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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 23 cents extra. 
 
 STELLAR MOTIONS. WITH SPECIAL REFERENCE TO 
 MOTIONS DETERMINED BY MEANS OF THE SPECTRO- 
 GRAPH. By William Wallace Campbell, Sc.D., LL.D., Director of the 
 Lick Observatory, University of California. 
 Price $4.00 net; postage 23 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 GEN- 
 ERAL 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 
 
 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. 
 
 ^'Ho^nry 
 
 M»«KSIS«,, '"^"' 
 
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 assist- 
 ance of my co-workers during the course of more than two 
 decades in the physiological laboratories of Jena, Gottingcn and 
 Bonn, to unite therewith the results obtained by other investi- 
 gators 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 zoologist, the l)otanist, 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 num- 
 ber 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 
 
viii PREFACE 
 
 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 Veszi 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 espe- 
 cially 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 
 
 Contents: Introductory. Earliest period. Francis Glisson as founder 
 of the doctrine of irritability. Alhrecht von Haller. The vitalists. 
 Borden and Barthez. John Brown's system. Johannes Midler 
 and the specific energy of living substance. Rudolf Virchoufs 
 doctrine of the irritability of the cell. Discovery of the inhibitory 
 effects of stimulation. Weber, Schiff, Goltz, Setschenow, Sher- 
 rington. Claude Bernard studies on narcosis. Tropisms. Ehren- 
 herg, Engelmann, Pfcffer, Strasshnrger, Stahl. Semons specu- 
 lations on mneme 
 
 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. Defi- 
 nition of the conception of stimulation 18 
 
 III 
 
 Contents: The quality of the stimulus. Positive and negative altera- 
 tions of the factors which act as vital conditions. Extent of the 
 alteration in vital conditions or intensity of the stimulus. Thresh- 
 old stimuli, sub-threshold, submaximal, maximal and supermaxi- 
 mal 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 Ncrnst 
 law ^^ 
 
X CONTENTS 
 
 IV 
 
 Contents: Various examples of the effects of stimulation. Metab- 
 olism of rest and metabolism of stimulation. Metabolic equilib- 
 rium. Disturbances of equilibrium by stimuli. Quantitative and 
 qualitative alterations of the metabolism of rest under the influ- 
 ence of stimuli. Excitation and depression. Specific energy of 
 living substance. Qualitative alterations of the specific metab- 
 olism and their relations to pathology. Functional and cytoplastic 
 stimuli. Relations of the cytoplastic effects of stimuli to the func- 
 tional. Hypertrophy of activity and atrophy of inactivity. Meta- 
 bolic alterations during growth of the cell. Primary and second- 
 ary 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 exci- 
 tations. 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 decre- 
 ment of the nerve after artificial depression of irritability by nar- 
 cosis. 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 
 
CONTENTS xi 
 
 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 refrac- 
 tory 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 role 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 Para- 
 mecia. 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 : Summa- 
 tion and inhibition of excitations. Theory of the processes of 
 inhibition. Hering-Gaskell Theory. Inhibition as an expression 
 of the refractory period. Individual possibilites 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 stim- 
 uli 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. Condi- 
 tions of inhibitions. Various types of inhibition. Interference of 
 two series of stimuli. Relations in the nervous system. Peculiari- 
 ties of the nerve fibers. Conversion of the nerve by relative 
 fatigue from an isobolic into a heterobolic system 189 
 
xii CONTENTS 
 
 IX 
 
 Contents: Necessity of cellular physiological analysis of toxic depres- 
 sions by pharmacology. Apparent variety of processes of depres- 
 sion. 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 dis- 
 integration. 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 anoxyda- 
 tive disintegration in narcosis. Increase of the same by stimuli. 
 Depression by narcosis as a form of acute asphyxiation. Hypothe- 
 sis on the mechanism of depression of oxygen exchange by nar- 
 cotics. 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. Bor- 
 deu and Barthez. John Brown's system. Johannes Miiller and the 
 specific energy of living substance. Rudolf Virchows doctrine of the 
 irritability of the cell. Discovery of the inhibitory effects of stimu- 
 lation. Weber, Schiff, Goltz, Setschenow, Sherrington. Claude Ber- 
 nard studies on narcosis. Tropisms. Ehrenherg, Engelmann, Pfcffer, 
 Strassbnrger, 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 sub- 
 stance. In this sense irritability presents a problem of funda- 
 mental physiological importance. For if we could analyze tlie 
 irritability of living substance to its essence, then the nature of 
 Hfe 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 informa- 
 tion 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. 
 
2 IRRITABILITY 
 
 To the thinkers both in the field of physiology and medicine of 
 ancient and mediaeval times the conception of irritability was 
 quite foreign. Even a com_prehension 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 organ- 
 ism. It was also known that heat and cold, light and darkness 
 had an effect upon disease. They likewise believed in the influ- 
 ence 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 mediaeval times was the state of knowl- 
 edge 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 sub- 
 stance is Francis Glisson (1597-1677), member of the Collegium 
 Medicum in London and at the same time Professor in Cam- 
 bridge. 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 suhstantice energetica"'^ 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 
 
 1 Franciscus Glissonius : "Tractatus de natura substantiae energetica seu de vita 
 natura ej usque tribus primis facultatibus perceptiva, appetitiva, motiva," etc. Londini 
 M D C L XXII. 
 
THE HISTORY OF THE SUBJECT 3 
 
 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 sub- 
 sistence 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 substanticc/' but 
 not finished until later and only published after his death. In 
 this "Tractatus de ventriculo et intestinis/'^ 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 forct, vcl, pcrpctuo 
 quiesceret, vet perpetuo idem ageret." The fundamental factor of 
 this irritability Glisson attributes to the "perccptio/^ which he dis- 
 tinguishes as a "perceptio naturalis, sensitira and animalis." 
 The want of clearness produced here by Glisson's artificial distinc- 
 tions and mode of expression is in part removed if we endeavor 
 
 1 Franciscus Glissonius: "Tractatus de ventriculo et intestinis cui praemittitur alius 
 de partibus continentibus in genere et in specie de iis abdominis." Amstelodami M D 
 C L XXVII. 
 
4 IRRITABILITY 
 
 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 ''Per- 
 ceptio 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 ah appe- 
 titu 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 sensa- 
 tion, 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 ah interna simiil per- 
 cipiatnr, non est cognitio sensitiva completa." Sensitivity is, 
 therefore, a special faculty, that is only based upon 'irritability. 
 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 
 
THE HISTORY OF THE SUBJECT 5 
 
 more so, because Glisson from the very first connected the irri- 
 tability of the Hving substance through its i)ossessing universal 
 energy with the phenomena in nature generally, just as we do 
 today two hundred years after, on the basis of the modern teach- 
 ings 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. l''irstly, 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 develo]) 
 his ideas. Secondly, his doctrines were so speculative and ditVi- 
 cult 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 Glissoii's expression "irritability" a 
 more concrete meaning was made by Holler (1708-1777)^ 
 Unfortunately, though, he confined this conception solely to 
 muscles, in that he understood by the term irritability "the capa- 
 bility of the muscles to contract, when stinuilated. as the result 
 of vital force {vi viva).'' He, therefore, applied the term "irri- 
 tabihty" 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 capabihty 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 
 
 I Albrecht v. Holier: "Elementa Physiologix corporis humani." Tomus IV. 
 Lausannae M D C L XVI. 
 
6 IRRITABILITY 
 
 system. ''Sola fibra miiscularis contrahitur vi viva; sentit solus 
 nervus et qua; 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 compari- 
 son to the correct fundamental thoughts of Glisson. This unfor- 
 tunate use of the term of ''irritability," "contractility" and 
 "sensitivity" has opened wide the gates to confusion and mis- 
 understanding. 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 "sensibilite generale" or a 
 common property of all living structures, both solid and fluid. 
 Besides this, each different part has according to him its "sensi- 
 bilite propre/' Here in place of the clear conception of irri- 
 tability we find one of more or less mythical nature possessing 
 traces of StahVs "anima." Nevertheless we observe here the 
 idea that all living organisms possess in common a capability to 
 respond to stimuli. Even though Borden s differentiation of the 
 "sensibilite propre" and the "sensibilite generale" is too artificial 
 and the coexistence of both not justifiable, his discussion of the 
 "sensibilite 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 funda- 
 mental 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 
 "sensibilite avec perception^ and "sensibilite sans perception", 
 using the term sensibility in the sense adopted by Bordeu and 
 which today we, with Glisson, call irritability. 
 
