current, alterations -of a slight degree are present which, after repeated stimulation, -become constantly greater and give to the system a heterobolic -character. As a result of fatigue, as we have already seen, the -refractory period becomes more and more prolonged. As the -individual shocks in faradic stimulation follow each other at -regular intervals, a necessary consequence is that the shocks are -operative before the refractory period has completely disappeared, -otherwise <i>Thörner</i> could not have obtained fatigue produced -by continued stimulation. The intervals of the individual -shocks must be somewhat shorter than the duration of the refractory -period, even in fatigue of a very slight degree. It is very -interesting in this connection that <i>Thörner</i> invariably obtained -positive evidences of fatigue by the application of stimuli at the -rate of 10–12 per second. When the number of stimuli per second -was less than this the above-mentioned result was not always -obtained. From this we can easily estimate the refractory period -of the nerve, which is present after reaching a state of equilibrium -under certain conditions. If we assume ten stimuli per -second to be the number required to produce slight fatigue when -stimulation is prolonged, we can conclude that the refractory -period in this state is somewhat longer than one tenth of a second. -Even though <i>Gotch</i> in his investigations already cited placed the -refractory period of the normal nerve at about .005 second, this -statement is in no way contradictory to the figure which we have -just given. <i>Gotch</i> measured simply the duration of the absolute -refractory period of the normal nerve, in other words, the duration -of the period in which no excitation at all could be brought<span class="pagenum" id="Page_233">233</span> -about. On the contrary, my estimate, based upon the investigations -of <i>Thörner</i>, refers to the <i>total</i> refractory period of the -nerve, that is, to the point of <i>complete</i> recovery of the equilibrium -of metabolism and of the specific irritability. Experimental proof -of this assumption is already under way.</p> - -<p>I have endeavored to show the elementary principles at the -basis of these extremely varied interference effects and to make -a few generalizations concerning the complicated conditions here -concerned. It has been shown that a great number of interference -effects possess characteristics in common if one takes into -consideration the process occurring in the course of a single -excitation. The altered state which exists in living substance -until the complete disappearance of excitation is the basis upon -which to explain the altered effects produced by a second stimulus. -This state alters during the whole course of the first stimulus -until the original equilibrium of the metabolism of rest is, by self-regulation, -again reached. It is, therefore, self-evident that the -second stimulus must have different effects depending upon the -momentary state of the living system at the time of its application. -The state of the system differs depending on the length -of the interval in which the second stimulation follows the first. -The most important factor is the phase of the excitation period -and the reduction of irritability. The second important factor -is the intensity of the second stimulus; the relation of the two -with each other determines the response. But the specific properties -of the given systems must also be taken into consideration. -It is important to know if the living system possesses isobolic -properties, that is, every intensity of stimulation produces a -<i>maximal</i> liberation of energy, or if it possesses a heterobolic -character, that is, stimuli of different strength bring about the -liberation of <i>different</i> amounts of energy. It is further important -to know the rapidity of reaction, whether the system rapidly -or slowly fatigues. In all cases it depends whether the second -stimulus produces a perceptible excitation or whether it occurs -in the refractory period and produces no perceptible effect. Upon -these factors depend the results of the interference of two -rhythmic series of stimuli, whether a summation or inhibition of<span class="pagenum" id="Page_234">234</span> -excitation takes place. Here is the key to the understanding of -the great variety of interference effects. By determination of -these various factors in a given case and their sequence, we can -anticipate the nature of the interference which will follow. The -complex actions brought about by the various factors, which we -cannot at first clearly understand, can be at once interpreted as -soon as we convert them into their elements.</p> -<hr class="chap x-ebookmaker-drop" /> - -<div class="chapter"> -<p><span class="pagenum" id="Page_235">235</span></p> - -<h2 class="nobreak" id="CHAPTER_IX">CHAPTER IX<br /> -<span class="title">THE PROCESSES OF DEPRESSION</span></h2> -</div> - - -<div class="blockquot"> - -<p class="pl2hi2"><i>Contents</i>: Necessity of cellular physiological analysis of toxic depressions -by pharmacology. Apparent variety of processes of depression. -Depression of oxydative disintegration as the most extended principle -in the processes of depression. Asphyxiation, fatigue, heat depression, -as a consequence of restriction of oxydative disintegration. -Narcosis. Theories of narcosis. The alteration of specific irritability -and conductivity in narcosis. Depression of oxydative processes in -narcosis. Asphyxiation of living substance when oxygen is present -during narcosis. Persistence of anoxydative disintegration in narcosis. -Increase of the same by stimuli. Depression by narcosis as -a form of acute asphyxiation. Hypothesis on the mechanism of -depression of oxygen exchange by narcotics. Possibility of combining -the facts with the observations of <i>Meyer</i> and <i>Overton</i>.</p> -</div> - - -<p>The processes of <i>excitation</i> of all the effects of stimulation are -those which have invariably claimed place in the interest of physiologists. -The study of the processes of <i>depression</i>, on the other -hand, has remained more or less in the background. This is -readily understood when it is considered how much more apparent -the processes of excitation are than those of depression. Nevertheless, -these latter possess no less importance for the course -of vital phenomena than those of excitation. Without depression -no excitation can take place in the vital activity of the organism, -for, as we have seen, every excitation is secondarily followed -by a refractory period. To this must be added the great -number of <i>primary</i> depressions, directly brought about by the -most varied stimuli, such as cold, want of oxygen, poisons, etc., -without the presence of a preceding excitation. Thus it is essential -that the processes of depression should be studied with no -less interest than those of excitation, and it is much to be desired -that the former should receive a more detailed analysis than has -up to now been the case. Even as it is, extensive material has<span class="pagenum" id="Page_236">236</span> -been obtained for the analysis of this group of reactions. With -the closer study of the process of excitation the facts in connection -with the refractory period and fatigue make it necessary -that the processes of depression be taken into consideration. -Toxicology and pharmacology likewise furnish innumerable -effects of depression produced by poisons and drugs. Unfortunately -the investigation of these reactions has been in the main -purely superficial. This arises from the recency of the development -of these sciences. Even later than physiology they are -only now beginning to extend their investigations, directed up to -the present to the grosser organic reactions, to the cellular analysis -of the effects of poisons. How rarely we find instances in which -the effect of some drug is studied at the point of attack and systematically -followed to the specific cell form, and its primary -excitating or depressing effect on this or that constituent process -of the metabolic activities ascertained. And how great, on the -other hand, is the number of “medicines” making their appearance -each year in pharmacology of which nothing further is -known than a few secondary effects on the action of the heart, -the blood pressure, the secretion and excretion and on some other -outwardly perceptible organic actions! This deplorable condition -of present-day pharmacology must be ascribed to the regrettable -circumstances that pharmacological research is only in a very -small degree the result of careful investigations, carried out by -biologically and chemically trained pharmacologists, but is for -the most part undertaken at the instigation of chemical manufacturers. -This eager haste to obtain superficially practical -results has lessened in great degree the interest in the close and -painstaking theoretical analysis of reaction to poisons. Thus it -happens that, in spite of the numberless examples of the depressing -effects of poisons discovered by pharmacologists, it is only -in rare instances that the physical nature of these processes is -more closely studied. Therefore, investigation in pharmacology -and toxicology in so far as they are carried out in a purely -scientific spirit and not influenced by the desire for merely superficial -results, may find here a wide field of research work, rich -in future promise. It is from such investigation that we may<span class="pagenum" id="Page_237">237</span> -expect an abundance of material for the closer analysis of the -processes of depression. For the present, however, we must -restrict ourselves to the consideration of some individual cases -which have been studied somewhat more in detail by physiologists.</p> - -<p>Simple reflection shows the possibility that depression, that is, -the retardation of the normal vital processes, can be brought -about in various ways. As on the one hand the normal metabolism -of rest is composed of very numerous chemical constituent -processes, and on the other hand the closest interdependence -exists between these individual constituent processes, it follows -that every factor which increases or retards even one of these -must secondarily influence the course of the entire activity. -Hence a wide range of possibilities exists for the processes of -depression. As the complicated works of a clock can, by the -stopping of a single moving part, be brought to a standstill, so in -like manner the metabolic activity can be depressed by very -different constituent members. In spite of this we have every -reason to assume that the greater number of all processes of -depression result from the primary effect of one or a few constituent -members. A primary simultaneous depression of all or -at least of numerous constituent processes of the entire metabolism -may only be assumed as possible, resulting from decrease -of temperature within certain limits. But even in the case of -“<i>cold depression</i>” it is not probable, owing to the great effect of -every alteration in the relations of masses in the cell, that depression -is solely the manifestation of a <i>uniform</i> retardation of all -individual constituent metabolic processes. If, therefore, the -greater part of the processes of depression are brought about by -the primary effects of an individual constituent process, then the -possibility must be admitted that <i>any</i> component of the chain can -by the means of some specific external influence form the starting -point for a depression. The number of the various kinds of -processes of depression would be, therefore, enormous. The -knowledge obtained up to the present shows, however, that this -variety is not quite as great as the above facts might lead one to -expect. Even though future investigation will certainly not do<span class="pagenum" id="Page_238">238</span> -away with the assumption of the existence of the most manifold -physical types of depression, the analysis of a few processes which -have been studied up to now demonstrates the singular fact that -a number of these which are brought about by quite different -external factors, are based on an absolute uniformity of their -mechanism. As we have previously seen, a certain constituent -of the metabolic chain can be <i>excitated</i> primarily by very different -kinds of stimuli. In like manner there exists in metabolic activity -a certain point of predilection for different kinds of stimuli, from -which their <i>depressing</i> effects proceed. Here the highly interesting -fact is shown that this point of predilection, which represents -that of the most frequent attack, is the same for <i>excitating</i> as for -<i>depressing</i> stimuli. These are the <i>oxydative</i> processes. As our -knowledge of the reactions to stimuli in anaërobic organisms is -still almost nil it is not possible at present to ascertain which -component in the metabolism of these organisms, adapted to life -without oxygen, plays an analogous rôle to that of the oxydative -in aërobic systems. Our investigations must, therefore, be restricted -to the world of aërobic organisms. Here we have seen -that the different stimuli which produce an excitating effect invariably -increase the oxydative disintegration of the living system -and we now find that these constituent processes of metabolism -likewise form a point from which <i>depressing</i> responses to stimuli -very readily proceed.</p> - -<p>The prototype of this group of processes of depression in -which this is manifested in a most striking manner, is that of a -simple <i>asphyxiation</i> by the withdrawal of the oxygen supply -from the exterior. If the supply of oxygen is withheld from an -aërobic organism, oxydative disintegration is gradually found to -be more and more decreased and further breaking down takes -place <i>an</i>oxydatively, as oxydative decomposition forms the chief -source of energy production, and energy production consequently -undergoes a gradual decrease. Excitating stimuli, therefore, meet -with less response than when a sufficient supply of oxygen is -present, that is, <i>irritability is diminished</i>. As a result of this -decrease, a corresponding decrement in the extension of excitation -takes place, which, in turn, is likewise manifested by the<span class="pagenum" id="Page_239">239</span> -restriction of the perceptible response to stimulation. In the -same degree in which oxydative disintegration becomes less, -<i>an</i>oxydative breaking down products are accumulated. The -accumulation of these products likewise plays a part in the production -of depression and increases the decrement in the conduction -of excitation. The decrease of energy production by -decline of the oxydative decomposition, as well as the accumulation -of anoxydative breaking down products, therefore, similarly -reduce irritability; that is, their effect is depressing. This -whole series of processes, which we have previously considered -in detail, takes place on the withdrawal of oxygen and leads to -the depression of asphyxiation. It can readily be observed in -the most varied kinds of aërobic organisms in rhizopods and -infusoria, in plant and ganglion cells, but finds its most complete -demonstration in the nerves. Here these processes can be easily -produced with any rapidity desired, accordingly as a relative or -absolute want of oxygen is brought about. These same typical -results are likewise shown in numerous processes in which the -external conditions are quite different in nature.</p> - -<p>We have previously become acquainted with such a case and -studied it in detail. This is the state of <i>fatigue</i>. Fatigue is a -typical state of depression, that is, a state in which the vital process -is retarded and irritability in response to stimuli correspondingly -decreased. Fatigue is, however, as we have found, -the result of a relative deficiency of oxygen. The amount of -oxygen at disposal is not sufficient to allow of disintegration, -increased by constant functional activity oxydatively taking place, -to develop to its full extent. In consequence the previously cited -sequence of processes takes place. A “depression of activity” is -produced. Fatigue is true asphyxiation and it is here evident -that depression proceeds from the same constituent processes of -metabolism as excitation, brought about by a single stimulus. -Excitation produced by constant stimuli gradually merges into -depression as the amount of oxygen at disposal, even if augmented -in the intact organism by the increased blood supply, for instance, -is still insufficient to meet the demand made by the increased -oxygen consumption as a result of continuous functional activity.