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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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