 In this way serious thinkers of that time trifled with the words 
 irritability, sensitivity, contractility, perception. This led to 
 
THE HISTORY OF THE SUBJECT 7 
 
 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, wdiich was the beginning of fur- 
 ther development, came from England in the works of John 
 Brozvn (1735-1788),^ a man who was as talented as he was dis- 
 solute. Brozvn was an independent thinker, not without genius, 
 w^hose 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 eft'ects, which the 
 "stimuli" produce on the irritable organs. This was an important 
 advance and from a wilderness of trifling conceptions his obser- 
 vations 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 wonder- 
 ful 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 patliology. 
 is the following: Every living, that is, excitable system, is con- 
 tinually influenced by stimuli. The stimuli consist of either exter- 
 nal factors, such as heat, food, foreign matter, poisons, etc., 
 or inner factors which result from the influence of the activity 
 
 1 /o/tn Brown; "Elementa medicinse." 1778. English translation. London 1778. 
 
8 IRRITABILITY 
 
 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 struc- 
 tures of the body, and even in the same individual at differ- 
 ent times under different circumstances. The strength of the 
 "excitement" depends on the one hand upon the degree of irri- 
 tability, 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 dura- 
 tion, 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 set- 
 back in the history of the teaching of irritability produced by the 
 confusions of conceptions created by Holler 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 medi- 
 cine does not contain teachings which in a hundred years will 
 also prove untenable. 
 
 Johannes Muller (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 Borden's term ''sensibilite pro pre" 
 or ''sensibilite particuliere." 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 
 
THE HISTORY OF THE SUBJECT 9 
 
 upon the kind of stimulus acting upon them. Johannes Miillcr, 
 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:^ "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 pro- 
 duced, 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 secre- 
 tory 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 Miiller- 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. 
 
 As Johannes Miillcr already clearly emphasizes, it is here not 
 
 1 Johannes Miiller: "tJber die phantastischen Gesichtserscheinungen. Eine physiolo- 
 gische Untersuchung mit einer physiologischen Urkunde des Aristotles iiber den 
 Traum, den Physiologen und den Arztcn gewidmet." Coblenz 1826. 
 
 2 Johannes Miiller: "Handbucli der Physiologic des Menschen fiir Vorlesungen." 
 Coblenz 1837. 
 
10 IRRITABILITY 
 
 the question of a law confined to the sense substance, but one 
 that apphes 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. Subse- 
 quently 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 founda- 
 tion 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 irri- 
 tability 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 momen- 
 tous conclusion, that disease must be considered as reactions of 
 the body cells to stimuli. In his epoch-making ''Cellular pathol- 
 ogic,"^ he has carried out this idea in a classical manner. By irri- 
 tability Virchozv understands "a property of the cells, by virtue 
 of which they are set into activity, when afifected 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 
 
 1 Rudolph Virchow: Die Zellularpathologie in ihrer Begrundung auf physiolo- 
 gische und pathologische Gewebelehre. 1 Aufl. Berlin 1858 — 4 Aufl. 1871. 
 
THE HISTORY OF THE SUBJECT 11 
 
 that a process of formative change may occur wliich prociuces 
 new elements in greater or less numbers. V ire how touches here 
 for the first time upon a question of extraordinary moment, the 
 important bearings of which have only now begun to be recog- 
 nized 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 grouj)s. is 
 hardly at all increased. It would be an error, however, to look 
 upon these different kinds of metabolism as quite indei)endent. 
 Considering the close correlation which all the phases of metal)- 
 olism 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, Virchoiv seems already to 
 have felt that a sharp division between the different ])hases 
 and parts of functional metabolism in the cell does not exist, for 
 he says: "It is true that it cannot be denied that, especially be- 
 tween 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, depend- 
 ing 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 dis- 
 turbance 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 
 
12 IRRITABILITY 
 
 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 per- 
 ceive, the nerve moves no bone, the cartilage does not think." 
 In this way Virchozu rediscovered in the domain of pathology 
 the law that his great teacher, Johannes Mitller, had already 
 clearly established in the field of physiology. But this law can 
 no longer be applied to all pathological disturbances of the nutri- 
 tive 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 con- 
 nected with the other before mentioned, of the relations between 
 functional and cytoplastic metabolism. 
 
 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 com- 
 pletely 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 indi- 
 rectly. No result, indeed, of present serology can alter in the 
 least degree the fact that every disease represents only a disturb- 
 ance 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 
 
THE HISTORY OF THE SUBJECT 13 
 
 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 fore- 
 ground of all researches and observations on irritability. It was 
 gradually, however, more and more recognized that the depress- 
 ing influence of stimuli played a great role in the vital process of 
 the organism. Brozvn 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 path- 
 ology. 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'^ in 1846 discovered the inhibitory effects of the 
 galvanic stimulation of the vagus upon the heart. 
 
 Since then the inhibitory processes in nerves have been fre- 
 quently investigated by Schiff (1823-1896), Golts (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 Sctscliowzv 
 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 Sctscliowzv 
 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 Sherring- 
 ton 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 
 
 1 Eduard Weber: "Muskelbewegung." Article in Wagner's Handwortcrbuch der 
 Physiologie, Bd. 3. Braunschweig 1846. 
 
14 IRRITABILITY 
 
 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 Ber- 
 nard (1813-1878)^ first discovered that the excitation of all living 
 substance could be depressed or totally suspended through the 
 influence of certain anaesthetics, 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 irri- 
 tability, but that it can also by means of certain substances be put 
 into the condition of "anaesthesia," 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 in- 
 creased by the addition of another group, which recently in con- 
 sequence 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 sur- 
 prising likeness to the mysterious attraction and repulsion in the 
 sphere of electricity and magnetism, occur universally in the vege- 
 table 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 
 
 1 Claude Bernard: "Lecons sur les phenomenes de la vie communs aux animaux et 
 aux vegetaux." Paris 1878. 
 
THE HISTORY OF THE SUBJECT 15 
 
 protistae had been often observed, especially by Jihrctibcrcf of 
 Berlin, well known for his researches on infusoria. Then 
 Engelmann, Pfcffer, Strassbunjcr, Stalil, 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 si)inal 
 cord reflexes of vertebrates. This divergence of oi)inion 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 enter- 
 tained 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 stimula- 
 tion, 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 intro- 
 duced 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 stinnili is jiroduced 
 
 1 Ehrenberg : "Die Infusionstiere als vollkommene Organismcii." Leipzig 1838. 
 
16 IRRITABILITY 
 
 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 dift'erence 
 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. 
 
 Finally, I should like to touch briefly upon a view of the irri- 
 tability of living substance which has recently been brought for- 
 ward by Semon} 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^ developed 
 many years ago and which later was accepted by Haeckel,^ 
 namely that heredity is a species of memory of the living sub- 
 stance. 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 reap- 
 pears. 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 
 
 1 Semon: "Die Mneme als erhaltendes Princip im Wechsel des organischen Gesche- 
 hens." Zweite verbesserte Auflage, Leipzig. 
 
 2 Ewald Hering: "Uber das Gedachtniss als allgemeine Function der organischen 
 Materie." Wein 1876. 
 
 3 Ernst Haeckel: "Die Perigenesis der Plastidule oder die Wellenzeugung der 
 Lebenstheilchen." Berlin 1876. 
 
THE HISTORY OF TIIK SUBJECT 1 
 
 •V 
 
 domain of the processes of heredity. Tliat wliich is termed 
 ''Mneme' and " Engramm" is not furtlier analyzed. Scmon 
 expressly declines to discuss the kind of alterations in which 
 the physical or chemical nature of an "lituiramm" consists. 
 Hence physiological analysis has not been advanced in any 
 way by Scmon's new formation of words api)lied 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 supijosing 
 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 con- 
 sider 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 "Ekplioric" of a state of 
 excitation that was once previously produced by an original 
 stimulus of some unknown kind, and of which the living sub- 
 stance of the muscle, in consequence of its "Mucmc," has retained 
 a latent "Engramm^f Here the deep gulf is apparent which 
 exists between the demands of a physiological analysis and the 
 futile explanation of the mneme doctrine. Physiological inves- 
 tigation must reject such a manner of treating its problems. 
 
 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 sim- 
 plest 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 lec- 
 tures 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. Con- 
 ception of cause. The conditional point of view applied to the investi- 
 gation of life. Conception of vital conditions. Definition of the 
 conception of stimulation. 
 