</p> - -<p><span class="pagenum" id="Page_240">240</span></p> - -<p>A further very interesting example of depression produced -by oxygen deficiency is furnished by <i>heat depression</i>. It has -long been known that with increasing temperature the vital manifestations -of all poikilothermic organisms at first undergo a -heightening of their intensity. If, however, after a maximum -is reached, the temperature is still further increased a sudden -depression sets in. The increase in the rapidity of the vital process -as a result of increased temperature is readily understood -when based on the well-known law discovered by <i>van’t Hoff</i>. -Numerous investigations on the rapidity of the course of special -vital manifestations, as, for instance the growth of the eggs of -the frog and sea urchin, the assimilation of carbon dioxide in -green plant cells, the number of vacuole pulsations in the infusoria -cells, the frequency of the heart rate of the frog and of the -mammal, etc., have shown that their increase does in fact follow -the <i>van’t Hoff</i> law, being doubled or tripled in amount with every -increase of ten degrees of temperature. The genesis of depression -produced by <i>heat</i>, developed in different organisms at various -heights of temperature, requires a closer analysis. This depression -takes place at temperatures below that in which coagulation -of proteins occurs. Therefore, under certain conditions, with -which we shall presently become acquainted, it is capable of being -recovered from, whereas in higher temperatures, in which albumen -coagulates, vital activity is permanently obliterated. Depression -produced by heat is, therefore, in itself not a necrobiotic -process, which, as such, must necessarily lead to death. But -rather like fatigue it must be looked upon as an asphyxiation -process. Its relations to oxygen exchange have been chiefly -demonstrated by <span class="nowrap"><i>Winterstein</i><a id="FNanchor_202" href="#Footnote_202" class="fnanchor">202</a></span> by his investigations on the central -nervous system of frogs and on medusæ. He found that when -placed in a heated chamber in a temperature of 32–40° the -activity and reflex excitability of the frog are at first augmented. -Within the lapse of a short time this increase has become so -great that the slightest touch produces tetanic contractions, similar<span class="pagenum" id="Page_241">241</span> -to those characteristic of strychnine poisoning. Very soon, -however, this state of high excitation is followed by one of depression, -in which no response to stimuli can be obtained. The -animal remains entirely motionless in any position in which it is -placed, in the same manner as a frog whose nerve centers have -been completely exhausted by strenuous activity. On the basis of -our knowledge of the rôle played by the deficiency of oxygen in -the bringing about of exhaustion the thought arose, if in this heat -depression exhaustion might not likewise be the result of oxygen -deficiency. This assumption has been most strikingly confirmed -by the investigations of <i>Winterstein</i>. It has been demonstrated -that recovery of the animal in a state of heat depression cannot -be obtained by mere cooling, but is only brought about when at -the same time a renewed oxygen supply is provided. For instance, -a frog is depressed in the warm chamber and even when a -strychnine injection has been introduced, does not show the -slightest reaction to stimuli. In the warm water bath artificial -circulation is now applied in the previously described manner with -an oxygen-free saline solution at 30° C., so that the blood is displaced -and thus the renewed oxygen supply to the nervous centers -prevented. The animal can now be cooled and the warm saline -solution be replaced by a cooled one without the least recovery -taking place. If, however, blood of the ox with contained oxygen -is substituted for the oxygen-free saline solution, the frog shows -signs of recovery within a few minutes and after ten or fifteen -minutes responds as a result of the strychnine to the merest touch -with tetanic contractions of the whole body. By modifying these -methods of investigation to a certain extent <span class="nowrap"><i>Bondy</i><a id="FNanchor_203" href="#Footnote_203" class="fnanchor">203</a></span> has confirmed -these results to the fullest extent. Later <i>Winterstein</i> by quantitative -determinations of oxygen consumption on medusæ showed -that at 30–35° C., at which temperature heat depression sets in, -the consumption of oxygen shows an increase of about three and -a half times compared to that in a temperature of 11–12° C. -These facts show that we have in heat depression a process which, -as far as its genesis is concerned, is completely analogous to that<span class="pagenum" id="Page_242">242</span> -of fatigue. In fatigue, a relative want of oxygen is produced by -the increased consumption following functional activity, in heat -depression by the increase of the entire metabolism producing a -corresponding increase of oxygen requirement. In both instances -we have an excitation produced by external stimuli which result -in an increase in the amount of oxygen required, and in both -instances the oxygen at disposal is not sufficient to permanently -meet the augmented demand. In both types, therefore, decomposition -must become more and more anoxydative and the well-known -series of processes is developed, which find their expression -in depression.</p> - -<p>In another direction likewise heat depression is of special -interest, that is, in regard to the theory of nature of the processes -in the living substance. According to the <i>van’t Hoff</i> law -we may assume that every individual constituent metabolic process, -if we imagine it as isolated and taking place in a test tube, -undergoes in more or less the same degree as all others an increased -rapidity of reaction as a result of increased temperature. -At the same time, in living substance we find on the contrary -that the <i>van’t Hoff</i> law is only within certain narrow limits more -or less applicable to the sum total of all metabolic processes. -Beyond certain degrees of temperature no further increase of -the vital process takes place, instead a retardation occurs. The -analysis of depression produced by heat shows us in the clearest -and simplest manner the reason for this apparent deviation from -the general law of <i>van’t Hoff</i>. This reasoning is based on the fact -that the rapidity of reaction of a chemical process is not merely -dependent upon the temperature, but likewise upon the mass -relations of the reacting substances. In spite of the effect of the -temperature in increasing the rapidity of reactions, the process -undergoes retardation which extends to a complete cessation if -the supply of material necessary to its existence does not keep -pace with the increase produced by temperature. In the present -instance the amount of reserve supplies for the building up of -the disintegrating molecules exists in abundance, and it is merely -the available oxygen which is in relatively a very small quantity. -As soon, however, as metabolism in its entirety, or even merely in<span class="pagenum" id="Page_243">243</span> -those parts in which oxygen is directly required, is increased by -whatever means, the oxydative processes would be the first to fail -and it must be from this point that the disturbance of the harmony -in the interacting of the individual metabolic processes proceeds. -This principle which we here see manifested in its simplest form -in the effect of temperature on oxygen exchange in the form of -a disturbance in the correlations of the individual constituent -processes based on an alteration of the mass relation and the -rapidity of reactions of individual members is, however, not -merely restricted to effects of temperature and the results quickly -following on a relative oxygen deficiency. It has, indeed, a much -more general significance for all manner of constituent metabolic -processes, for it is applicable to all nutrition and to all growth, -and forms one of the most important factors which influence the -process of development, that is, the gradual “metachronic” alterations -in metabolism to which all living systems are subjected as -long as life endures.</p> - -<p>A very extensive group of depression processes is produced -by the action of chemical stimuli. Among these the processes -to which we apply the collective term of “<i>narcosis</i>” must claim -our special interest. As is well known, an enormous number of -substances of very different chemical nature, such as carbon -dioxide, alcohol, ether, chloroform, chloral hydrate, etc., exist, -which, possessing the property of producing cessation of the -vital activities in all living systems, after withdrawal of their -application, if it has not been too prolonged or intense, permit -a complete restoration to normal vitality. These are the <i>general</i> -narcotics. Besides these there are a series of substances which -have a depressing effect only upon certain forms of living substance, -and which we may, therefore, term <i>special</i> narcotics. As, -however, the particular nature of depression following the -application of chemical substances has hitherto been closely -studied only in a very few instances, we are not, at present, in a -position to sharply define the limitations of the conception of -narcosis, a conception which originally had hardly any further -meaning than the production of unconsciousness by chemical -means. In the following discussion, therefore, we shall deal<span class="pagenum" id="Page_244">244</span> -merely with narcosis produced by the well-known general narcotics, -such as carbon dioxide, alcohol, ether, chloroform, etc. -From the time of the introduction of ether narcosis into medical -practice by <i>Jackson</i> and <i>Morton</i> in the year 1848 up to the present -day, the theory of this process has awakened the liveliest interest. -Many attempts have since been made to explain the physical -nature of this interesting process without, however, any generally -acknowledged theory of narcosis being established. I will refrain -from entering into these former theories in detail as they have -been exhaustively treated by <span class="nowrap"><i>Overton</i><a id="FNanchor_204" href="#Footnote_204" class="fnanchor">204</a></span> in his studies on narcosis.</p> - -<p>In connection with our present observations, however, I will -more closely analyze the process itself, following the results of -investigations extending over more than ten years carried out by -my coworkers and myself. In these investigations it has been -found that narcosis belongs to this group of depressing processes. -A satisfactory theory of narcosis, however, and this I must explain -from the first, can even today not be arrived at. Such a -theory would require the ascertainment of all primary and secondary -alterations produced by the narcotic in the course of normal -vital activity. For this, however, a number of minute details -are still lacking. Nevertheless, the careful and detailed investigations -during the last ten years have acquainted us with a large -number of alterations, which, acting as conditioning factors for -the process of narcosis, must be taken into consideration, and -which to a certain extent give us an idea of the mechanism of this -process. They are equally interesting from a theoretical as well -as from a practical point of view. The presentation will become -more detailed as more of such conditioning factors are established -by the deeper penetrating of future analysis. I will deal here with -the facts found up to the present and then proceed to the deductions -which these furnish for the theory of narcosis.</p> - -<p>In the first place narcosis is stamped as a typical process of -depression, being characterized by a <i>decrease of irritability with -a corresponding decrement of the extent of excitation</i>. The chief -feature of all narcotized systems is, that in slight narcosis excitating<span class="pagenum" id="Page_245">245</span> -stimuli produce a greatly weakened excitation, and that -in deep narcosis no perceptible response is obtained. This can -readily be ascertained in the various forms of living substance. -According to the previous observations on the inseparable relations -between conduction of excitation and irritability, it is self-evident -that with decrease of irritability there must be a corresponding -decrease in the capability of the conduction of excitation -from the point of stimulation. This decrease in conductivity -must, therefore, be the greater the more irritability is reduced; -that is, the deeper the narcosis, the greater must be the -decrement undergone by the wave of excitation in its extension -from the point of stimulation. These facts can be observed in -the highest perfection in the nerve, and have, as we have seen, -been demonstrated by the investigations of <i>Werigo</i>, <i>Dendrinos</i>, -<i>Noll</i>, <i>Boruttau</i> and <i>Fröhlich</i><span class="nowrap">.<a id="FNanchor_205" href="#Footnote_205" class="fnanchor">205</a></span> Upon deeper analysis of this process -of depression, the next task for the investigator must be the -ascertainment of the special components of the metabolic activity, -which are depressed as a result of the narcotic.</p> - -<p>As a consequence of the result of my investigations on fatigue, -the idea occurred to me to test if possibly oxygen exchange likewise -undergoes depression during narcosis. The spinal cord -centers of the frog, which had served me in ascertaining the rôle -played by oxygen in the bringing about of the depression of -activity, appeared likewise a favorable object for this investigation. -Indeed, the question if consumption of oxygen takes -place during narcosis, could be experimentally determined in -direct connection with the investigations on fatigue. This was -based on the following consideration. If an oxygen-free saline -solution is introduced into the aorta of a frog and in order to -increase the activity of the spinal cord centers to the maximum -the animal is poisoned with strychnine, after a very short time -complete exhaustion takes place as a result of oxygen deficiency. -This exhaustion can only be removed by the introduction of -oxygen. In this condition the oxygen requirement of the centers<span class="pagenum" id="Page_246">246</span> -is enormously increased. If the centers are narcotized by adding -a narcotic to the oxygen-free circulating fluid in amounts which, -as experience has found, would produce complete loss of reaction -in the normal animal, for example, about 5 per cent. of alcohol, -it can then be tested if, in this state of narcosis, the centers are -capable of oxygen consumption. It is merely necessary to replace -the oxygen-free saline solution containing alcohol by blood -rich in oxygen, containing alcohol in an amount sufficient to continue -the narcosis, but supplying an abundance of oxygen. If, -after this artificial circulation has lasted for a sufficient period, -the blood is then displaced by an oxygen-free saline solution -containing alcohol, and then this, in turn, is replaced by an -oxygen- and alcohol-free saline solution, so that cessation of the -narcosis is now produced, it can be ascertained by the responses -of the animal if consumption of the oxygen, when at the disposal -of the centers during narcosis, has taken place or not. If -the former is the case, then on the cessation of narcosis reflex -contraction must occur in the same manner as in every strychninized -frog totally exhausted by oxygen deficiency and into -which a saline solution containing oxygen is reintroduced. If -during narcosis, on the other hand, oxygen has not been consumed -by the centers, depression must continue to be present -after cessation of narcosis. Testing the recovery of the animal -on the introduction of blood, rich in oxygen, serves as an indicator -for the vital activity and capability of recovery of the -centers. A great number of experiments based on this scheme -of investigation were undertaken at my request by <i>Winterstein</i><span class="nowrap">.<a id="FNanchor_206" href="#Footnote_206" class="fnanchor">206</a></span> -These were carried out with alcohol, ether, chloroform and also -carbon dioxide. His experiments have shown in the most -uniform manner that, in spite of the requirement of oxygen by -the centers being increased to its highest extent, and notwithstanding -the most ample oxygen supply during narcosis, after -cessation of the same and the introduction of an oxygen-free -saline solution <i>no trace of recovery occurred</i>, whereas after a -supply of oxygen was introduced tetanic contractions reappeared<span class="pagenum" id="Page_247">247</span> -at once. <i>During narcosis, therefore, the centers, in spite of their -great requirement of oxygen, lose their capability of oxydative -splitting up and consumption of oxygen.</i></p> - -<p>After the methods for asphyxiation of the <i>nerve</i> had been -worked out and perfected the wish arose likewise to carry out -for these structures an analogous series of experiments to that -employed for the centers and based on the same chain of reasoning. -These investigations have the advantage of essentially -simpler conditions. After having convinced myself by experiments, -that the results on the nerve were in complete conformity -with those on the spinal cord, at my suggestion <span class="nowrap"><i>Fröhlich</i><a id="FNanchor_207" href="#Footnote_207" class="fnanchor">207</a></span> repeated -and continued these experiments on a more extended scale. -A nerve was asphyxiated by the previously described method. -This is accomplished in the simplest manner by the opening -or closing of stop cocks in the apparatus I have employed -which permit of pure nitrogen, or nitrogen with ether, and finally -also oxygen with ether or pure oxygen being conducted at will -through the glass chamber. If the nerve was so far depressed -in pure nitrogen that conductivity became obliterated for about -two cm. of the asphyxiated stretch, it was then narcotized in -nitrogen. Following this oxygen with ether was supplied for a -time. Then the oxygen-ether mixture was displaced by one of -nitrogen and ether and finally by pure nitrogen. Even after a -prolonged period, a recovery in pure nitrogen never took place. -On the other hand, the nerve recovered at once, as soon as oxygen -without ether was introduced. The results of these investigations -are, therefore, completely in harmony with those undertaken by -<i>Winterstein</i> on the nervous centers. They were later likewise -entirely confirmed by similar experiments of <i>Heaton</i><span class="nowrap">.<a id="FNanchor_208" href="#Footnote_208" class="fnanchor">208</a></span> All these -investigations furnished the proof <i>that in narcosis, living substance, -notwithstanding even the greatest oxygen deficiency, is -not capable of producing oxydation, neither can consumption of -oxygen take place, with which, after cessation of the narcosis, -oxydative splitting up can be carried out</i>.</p> - -<p><span class="pagenum" id="Page_248">248</span></p> - -<p>Recently <span class="nowrap"><i>Warburg</i><a id="FNanchor_209" href="#Footnote_209" class="fnanchor">209</a></span> has likewise found an oxydative depression -during narcosis in the eggs of the sea urchin and in the red corpuscles -of geese, and the same fact has lately been also demonstrated -by <span class="nowrap"><i>Joannovics und Pick</i><a id="FNanchor_210" href="#Footnote_210" class="fnanchor">210</a></span> for the oxydative activity of the -liver cells of the dog.</p> - -<p>This fundamental establishment of the fact that narcosis prevents -oxydations in living substance is at once followed by the -further problem, in what <i>manner</i> do the disintegration processes -undergo alterations during narcosis? <i>That</i> they must be altered, -and this in the form of a reduced energy production, is clearly -shown by the decrease of irritability and the increase of the -decrement of the conduction of excitation. Both become the -greater the deeper the narcosis. The observations just discussed -render these facts at once self-evident. They follow as a simple -and necessary result of the elimination of the oxydative processes. -If these are suppressed further breaking down, if not -influenced by addition of other factors, proceeds anoxydatively. -The previously observed series of processes is developed, which -invariably take place when oxygen deficiency occurs and which -produce in the clearest form the results of asphyxiation on the -withdrawal of oxygen supply. If, therefore, the disintegration -processes are not influenced in some other manner during narcosis, -they must then take place in the same way as in the withdrawal -of the oxygen supply. The question, if this is actually the -case, can be experimentally decided by comparing, on the one -hand, the development of the course of asphyxiation during narcosis, -and on the other, the withdrawal of the oxygen supply. -We have carried out this comparison for the spinal cord centers -as well as for the medullated nerve. A prolonged series of experiments -have been made by <span class="nowrap"><i>Bondy</i><a id="FNanchor_211" href="#Footnote_211" class="fnanchor">211</a></span> with the apparatus constructed<span class="pagenum" id="Page_249">249</span> -for this purpose by <i>Baglioni</i><span class="nowrap">.<a id="FNanchor_212" href="#Footnote_212" class="fnanchor">212</a></span> Two frogs under uniform conditions -of temperature were submitted to artificial circulation, the -one merely with an oxygen-free fluid, the other with the same, -but with the addition of 5 per cent. of alcohol. In order to render -the least trace of irritability perceptible, responsivity was increased -in both animals by the employment of strychnine. It -then appeared that, on the average, irritability was obliterated in -the narcotized frog in about the same time as in the animal -simply asphyxiated. These experiments were controlled by introducing -at their conclusion a saline solution containing oxygen -into both frogs and by ascertaining the degree of recovery. In -like manner <span class="nowrap"><i>Fröhlich</i><a id="FNanchor_213" href="#Footnote_213" class="fnanchor">213</a></span> has established the same fact for the nerve. -The period of asphyxiation for the nerve in a nitrogen-ether -mixture is approximately the same as in pure nitrogen. Analogous -experiments have been carried out in amœbæ by <i>Ishikawa</i><span class="nowrap">.<a id="FNanchor_214" href="#Footnote_214" class="fnanchor">214</a></span> -Here also it has been shown that living substance becomes -asphyxiated in narcosis and can finally recover only when oxygen -is supplied. In more than a hundred experiments <i>Ishikawa</i> has, -however, obtained the uniform result that amœbæ asphyxiate -rather sooner in narcosis than in pure nitrogen. The most striking -experiments are those which <span class="nowrap"><i>Heaton</i><a id="FNanchor_215" href="#Footnote_215" class="fnanchor">215</a></span> has carried out on the -nerve. Using both sciatic nerves of the same frog, he passed -each one through a separate glass chamber, as previously described, -and laid the central stumps projecting from the chamber -over a pair of platinum electrodes, while the stretch within was -likewise placed on platinum electrodes. The muscles served as -indicator of the capability of conduction and irritability. The -alterations thereof were tested by the ascertainment of the -threshold of stimulation. The nerve in the <i>one</i> chamber was -then subjected to a pure nitrogen current, that in the <i>other</i> merely -to one of pure air with ether. In order to test the degree of<span class="pagenum" id="Page_250">250</span> -asphyxiation the air-ether current in the latter chamber was -replaced from time to time by an ether-nitrogen current, and -then by one of pure nitrogen, so that the narcosis was interrupted -without the entrance of oxygen being possible in the mean time. -During this suspension of the narcosis, the nerve recovered each -time in nitrogen, its irritability again increasing and its capability -of conduction returning with every test. However, recovery -showed itself as less and less complete. Finally irritability -had sunk so low that the capability of conduction disappeared -entirely. At the end of the experiment as control, nitrogen -was displaced by air in the two chambers and in both nerves -recovery took place.</p> - -<p>In both cases recovery could only be brought about by an introduction -of oxygen. From the sum of all these experiments it -results that during narcosis in air the nerve, even when a sufficiency -of oxygen is present, gradually asphyxiates and loses -its capability of conduction, and this in about the same length -of time as the other nerve in pure nitrogen. These investigations -furnish two important facts for the theory of narcosis. -First, that in narcosis living substance becomes asphyxiated notwithstanding -the presence of an ample oxygen supply, and -secondly, that asphyxiation occurs in the same time, or somewhat -more rapidly, in pure nitrogen under otherwise similar -conditions than without narcosis. In other words, it is shown -that the breaking down processes of metabolism continue in narcosis -as anoxydative disintegration. <i>In narcosis, therefore, -asphyxiation takes place with approximately the same or a somewhat -greater rapidity than that in an oxygen-free medium.</i></p> - -<p>The fact here established explains in the simplest manner the -often described observation that in the human being and in mammals -during prolonged anæsthesia typical products of insufficient -combustion, such as fatty acids, lactic acid and above all aceton, -in not inconsiderable quantities are eliminated, as the case may -be, by the urine or the respiratory air<span class="nowrap">.<a id="FNanchor_216" href="#Footnote_216" class="fnanchor">216</a></span> If, as has been shown by<span class="pagenum" id="Page_251">251</span> -the foregoing experiments, the processes of disintegration can -continue to anoxydatively take place during narcosis, the problem -arises, if this anoxydative breaking down can be further -increased by excitating stimuli. This question has been answered -likewise by means of experiments on the nerve made by <i>Heaton</i><span class="nowrap">.<a id="FNanchor_217" href="#Footnote_217" class="fnanchor">217</a></span> -The two sciatic nerves of the same frog were drawn through -a double glass chamber of the form previously described so that -each nerve lay on an electrode and with the central stump protruding -out of the chamber hanging likewise over an electrode. -As in the former instances the muscle contraction of the shank -again served as indicator. Both nerves were then subjected to -the same current of nitrogen-ether. When, as a result of the -narcosis, their irritability has sunk to the level of “stromschleifen” -the central stump of the one nerve was continuously stimulated -with faradic shocks during a prolonged period, while the other -nerve remained at rest. Finally, by displacement of the current -of nitrogen-ether with one of pure nitrogen, cessation of narcosis -was brought about. It was then seen that the irritability of the -continuously stimulated nerve showed a much greater decrease -than that of the nonstimulated. The control made by introduction -of air demonstrated that both nerves recovered in an oxygen -supply. <i>There can, therefore, be no doubt, by comparative experiments -we find, that during narcosis anoxydative disintegration -can be still further increased by the action of stimuli.</i></p> - -<p>In view of this knowledge of the influence of narcotics on -oxygen exchange it may be considered as a firmly established -fact, that a process of depression is developed during narcosis, -which can be classified with the large group of depressions, resulting -from deficiency of oxygen. This is followed by the important -problem, is it possible to attribute the whole series of alterations, -produced by the narcotic, solely to this <i>one</i> factor? In other -words, is narcosis the result of acute suppression of the oxydative -processes?</p> - -<p>If the individual symptoms which characterize narcosis are -investigated from this point of view, one must indeed confess -that they are all readily understood when regarded as the results<span class="pagenum" id="Page_252">252</span> -of suppression of the oxydative processes. Indeed, the disappearance -of the perceptible vital activities, the decrease of -irritability, the restriction of the conduction of excitation, the continuance -of an anoxydative breaking down, the recovery on cessation -of narcosis, provided oxygen is present, etc., in short, all -the characteristics of narcosis so far known must be expected -and <i>demanded</i> if a suppression of the oxydative processes exists -during narcosis.</p> - -<p>There is only <i>one</i> point which at the first glance would not -seem to agree entirely with the assumption. This is the fact that -depression sets in with a relatively greater rapidity in narcosis -than when the supply of oxygen is completely withdrawn. -Depression of the centers in the spinal cord, which begins in -about five to ten minutes after artificial circulation of an oxygen-free, -alcohol-containing, saline solution, is not brought about for -more than an hour when the same saline solution but without -alcohol is introduced. This difference is still more strikingly -apparent in the nerve. The same degree of depression, which is -produced in the nerve in a nitrogen-ether mixture within about -<i>five</i> minutes, is not reached in pure nitrogen without ether until -after the lapse of from <i>two</i> to <i>four</i> hours. In order to investigate -this relation somewhat more closely I have questioned if it -is possible for a living system, which has been narcotized to a -certain extent, to regain its irritability in a completely oxygen-free -medium, if cessation of the narcosis takes place after a -period essentially shorter than the time of asphyxiation of the -system under equal conditions. If the depression of narcosis is -founded exclusively on asphyxiation, it would be expected that -no recovery could occur. Experiments which I have made on -the spinal cord centers as well as on the peripheral nerves have, -however, demonstrated exactly the contrary. If a frog is -subjected to an artificial circulation of an oxygen-free saline -solution containing 5 per cent. of alcohol until reaction is lost, -being certain of this by the injection of a weak dose of strychnine, -and if now a cessation of the narcosis is brought about by -the transfusion of oxygen-free saline solution, the centers of the -animal recover completely within ten to fifteen minutes, as shown<span class="pagenum" id="Page_253">253</span> -by typical strychnine tetanus. If a nerve is placed in a gas chamber -through which a mixture of nitrogen and ether is allowed to -flow until irritability is greatly decreased, and is then displaced -by pure nitrogen, irritability increases more or less completely -according to the time which has passed from the beginning of -asphyxiation. This investigation proves that living substance, -even after the deepest narcotic depression, may recover on cessation -of the narcosis, although in an entirely oxygen-free medium. -<i>Fröhlich</i>, <i>Bondy</i> and <i>Heaton</i>, by the methods of their experiments -above described, have proved this fact in a great number -of instances. On the other hand, <i>Ishikawa</i> could not observe -a pronounced recovery in amœbæ from narcosis in pure nitrogen. -But it is possible that here the difference is perhaps merely -quantitative.</p> - -<p>What position should be taken in the face of these facts? Does -recovery of a deeply narcotized tissue in an oxygen-free medium -really make it difficult to suppose that narcosis is the result of -an acute suppression of the processes of oxydation? On closer -view, it will be found that this difficulty is merely apparent. In -reality it is quite possible to bring these facts into harmony with -the assumption that narcosis consists in a suppression of these -processes. If one proceeds from the supposition that living substance -possesses a certain, even though merely a small supply of -oxygen in its interior, then it is at once evident that a more or -less complete recovery of irritability from narcosis depression is -possible, even in an oxygen-free medium. It can take place at -the cost of the oxygen still present in the living substance and -which during the narcosis, on account of the suppression of the -oxydation processes, could not be consumed. If the presence of -a certain oxygen reserve in living substance is entirely set aside -and a different explanation sought for the primary continuance -of irritability after a complete withdrawal of the oxygen supply -from without, the great difference of time in the setting in of the -depression in narcosis and that of the complete elimination of the -oxygen supply from without would make it necessary to assume -the processes occurring in narcosis are entirely different in nature. -The explanation that narcosis is the result of suppression of the<span class="pagenum" id="Page_254">254</span> -oxydative processes would indeed be out of the question in such -a view.