 The common problem of all scientific research is the investi- 
 gation and formulation of natural laws. The assumption of a 
 unity in the happenings and of existence in the world, in accord- 
 ance 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 scien- 
 tific 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 
 
THE NATURE OF STIMULATION 19 
 
 simply a method of expression of our thoughts and indeed tlie 
 most satisfactory form we have. We must, tlierefore. use lliose 
 symbols which are most closely adajned U) facts as the must 
 precise expression of these existing laws. What forms of 
 expression have we? 
 
 It might appear that a discussion of this fundamental cjuestion 
 has not a close connection with our special subject of i)hysiol()gy 
 of stimulation. This, however, is not the case. Indeed, it is an 
 irremissibly previous requirement not only for the ehicidation, 
 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 ijeing and haj)- 
 penings in accordance with natural laws, which today is widely 
 accepted in the scientific world as the only exact one, imi)lies the 
 assumption of a ''causation" according to which things are ex- 
 plained by the law of "cause" and "effect." V 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 prin- 
 ciples. 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? 
 
 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 pakxolithic cul- 
 ture. 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 cxtraor- 
 
 1 Compare with this Max Verxvorn: "Die Entwickelutig des mcnschlichcn Gcistcs." 
 Jena, Gustav Fischer, 1910. 
 
 Max Verworn: "Die Erforschung des Lebens." II Auflage. Jena, Gustax' Fischer, 
 1911. 
 
 The same: "Die Fragen nach den Grenzen der Erkenntniss." Jena, Gustav Fischer, 
 
 1908. 
 
 The same: "Allgemeine Physiologic." V Auflage. Gustav Fischer, 1909. 
 
20 IRRITABILITY 
 
 dinary degree to explain all happenings in the world anthropo- 
 morphously. 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 con- 
 ception which gave the impetus for the transition of human 
 thought from the era of the naively practical to the era of the 
 theoretical spirit in that far removed age. In this anthropo- 
 morphic 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 gen- 
 erally 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 naive specu- 
 lation. Even if a later evolution of human thought shows a con- 
 tinued endeavor to dismantle the conception of cause of its primi- 
 tive 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 exact- 
 ness, 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 mag- 
 net attracts iron, etc. In short, one has introduced a mysterious 
 
THE NATURE OF STIMULATION 21 
 
 unknown factor instead of being content willi the sinii)Ic descrip- 
 tion of facts, such as Kirchhop has advanced in llie field of 
 mechanics. Although of late natural science has also dispensed 
 more and more with conception of force as a means of explana- 
 tion, it is still today not wholly done away with. That which 
 applies to the conception of force is likewise true of the concej>- 
 tion of cause. 
 
 Another point concerning the application of the conception of 
 cause seems to me, however, to be of much more inii)ortancc, 
 namely that a single cause is held responsible for the taking 
 place of a process. One endeavors to explain a process in gen- 
 eral 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 hered- 
 ity, 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 w(^rld 
 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 ])rocess. 
 Such a view, however, which considers that two ditTereiU factors 
 existing at the same time are necessary to the acc(^mplishinent <>f 
 
 1 Gustav Kirchhoff: "Vorlesungen iiber mathematische Physik. Mcchanik." LcipziK 
 1876. 
 
22 IRRITABILITY 
 
 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 condi- 
 tions? 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 amoeboid cells on the oxygen of the 
 medium, and had found that the expansion phase of proto- 
 plasmic 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 sur- 
 rounding 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, with- 
 out our being able to agree. We were not in a position to dis- 
 tinguish 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 concep- 
 tion 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 neces- 
 sary 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 
 
THE NATURE OF STIMULATION 23 
 
 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 promi- 
 nent 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 hring 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 exist- 
 ence 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 tliex are 
 all necessary. 
 
 If one attempts to prove by means of concrete exami)les 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. .\n 
 example may serve to make this clear. I pour diluted hydro- 
 chloric 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 
 
24 IRRITABILITY 
 
 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 con- 
 tracts. The electric stimulus is the condition for the muscle con- 
 traction. But I can substitute for the induction shock a mechani- 
 cal 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 pro- 
 cesses, 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 
 
 ***^a 
 
 ■»*«; 
 
THE NATURE OF STIMULATKJN 25 
 
 individual conditioning components are themselves in their turn 
 contained as constituents of other complexes and are condi- 
 tioned 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 inter- 
 dependence between all things in the world. Ei'cr\ thing in the 
 world is indirectly dependent ui)on every other, altliougli often so 
 remotely that we are not able to trace the connection. Abs(jlute 
 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 depenci- 
 ence of one factor upon another. Nevertheless if we understand 
 by. conditions those which are connected by multitudinous inter- 
 mediate 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 ai)par- 
 ently 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 thor- 
 ough knowledge of the constancy of existence and happenings in 
 the world. 
 
 This analytical process, it is true, only advances very grad- 
 
26 IRRITABILITY 
 
 ually, and we must accept for the present, especially in the com- 
 plex biological processes, that a whole complexity of members 
 appear conditioned, and that a complex aggregate is a con- 
 dition 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 t<3 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 con- 
 dition 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 role. 
 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 charac- 
 teristic effect had not the other conditions been already previously 
 combined, had not certain special atoms in the molecule of the 
 
THE NATURE OF STIMULATION 27 
 
 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 pro- 
 cesses and the conditions brought about by them in the system 
 of the explosive substances or the muscle, and simj)ly know the 
 condition added last, then I have learned nothing of the process 
 itself, have explained nothing. The time of a])plication of a new 
 condition does not justify in any degree the assignment of a domi- 
 nant 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 pro- 
 cesses. 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 tzco 
 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 tlie 
 formation of carbon dioxide take place. Here water would be 
 considered the cause. Hence every condition would be in suc- 
 cession the cause for one and the same process. Under some 
 circumstances the same process would have scleral and in others 
 
28 IRRITABILITY 
 
 no cause at all. It is scarcely necessary for further comments 
 upon the value of the conception of cause for the scientific expla- 
 nation of a state or process. If we do not seek to introduce 
 into exact science the antiquated symbols which have become use- 
 less 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 super- 
 fluous 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 formulat- 
 ing 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 inde- 
 pendently of a thing. Every thing is equal to the sum of all its 
 conditions and depending upon the uniform constancy in accord- 
 ance with natural laws is solely determined by its conditions. 
 
THE NATURE OF STIMULATION 29 
 
 The problem of all scientific research consists wholly in the 
 ascertaining of the conditional interdependcncy. 
 
 A state or process is solely determined by the sum total of its 
 conditions. A state or process is identical zvith all of its condi- 
 tions in totality. From this it follows that c(jual states or pro- 
 cesses are always the expression of cfiual conditions and wherc- 
 ever unequal conditions exist, une(iual 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 en- 
 graved over the portals to the entrance of every scientific inves- 
 tigation. 
 
 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 emi)loy 
 the old conception of cause, for it belongs to that group of pro- 
 cesses 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 wdiat 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 ad- 
 vanced 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 con- 
 stituents of the wdiole complex process ui)on one aiK^thcr. For 
 
30 IRRITABILITY 
 
 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 pro- 
 cesses 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 condi- 
 tions. 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 indi- 
 vidual 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 surround- 
 ings. It is a deception resulting from the selective action of our 
 sensory organs, if we consider the bodies as separated and iso- 
 lated 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 experi- 
 mental 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 fur- 
 ther into the infinity of the world. An organism is consequently 
 no deliminated system and the vital process cannot, therefore, be 
 sharply separated from the processes in the medium. We can- 
 not 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 NATURE OF STIMULATION 31 
 
 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 knowl- 
 edge derived therefrom, is such that we are obliged to arbitrarily 
 take into consideration merely fragments from the endless inter- 
 dependence 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 com- 
 ponents 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, tempera- 
 ture, light, etc. But this distinction has only a practical value 
 for the study of the organism as an independent system. Theo- 
 retically 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 reach- 
 ing 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 rouglily for the 
 present define the conception of stimulus as follows : 
 
 A stimulus is every change in the zntal conditions. 
 