</p> - -<p>The assumption, however, that in a living system at the same -moment when oxygen is removed from the neighborhood, let us -say by a stream of nitrogen, no oxygen would be present and -that in consequence every oxydative process must cease, contains -so little probability that I have rejected it on various occasions<span class="nowrap">.<a id="FNanchor_218" href="#Footnote_218" class="fnanchor">218</a></span> -The way in which irritability is lost in asphyxiation of the nerve -likewise very clearly demonstrates the untenability of this view. -The recent investigations of <span class="nowrap"><i>Lodholz</i><a id="FNanchor_219" href="#Footnote_219" class="fnanchor">219</a></span> have shown that decrease of -irritability takes place after a sudden displacement of all oxygen -from the surrounding medium uniformly and gradually in the -form of a logarithmic curve. If at the moment of oxygen withdrawal -from the outer medium, metabolism became entirely -anoxydative, the curve of irritability must under all circumstances -show a sudden <i>steep decline</i> at this point, and subsequent to this -a further <i>slower</i> decrease. For, as the oxydative processes constitute -by far the <i>chief</i> part in the energy production of living -substance, the production of energy, and with this irritability, -would undergo considerable loss at the same moment in which -oxydative was replaced by anoxydative disintegration. The curve -of decrease of irritability during the transition period from -oxygen supply to oxygen withdrawal shows, on the contrary, a -completely uniform course and it is not until later that a very -slow decline takes place, which only after a prolonged time assumes -increasing rapidity. But the assumption that at the -moment when the supply of oxygen ceases, anoxydative breaking -down could acquire such enormous dimensions that it furnishes -just exactly the same amount of energy as was before supplied -oxydatively, is a view which no one will seriously entertain. In -connection with this I wish to call attention to the experiments -of <span class="nowrap"><i>Fröhlich</i><a id="FNanchor_220" href="#Footnote_220" class="fnanchor">220</a></span> in which he compared the time required for asphyxiation -to take place in the nerves, when, on the one hand, the frogs -had been kept several days previous to the experiment in temperature<span class="pagenum" id="Page_255">255</span> -of 14–40° C., and on the other, in one merely a few degrees -above zero. He found that the nerves of the cooled frogs required -on an average twice or three times as long for their irritability -to sink to the same degree as those of the heated frog, -although during the experiment the same temperature was present -in both. It was also shown that the asphyxiation period was prolonged -up to a certain limit, depending upon the length of time the -animals were kept at a low temperature. It would seem to me -that these facts admit of no other explanation than that in a low -temperature a greater amount of oxygen is stored in the nerve -than in high temperatures. From the standpoint that from the -moment of withdrawal of oxygen from without, disintegration -likewise takes place exclusively anoxydatively, these facts would -be completely incomprehensible. When, however, the assumption -is made, and this would appear to me as inevitable, that living -substance contains in itself a certain even though a very slight -quantity of oxygen, which in low temperature is greater, in a -high temperature less, the recovery from narcosis, when oxygen -is withheld, is not at all surprising. The comparatively rapid -setting in of depression in narcosis finds a simple explanation in -the <i>violent</i> manner in which the oxydative breaking down, notwithstanding -the presence of oxygen, is suddenly suppressed by -the flooding by the narcotic. Finally, this view receives unlooked-for -support by a group of facts which at the first glance would -appear to bear no relation whatever to the process of narcosis.</p> - -<p>In a series of investigations on the mechanism of movement in -naked protoplasm<span class="nowrap">,<a id="FNanchor_221" href="#Footnote_221" class="fnanchor">221</a></span> I have pointed out the rôle played by oxygen -in the genesis of the amœboid protoplasm movement. We can -distinguish two antagonistic phases in the movement of amœboid -cells, the expansion phase and the contraction phase. The first -consists in an increase, the latter in a diminution of the surface, -the mass remaining the same. The expansion phase is manifested<span class="pagenum" id="Page_256">256</span> -in the stretching out of the pseudopods by a centrifugal outflowing -of the protoplasm into the surrounding medium, the contraction -phase by the indrawing of the pseudopods by the centripetal -inflowing of the protoplasm to the cell body. In total contraction, -such as occurs, for instance, in strong excitation following stimuli, -the cell body becomes ball shaped. In local contraction of the -long thread or net-shaped outstretched pseudopods of the sea -rhizopoda, the protoplasm of the retracting pseudopod forms balls -and spindles. Considered from a physical point of view the -expansion phase of amœboid movement is an expression of decrease, -the contraction phase an increase of the surface tension. -I have shown that the factor which under physiological conditions -decreases the surface pressure and thereby brings about the -expansion phase is the introduction of oxygen into the living -substance. With removal of oxygen the stretching out of the -pseudopods ceases. The cell gradually draws in all pseudopods -and assumes the shape of a ball. On the reintroduction of oxygen -the outflow of the pseudopods begins anew. This fact can be -observed in all amœboid cells. When, therefore, consumption of -oxygen and oxydative changes is suppressed during narcosis it is -to be expected that all naked protoplasm masses by being narcotized -lose their capability of assuming the expansion phase of -movement and contract into the shape of balls. Experimentation -confirms this deduction in the most striking manner. When -amœbæ are placed in a drop of water under the microscope in a -gas cell through which air and a little ether are allowed to flow, -the pseudopod formation of the amœbæ ceases within a few -minutes and they all assume the shape of a ball. (Figure <a href="#i_257">62</a>.) In -asphyxiation in pure nitrogen, the changes in the amœbæ take -place in exactly the same manner with the exception that in this -case a longer period ensues according to the size and activity of -the animals. About 20 to 60 minutes elapse before depression -becomes complete. If larger sea rhizopoda are narcotized in the -same manner all pseudopods are more or less retracted and the -contained protoplasm flows centripetally and contracts in the -characteristic manner into balls and spindles. (Figure <a href="#i_258">63</a>.) If -the narcosis is removed by displacing the ether by pure air, the<span class="pagenum" id="Page_257">257</span> -stretching out of the pseudopods then begins anew, provided the -narcosis has not been too deep or too prolonged.</p> - -<div class="figcenter illowe21_25" id="i_257"> - <img class="w100" src="images/i_257.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 62.</p> - -<p class="tac">Amoeba limax. <i>A</i>—In normal state. <i>B</i>—Narcotized by ether.</p></div> -</div> - -<div class="figcenter illowe27_5" id="i_258"> - <img class="w100" src="images/i_258.jpg" alt="" /> - <div class="caption"><p class="tac">Fig. 63.</p> - -<p class="tac">Rhizoplasma Kaiseri. Effect of chloroform.</p></div> -</div> - -<p>In the face of all this evidence there can be indeed no further -barrier to the assumption that the symptoms in narcosis are a -result of a suppression of the oxydative processes. Nevertheless, -I would not at present venture to maintain that the entrance -of the narcotic into living substance produces no alterations whatever, -except just this oxydative suppression. For the present -it seems to me that the possibility is in no way precluded that<span class="pagenum" id="Page_258">258</span> -the same process, which is expressed in the oxydative suppression, -is connected with other alterations in the living substance, -of which we are as yet ignorant. As far as the effects of larger -doses of narcotics are concerned, the assumption that other -alterations take place in the living substance can in any case -hardly be avoided. An application of larger quantities of narcotics -brings about destruction of the living system with great -rapidity. Here the alterations in the optical properties of the -cell are of such magnitude that the changes are directly perceptible -under the microscope. <span class="nowrap"><i>Binz</i><a id="FNanchor_222" href="#Footnote_222" class="fnanchor">222</a></span> has observed such alterations -in the nerve cell and looked upon them as coagulation. In unicellular -organisms these optical alterations can readily be followed. -If amœbæ, sea rhizopods or infusoria are narcotized -with stronger doses of ether or chloroform, the protoplasm becomes<span class="pagenum" id="Page_259">259</span> -opaque and granulated, it appears darker than formerly -and in many cases displays a yellowish brown color in transmitted -light. Cells altered in this way no longer recover after -removal of the narcotic. These intense and rapidly appearing -alterations of protoplasm resulting from the application of -stronger doses of the narcotic can scarcely be explained as simply -the result of a mere decrease of the oxydative processes. They -would seem to consist rather, as suggested by <i>Binz</i>, as coagulation, -in an alteration of the state of certain components of living substance. -Whether these alterations are already present in a correspondingly -slight amount in those degrees of narcosis after which -complete recovery can take place and further whether in this -case they are in any way concerned in bringing about the individual -symptoms of the former, are questions the decision of -which must be left to future investigations. <span class="nowrap"><i>Höber</i><a id="FNanchor_223" href="#Footnote_223" class="fnanchor">223</a></span> indeed -makes such an alteration of the colloidal state of the lipoid the -basis of a theory of narcosis. But such assumptions are scarcely -more than speculations. This is one of the points in which our -present knowledge is lacking.</p> - -<p>Even if we restrict ourselves to the actually established alterations -produced by the narcotic in living substance, new problems -present themselves, the investigation of which requires further -effort. Above all, the question arises as to the finer mechanism of -oxydative depression. In what manner does the narcotic molecule, -entering into the living substance, suppress the oxydative -processes? Here there are very different possibilities to be taken -into consideration and up to the present in our investigations of a -suppression of the oxydative processes resulting from narcosis, -we have stood on the firm ground of assured facts. However, the -discussion of the nature of this suppression leads us into the -domain of <i>hypothesis</i>. But without hypothesis there can be no -progress in knowledge. In all branches of scientific research, -working hypotheses are required for the obtainment of new facts.</p> - -<p>On closer reflection, there are chiefly <i>three</i> possibilities, which,<span class="pagenum" id="Page_260">260</span> -considered from the standpoint of our present knowledge of the -processes in living substance, offer an explanation of the oxydative -suppression as a result of narcosis.</p> - -<p>One of these possibilities is, that the <i>narcotic itself consumes -the oxygen which activates living substance</i> and uses it for its -<i>individual</i> oxydation, so that the specific oxydable material of -living substance receives less oxygen from the oxygen carriers. -Based on a series of interesting experiments this view has been -recently maintained by <i>Bürker</i><span class="nowrap">.<a id="FNanchor_224" href="#Footnote_224" class="fnanchor">224</a></span> He observed that with the -electrolysis of acidulated water, to which a small per cent. of ether -was added, a much less amount of oxygen was at the anode than -in one used as means of control, containing acidulated water -without ether. The oxygen was replaced at the anode by -oxydation products of the ether, such as carbonic oxide, carbon -dioxide, acetate aldehyde and acetic acid. In experiments with -various narcotics he likewise found that the stronger the effect -produced by narcosis, the greater the oxygen amount required -for the oxydation taking place of electrolysis. <i>Bürker</i> applies -these results obtained for electrolysis to the processes in living -substance and takes the view that the narcotic seizes on the -active oxygen, and so withdraws it from the masses of living substance -possessing a great oxygen requirement. It cannot be -denied that this conception of the nature of certain narcotics -deserves careful investigation. It seems to me, however, that -before considering it in the light of a serious probability a grave -difficulty would first have to be removed. In living substance -the narcotic would occur under conditions essentially different -from those existing during the experiment in the voltameter. -In the former case there would be the struggle for oxygen -of the specific oxydable cell masses to be met with. Considering -the small amount of chemical activity of the greater number of -narcotics it would appear at least doubtful if in this battle for -supremacy the latter would achieve a victory. For some narcotics, -as, for instance, carbon dioxide, this method of a depression -of the oxydative processes would have no bearing whatever.<span class="pagenum" id="Page_261">261</span> -This is rather to be looked for in the effects of oxydative suppression -of the aldehydes, which <span class="nowrap"><i>Warburg</i><a id="FNanchor_225" href="#Footnote_225" class="fnanchor">225</a></span> has recently observed and -investigated. Here, however, it is not a true narcosis which is -concerned.</p> - -<p>A second possibility of a suppression of oxydation would be -the <i>fixation of the molecules of the oxydable substances by chemical -or physical combinations</i> in that they would lose their capability -of oxydative disintegration. Such a supposition would, -however, likewise contain but few elements of probability. As -has been shown, an anoxydative breaking down continues during -narcosis, which, and this we may assume with certainty, furnishes -very different products in great variety. These anoxydative disintegration -products, as recovery on the cessation of narcosis -shows, are removed during recovery by oxydation. If the effect -of the narcotic consisted in the prevention in spite of the presence -of oxygen of the oxydation by combination, it would be necessary -to assume that the narcotic was bound to a mass of completely -heterogeneous substances, a conclusion we should find -difficult to entertain.</p> - -<p>If, however, depression of the oxydative processes is founded -neither on the seizure of oxygen by the narcotic nor the fixation -of oxydable substances by the former, there remains the possibility -<i>that the narcotic suppresses the transmission of oxygen to -these points of consumption</i>. We assume that the oxygen transmission -to those points where its consumption takes place is carried -out by special substances, the existence of which has been -established in the most varied vegetable and animal cell forms. -Unfortunately we only know these oxygen-carrying substances -by their effects. Of their chemical constitution we have no -knowledge, but we usually assume that the transmission of oxygen -occurs in the same manner as in catalytic processes. On -another occasion I have previously expressed the suggestion<span class="nowrap">,<a id="FNanchor_226" href="#Footnote_226" class="fnanchor">226</a></span> -that the narcotic suppresses oxydation by producing incapability -of the groups acting as oxygen carriers to carry out this function.<span class="pagenum" id="Page_262">262</span> -If we assume that the substances possessing the character -of oxygen carriers, which activate the molecular oxygen and so -render it capable of attacking the oxydable substances, lose this -capability under the influence of narcotics, this supposition would -not only make all of the facts of suppression of oxygen exchange -in narcosis comprehensible, considered from one point, but likewise, -as careful investigation has shown, be in complete harmony -with all knowledge obtained up to the present of the process of -narcosis.</p> - -<p>Here is the point where the interesting observations of <span class="nowrap"><i>Hans -Meyers</i><a id="FNanchor_227" href="#Footnote_227" class="fnanchor">227</a></span> and <span class="nowrap"><i>Overton</i><a id="FNanchor_228" href="#Footnote_228" class="fnanchor">228</a></span> on the relations of the depressing influence -of narcotics to their solubility of fat and water may be connected -with the facts of the suppression of oxydation. <i>Meyer</i> and <i>Overton</i> -have quite independently of each other made the same observation, -that the depressing effect of a narcotic is the greater, the -larger the coefficient of distribution between substances of a fatty -nature and water. Those narcotics produce the strongest effects -which are readily soluble in substances of a fatty nature, but not -easily so in water, that is, in which the coefficient distribution -between fat and water is very great. This law, which -has been demonstrated by <i>Meyer</i> and <i>Overton</i> for a large number -of narcotic processes, is in itself not a theory of narcosis, as -has been often erroneously assumed. It shows us, however, -an important condition, which must be considered in every -theory of narcosis. It demonstrates that it is the ease with -which transmission in the lipoid occurs which allows a substance -to develop narcotic effects. These facts would seem to indicate -that the lipoids of the cell are connected in some way or other -with the exchange of oxygen. If we assume that the oxygen -carriers, the chemical constitution of which is so far not known, -bear the character of lipoids and belong, say, to the generally -extended group of phosphatides, there results at once an apparent<span class="pagenum" id="Page_263">263</span> -connection of the law established by <i>Meyer</i> and <i>Overton</i> with the -nature of narcosis.</p> - -<p>The depressing effect of the narcotic would then consist in -producing incapability of the lipoids transmitting oxygen to act -as carriers of the same, and it is, therefore, self-evident that the -effect of the narcotic would be the stronger the more readily it -found entrance into the lipoids. It is perhaps not without interest -that in similar manner <span class="nowrap"><i>Mansfeld</i><a id="FNanchor_229" href="#Footnote_229" class="fnanchor">229</a></span> has attempted to establish a -connection between the facts which <i>Meyer</i> and <i>Overton</i> have -found and those ascertained by my coworkers and myself. He -expressed the view that the lipoids of the cells represent the -channels followed by the oxygen on its entrance, and that in consequence -of their accumulation in the lipoids, the narcotics bring -about asphyxiation by physically obstructing the transmission -of the oxygen from the outer medium through the surface layer -of the lipoid into the protoplasm. The divergence in our views -is not essential in their nature, and I attach the less importance -to them as we find ourselves here, as I must again emphasize, -on purely hypothetical ground.</p> - -<p>In consideration of these observations we may perhaps establish -the following hypothesis of the effect of the oxydative suppression -of narcotics: The narcotics obstruct, either by absorption -or loose chemical combination the oxygen carriers of the cell and -render them incapable to activate the molecular oxygen. In consequence, -oxydation of the oxydable substances cannot take place -and disintegration occurs of an <i>an</i>oxydative form. The cell -asphyxiates.</p> - -<p>In conclusion I wish to warn against erroneous assumption -that <i>all</i> oxydative depressions by chemical substances are <i>narcosis</i> -and that the mechanism is the same. It is true that a number -of chemical substances depress the processes of oxydation. -But the latter can be brought about in very varying ways. I -would like to mention the effect of oxydative depression of -aldehydes. To this <span class="nowrap"><i>Warburg</i><a id="FNanchor_230" href="#Footnote_230" class="fnanchor">230</a></span> has added hydrocyanic acid,<span class="pagenum" id="Page_264">264</span> -arsenic acid, ammonia and substitution compounds of ammonia. -These substances do not follow the <i>Meyer-Overton</i> law of the -coefficient of distribution. We cannot consider them, therefore, -as narcotics. Future investigation will establish the existence of -a large number of substances belonging to this great group of -oxydation suppressing poisons, which are not narcotics. And -it is likewise certain that depressing substances will be found, the -depressing effects of which will not have their point of attack in -the oxygen exchange, but will be shown to exist in other constituents -of the metabolic chain. Our research in these fields, as -already said, is still in the first beginnings and its perspective -reaches into infinite space.</p> - - -<div class="footnotes"><h3>FOOTNOTES:</h3> - -<div class="footnote"> - -<p><a id="Footnote_1" href="#FNanchor_1" class="label">1</a> -<i>Franciscus Glissonius</i>: “Tractatus de natura substantiæ energetica seu de vita -natura ejusque tribus primis facultatibus perceptiva, appetitiva, motiva,” etc. Londini -M D C L XXII.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_2" href="#FNanchor_2" class="label">2</a> -<i>Franciscus Glissonius</i>: “Tractatus de ventriculo et intestinis cui præmittitur alius -de partibus continentibus in genere et in specie de iis abdominis.” Amstelodami M D -C L XXVII.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_3" href="#FNanchor_3" class="label">3</a> -<i>Albrecht v. Haller</i>: “Elementa Physiologiæ corporis humani.” Tomus IV. -Lausannæ M D C L XVI.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_4" href="#FNanchor_4" class="label">4</a> -<i>John Brown</i>: “Elementa medicinæ.” 1778. English translation. London 1778.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_5" href="#FNanchor_5" class="label">5</a> -<i>Johannes Müller</i>: “Über die phantastischen Gesichtserscheinungen. Eine physiologische -Untersuchung mit einer physiologischen Urkunde des Aristotles über den -Traum, den Physiologen und den Arzten gewidmet.” Coblenz 1826.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_6" href="#FNanchor_6" class="label">6</a> -<i>Johannes Müller</i>: “Handbuch der Physiologie des Menschen für Vorlesungen.” -Coblenz 1837.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_7" href="#FNanchor_7" class="label">7</a> -<i>Rudolph Virchow</i>: Die Zellularpathologie in ihrer Begründung auf physiologische -und pathologische Gewebelehre. 1 Aufl. Berlin 1858–4 Aufl. 1871.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_8" href="#FNanchor_8" class="label">8</a> -<i>Eduard Weber</i>: “Muskelbewegung.” Article in Wagner’s Handwörterbuch der -Physiologie, Bd. 3. Braunschweig 1846.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_9" href="#FNanchor_9" class="label">9</a> -<i>Claude Bernard</i>: “Lecons sur les phénomènes de la vie communs aux animaux et -aux végétaux.” Paris 1878.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_10" href="#FNanchor_10" class="label">10</a> -<i>Ehrenberg</i>: “Die Infusionstiere als vollkommene Organismen.” Leipzig 1838.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_11" href="#FNanchor_11" class="label">11</a> -<i>Semon</i>: “Die Mneme als erhaltendes Princip im Wechsel des organischen Geschehens.” -Zweite verbesserte Auflage, Leipzig.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_12" href="#FNanchor_12" class="label">12</a> -<i>Ewald Hering</i>: “Uber das Gedächtniss als allgemeine Function der organischen -Materie.” Wein 1876.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_13" href="#FNanchor_13" class="label">13</a> -<i>Ernst Haeckel</i>: “Die Perigenesis der Plastidule oder die Wellenzeugung der -Lebenstheilchen.” Berlin 1876.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_14" href="#FNanchor_14" class="label">14</a> -Compare with this <i>Max Verworn</i>: “Die Entwickelung des menschlichen Geistes.” -Jena, Gustav Fischer, 1910.</p> - -<p><i>Max Verworn</i>: “Die Erforschung des Lebens.” II Auflage. Jena, <i>Gustav Fischer</i>, -1911.</p> - -<p>The same: “Die Fragen nach den Grenzen der Erkenntniss.” Jena, <i>Gustav Fischer</i>, -1908.</p> - -<p>The same: “Allgemeine Physiologie.” V Auflage. <i>Gustav Fischer</i>, 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_15" href="#FNanchor_15" class="label">15</a> -<i>Gustav Kirchhoff</i>: “Vorlesungen über mathematische Physik. Mechanik.” Leipzig -1876.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_16" href="#FNanchor_16" class="label">16</a> -<i>Max Verworn</i>: “Die polare Erregung der lebendigen Substanz durch den -galvanischen Strom.” In Pflügers Archiv. f. d. ges. Physiologie Bd. 65, 1896.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_17" href="#FNanchor_17" class="label">17</a> -<i>Th. W. Engelmann</i>: “Bacterium photometricum ein Beitrag zur vergleichenden -Physiologie des Licht-und Farbensinns.” In Pflügers Archiv. Bd. 30. 1883.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_18" href="#FNanchor_18" class="label">18</a> -<i>Jennings</i>: “Behavior of the lower organisms.” New York 1906.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_19" href="#FNanchor_19" class="label">19</a> -<i>Max Verworn</i>: “Physiologisches Prakticum für Medizinen.” Jena 1907.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_20" href="#FNanchor_20" class="label">20</a> -<i>Julius Vészi</i>: “Der einfachste Reflexbogen im Rückenmark.” In Zeitschrift f. -allgemeine Physiologie Bd. XI, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_21" href="#FNanchor_21" class="label">21</a> -<i>Weber</i>: “Annotationes anatomicæ et physiologicæ.” Lips. 1851. The same: “Der -Tastsinn und das Gemeingefühl,” in Wagner’s Handwörterbuch d. Physiologie Bd. III. -2. Braunschweig 1846.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_22" href="#FNanchor_22" class="label">22</a> -<i>Ziehen</i>: “Leitfaden der physiologischen Psychologie in 15 Vorlesungen.” VI -Auflage. Jena 1902.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_23" href="#FNanchor_23" class="label">23</a> -<i>Fechner</i>: “Elemente der Psychophysik.” Leipzig 1860. 2 Auflage 1889.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_24" href="#FNanchor_24" class="label">24</a> -<i>Preyer</i>: “Das myophysische Gesetz.” Jena 1874.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_25" href="#FNanchor_25" class="label">25</a> -<i>Pfeffer</i>: “Ueber chemotaktische Bewegungen von Bacterien, Flagellaten und -Volvocineen.” Untersuchungen aus dem botanischen Institut zu Tübingen. Bd. II, -1888.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_26" href="#FNanchor_26" class="label">26</a> -<i>Bowditch</i>: “Ueber die Eigentümlichkeiten der Reizbarkeit, welche die Muskelfasern -des Herzens zeigen.” In Arbeiten aus der physiologischen Anstalt zu Leipzig -VI. Jahrgang 1872.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_27" href="#FNanchor_27" class="label">27</a> -<i>Kronecker</i>: “Das characteristische Merkmal der Herzmuskelbewegung.” In -Beiträge zur Anat. und Physiol. Als. Festgabe Carl Ludwig gewidmet von seinen -Schülern. Leipzig 1874.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_28" href="#FNanchor_28" class="label">28</a> -<i>McWilliams</i>: “On the rhythm of the mammalian heart.” Journal of Physiology, -Vol. IX, 1888.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_29" href="#FNanchor_29" class="label">29</a> -<i>Gotch</i>: “The submaximal electrical response of nerve to a single stimulus.” -Journal of Physiology, Vol. XXVIII, 1902.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_30" href="#FNanchor_30" class="label">30</a> -<i>Keith Lucas</i>: “On the graduation of activity in a skeletal muscle fibre.” Journal -of Physiology, Vol. XXXIII, 1905–06.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_31" href="#FNanchor_31" class="label">31</a> -<i>Keith Lucas</i>: “The all or none contraction of skeletal muscle fibre.” Journal of -Physiology, Vol. XXXVIII, 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_32" href="#FNanchor_32" class="label">32</a> -<i>Vészi</i>: “Zur Frage des Alles oder Nichts-Gesetzes beim Strychninfrosch.” Zeitschrift -für allgemeine Physiologie Bd. XII, 1911.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_33" href="#FNanchor_33" class="label">33</a> -Vergl. <i>Julius Schott</i>: “Ein Beiträg zur electrischen Reigung des quergestreiften -Muskels von seinen Nerven aus.” Pflügers Archiv Bd. 48, 1891.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_34" href="#FNanchor_34" class="label">34</a> -<i>Max Verworn</i>: “Untersuchungen über die polare Erregung der lebendigen -Substanz durch den constanten Strom.” III Mitteilung, Pflügers Arch. Bd. 62, 1896.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_35" href="#FNanchor_35" class="label">35</a> -<i>Du Bois-Reymond</i>: “Untersuchungen über tierische electricität.” Bd. I. Berlin -1848, p. 258.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_36" href="#FNanchor_36" class="label">36</a> -<i>Kühue</i>: “Untersuchungen über das Protoplasma und die Contractilität.” Leipzig -1864. <i>Max Verworn</i>: “Die polare Erregung der Protisten durch der galvanischen -Strom.” Pflügers Arch. Bd. 35, 45, 1889.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_37" href="#FNanchor_37" class="label">37</a> -<i>A. Fick</i>: “Beiträge zur vergleichenden Physiologie der irritablen Substanzen.” -Braunschweig 1863.</p> - -<p>The same: “Untersuchungen über die electrische Nervenreizung.” Braunschweig -1864.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_38" href="#FNanchor_38" class="label">38</a> -<i>Max Verworn</i>: “Untersuchungen über die polare Erregung der lebendigen Substanz,” -etc. III Pflügers Arch. Bd. 62, 1896.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_39" href="#FNanchor_39" class="label">39</a> -<i>Grützner</i>: “Über die Reizwirkungen der Stöhrer’schen Maschine auf Nerv und -Muskel.” Pflügers Arch. Bd. 41, 1887.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_40" href="#FNanchor_40" class="label">40</a> -<i>Nernst und Barratt</i>: “Ueber electrische Nervenreizung durch Wechselströme.” -Zeitschrift für Electrochemie 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_41" href="#FNanchor_41" class="label">41</a> -<i>E. Hering</i>: “Zur Theorie der Vorgänge in der lebendigen Substanz.” In Lotos, -Bd. 9, Prag. 1888.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_42" href="#FNanchor_42" class="label">42</a> -<i>Max Verworn</i>: “Allgemeine Physiologie. Ein Grundriss der Lehre vom Leben.” -V. Aufl. Jena 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_43" href="#FNanchor_43" class="label">43</a> -<i>Ostwald</i>: “Ueber Katalyse.” Verhandl. d. Ges. Deutscher Naturf. und Aerzte zu -Hamburg 1901.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_44" href="#FNanchor_44" class="label">44</a> -<i>Cremer</i>: “Die allgemeine Physiologie der Nerven.” In Nagels Handbuch der -Physiologie des Menschen. Bd. IV, Braunschweig 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_45" href="#FNanchor_45" class="label">45</a> -In the first edition of my “<i>General Physiology</i>” in 1895 I have sharply and clearly -defined it as such, stating in formulating the general law of stimulation: that every -excitation is an increase either of individual parts or the whole of vital phenomena, -depression every decrease in the individual part or the whole of vital phenomena.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_46" href="#FNanchor_46" class="label">46</a> -Compare: <i>Rudolf Weinmann</i>: “Die Lehre von den specifischen Sinnesenergien.” -Hamburg 1895.