 The most essential point in this definition is the relaticMi of 
 the conception of stimulus to that of vital conditions. These 
 relations, however, call for a brief exi)lanation. Here again the 
 
32 IRRITABILITY 
 
 conditional method of observation saves us from error, for it 
 v^ould 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 con- 
 stituent 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 Amoeba Umax 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 Amoeba proteus with short, broad, lobate pseudopods. (Figure 
 1, A.) After a period of rest, however, they gradually assume the 
 characteristic elongated Umax 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 amoebae first 
 assume the shape of a ball (Figure 1, C), and then after a time, 
 stretch out long, pointed pseudopods, which give them the charac- 
 teristic form of Amoeba radiosa. (Figure 1, D and E.) They 
 remain permanently^ in this form. I have observed them for sev- 
 eral hours at a time. They move in the same manner as Amoeba 
 radiosa. They draw in one pseudopod, stretch out another and 
 float freely in the water in contrast to their Umax 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 
 
 1 Max Verworn: "Die polare Erregung der lebendigen Substanz durch den 
 galvanischen Strom." In Pfliigers Archiv f. d. ges. Physiologie Bd. 65, 1896. 
 
Fig. 1. 
 
34 IRRITABILITY 
 
 the amoebse under the vital conditions existing in tap water have 
 Umax form. The vital conditions undergo a change by the addi- 
 tion 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 Umax form, whilst for the 
 state of the system which shows itself in the radiosa form, it is a 
 vital condition. If I place the amoebae of the radiosa form once 
 again in tap water, they assume the proteus and then the Umax 
 form. The withdrawal of the solution of caustic potash, the pres- 
 ence 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, accord- 
 ing 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. 
 
 These facts show clearly that some stimuli can also be con- 
 sidered as vital conditions. In the absence of certain stimuli, 
 life could not exist for any length of time. Iil the highly dif- 
 ferentiated 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 chemi- 
 cal 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 
 
THE NATURE OF STIMULATION 35 
 
 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 nui>t 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 con- 
 tinuously 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 pro- 
 cesses, 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 condi- 
 tions another, by which it is followed. No state can perma- 
 nently exist as such. Every state is the product of the pre- 
 ceding, as it in turn conditions its successor. Consequently the 
 relations of the system to the surrounding medium also undergc* 
 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. Those 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 la>t phase 
 of development. The individual constituent processes of metab- 
 olism gradually change to such a degree that they can no longer 
 work harmoniously together. Then the cliain of processes is 
 interrupted at one point or another. The system develops into 
 
36 IRRITABILITY 
 
 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 con- 
 ception, which we have already stated, proves untenable on closer 
 analysis, but it, however, is based on the nature of the meth- 
 ods 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 sur- 
 roundings as an independent system, which leads us in conse- 
 quence 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 ner- 
 vous impulse is conducted from the cerebral cortex through the 
 pyramidal tract to a skeletal muscle, this impulse acts upon the 
 
THE NATURE OF STIMULATION 37 
 
 muscle cells as a stimulus. Although the explosion of the im- 
 pulse 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 stinuilus 
 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 stimu- 
 lation, like all artificial divisions wdiich we make in nature, must 
 always contain an arbitrary note, as in reality isolated systems 
 do not exist in the w^orld. I wished to show that, for this reason, 
 the conception of vital system, the conception of life, the con- 
 ception 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 con- 
 ditions, 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 work- 
 ing value. The definition in short is: ''Stimulus is every altera- 
 tion in the external vital conditions." 
 
 This definition gives to the conception of stinuilation its most 
 complete, that is to say, its generally applicable and simplest 
 form. The great importance from a methodical standpoint of 
 
38 IRRITABILITY 
 
 this definition of stimulation for the research of Hfe 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 betv^^een 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 per- 
 sistent stimuli. Series of individual stimuU. 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 pro- 
 cesses. 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 dilYeren- 
 tiates and presents in comprehensive order those various ele- 
 mentary factors which, among the innumerable varieties of stim- 
 uli, 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 quaUty 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 cer- 
 
40 IRRITABILITY 
 
 tain 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 inten- 
 sity and duration that it has become in the hand of the physiolo- 
 gist an invaluable means of research. 
 
 Alterations in those factors which act as vital conditions com- 
 pose the great mass of physiological stimuli which act continu- 
 ously 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 pres- 
 sure. The strength of the electric current, which may be applied, 
 can also be regulated. In accordance with the definition of stimu- 
 lation 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 per- 
 mitted 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 limi- 
 tation of the conception of stimuli would only result from the 
 one-sided consideration of an all too limited circle of facts. Con- 
 sidered from the point of view which results from a broader 
 range of experience, this narrow view becomes untenable. 
 
THE CHARACTERISTICS OF STIMri.I 41 
 
 In the first place it does not follow that only positive fluctua- 
 tions of a factor, acting as a vital condition, result in excitation 
 in the existing vital processes. The ivithdraival of water pro- 
 duces a diametrically opposite effect. .'\ muscle, from which 
 water has been removed, if exjjosed to dry air or placed in a 
 hypertonic salt solution, shows violent excitation, which manifests 
 itself in great increase of irritability and develoi)ment (jf lil)rillary 
 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^ 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.'^ 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 
 eiYect, are compelled to regard these alterations as stimuli, in 
 spite of the fact that they are negative variations of external 
 vital conditions. 
 
 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, ntnv a 
 depressing effect on the vital processes. This fact can be readily 
 
 1 Th. W. Engelmann: "Bacterium photometricum cin Bcitrag zur vcrglcichcndcn 
 Physiologic des Licht-und Farbensinns." In Pflugcrs .Xrchiv. lid. 30. 1883. 
 
 2 Jennings: "Behavior of the lower organisms." New Vork 1906. 
 
42 IRRITABILITY 
 
 demonstrated^ 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 tem- 
 perature to further increase only a few degrees the ciliary move- 
 ments are suddenly greatly retarded. The infusoria now swim 
 sluggishly through the field of vision and finally remain station- 
 ary. In this case the increase in the temperature has had a depress- 
 ing 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 con- 
 fronted by the same question. Nevertheless it is not at all neces- 
 sary 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 mus- 
 culus Gastrocnemius of the same side is connected with a writing 
 lever, one obtains, as Veszi~ 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, how- 
 ever, the excitation in the form of a tetanic contraction lasts for 
 
 1 Max Verworn: "Physiologisches Prakticum fur Medizinen." Jena 1907. 
 
 2 Julius Veszi: "Der einfachste Reflexbogen im Riickenmark." In Zeitschrift f. 
 allgemeine Physiologic Bd. XI, 1910. 
 
THE CHARACTERISTICS OF STIMULI 
 
 43 
 
 some time, provided that the stimulation is not at once stopped. H 
 now during tetanic stimulation of the ninth root the cij^dnh is at 
 the same time stimulated, with a strength of current equal to 
 that which previously hrought ahout contraction of the muscle, 
 
 Fig. 2. 
 
 Lower thick line shows duration of stimulation of 9th root; upper thick line that of 
 
 8th root. 
 
 instead of an increase and a strengthcti'uiy 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 stimu- 
 lation of the ninth root is interrupted and the eighth root now 
 again stimulated, one obtains once more, as in the begiiming. with 
 each stimulation a contraction of the muscle. This fact is illus- 
 trated by the accompanying tracings. (Figure 2.) In this inves- 
 tigation undertaken in the Gottingen 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 eft'ects could be jiroduced 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 conse- 
 quences it leads if the conception of stimulation is limited solely 
 to the cases in which an external factor has an exciting eflecl ; 
 
44 IRRITABILITY 
 
 and yet an immense number of instances of a like nature could 
 be cited to show the untenability of this view. 
 
 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 altera- 
 tion 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 con- 
 ception 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 deter- 
 mines the intensity of the stimulus. In relation to the intensity, 
 a differentiation of stimulation has been introduced, which is not 
 
THE CHARACTERISTICS OF STIMULI 45 
 
 dependent upon the absolute intensity of the stinuihis, 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 supcrmaximal stimu- 
 lation. 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 sutYi- 
 cient to bring about a perceptible response. The threshold of 
 stimulation is low, that is, the irritability is great, when the inten- 
 sity 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 concep- 
 tion of the threshold of stimulation originated in the field of 
 muscle physiology and that of the special senses. Here the indi- 
 cator 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 i)roduce 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 role under certain condi- 
 tions in the activities of the central nervous system. It only 
 depends upon the sensitivity of our special senses, or the indi- 
 cators used for this purpose, as to whether the alterations can 
 
46 IRRITABILITY 
 
 be observed or not. The conception of the threshold of stim- 
 ulation, 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 Hmit 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 
 suhmaximal 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 inten- 
 sities is never equal, even though it may appear so, when meas- 
 ured 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 pro- 
 duced, which is manifested, for instance, in the muscle contrac- 
 tion 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 stimu- 
 lus 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 rela- 
 tion between the intensity of stimulus and the amount of response. 
 It is well known that this question has met in one special field 
 
THE CHARACTERISTICS OF STIMULI 47 
 
 of physiology with a very detailed and comprehensive treatment. 
 I allude to the teaching concerning sensation. Ernst llcmrich 
 Weber^ 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 pres- 
 sure necessary to produce a perceptible increase of sensation 
 always bears the same ratio to the amount of the stimulus already 
 applied." 
 