</p> - -<p>Further: <i>Eugen Minkowski</i>: “Zur Müllerschen Lehre von den specifischen Sinnesenergien.” -In Zeitschrift f. Sinnesphysiologie, Bd. 45, 1911.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_47" href="#FNanchor_47" class="label">47</a> -<i>Fick und Wislicenus</i>: “Ueber die Entstehung der Muskelkraft.” Vierteljahresschrift -d. Züricher Naturforschenden Gesellschaft. Bd. 10, 1865.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_48" href="#FNanchor_48" class="label">48</a> -<i>Voit</i>: “Ueber die Entwicklung der Lehre der Quelle der Muskelkraft and einiger -Theile der Ernährung seit 25 Jahren.” Zeitschrift f. Biologie Bd. VI, 1870.</p> - -<p>Derselbe: Physiologie des allgemeinen Stoffwechsels u. d. Ernährung. In Hermanns -Handbuch d. Physiologie, Bd. VI, 1881.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_49" href="#FNanchor_49" class="label">49</a> -<i>Ehrlich</i>: “Das Sauerstoffbedürfniss des Organismus. Eine farbenanalytische -Studie.” Berlin 1885. Compare further: <i>L. Aschoff</i>: “Ehrlich’s Seitenkettentheorie -und ihre Anwendung auf die künstlichen Immunisierungsprozesse. Zusammenfassende -Darstellung.” Zeitschr. f. allgemeine Physiologie, Bd. I, 1902.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_50" href="#FNanchor_50" class="label">50</a> -<i>Max Verworn</i>: “Die Biogenhypothese. Eine kritisch-experimentelle Studie über -die Vorgänge in der lebendigen Substanz.” Jena 1905.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_51" href="#FNanchor_51" class="label">51</a> -<i>Berger</i>: “Experimentell-anatomische Studien über die durch den Mangel optischer -Reize veranlassten Entwickelungschemmungen im Occipitallappen des Hundes and -der Katze.” Arch. f. Psychiatrie, Bd. 33, 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_52" href="#FNanchor_52" class="label">52</a> -<i>Max Verworn</i>: “Die cellularphysiologische Grundlage des Gedächtnisses.” -Zeitschrift f. allgemeine Physiologie, Bd. VI, 1907.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_53" href="#FNanchor_53" class="label">53</a> -<i>Max Verworn</i>: “Allgemeine Physiologie.” V. Aufl. 1909, pages 649–671.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_54" href="#FNanchor_54" class="label">54</a> -<i>Ewald Hering</i>: “Zur Theorie der Vorgänge in der lebendigen Substanz.” In -Lotos, Bd. 19, Prag. 1888.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_55" href="#FNanchor_55" class="label">55</a> -<i>Helmholtz</i>: “Messungen über den zeitlichen Verlauf der Zuckungen animalischer -Muskeln and die Fortpflanzungsgeschwindigkeit der Reizung in den Nerven.” Archiv -für Physiologie Jahrgang 1850.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_56" href="#FNanchor_56" class="label">56</a> -<i>Robert Tigerstedt</i>: “Untersuchungen über die Latenzdauer der Muskelzuckung -in ihrer Abhängigkeit von verschiedenen Variablen.” Arch. f. Physiologie Jahrgang -1885 Suppl.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_57" href="#FNanchor_57" class="label">57</a> -<i>Nernst</i>: “Zur Theorie der electrischen Reizung.” Nachrichten der Königl. -Gesellsch. d. Wissensch. zu Göttingen. Math. physik. Klasse 1899.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_58" href="#FNanchor_58" class="label">58</a> -<i>Paul Jensen</i>: “Das Problem der trophischen Nerven.” Medicinisch-naturwissen-schaftliches -Archiv. Bd. II, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_59" href="#FNanchor_59" class="label">59</a> -<i>A Pütter</i>: “Der Stoffwechsel des Blutegels (Hirudo medicinalis L).” I Theil. -Zeitschrift für allgemeine Physiologie Bd. VI, 1907. II Teil. ebenda Bd. VII, 1908.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_60" href="#FNanchor_60" class="label">60</a> -<i>Max Verworn</i>: “Ermüdung Erschöpfung und Erholung der nervösen Centren -des Rückenmarks. Ein Beitrag zur Kenntniss der Lebensvorgänge in den Neuronen.” -Archiv. f. Anat. u. Physiologie. physiol. Abteil. 1900 Suppl.</p> - -<p>The same: “Ermüdung und Erholung.” In Berliner Klin. Wochenschrift 1901.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_61" href="#FNanchor_61" class="label">61</a> -<i>H. v. Baeyer</i>: “Das Sauerstoffbedürfniss des Nerven.” Zeitschrift f. allgemeine -Physiologie Bd. II, 1903.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_62" href="#FNanchor_62" class="label">62</a> -<i>Fr. W. Fröhlich</i>: “Das Sauerstoffbedürfniss des Nerven.” Zeitschrift f. allgem. -Physiologie Bd. III, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_63" href="#FNanchor_63" class="label">63</a> -<i>H. Fillié</i>: “Studien über die Erstickung des Nerven in Flüsigkeiten.” Zeitschrift -f. allgemeine Physiologie, Bd. VIII, 1908.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_64" href="#FNanchor_64" class="label">64</a> -<i>H. v. Baeyer</i>: “Zur Kenntniss des Stoffwechsels in den nervösen Centren.” Zeitschr. -f. allgem. Physiol. Bd. I, 1902.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_65" href="#FNanchor_65" class="label">65</a> -<i>Gustav Mann</i>: “Histological changes induced in sympathetic motor and sensory -nerve cells by functional activity.” In Journ. of Anat. and Physiol. 1894. Further: -<i>Gordon Holmes</i>: “On morphological changes in exhausted ganglion cells.” Zeitschrift -f. allgem. Physiol. Bd. II, 1903.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_66" href="#FNanchor_66" class="label">66</a> -<i>Wallengren</i>: “Inanitionserscheinungen der Zelle.” Zeitschrift f. allgem. Physiol. -Bd. I, 1902.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_67" href="#FNanchor_67" class="label">67</a> -<i>W. Pfeffer</i>: “Ueber die regulatorische Bildung von Diastase.” In der math. phys. -Klasse d. Königl. Sächs Ges. d. Wiss. zu Leipzig 1896.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_68" href="#FNanchor_68" class="label">68</a> -<i>De Bary</i>: “Sur la fermentation de la cellulose.” In Bull. de la Soc. bot. de -France 1879.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_69" href="#FNanchor_69" class="label">69</a> -<i>Rosenthal</i>: “Untersuchungen über den respiratorischen Stoffwechsel.” Arch. f. -Anat. u. Physiologie physiolog. Abt. 1902 und Suppl. 1902.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_70" href="#FNanchor_70" class="label">70</a> -<i>Falloise</i>: “Influence de la réspiration d’une atmosphère suroxygéné sur l’absorption -d’oxygène.” Traveaux du laborat. de physiol. de L. Fredéric Liège, T. VI.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_71" href="#FNanchor_71" class="label">71</a> -<i>Durig</i>: “Ueber Aufnahme und Verbrauch von Sauerstoff bei Aenderung seines -Partialdruckes in der Alveolarluft.” Arch. f. Anat. u. Physiol. physiol. Abt. 1903 -Suppl.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_72" href="#FNanchor_72" class="label">72</a> -<i>Winterstein</i>: “Ueber den Mechanismus der Gewebeatmung.” Zeitschr. f. allgem. -Physiol. Bd. VI, 1907.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_73" href="#FNanchor_73" class="label">73</a> -<i>Lesser</i>: “Die Wärmeabgabe der Frösche in Luft and sauerstofffreien Medien. -Ein experimenteller Beweis dass die CO<sub>2</sub> Production der Frösche im sauerstofffreien -Raum nicht auf Kosten gespeicherten Sauerstoffs geschieht.” Zeitschr. f. Biologie -Bd. 51, 1908.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_74" href="#FNanchor_74" class="label">74</a> -<i>Max Verworn</i>: “Ermüdung, Erschöpfung and Erholung der nervösen Centra des -Rückenmarks.” Arch. f. Anat. u. Physiol. physiol. Abt. Suppl. 1900.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_75" href="#FNanchor_75" class="label">75</a> -<i>Max Verworn</i>: “Die Biogenhypothese.” Jena 1903. Compare also <i>Max Verworn</i>: -“Allgemeine Physiologie.” V. Aufl. Jena 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_76" href="#FNanchor_76" class="label">76</a> -<i>Max Verworn</i>: “Die cellularphysiologische Grundlage des Gedächtnisses.” Zeitschr. -f. allgem. Physiol. Bd. VI, 1907.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_77" href="#FNanchor_77" class="label">77</a> -<i>Schwarz und Lemberger</i>: “Über die Wirkung Kleinster Säuremengen auf die -Blutgefässe.” Pflügers Arch. Bd. 141, 1911.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_78" href="#FNanchor_78" class="label">78</a> -These investigations have not yet been published.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_79" href="#FNanchor_79" class="label">79</a> -<i>Max Verworn</i>: “Zur Physiologie der nervösen Hemmungserscheinungen.” Arch. f. -Anat. u. Physiol. physiol. Abt. Suppl. 1900.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_80" href="#FNanchor_80" class="label">80</a> -<i>Max Verworn</i>: “Psycho-physiologische Protistenstudien. Experimentelle Untersuchungen.” -Jena 1889.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_81" href="#FNanchor_81" class="label">81</a> -<i>Max Verworn</i>: “Die Bewegung der lebendigen Substanz. Eine vergleichend physiologische -Untersuchung der Contractionserscheinungen.” Jena 1892.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_82" href="#FNanchor_82" class="label">82</a> -<i>Du Bois-Reymond</i>: “Untersuchungen über tierische Electricität.” II Band. 1849.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_83" href="#FNanchor_83" class="label">83</a> -<i>H. Helmholtz</i>: “Messungen über den zeitlichen Verlauf der Zuckung animalischer -Muskeln und die Fortpflanzungsgeschwindigkeit der Reizung des Nerven.” Müller’s -Archiv. 1850.</p> - -<p>The same: “Messungen über die Fortpflanzungsgeschwindigkeit der Reizung in den -Nerven.” Zweite Reihe, Müller’s Arch. 1852.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_84" href="#FNanchor_84" class="label">84</a> -Compare: <i>Hermann</i>: “Handbuch der Physiologie.” II, 1 Leipzig 1879.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_85" href="#FNanchor_85" class="label">85</a> -<i>Piper</i>: “Ueber die Leitungsgeschwindigkeit in dem markhaltigen menschlichen -Nerven.”</p> - -<p>The same: “Weitere Mitteilungen über die Geschwindigkeit der Erregungsleitung im -markhaltigen menschlichen Nerven.” Pflügers Arch. Bd. 127, 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_86" href="#FNanchor_86" class="label">86</a> -<i>R. Du Bois-Reymond</i>: “Ueber die Geschwindigkeit des Nervenprincips.” Arch. -f. Anat. u. Physiol. physiol. Abt. Suppl. 1900.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_87" href="#FNanchor_87" class="label">87</a> -<i>Engelmann</i>: “Graphische Untersuchungen über die Fortpflanzungsgeschwindigkeit -der Nervenerregung.” Arch. f. Anat. u. Physiol. physiol. Abt. 1901.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_88" href="#FNanchor_88" class="label">88</a> -<i>G. Weiss</i>: “La conductibilité et l’excitabilité des nerfs.” In Journ. de Physiol. -et de Pathol. générale 1903.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_89" href="#FNanchor_89" class="label">89</a> -<i>Gotch</i>: “The submaximal electric response of nerve to a single stimulus.” Journal -of Physiology, Vol. XXVIII, 1902.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_90" href="#FNanchor_90" class="label">90</a> -<i>Piper</i>: Ueber die Leitungsgeschwindigkeit in den markhaltigen menschlichen -Nerven. Pflügers Arch. Bd. 124, 1908, und Bd. 127, 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_91" href="#FNanchor_91" class="label">91</a> -<i>Nicolai</i>: “Ueber Ungleichförmigkeiten in der Fortpflanzungsgeschwindigkeit des -Nervenprincips, nach Untersuchungen am marklosen Riechnerven des Hechts.” Arch. -f. Physiologie 1905.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_92" href="#FNanchor_92" class="label">92</a> -<i>Schiff</i>: “Über die Verschiedenheit der Aufnahmsfähigkeit und Leitungsfähigkeit in -dem peripherischen Nervensystem.” Henle u. Pflügers Zeitschr. 1866.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_93" href="#FNanchor_93" class="label">93</a> -<i>Erb</i>: “Zur Pathologie und pathologischen Anatomie peripherischer Paralysen.” -Deutsches Arch. f. Klin. Med. 1869.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_94" href="#FNanchor_94" class="label">94</a> -<i>Grünhagen</i>: “Versuche über intermittierende Nervenreizung.” Pflügers Archiv. -Bd. 6, 1872.—<i>Funke-Grünhagen.</i> Lehrbuch der Physiologie Bd. I, 1876.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_95" href="#FNanchor_95" class="label">95</a> -<i>Effron</i>: “Beiträge zur allgemeinen Nervenphysiologie.” Pflügers Arch. Bd. 36, -1885.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_96" href="#FNanchor_96" class="label">96</a> -<i>Hirschberg</i>: “In welcher Beziehung stehen Leitung und Erregung der Nervenfaser -zu einander?” Pflügers Arch. Bd. 39, 1886.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_97" href="#FNanchor_97" class="label">97</a> -<i>G. Weiss</i>: “La conductibilité et l’excitabilité des nerfs.” Journ. de physiol. et de -pathol. générale. T. V. 1903.—“Influence des variations de temperature et des actions -méchaniques sur l’excitabilité et la conductibilité des nerfs.” <i>Ibidem.</i></p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_98" href="#FNanchor_98" class="label">98</a> -<i>Hermann</i>: “Handbuch der Physiologie.” Bd. II, I Leipzig 1879.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_99" href="#FNanchor_99" class="label">99</a> -<i>Szpilmann und Luchsinger</i>: “Zur Beziehung von Leitungs- und Erregungsvermögen -der Nervenfaser.” Pflügers Arch. Bd. 24, 1881.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_100" href="#FNanchor_100" class="label">100</a> -<i>Gad</i>: “Ueber Trennung von Reizbarkeit und Leitungsfähigkeit des Nerven.” -(Nach Versuchen des Herrn Sawyers) Arch. f. Anat. u. Physiol. physiol. Abt. 1888.</p> - -<p>Derselbe: “Ueber Leitungsfähigkeit und Reizbarkeit des Nerven in ihren Beziehungen -zur Längs- und Querschnitts erregbarkeit.” Nach Versuchen des Herrn Piotrowski -Arch. f. Anat. und Physiol. physiol. Abt. 1889.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_101" href="#FNanchor_101" class="label">101</a> -<i>Piotrowski</i>: “Ueber Trennung von Reizbarkeit und Leitungsfähigkeit des Nerven.” -Arch. f. Anat. u. Physiol. physiol. Abt. 1893.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_102" href="#FNanchor_102" class="label">102</a> -<i>Wedenski</i>: “Die fundamentalen Eigenschaften des Nerven unter Einwirkung -einiger Gifte.” Pflügers Arch. Bd. 82, 1900.</p> - -<p>The same: “Excitation, inhibition et narcose.” Compt. rendus du v. Congres -internat. de Physiologie à Turin 1901.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_103" href="#FNanchor_103" class="label">103</a> -<i>Werigo</i>: “Zur Frage über die Beziehungen zwischen Erregbarkeit und Leitungsfähigkeit -des Nerven.” (Nach Versuchen von stud. Rajmist.) Pflügers Arch. Bd. 76, -1899.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_104" href="#FNanchor_104" class="label">104</a> -<i>Dendrinos</i>: “Ueber das Leitungsvermögen des motorischen Froschnerven.”</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_105" href="#FNanchor_105" class="label">105</a> -<i>Noll</i>: “Ueber Erregbarkeit und Leitungsvermögen des motorischen Nerven unter -dem Einfluss von Giften und Kälte.” Zeitsch. f. Allgem. Physiol. Bd. III, 1907.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_106" href="#FNanchor_106" class="label">106</a> -<i>Fr. W. Fröhlich</i>: “Erregbarkeit und Leitfähigkeit des Nerven.” Zeitschr. f. -allgem. Physiol. Bd. III, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_107" href="#FNanchor_107" class="label">107</a> -<i>Boruttau und Fröhlich</i>: “Erregbarkeit und Leitfähigkeit des Nerven.” Zeitschrift -f. allgem. Physiologie Bd. IV, 1904. The same: “Electropathologische Untersuchungen -ueber die Veränderungen der Erregungswelle durch Schädigung des Nerven.” Pflügers -Arch. Bd. 105, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_108" href="#FNanchor_108" class="label">108</a> -<i>Fröhlich</i>: “Die Verringerung der Fortpflanzungsgeschwindigkeit der Nervenerregung -durch Narkose and Erstickung des Nerven.” Zeitschrift allgem. Physiologie Bd. -III, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_109" href="#FNanchor_109" class="label">109</a> -<i>Izuo Koike</i>: “Ueber die Fortleitung des Erregungsvorgangs in einer narkotisierten -Nervenstrecke.” Zeitsch. f. Biologie Bd. 5, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_110" href="#FNanchor_110" class="label">110</a> -<i>Gotch</i>: “The submaximal electrical response of nerve to a single stimulus.” -Journal of Physiology, Vol. XXVIII, 1902.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_111" href="#FNanchor_111" class="label">111</a> -<i>Fröhlich</i>: “Erregbarkeit und Leitfähigkeit des Nerven.” Zeitschr. f. allgem. Physiologie, -Bd. III, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_112" href="#FNanchor_112" class="label">112</a> -<i>Keith Lucas</i>: “On the gradation of activity in a skeletal muscle fiber.” Journal -of Physiology, Vol. IX, 1888. The same: The “all or none” contractions of the -amphibian skeletal muscle-fiber. Journ. of Physiology, Vol. XXXVIII, 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_113" href="#FNanchor_113" class="label">113</a> -Compare <i>Pflüger</i>: “Ueber die physiologische Verbrennung in den lebendigen Organismen.” -In Pflügers Archiv. Bd. 10, 1875. Further: <i>L. Hermann</i>: “Handbuch der -Physiologie, Bd. II, Allgemeine Nervenphysiologie,” 1879.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_114" href="#FNanchor_114" class="label">114</a> -The enormously extensive literature on this subject up to the most recent date is -quoted in <i>Cremer</i>: “Die allgemeine Physiologie der Nerven.” In <i>Nagels</i> Handbuch der -Physiologie des Menschen, Bd. IV, 1909. Braunschweig.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_115" href="#FNanchor_115" class="label">115</a> -<i>M. Wolff</i>: “Ueber die fibrillaren Structuren in der Leber des Frosches.” Anatom. -Anzeiger Bd. 26, 1905.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_116" href="#FNanchor_116" class="label">116</a> -<i>Max Verworn</i>: “Bemerkungen zum heutigen Stand der Neuronlehre.” Medicin. -Klinik, Jahrg. IV, 1908.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_117" href="#FNanchor_117" class="label">117</a> -<i>M. v. Lenhossek</i>: “Ueber die physiologische Bedeutung der Neurofibrillen.” -Anatom. Anzeiger Bd. 36, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_118" href="#FNanchor_118" class="label">118</a> -<i>Richard Goldschmidt</i>: “Das Nervensystem von Ascaris lumbricoides und megalocephala. -Ein Versuch in den Aufbau eines einfachen Nervensystems einzudringen.” -III Teil. Festschrift zum 60 Geburtstage Richard Hertwigs Bd. II, 1910, Jena.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_119" href="#FNanchor_119" class="label">119</a> -<i>Marey</i>: “Des excitations artificielles du cœur.” Travaux du lab. de M. <i>Marey</i> -II, 1875. The same: “Des mouvements qui produit le cœur lorsqu’il est soumis à des -excitations artificielles.” Comptes rendues de l’academie des sciences T. L. XXXII, -1876.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_120" href="#FNanchor_120" class="label">120</a> -<i>Bowditch</i>: “Ueber die Eigenthümlichkeiten der Reizbarkeit welche die Muskelfasern -des Herzens Zeigen.” Arbeiten aus der physiologischen Anstalt zu Leipzig, 1872.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_121" href="#FNanchor_121" class="label">121</a> -<i>Kronecker</i>: “Das charakteristische Merkmal der Herzmuskelbewegung.” Beiträge -zur Anatomie und Physiologie als Festgabe f. Carl Ludwig zum 15, Oct. 1874, gewidmet -von seinen Schülern. Leipzig 1874.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_122" href="#FNanchor_122" class="label">122</a> -<i>Th. W. Engelmann</i>: “Beobachtungen und Versuche am suspendierten Herzen -III. Refractäre Phase und compensatorische Ruhe in ihrer Bedeutung für den Herzrhythmus.” -Pflügers Arch. Bd. 59, 1895.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_123" href="#FNanchor_123" class="label">123</a> -<i>Broca et Richet</i>: “Période réfractaire dans les centres nerveux.” Comptes rendus -de l’academie des sciences 1897. Further <i>Richet</i>: “La vibration nerveuse.” Revue -scientific Déc. 1899.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_124" href="#FNanchor_124" class="label">124</a> -<i>Zwaardemaker und Lans</i>: “Ueber das Stadium relativer Unerregbarkeit als -Ursache des intermittierenden Charakters des Lidschlagreflexes.” Centralblatt für -Physiol. XIII, 1899.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_125" href="#FNanchor_125" class="label">125</a> -<i>Zwaardemaker</i>: “Sur une phase réfractaire du reflex déglutition.” Arch. international -de physiologie Vol. I, 1900.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_126" href="#FNanchor_126" class="label">126</a> -<i>Max Verworn</i>: “Zur Kenntniss der physiologischen Wirkungen des Strychnins.” -Arch. f. Anat. u. Physiol. physiol. Abth., 1900. “Ermüdung Erschöpfung and Erholung -der nervösen Centra des Rückenmarks.” Ibidem, 1900. “Die Biogenhypothese.” -Jena 1903. “Die Vorgänge in den Elementen des Nervensystems.” Zeitsch. f. allgem. -Physiologie Bd. VI, 1907.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_127" href="#FNanchor_127" class="label">127</a> -<i>Dodge</i>: “A systematic exploration of a normal knee jerk, its technique, the form -of the muscle contraction, its amplitude, its latent time and its theory.” Zeitsch. f. -allgem. Physiol. Bd. XII, 1911.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_128" href="#FNanchor_128" class="label">128</a> -<i>Gotch and Burch</i>: “The electrical response of nerve to two stimuli.” Journ. of -Physiology, Vol. XXIV, 1899.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_129" href="#FNanchor_129" class="label">129</a> -<i>Florence Buchanan</i>: “The electrical response of muscle in different kinds of persistent -contraction.” Journ. of Physiology, Vol. XXVII, 1901–1902.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_130" href="#FNanchor_130" class="label">130</a> -<i>Keith Lucas</i>: “On the refractory period of muscle and nerve.” Journ. of Physiology, -Vol. XXXIX, 1909–1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_131" href="#FNanchor_131" class="label">131</a> -<i>Massart</i>: Annales de l’Institut Pasteur 1901.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_132" href="#FNanchor_132" class="label">132</a> -<i>Jennings</i>: “Studies on reactions to stimuli in unicellular organisms.” IX. -American Journal of Physiology, 1902.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_133" href="#FNanchor_133" class="label">133</a> -<i>Bowditch</i>, 1. c.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_134" href="#FNanchor_134" class="label">134</a> -<i>Hidetsurumaru Ishikawa</i>: “Ueber die scheinbare Bahnung.” Zeitschrift f. allgem. -Physiologie Bd. XI, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_135" href="#FNanchor_135" class="label">135</a> -<i>Langendorff u. Winterstein</i>: “Beiträge zur Reflexlehre.” Pflüger’s Arch. Bd. 127, -1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_136" href="#FNanchor_136" class="label">136</a> -<i>Fr. W. Fröhlich</i>: “Beiträge zur Analyse der Reflexfunction des Rückenmarks -mit besonderer Berücksichtigung von Tonus, Bahnung und Hemmung.” Zeitschrift f. -allgem. Physiologie Bd. IX, 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_137" href="#FNanchor_137" class="label">137</a> -<i>Julius Vészi</i>: “Der einfachste Reflexbogen im Rückenmark.” Zeitschr. f. allgem. -Physiologie Bd. XI, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_138" href="#FNanchor_138" class="label">138</a> -<i>H. Kronecker</i>: “Das charakteristische Merkmal der Herzmuskelbewegung.” -Beiträge zur Anatomie and Physiologie als Festgabe Carl Ludwig zum 15 October -1874 gewidmet. Leipzig 1874.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_139" href="#FNanchor_139" class="label">139</a> -<i>Max Verworn</i>: “Allgemeine Physiologie.” V. Auflage. Jena 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_140" href="#FNanchor_140" class="label">140</a> -<i>Max Verworn</i>: “Ermüdung Erschöpfung und Erholung der nervösen Centra des -Rückenmarks.” Arch. f. Anat. u. Physiol. physiol. Abt. Suppl. 1900. The same: -Ermüdung und Erholung. Berliner Klin. Wochenschrift 1901.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_141" href="#FNanchor_141" class="label">141</a> -As I have not yet described this method elsewhere the above figure will suffice -for demonstration.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_142" href="#FNanchor_142" class="label">142</a> -<i>Tiedemann</i>: “Untersuchungen über das absolute Refractäerstadium and die -Hemmungsvorgaenge im Rückenmark des Strychninfrosches.” Zeitschrift f. allgem. -Physiologie Bd. X, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_143" href="#FNanchor_143" class="label">143</a> -<i>Alexander Lipschütz</i>: “Ermüdung und Erholung des Rückenmarks.” Zeitschr. -f. allgem. Physiologie Bd. VIII, 1908.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_144" href="#FNanchor_144" class="label">144</a> -<i>Fillié</i>: “Studien über die Erstickung und Erholung des Nerven in Flüssigkeiten.” -Zeitschr. f. allgem. Physiologie Bd. VIII, 1908.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_145" href="#FNanchor_145" class="label">145</a> -<i>Bowditch</i>: “Ueber die Eigenthümlichkeiten der Reizbarkeit, welche die Muskelfasern -des Herzens zeigen.” Arbeiten aus der physiologischen Anstalt zu Leipzig VI -Jahrgang 1871, Leipzig 1872.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_146" href="#FNanchor_146" class="label">146</a> -<i>Tiegel</i>: “Ueber den Einfluss einiger willkürlichen Veränderungen auf die -Zuckungshöhe des untermaximal gereizten Muskels.” Arbeiten aus der physiol. -Anst. zu Leipzig X Jahrgang 1875, Leipzig 1876.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_147" href="#FNanchor_147" class="label">147</a> -Minot: “Experiments on tetanus.” Journ. of Anat. and Physiol. Vol. XII.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_148" href="#FNanchor_148" class="label">148</a> -<i>Fr. W. Fröhlich</i>: “Ueber die scheinbare Steigerung der Leistungsfähigkeit des -quergestreiften Muskels im Beginn der Ermüdung. (Muskel Treppe), der Kohlensäurewirkung -und der Wirkung anderer Narcotica (Aether, Alkohol).” Zeitschr. f. -allgem. Physiologie Bd. V, 1905.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_149" href="#FNanchor_149" class="label">149</a> -<i>Frederic S. Lee</i>: “The cause of the Treppe.” Americ. Journ. of Physiol. Vol. -XVIII, 1907.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_150" href="#FNanchor_150" class="label">150</a> -<i>Alexander Rollet</i>: “Ueber die Veränderlichkeit des Zuckungsverlaufs quergestreifter -Muskeln bei fortgesetzter periodischer Erregung und bei der Erholung -nach derselben.” Pflügers Arch. Bd. 64, 1896.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_151" href="#FNanchor_151" class="label">151</a> -<i>Hidetsurumaru Ishikawa</i>: “Ueber die scheinbare Bahnung.” Zeitschr. f. allgem. -Physiologie Bd. XI, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_152" href="#FNanchor_152" class="label">152</a> -<i>Hermann</i>: “Untersuchungen über den Stoffwechsel der Muskeln ausgehend vom -Gaswechsel derselben.” Berlin 1867.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_153" href="#FNanchor_153" class="label">153</a> -<i>Joteyko</i>: “La fatigue et la respiration élémentaire du muscle.” Paris 1896.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_154" href="#FNanchor_154" class="label">154</a> -<i>Julius Vészi</i>: “Zur Frage des Alles oder Nichts Gesetzes beim Strychninfrosch.” -Zeitschr. fur allgem. Physiologie Bd. XII, 1911.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_155" href="#FNanchor_155" class="label">155</a> -<i>Hidetsurumaru Ishikawa</i>: “Ueber die scheinbare Bahnung.” Zeitschr. f. allgem. -Physiologie Bd. III, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_156" href="#FNanchor_156" class="label">156</a> -<i>Fr. W. Fröhlich</i>: “Das Sauerstoffbedürfniss des Nerven.” Zeitschr. f. allgem. -Physiologie Bd. III, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_157" href="#FNanchor_157" class="label">157</a> -<i>K. H. Baas</i>: “Zur Frage nach dem Sauerstoffbedürfniss des Froschnerven.” -Pflügers Arch. Bd. 103, 1904.</p> - -<p><i>K. Frick</i>: “Die Abhängigkeit der Erregbarkeit des peripherischen Nerven vom -Sauerstoff.” Inaugural Dissertation vorgelegt der medicinischen Facultät der Univers. -Berlin (Aus dem physiologischen Institut der Univers.). Berlin 1904.</p> - -<p><i>Uchtomsky und Dernoff</i>: “Zur Frage nach dem Sauerstoffbedürfniss der Nerven.” -Travaux du laboratoire de Physiologie a l’université de St. Petersbourg II Année -1907.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_158" href="#FNanchor_158" class="label">158</a> -<i>Fr. W. Fröhlich</i>: “Die Ermüdung des markhaltigen Nerven.” Zeitschr. f. allgem. -Physiologie Bd. III, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_159" href="#FNanchor_159" class="label">159</a> -<i>Wedensky</i>: “Die fundamentalen Eigenschaften des Nerven unter Einwirkung -einiger Gifte.” Pflügers Arch. Bd. 82, 1900.</p> - -<p>The same: “Erregung, Hemmung und Narkose.” In the same place. Bd. 100, -1903.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_160" href="#FNanchor_160" class="label">160</a> -<i>Thörner</i>: “Die Ermüdung des markhaltigen Nerven.” Zeitschr. f. allgem. Physiologie -Bd. VIII, 1908.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_161" href="#FNanchor_161" class="label">161</a> -<i>Thörner</i>: “Weitere Untersuchungen über die Ermüdung des markhaltigen Nerven. -Die Ermüdung in Luft und die scheinbare Erregbarkeitssteigerung.” Zeitschr. f. -allgem. Physiologie Bd. X, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_162" href="#FNanchor_162" class="label">162</a> -<i>Thörner</i>: “Weitere Untersuchungen über die Ermüdung des markhaltigen Nerven. -Die Ermüdung und Erholung unter Ausschluss von Sauerstoff.” Zeitschr. f. allgem. -Physiologie Bd. X, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_163" href="#FNanchor_163" class="label">163</a> -<i>Ranke</i>: “Untersuchungen über die chemischen Bedingungen der Ermüdung des -Muskels.” Arch. f. Anat. u. Physiol. 1863 u. 1864.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_164" href="#FNanchor_164" class="label">164</a> -<i>Nagai</i>: “Der Einfluss verschiedener Narcotica, Gase and Salze auf die Schwimmgeschwindigkeit -von Paramæcium.” Zeitschr. f. allgem. Physiologie Bd. VI, 1907.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_165" href="#FNanchor_165" class="label">165</a> -<i>Herbert S. Jennings</i>: “Studies on reactions to stimuli in unicellular organisms. -I. Reactions to chemical, osmotic and mechanical stimuli in the ciliate infusoria.” -Journal of Physiology, Vol. XXI, 189 F.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_166" href="#FNanchor_166" class="label">166</a> -<i>Pütter</i>: “Studien über Thigmotaxis bei Protisten.” Arch. f. Anat. and Physiologie, -physiol. Abt. Suppl. 1900.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_167" href="#FNanchor_167" class="label">167</a> -<i>Pütter</i>: l. c.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_168" href="#FNanchor_168" class="label">168</a> -<i>Max Verworn</i>: “Allgemeine Physiologie.” V Aufl. Jena 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_169" href="#FNanchor_169" class="label">169</a> -<i>M. Schiff</i>: “Lehrbuch der Physiologie des Menschen.” Bd. I, Lahr 1858.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_170" href="#FNanchor_170" class="label">170</a> -<i>Gaskell</i>: “On the innervation of the heart with especial reference to the heart of -the tortoise.” Journ. of Physiology, Vol. IV, 1884.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_171" href="#FNanchor_171" class="label">171</a> -<i>Ewald Hering</i>: “Zur Theorie der Vorgänge in der lebendigen Substanz.” Lotos -IX. Prag 1888.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_172" href="#FNanchor_172" class="label">172</a> -<i>Meltzer</i>: “Inhibition.” New York Medical Journal, 1899.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_173" href="#FNanchor_173" class="label">173</a> -<i>Max Verworn</i>: “Erregung und Lähmung. Vortrag gehalten in der allgemeinen -Sitz. der Gesellsch.” Deutsch. Naturf. u. Aerzte zu Frankfurt a. M. 1896. Verh. d. -Ges. Deutsch. Nat. u. Aerzte 1896.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_174" href="#FNanchor_174" class="label">174</a> -<i>Max Verworn</i>: “Zur Kenntniss der physiologischen Wirkungen des Strychnins.” -Arch. f. Anat. u. Physiol. physiolog. Abth. 1900. The same: “Ermüdung, Erschöpfung -and Erbolung.” Ibidem Suppl. 1900.