 If in accordance with Ziehen'- 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,^ who indeed attempted to apply this law, applical)le 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 arith- 
 metical progression, whereas the intensity of the stiinulns in- 
 creases in geometrical progression." From this Fechner has 
 worked out a psychophysical formula, which today is generally 
 termed the Fechner laiv. This is the law : The intensity of sensa- 
 tion varies with the logarithm of the intoisity of the stimulus. 
 
 Soon the Weber as well as the Fechner law had been extended 
 over the whole field of sensation and stimulation. In this con- 
 nection Preyer^ has formulated his "myoi)hysical law." which 
 states that there is the same relation between strength of stimulus 
 and the intensity of response of the nui.scle as is laid down by the 
 
 1 Weber: "Annotationes anatomicx et physiologica-." Lips. 1851. The s.imc: "Der 
 Tastsinn und das Gemeingefuhl," in Wagner's Handw^rterbuch d. Physiologic Bd. III. 
 2. Braunschweig 1846. 
 
 2 Ziehen: "Leitfaden der physiologischen Psychologic in 15 Vorlcsungcn." VI 
 
 Auflage. Jena 1902. 
 
 3 Fechner: "Elemente der Psychophysik." Leipzig 1860. 2 Auflage 1889. 
 4Preyer: "Das myophysische Gesetz." Jena 1874. 
 
48 IRRITABILITY 
 
 Fechner law for stimulation and sensation. Pfeffer^ 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 Weher-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 Lowitt, 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 cer- 
 tainty concerning the relation between the intensity of stimulus 
 and the amount of response is as follows : A law generally appli- 
 cable 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 fol- 
 lowing : With increase of the intensity of stimulation the response 
 at first increases rapidly and later more and more slowly. 
 
 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 
 
 1 Pfeffer: "Ueber chemotaktische Bewegungen von Bacterien, Flagellaten und 
 Volvocineen." Untersuchungen aus dem botanischen Institut zu Tubingen. Bd. II, 
 1888. 
 
THE CHARACTERISTICS OF STIMULI 4!) 
 
 considerably in different living substances. In iliis connection 
 there are several forms of living substance which call for our 
 special attention. In these the suri)rising 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 })rf)duces 
 a maximal response. Bozvditch^ first observed this behavior in 
 the frog's heart and this has also been confirmed by Kroncckcrr 
 The induction current produces, as Boivditch says, cither a con- 
 traction or nothing. If the former, it is the strongest contrac- 
 tion which can be produced by an induction shock at the given 
 time. Here for the first time a constancy of response was dis- 
 covered which has been termed the all or none lazu. Mcll'illiams^ 
 has later verified the same fact for the mammalian heart. 
 Gotch'^ 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 differ- 
 ence 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 a])plicable 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 con- 
 clusion has been reached by Keith Lucas-' for the single cross- 
 striated fiber of the skeletal muscle, founded on the fact that 
 
 1 Bowditc It: "Ueher die Eigentiimlichkeiten der Rtizbarkeit, wclchc die Muskcl- 
 fasern des Herzens zeigen." In Arbeiten aus der physiologischen Anstalt zu Leipzig 
 VI. Jahrgang 1872. 
 
 2 Kroneckcr: "Das characteristische Merkmal der Herzmuskelbcwegung." In 
 Beitrage zur Anat. und Physiol. Als. Festgabe Carl Ludwig gewidmet von seinen 
 Schiilern. Leipzig 1874. 
 
 3 MclVilliams: "On the rhythm of the mammalian heart." Journal of Physiology. 
 
 Vol. IX, 1888. 
 
 4Gotch: "The submaximal electrical response of nerve to a single stimuhi*." 
 Journal of Physiology, Vol. XXVIII, 1902. 
 
 5 Keith Lucas: "On the graduation of activity in a skeletal muscle fibre." Journal 
 of Physiology, Vol. XXXIII, 1905-06. 
 
50 IRRITABILITY 
 
 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^ came to the same con- 
 clusion 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 con- 
 duction of excitation is concerned, by the sarcolemma. Finally, 
 the recent investigations of Veszr with strychnine poisoned gan- 
 glia cells of the posterior horns of the spinal cord, have made it 
 appear probable that "the all or none law" can be appHed like- 
 wise 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 summa- 
 tion 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 dififerences 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. 
 
 1 Keith Lucas: "The all or none contraction of skeletal muscle fibre." Journal of 
 Physiology, Vol. XXXVIII, 1909. 
 
 2 I'essi: "Zur Frage des Alles oder Nichts-Gesetzes beim Strychninfrosch." Zeit- 
 schrift fiir allgemeine Physiologic Bd. XII, 1911. 
 
THE CHARACTERISTICS OF STIMULI 51 
 
 Such are the instances to which one has up to llic present 
 appHed the "all or none law." The (juestion if, as a matter of 
 fact, such a condition has ever been realized in any living sub- 
 stance has until now found no linal answer. Most authors, who 
 accept the validity of the "all or none law" for certain living sub- 
 stances, do so with a certain reserve and speak only of the possi- 
 bility or probability of such behavior. 'Hie subject has. how- 
 ever, 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 rela- 
 tions 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 altera- 
 tion in vital conditions, an equally important factor is the dura- 
 tion of the alteration. The time relations, under which a devia- 
 tion 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 l)y the move- 
 ment 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 al)scissa. 
 
52 
 
 IRRITABILITY 
 
 (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. 
 
 Fig. 3. 
 
 The rapidity of alterations in vital conditions has quite an 
 important influence on the development of the response to stimu- 
 lation. 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 CHARACTERISTICS OF STIMULI 53 
 
 the rapidity of the alterations in the factors which act as stiniuh, 
 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 variati(jns may 
 be mentioned. They always act relatively slowly. ( )n the con- 
 trary there are forms of stimuli which have now a rai)id, now a 
 slow, ascent or descent of their intensity, such as the jjhotic 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 sub- 
 stance concerned. The rapidity of the reaction to stinnili is very 
 different in various forms of living substance. ( )n 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 posi- 
 tions 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.^ 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 
 
 1 Vergl. Julius Sclwtt: "Ein Beitriig zur electrischen Reigung des qucrgcstrciften 
 Muskels von seinen Nerven aus." Pflugers Archiv Bd. 48, 1891. 
 
54 
 
 IRRITABILITY 
 
 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.) 
 
 Fig. 4. 
 
 Course of induction shocks. 1 and 2 make and break of the primary current, 
 li and 2i 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 f aradic current, 
 
o 
 
56 IRRITABILITY 
 
 also, the intensity of which I found quite unbearable, remained 
 utterly without effect/ 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. 
 
 A further point for consideration in the duration of an altera- 
 tion 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 consider- 
 ably. The stimulus may remain indefinitely at a certain level, 
 when this is once reached. (Figure 5, A.) The alteration like- 
 wise 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, imme- 
 diately 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 experi- 
 mental 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 role in older physiology and led to prolonged discus- 
 sions for the reason that a special case was taken into considera- 
 tion in this connection, which at that time was not clearly under- 
 stood. Du Bois-Reymond,- 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 exci- 
 tation of the nerve and contraction of its muscle, but an alteration 
 
 1 Max Verworn: "Untersuchungen iiber die polare Erregung der lebendigen 
 Substanz durch den constanten Strom." Ill Mitteilung, Pflugers Arch. Bd. 62, 1896. 
 
 2 Du Bois-Reymond: "Untersuchungen iiber tierische electricitat." Bd. I. Berlin 
 1848, p. 258. 
 
THE CHARACTERISTICS OF STIMULI 57 
 
 of the intensity from one moment to another. The more rapidly 
 these changes are produced, the greater is the excitati(jn. His 
 arguments were based upon the fact that a contraction can only 
 take place on the "making" or "breaking," or by rapidly streiigtii- 
 ening 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 stinui- 
 lating 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 contiiuicd 
 duration, one would commit the error of judging the occurrence 
 of a stimulus only by the unsatisfactory criterion of an al)rupt 
 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, how- 
 ever, 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 excita- 
 bility 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 local- 
 ized 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 .Ictino- 
 sphccrium,^ the straight, smooth, ray-shaped pseudopods of the 
 cell body at the moment of "making," show evidence of con- 
 traction by being drawn in, particularly those directed towards 
 
 1 KUIiue: "Untersuchungen uber das Protoplasma uiid die Contractilitat." Leipzig 
 1864. Max Verworn: "Die polare Erregung der Protisten durcli dcr galvanischcn 
 Strom." Pfliigers Arch. Bd. 35. 45. 1889. 
 
58 
 
 IRRITABILITY 
 
 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 con- 
 tinuance, 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 
 
 ■+-> 
 
 
 
 
 
 
 Fig. 6. 
 
 Actinosphaerium eichhomii. Four stages showing the progressive influence 
 
 of a constant current. Protoplasmic disintegration at 
 
 the side toward the anode. 
 
 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 
 
THE CHARACTERISTICS OE STIMULI 59 
 
 concisely : the effect of the stimulus never wholly disappears 
 unless the changes in the external vital conditions return to their 
 original state. 
 
 But more, an effect of the stimulus cannot indeed take place 
 without a certain duration of stimulation, which i.^ related in its 
 turn to the rapidity of reaction of particular living system. This 
 can be much more readily observed in more slowly reacting sub- 
 stances. Fick'^ first proved this fact on the muscle of the Ano- 
 donta. I have also been able to demonstrate the same fact in the 
 slowly reacting sea rhizopods- by the use of the constant current. 
 When Orbitolitcs 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 emi)loyed. 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 centrij)etal 
 direction towards the central cell body. (Eigure T.) 
 
 Two effects can be realized by the alteration in the living 
 system as the result of prolonged stimulation, bjlher a new 
 state of equilibrium is established by the prolonged action, or 
 sooner or later death develops. In considering both results, huw- 
 ever, 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 equilibrum of the living system be spoken of. 
 
 \ A. Pick: "Beitrage zur vcrgleichenden Physiologic der irritablcn Substanzcn." 
 
 Braunschweig 1863. 
 
 The same: "Untersuchungen uber die electrische Nervenrcizung." Braunschweig 
 
 1864. 
 
 2 Max Verworn: "Untersuchungen iiber die polare Errcgung dcr Icbcndigcn Sub- 
 
 stanz," etc. Ill Pfliigers Arch. Bd. 62, 1896. 
 
e 
 t 
 
 3 
 U 
 
 PQ ^ 
 
 s 
 
 (A 
 
 e 
 
 8 
 
 c 
 I 
 
 03 
 
 o 
 
 BO a 
 
 3 
 
 6 
 
 I 
 
 OQ 
 I 
 
 8 
 I 
 
 •S 
 
 =— ^ < 
 
THE CHARACTERISTICS OF STIMULI 61 
 
 It is sometimes the case that under the iiitluence of a stimulus 
 a new equiHbrium is developed, uhicii may remain as long as 
 the stimulus persists. This most frccjuently occurs as a result 
 of weak stimuli. That which is usually termed "individual 
 adaptation" belongs in this category. Likewise some of the nat- 
 ural and artificial immunizations may also be included. The con- 
 tinued stimulation in such cases of adajjtation as we learned 
 before in the example of Ama:ha Umax and radiosa or liranchipiis 
 stagnalis and Artcmia 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 per- 
 sist 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 stinuili as used for 
 experimental purposes, it is not a question of a i)ermanent 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 altera- 
 tion at its termination. The latter takes place with difTcrent 
 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 stinuilus 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 (|uick alteration calls forth a 
 strong and sudden excitation (in the muscle contraction) : the 
 continuation of the current maintains weak excitation of ccjual 
 
62 IRRITABILITY 
 
 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 Griitzner,^ 
 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 experi- 
 mental purposes. 
 
 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 rhyth- 
 mical 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 under- 
 stood 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 stand- 
 points 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 stimu- 
 lation 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 
 
 1 Grutzner: "Uber die Reizwirkungen der Stohrer'schen Maschine auf Nerv und 
 Muskel." Pfliigers Arch. Bd. 41, 1887. 
 
THE CHARACTERISTICS OF STIMULI 63 
 
 allow the living system time to completely recover from the cfTect 
 of the preceding stimulus. In the cases, for instance, where we 
 have recovery, we have the same rhythm of stinuilation as that 
 of response. When recovery does not occur, interferences of the 
 response are developed, which are of great physiological impor- 
 tance, with the analysis of which we shall later on lind 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 he 
 combined with all those factors previously discussed in connec- 
 tion with the single stimulus. In consequence another compli- 
 cation 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 frecjuency 
 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 dura- 
 tion of stimulus, it is evident that, depending upon the rai)idity 
 of response of the living system, sooner or later the rhytlimical 
 stimulation must become ineflfectual. Nevertheless, this effect 
 of shortening the duration of the single stimulus can be compen- 
 sated by a corresponding increase of its intensity. In this con- 
 nection Nernst^ showed a very simple relation for induction cur- 
 rents of higher frequency of interruption, which furnishes a law 
 according to which such a compensation takes place. In conjunc- 
 tion with Barratt he found, namely, that the intensity must in- 
 crease 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: V^^i = const., in which / 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. 
 
 This exhausts the small numl)er of elementary factors con- 
 cerned in the course of the stimulation, and which are of imi)or- 
 
 1 Nernst und Barratt: "Uel)er electrische Nervenreizung diirch Wcchsclstromc." 
 Zeitschrift fur Electrochemie 1904. 
 
64 IRRITABILITY 
 
 tance 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 altera- 
 tions 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. Dis- 
 turbances 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 systeinatic 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 condi- 
 tional method of observation, however, will remain our guide. 
 
 We have already pointed out the relations between the con- 
 ception of stimulation and that of vital conditions, now we will 
 consider that of the effect of stimulation with that of vital pro- 
 cesses. Nevertheless, the effect of stimulation being a manifesta- 
 tion 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 infusoriiun Penuirma 
 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 a.xis of the Ix^ly and 
 
66 
 
 IRRITABILITY 
 
 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. 
 
 \ 
 
 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 fer- 
 tilized 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 devel- 
 opment. 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 
 
THE GENERAL EFFECT OF STIMULATION 67 
 
 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 phosphorcscn^s having 
 been bred upon a putrid hsh are ex|)osed in the culture thiid lo 
 the air. In the dark the bacteria give forth a |)hosphoresccnl 
 light. Then the culture fluid containing the bacteria i> i)ut into 
 a glass receptacle, which can be rendered air-tight and all oxygen 
 excluded. After a short time the light formation ceases com- 
 pletely. 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 comi)lete rest is examined for a pro- 
 longed 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 tread- 
 mill. 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 re- 
 curring 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 re- 
 sponse 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 stinuilus. This 
 is a fact, however, which could be expected from the beginning 
 and is self-evident, for stimuli are alterations in the vital condi- 
 tions, and when these are altered the state of the system or the 
 happenings thereof must also alter. The cjuestion 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 stimu- 
 lus. The instances of resi)onse to stimuli already cite<l furnish 
 us with information in both kinds. 
 
68 IRRITABILITY 
 
 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 condi- 
 tion 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 con- 
 sider 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 meth- 
 ods 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 difi:erentiation of 
 the processes. The atomistic terminology is, for this reason, 
 preeminently 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 metab- 
 olism 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 
 
THE GENERAL EFFECT OF STIMULATION 69 
 
 rifle balls, the boundary between cell and medium would repre- 
 sent 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 w^ould 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 pro- 
 cesses 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 pre- 
 sentation. This method is of great help in aiding our under- 
 standing, 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 re- 
 sponses 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, liowever, 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 slinuilation is made 
 possible. That which we are in the habit of calling metabolism 
 
70 IRRITABILITY 
 
 of rest, would, therefore, be metabolism of stimulation, but one 
 that is characterized by a constantly existing metabolic equilib- 
 rium. 
 
 This "equilibrium of metabolism" distinguishes the metabolism 
 of rest from that form which is developed in response to tem- 
 porary 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 char- 
 acterize 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 con- 
 stantly 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, never- 
 theless they are the basis of all our thinking and a definite under- 
 standing 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 lasst 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 defini- 
 tions of all conceptions. If we seek to penetrate more deeply 
 into the varied happenings in concrete conditions, we must recon- 
 
THE GENERAL EFFECT OF STIMULATIOX 71 
 
 cile ourselves to dry pedantic definitions. In the case of tliat 
 of the equilibrium of metabolism indeed we liave before us one 
 of the most important conceptions in ])hysiology. 
 