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_175" href="#FNanchor_175" class="label">175</a> -<i>Tiedemann</i>: “Untersuchungen über das absolute Refractärstadium und die -Hemmungsvorgänge im Rückenmark des Strychninfrosches.” Zeitschr. f. allgem. -Physiologie Bd. X, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_176" href="#FNanchor_176" class="label">176</a> -<i>Fr. W. Fröhlich</i>: “Die Analyse der an der Krebsschere auftretenden Hemmungen.” -Zeitschr. f. allgem. Physiologie Bd. VII, 1907. The same: “Der Mechanismus -der nervösen Hemmungsvorgänge.” Medizin. naturwiss. Arch. Bd. I, 1907. The -same: “Beiträge zur Analyse der Reflexfunction des Rückenmarks mit besonderer -Berücksichtigung von Tonus, Bahnung und Hemmung.” Zeitschr. f. allgem. -Physiologie Bd. IX, 1909. The same: “Experimentelle Studien am Nervensystem der -Mollusken 12. Summation und scheinbane Bahnung, Tonus, Hemmung und -Rhythmus am Nervensystem von Aplysia limacina.” Zeitschr. f. allgem. Physiol. Bd. -XI, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_177" href="#FNanchor_177" class="label">177</a> -<i>Marey</i>: “Des excitations artificielles du cœur.” Trav. du lab. de M. <i>Marey</i> II, -1875. The same: “Des mouvements que produit le cœur lorsqu’il est soumis à des -excitations artificielles.” Compt. rend. de l’acad. des sciences T. LXXXVII, 1876.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_178" href="#FNanchor_178" class="label">178</a> -<i>Samojloff</i>: “Actionsströme bei summierten Muskelzuckungen.” Arch. f. Physiologie -Suppl. 1908. The same: “Über die Actionsstromkurve des quergestreiften -Muskels bei zwei rasch aufeinanderfolgenden Reizen.” Zentralblatt f. Physiol. 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_179" href="#FNanchor_179" class="label">179</a> -<i>Keith Lucas</i>: “On the refractory period of muscle and nerve.” Journ. of Physiology, -XXXIX, 1909–10. The same: “On the recovery of muscle and nerve after the -passage of a propagated disturbance.” <i>Ibid.</i> XXXXI, 1910–11.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_180" href="#FNanchor_180" class="label">180</a> -<i>Gotch</i>: “The delay of the electrical response of nerve to a second stimulus.” -Journ. of Physiology, XXXX, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_181" href="#FNanchor_181" class="label">181</a> -<i>Waller</i>: “Observations on isolated nerve.” Croonian Lecture, Philosophical -transactions. 1897.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_182" href="#FNanchor_182" class="label">182</a> -<i>Boruttau</i>: “Die Actionsströme und die Theorie der Nervenleitung.” Pflügers Arch. -Bd. 84, 1901.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_183" href="#FNanchor_183" class="label">183</a> -<i>Boruttau und Fröhlich</i>: “Electropathologische Untersuchungen. Ueber die -Aenderung der Erregungswelle durch Schädigung des Nerven.” Pflügers Arch. Bd. -105, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_184" href="#FNanchor_184" class="label">184</a> -<i>Thörner</i>: “Die Ermüdung des markhaltigen Nerven.” Zeitschr. f. allgem. Physiologie -Bd. VIII, 1908, und Bd. N, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_185" href="#FNanchor_185" class="label">185</a> -<i>Fr. W. Fröhlich</i>: “Ueber die scheinbare Steigerung der Leistungsfähigkeit des -quergestreiften Muskels im Beginn der Ermüdung (Muskeltreppe), der Kohlensäurewirkung -und Wirkung anderer Narkotica (Aether, Alkohol).” Zeitschr. f. allgem. -Physiologie Bd. V, 1905. The same: “Das Princip der scheinbaren Erregbarkeitssteigerung.” -Zeitschr. f. allgem. Physiologie Bd. IX, 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_186" href="#FNanchor_186" class="label">186</a> -<i>Fr. Reinecke</i>: “Ueber die Entartungsreaction und eine Reihe mit ihr verwandter -Reactionen.” Zeitschr. f. allgem. Physiologie Bd. VIII, 1908.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_187" href="#FNanchor_187" class="label">187</a> -<i>Max Verworn</i>: “Psychophysiologische Protistenstudien. Experimentelle Untersuchungen.” -Jena 1889.</p> - -<p>The same: “Die physiologische Bedeutung des Zellkerns.” Pflügers Arch. Bd. 51, -1892.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_188" href="#FNanchor_188" class="label">188</a> -<i>Thörner</i>: “Weitere Untersuchungen über die Ermüdung des markhaltigen Nerven. -Die Ermüdung in Luft.” Zeitschr. f. allgem. Physiologie Bd. X, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_189" href="#FNanchor_189" class="label">189</a> -<i>Fr. W. Fröhlich</i>: “Ueber die scheinbare Steigerung,” etc. Zeitschr. f. allgem. -Physiol. Bd. V, 1905.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_190" href="#FNanchor_190" class="label">190</a> -<i>Keith Lucas</i>: “On the gradation of activity in a skeletal muscle fiber.” Journ. -of Physiology, Vol. XXXIII, 1905–06. The same: “The all or none law of contraction -of the skeletal muscle-fiber.” Journ. of Physiology, Vol. XXXIII, 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_191" href="#FNanchor_191" class="label">191</a> -<i>Sherrington</i>: “Ueber das Zusammenwirken der Rückenmarksreflexe and das -Princip der gemeinsamen Strecke.” Ergebnisse der Physiologie. Jahr. IV, 1905.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_192" href="#FNanchor_192" class="label">192</a> -<i>Sherrington</i>: “The integrative action of the nervous system.” New York 1906.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_193" href="#FNanchor_193" class="label">193</a> -<i>Fr. W. Fröhlich</i>: “Der Mechanismus der nervösen Hemmungsvorgänge.” Med. -Natur. Arch. Bd. I, 1907. The same: “Beiträge zur Analyse der Reflexfunction des -Rückenmarks, etc.” Zeitschr. f. allgem. Physiologie Bd. IX, 1909. The same: “Das -Princip der scheinbaren Erregbarkeitssteigerung.” <i>Ibid.</i></p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_194" href="#FNanchor_194" class="label">194</a> -<i>Julius Vészi</i>: “Der einfachste Reflexbogen im Rückenmark.” Zeitschr. für allgem. -Physiol. Bd. IX, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_195" href="#FNanchor_195" class="label">195</a> -<i>Tiedemann</i>: “Untersuchungen über das absolute Refractärstadium und die -Hemmungsvorgänge im Rückenmark des Strychninfrosches.” Zeitschr. f. allgem. -Physiologie Bd. X, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_196" href="#FNanchor_196" class="label">196</a> -<i>Satake</i>: The researches are not yet published.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_197" href="#FNanchor_197" class="label">197</a> -<i>Sherrington</i>: “Experimental note on two movements of the eye.” Journ. of Physiology -XVII, 1895. The same: “On the reciprocal Innervation of antagonistic muscles.” -Proceed. of the Royal Soc., 1897.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_198" href="#FNanchor_198" class="label">198</a> -<i>Max Verworn</i>: “Die einfachsten Reflexwege im Rückenmark.” Zentralblatt f. -Physiologie Bd. XXIII. <i>Tiedemann</i>: “Untersuchungen über das absolute Refractärstadium -und die Hemmungsvorgänge im Rückenmark des Strychninfrosches.” Zeitschr. -f. allgem. Physiologie Bd. X, 1910. <i>Julius Vészi</i>: “Der einfachste Reflexbogen im -Rückenmark.” Zeitschr. f. allgem. Physiologie Bd. XI, 1910. <i>Oinuma</i>: “Ueber die -asphyktische Lähmung des Rückenmarks strychninisierter Frösche.” Zeitschr. f. -allgem. Physiol. Bd. XII, 1911. <i>Satake</i>: Not yet published.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_199" href="#FNanchor_199" class="label">199</a> -<i>Gotch</i>: “The submaximal electrical response of nerve to a single stimulus.” -Journ. of Physiology, Vol. XXVIII, 1902.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_200" href="#FNanchor_200" class="label">200</a> -<i>Thörner</i>: “Weitere Untersuchungen über die Ermüdung des markhaltigen Nerven: -Die Ermüdung in Luft,” etc. Zeitschr. f. allgem. Physiologie Bd. X, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_201" href="#FNanchor_201" class="label">201</a> -<i>Vészi</i>: “Zur Frage des Alles oder Nichtsgetzes beim Strychninfrosche.” Zeitschr. -f. allgem. Physiologie Bd. XII, 1911.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_202" href="#FNanchor_202" class="label">202</a> -<i>H. Winterstein</i>: “Ueber die Wirkung der Wärme auf den Biotonus der Nervenzentren.” -Zeitschr. f. allgem. Physiol. Bd. I, 1902. The same: “Wärmelähmung und -Narkose.” <i>Ibid.</i></p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_203" href="#FNanchor_203" class="label">203</a> -<i>Oskar Bondy</i>: “Untersuchungen über die Sauerstoffaufspeicherung in den Nervenzentren.” -Zeitschr. f. allgem. Physiol. Bd. II, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_204" href="#FNanchor_204" class="label">204</a> -<i>E. Overton</i>: “Studien über die Narkose, zugleich ein Beitrag zur allgemeinen -Pharmakologie.” Jena 1901.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_205" href="#FNanchor_205" class="label">205</a> -I have previously on another occasion briefly communicated the conclusions derived -from the investigations made at the Göttingen laboratory by my coworkers and myself. -Compare: <i>Max Verworn</i>: “Ueber Narkose.” Deutsche medicin. Wochenschrift, 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_206" href="#FNanchor_206" class="label">206</a> -<i>H. Winterstein</i>: “Zur Kenntniss der Narkose.” Zeitschr. für allgem. Physiol. -Bd. I, 1902.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_207" href="#FNanchor_207" class="label">207</a> -<i>Fr. W. Fröhlich</i>: “Zur Kenntniss der Narkose des Nerven.” Zeitschr. f. allgem. -Physiol. Bd. III, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_208" href="#FNanchor_208" class="label">208</a> -<i>Trevor B. Heaton</i>: “Zur Kenntniss der Narkose.” Zeitschr. f. allgem. Physiol. -Bo. 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_209" href="#FNanchor_209" class="label">209</a> -<i>Otto Warburg</i>: “Ueber die Oxydationen in lebenden Zellen.” Zeitschr. f. -physiol. Chemie Bd. 66, 1910. The same: “Ueber Beeinflussung der Oxydationen in -lebenden Zellen nach Versuchen an roten Blutkörperchen.” Zeitschr. f. physiol. -Chemie Bd. 69, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_210" href="#FNanchor_210" class="label">210</a> -<i>Joannovics und Pick</i>: “Intravitale Oxydationshemmung in der Leber durch Narkotica.” -Pflügers Arch. Bd. 140, 1911.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_211" href="#FNanchor_211" class="label">211</a> -<i>Bondy</i>: “Untersuchungen über die Sauerstoffspeicherung in den Nervencentren.” -Zeitschr. f. allgem. Physiol. Bd. III, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_212" href="#FNanchor_212" class="label">212</a> -<i>Baglioni</i>: “Bezichungenzwishen physiologischer Wirkung und chemischer Constitution.” -Zeitschr. f. allgem. Physiologie Bd. III, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_213" href="#FNanchor_213" class="label">213</a> -<i>Fr. W. Fröhlich</i>: “Zur Kenntniss der Narkose des Nerven.” Zeitschr. f. allgem. -Physiologie Bd. III, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_214" href="#FNanchor_214" class="label">214</a> -The experiments of <i>Ishikawa</i> have not as yet been published.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_215" href="#FNanchor_215" class="label">215</a> -<i>Trevors B. Heaton</i>: “Zur Kenntniss der Narkose.” Zeitschr. f. allgem. Physiologie -Bd. X, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_216" href="#FNanchor_216" class="label">216</a> -For the very extensive literature on this subject see <i>Reicher</i>: “Chemischexperimentelle -Studien zur Kenntniss der Narkose.” Zeitschr. f. klinische Medicin -Bd. 65, 1908.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_217" href="#FNanchor_217" class="label">217</a> -<i>Heaton</i>: l. c.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_218" href="#FNanchor_218" class="label">218</a> -Compare lecture V; lecture VII.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_219" href="#FNanchor_219" class="label">219</a> -The investigations have not yet been published.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_220" href="#FNanchor_220" class="label">220</a> -<i>Fr. W. Frölich</i>: “Das Sauerstoffbedürfniss des Nerven.” Zeitschr. f. allgem. -Physiol. Bd. III, 1904.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_221" href="#FNanchor_221" class="label">221</a> -<i>Max Verworn</i>: “Die physiologische Bedeutung des Zellkerns.” Pflügers Arch. -Bd. 51, 1891.</p> - -<p>The same: “Die Bewegung der lebendigen Substanz. Eine vergleichend-physiologische -Untersuchung der Contractionserscheinungen.” Jena 1892.</p> - -<p>The same: “Allgemeine Physiologie.” V Auflage. Jena 1909. In the last place -the same theory of the contraction movements with some new corrections is described.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_222" href="#FNanchor_222" class="label">222</a> -<i>Binz</i>: “Vorlesungen über Pharmakologie für Aerzte und Studierende.” II Aufl. -Berlin 1891.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_223" href="#FNanchor_223" class="label">223</a> -<i>Höber</i>: “Beiträge zur physikalischen Chemie der Erregung und der Narkose.” -Pflügers Arch. Bd. 120, 1907. The same: “Die physikalisch-chemischen Vorgänge der -Erregung.” Sammelreferat. Zeitschr. f. allgem. Physiol. Bd. X, 1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_224" href="#FNanchor_224" class="label">224</a> -<i>Bürker</i>: “Eine neue Theorie der Narkose.” Münchener Med. Wochenschrift, -1910.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_225" href="#FNanchor_225" class="label">225</a> -<i>Warburg</i>: “Ueber Beeinflussung der Sauerstoffathmung. II Mitteilung. Eine -Beziehung zur Constitution.” Zeitschr. f. physiolog. Chemie Bd. 71, 1911.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_226" href="#FNanchor_226" class="label">226</a> -<i>Max Verworn</i>: “Ueber Narkose.” Deutsche med-Wochenschrift, 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_227" href="#FNanchor_227" class="label">227</a> -<i>Hans Meyer</i>: “Welche Eigenschaft der Anaesthetica bedingt ihre narkotische -Wirkung?” Arch. experimentelle Pathol. u. Pharmacol. Bd. 42, 1899. Further: <i>Fritz -Baum</i>: “Ein physiologisch-chemischer Beitrag zur Theorie der Narkotica.” <i>Ibidem.</i></p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_228" href="#FNanchor_228" class="label">228</a> -<i>Overton</i>: The first communication of the results obtained by <i>Overton</i> were made -by <i>Rost</i>: “Zur Theorie der Narkose” in the Naturwiss. Rundschau Jarhrg. 1899. -<i>Overton</i> has treated the subject in detail in his work, “Studien über die Narkose -zugleich ein Beitrag zur allgemeinen Pharmakologie.” Jena 1901.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_229" href="#FNanchor_229" class="label">229</a> -<i>Mansfeld</i>: “Narkose und Sauerstoffmangel.” Pflügers Arch. Bd. 129, 1909.</p> - -</div> - -<div class="footnote"> - -<p><a id="Footnote_230" href="#FNanchor_230" class="label">230</a> -<i>Warburg</i>: “Ueber Beeinflussung der Sauerstoffatmung. II Mitteilung: Eine -Beziehung zur Constitution.” Zeitschrift f. physiol. Chemie Bd. 71, 1911.</p> - -</div> -</div> - -<div class="transnote mt3em"> -<a id="Spelling_corrections"></a> -<p>Return to <a href="#Transcribers_notes">transcriber’s notes</a></p> -<p><b>Spelling corrections</b>:<br /> -possibilites → possibilities<br /> -deliminated → delimitated<br /> -equilibrum → equilibrium<br /> -fur → für<br /> -künstliche Immunisirungsprocesse → künstlichen Immunisierungsprozesse<br /> -methan → methane<br /> -aldehyd → aldehyde<br /> -Rüchenmarks → Rückenmarks<br /> -metronom → metronome<br /> -irrritability → irritability<br /> -tranverse → transverse<br /> -the the → the<br /> -Mittleilung → Mitteilung<br /> -whereever → wherever<br /> -oxdyative → oxydative<br /> -anoxdyative → anoxydative</p> - -<p><b>Spelling inconsistencies</b>:<br /> -ae/æ/e (inconsistent ligatures)<br /> -cannot/can not<br /> -cell-pathology/cell pathology (inconsistent hyphenation)<br /> -æthyl/ethyl -</p> - -<p>Return to <a href="#Transcribers_notes">transcriber’s notes</a></p> -</div> - -<div style='display:block; margin-top:4em'>*** END OF THE PROJECT GUTENBERG EBOOK IRRITABILITY ***</div> -<div style='text-align:left'> - -<div style='display:block; margin:1em 0'> -Updated editions will replace the previous one—the old editions will -be renamed. -</div> - -<div style='display:block; margin:1em 0'> -Creating the works from print editions not protected by U.S. copyright -law means that no one owns a United States copyright in these works, -so the Foundation (and you!) can copy and distribute it in the United -States without permission and without paying copyright -royalties. 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