 The justification to speak of an c(|uilil)rium of metabolism 
 arises from investigations of metabolism in mammals. The clas- 
 sical experiments of the previous century, as is well known, have 
 shown that in the adult mammal receiving a necessary quantitv 
 of nourishment and in a state of rest, the intake and outgo of 
 the constituent elements are the same. The carbon, iiydrogen, 
 nitrogen, oxygen, sulphur, phosphorus, etc., taken in during 
 a lengthened period in the form of food and resi)ired air. 
 appear again in equal quantity, in other combinations, in the 
 products of excretion of the organisms. Calorimetric exi)eriments 
 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 api)ly 
 to the individual cell, that is, for all living substance. The quan- 
 titative relations of the foodstufTs taken /;/. and the excreted meta- 
 bolic 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 dis- 
 integration 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 sub- 
 stances. And so the building up and breaking down ])rocesses 
 form the two great processes of metabolism, which with llcrimf 
 we can briefly call ''assimilation" and "iiissimilation." In the 
 terms assimilation and dissimilation are comprised the sum of all 
 processes of construction and disintegration in the living organ- 
 ism. It is apparent that equilibrium of metabolism occurs when 
 assimilation and dissimilation are equal. The formula .X : 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 i)rocesses, for u\kh\ its 
 
 1 E. Hcring: "Zur Theorie der Vorgange in dcr Icbendigcn Siihstanz." In Lotos. 
 Bd. 9, Prag. 1888. 
 
72 IRRITABILITY 
 
 value depends individual vital manifestation, and, in fact, the con- 
 tinuation of life. I have, therefore, designated the formula 
 A = D ''Biotonus." The equilibrium of metabolism would then 
 be characterized by the biotonus^ 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 altera- 
 tion of the biotonus. But is this state of living substance strictly 
 speaking ever realized? 
 
 In considering the nature of the equilibrium of metabolism 
 one factor has been disregarded which must be taken into ac- 
 count 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, origi- 
 nating from experience with rather too restricted boundaries. 
 But an error of which one is aware is not dangerous. In mathe- 
 matics 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 tgg 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 food- 
 stuffs. 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 altera- 
 tions in growth take place with such imperceptible slowness that 
 
 1 Max Verworn: "Allgemeine Physiologic. Ein Grundriss der Lehre vom Leben." 
 V. Aufl. Jena 1909. 
 
THE GENERAL EFFECT OF STIMTLATIOX 73 
 
 the resultant error is inconsiderably minute. This period of time 
 is of greatly varying length in different living organisms and tiiis 
 fact must be taken into account in every living form. ( )nly witli 
 this restriction can we justify the use of the term "e(iuilibrium 
 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 ccjuilibrium of 
 metabolism through the effect of stimuli. 
 
 The question here follows: Is there a constancy of this inter- 
 ruption of the equilibrium of rest produced by the stimulus whicli 
 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 proj)- 
 erties can undergo alteration in its metabolism in various direc- 
 tions. Thereby results an infinite number of manifold reactions 
 to stimuli. However, in answer to the question, in which direc- 
 tion 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 rai)idity 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 rai)idity : on the otiier. 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 mani- 
 fested 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 Ostzcald's^ well-known defi- 
 nition 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 
 
 1 Ostzvald: "Ueber Katalyse." Verhandl. d. Ges. Dcutschcr Naturf. und Acrzle zu 
 
 Hamburg 1901. 
 
U IRRITABILITY 
 
 excitation, and when there is decrease in the vital processes, we 
 speak of a depression. 
 
 The conception of excitation and depression are purely empiri- 
 cal. 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'^ has recently made the 
 extraordinary statement that I have introduced hypothetical pro- 
 cesses 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.^ 
 If, however, the excitation process is to be regarded as something 
 absolute, as a mysterious state siii generis, which is entirely inde- 
 pendent 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 meaning- 
 less word. Excitation and depression are relative conceptions 
 and can only acquire meaning when the process which is exci- 
 tated 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 pro- 
 cess, 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 
 
 1 Cremer: "Die allgemeine Physiologic der Nerven." In Nagels Handbuch der 
 Physiologic des Menschcn. Bd. IV, Braunschweig 1909. 
 
 2 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. 
 
THE GENERAL EFFECT OF STIMULATION 73 
 
 excitation or depression produced hy 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 Mullcr has 
 termed ''specific energy:' We give, however, the doctrine of 
 specific energy a more general applicali(;n in so far as it com- 
 prehends not only the increase but likewise the decrease of activity 
 in response to stimuli. Johannes Midler s doctrine of specific 
 energy of the living substance at all times has been the subject 
 of most animated discussion. When I refer here h) the specific 
 energy of living substance, it is with the knowledge that Johannes 
 Midler 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 doc- 
 trine 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 con- 
 troversies on this subject are still far from settled.' 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 .sub- 
 stances, a fact. In that the psychical ca])al)iliiy of these sense 
 substances, in which we include not only the peripheral, i)ui also 
 the central portion, are dependent upon their specific vital pro- 
 cesses, it must be self-evident that the excitation and the sup- 
 pression of sense sensation can be brought about by adecjuate and 
 
 1 Compare: Rudolf Weinmann: "Die I.chre von den spccifischcn Sinncscncrgicn." 
 Hamburg 1895. 
 
 Further: Eugen Minkowski: "Zur Miillerschcn I.ehre von den specifischcn Sinncs- 
 
 energien." In Zeitschrift f. Sinn(.si)Iiysiolofiic. Hd. 45. 1*>11. 
 
76 IRRITABILITY 
 
 inadequate stimuli, no matter what one may think of the relations 
 between physical and psychical phenomena. 
 
 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 ques- 
 tion. Nevertheless, we will here refer to a fact which, upon a 
 superficial observation, seems to restrict the validity of the con- 
 ception 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 stimula- 
 tion 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 fre- 
 quently 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 
 
THE GENERAL EFFECT OF STIMULATION 
 
 i < 
 
 these qualitative alterations of the normal vital j)roccss produced 
 by continuous stimulation which have up to now hccn least ana- 
 lyzed. In this field we expect much from pathological inves- 
 tigation which alone has the immense amount of material at its 
 command. This will take i)lace only when i)ath()lo^ry adds to the 
 almost exclusively histological direction of investigation, that also 
 of experimental physiology. It is true that the i)r()hlems of the 
 qualitative alterations of a vital process by chronic stimulation 
 are much more complicated than those of the rai)id 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 deei)er knowl- 
 edge 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 pro- 
 duce 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 con- 
 stituent processes of the same are afYected by the action of exci- 
 tation. This is the more noticeable, as, considering the close corre- 
 lation which all the individual links of the chain of metabolism 
 bear to each other, it is to be expected that the alteration in rapid- 
 ity 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 atYected. is 
 that of the specific activity of a muscle which is rejieatedly stimu- 
 lated by nervous impulses. Since the classical investigation of 
 Fiek and IVislieenns^ on themselves, and of Voit' 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 
 
 1 Pick und Wislicenus: "Uebcr die Entstchung der Muskclkraft." Vicrtcljahrc*- 
 schrift d. Ziiricher Naturforschenden Gesellschaft. Rd. 10, 1865. 
 
 2 I'oit: "Ueber die Entwicklung dcr I,clire dcr Quelle dcr Muskclkraft luid ciniger 
 Theile der Ernahrung scit 25 Jahrcn." Zeitschrift f. BioloRic Hd. VI. 1870. 
 
 Derselbe: Physiologie des aligemcinen StofTwcchscIs u. d. Ernahrung. In Her- 
 manns Handbuch d. Physiologie. Bd. VI, 1881. 
 
78 IRRITABILITY 
 
 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 forma- 
 tion, the individual members spreading in various directions. An 
 alteration in an individual member can occur without an imme- 
 diate 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. 
 
 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 pro- 
 ducing 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,'^ in another field involving other condi- 
 tions 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.- 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 
 
 1 Ehrlich : "Das SauerstoiTbediirfniss des Organismus. Eine farbenanalytische 
 Studie." Berlin 1885. Compare further: L. Aschoff : "Ehrlich's Seitenkettentheorie 
 und ihre Anwendung auf die kiinstliche Immunisirungsprocesse. Zusammenfassende 
 Darstellung." Zeitschr. f. allgemeine Physiologic, Bd. I, 1902. 
 
 2 Max Verworn: "Die Biogenhypothese. Eine kritisch-experimentelle Studie iiber 
 die Vorgange in der lebendigen Substanz." Jena 1905. 
 
THE GENERAL EFFECT OF STIMULATION 79 
 
 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 sui)ply of 
 food, water, oxygen, the prolonged or stronger influence of 
 extraneous chemical matter, etc. 
 
 Considering the close correlation of the individual part pro- 
 cesses 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 con- 
 stituent processes, particularly when this is of prolonged duration 
 and involves to a considerable extent the alterations in rapiditv, 
 for the individual constituent processes are dependent in a 
 high degree upon the quantity of the particular chemical sub- 
 stances 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 disin- 
 tegration products, and also the increase of the substances for 
 their replacement, there would result, during this time, an altera- 
 tion in the amount of interaction of the molecules of the other 
 constituent processes, so that these processes secondarily sutler 
 an alteration in rapidity which is perceptil)le 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 fol- 
 lowed, although to a less extent, by an increase in the entire 
 cytoplastic metabolism. Argutinski showed this on liimsclf in 
 1890 in Pfliigcr's laboratory. He found, namely, that after tlie 
 exertion of a long walk in a hilly district, a considerable increase 
 of nitrogen excretion in the urine took place, which extended 
 
80 IRRITABILITY 
 
 over the succeeding two or three days. This increase of the 
 nitrogen metaboHsm in its totaHty 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 uni- 
 versal 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,^ 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 stim- 
 uli (Figure 9, B), coming from the eye, whereas they remain in 
 the embryonic state when these light stimuli are eliminated. (Fig- 
 ure 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. 
 
 1 Berger: "Experimentell-anatomische Studien iiber die durch den Mangel optischer 
 Reize veranlassten Entwickelungschemmungen im Occipitallappen des Hundes und 
 der Katze." Arch. f. Psychiatrie, Bd. 33, 1909. 
 
H 
 
 FiU. 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 «an«lia cells in the same 
 
 rnciinn n( 1 nnrmil i\nii n{ the '^Tmc acc. I Aftcr licracT.) 
 
82 IRRITABILITY 
 
 The increase in volume under the influence of stimuH 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 altera- 
 tions of the vital process. Simple observation shows us that a 
 qualitative change of individual constituent processes must neces- 
 sarily result from the increase of volume of a cell, and that con- 
 sidering the close correlation of all the individual processes a 
 profound alteration of the entire metabolism must be produced. 
 I have already at another place 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 there- 
 fore 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 inter- 
 workings of the individual constituent processes, the rapidity of 
 action of all which is intimately connected, are, therefore, fol- 
 lowed by corresponding alterations in the entire metabolism. 
 Sooner or later a stage is reached in which the individual constit- 
 uent 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 
 
 1 Max Verworn: "Die cellularphysiologische Grundlage des Gedachtnisses." 
 Zeitschrift f. allgemeine Physiologic, Bd. VI, 1907. 
 
 2 Max Verworn: "Allgemeine Physiologic." V. Aufl. 1909, pages 649-671. 
 
THE GENERAL EFFECT OF STIMULATION 83 
 
 alterations of the relations of the cell to its surrounding niediuin. 
 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 "dcvclopmcyit." and 
 wdiich by constant progression, leads either to a process of cell 
 division, and with this to a correction of exi>ling 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, liowever, 
 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 frecjuent recurrence, 
 secondarily effect a change of volume of the entire living organ- 
 ism. One can, therefore, hardly reject the conclusion that seeing 
 the close interworkings of the individual part process of metab- 
 olism, every change of rapidity of a single member, if of pro- 
 longed duration or of frequent occurrence, must finally lead to 
 qualitative alterations of the entire metabolism. In consequence 
 there results an important dependence between catalytic stimula- 
 tion and metamorphic reaction. Indeed, it is not unlikely that 
 the metamorphic reactions, which are especially seen in the con- 
 tinued effect of weak stimuli, result from alterations of rapidity, 
 w^hich the individual members of the vital processes have 
 primarily undergone from this influence. 
 
 It is perhaps expedient to cite a concrete instance in illustration. 
 A simple example is furnished by as])hyxiation. 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 sub- 
 stance 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 disintegra- 
 tion of nitrogen-free groups into carl)on dioxide and water took 
 place, both of which could easily be eliminated from the cell, the 
 anaerobic disintegration furnishes only complex ])r(Hlucts. having 
 a higher carbon content, such as lactic acid, fatty acids, aceton. 
 
84 IRRITABILITY 
 
 etc. These, being more difficult to excrete from the cell, accumu- 
 late. 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 accumu- 
 late 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 particu- 
 lar cells. 
 
 The relation here described, of the catalytic stimuli to the pro- 
 duction of the metamorphic processes, leads us to the dis- 
 tinctions 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 stimu- 
 lation applies to all stimuli, is a question which only the future 
 can answer. 
 
 The metamorphic processes are not, however, the only sec- 
 ondary 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 re- 
 sponse. 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 
 
THE GENERAL EFFECT OF STIMULATION 85 
 
 secondary effect, which ])lays a very imi)ortant jKirt in ilie activity 
 of the organism. I refer to fatigue. Here a secondary depres- 
 sion is developed in connection with tlie primary excitation, for 
 fatigue of a hving organism must be cliaracterized as a depression 
 of activity. This case shows that we liavc to distinguish between 
 a primary depression, as for exanii)lc. i)r()(hiced by tcmj)craturc 
 reduction, withdrawal of food, deficiency of oxygen, etc., which 
 occurs as a direct effect of stimulation, and secoudary depression, 
 W'hich as in fatigue is an indirect result of primary excitation. 
 
 After the cessation of a briefly catalytic stimulus, n(ji exceed- 
 ing the physiological limit of intensity, another secondary result 
 is observed, which is of the greatest importance for the con- 
 tinued existence of the living substance. The catalytic stimulus 
 brings about a disturbance of the ecjuilibrium of metabolism, 
 which after cessation of the stimulus is reestablished l)y the living 
 substance. In other words: recovery takes j)lace. This funda- 
 mental principle has been known for a long time as the result 
 of observation. If a skeletal muscle of our body has been acti- 
 vated 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 fmds 
 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. Herincf has aptly termed this restitution as "the inter- 
 nal self-regulation of metabolism." All recovery after disease is 
 based on this self-regulation. The physician simjily jirovides. by 
 means of therapy, for the possibility of its taking i)lacc. Healing 
 itself is brought about by the organism. 'W'atura sanat. medieus 
 curat." 
 
 1 Ewald Herxng: "Zur Theorie der Vorgiiiigc in dcr IcbcntliRcn Sub»tan/." In 
 Lotos, Bd. 19, Prag. 1888. 
 
86 IRRITABILITY 
 
 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 pri- 
 marily 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 neigh- 
 boring 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 inten- 
 tionally 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 ques- 
 tions, however, demand a closer analysis. Here we were con- 
 cerned 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 mech- 
 anism and genesis. Our further task must, therefore, be a more 
 thorough analysis of this field. 
 
chapti^:r V 
 
 THE ANALYSIS OF THE PROCESS OF ICXCFIATIOX 
 
 Contents: Indicators for the invcsti^^ation of the process of excitation. 
 Latent period. The question of the existence of assimilatory excita- 
 tions. Dissimilatory excitations. Excitations of the partial compo- 
 nents of functional metabolism. Production of energy in the chemi- 
 cal splitting up processes. Oxydative and anoxydative disinteRration. 
 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 con- 
 dition of chemical equilibrium. Functional hypertrophy. 
 
 If it is true that all primary eflfects of .'Stimulation consist cither 
 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 investiga- 
 tion 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 depres- 
 sion and its results. 
 
 The investigation of the more obscure processes in the living 
 substance places us in a difiicult position, for their details cannot 
 be observed bv the unaided senses. That which we can perceive 
 is merely the grosser vital action, consisting of a c()mi>lex combi- 
 nation of the individual processes, the total result of a nuiltitude 
 of different components. For this reason the conception of exci- 
 tation can only be established by observations based upon the 
 combined vital actions, which are produced by the effect of stinui- 
 
88 IRRITABILITY 
 
 lation 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 pro- 
 cess of conductivity. Even graphic registration is merely an 
 expression of the phenomena composed of a great mass of indi- 
 vidual 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 dis- 
 torting 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 compara- 
 tive 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 activi- 
 ties 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 sub- 
 stance 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 pos- 
 sess 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 
 
THE PROCESS OE EXCITATION' 89 
 
 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 proi)erties, showing us the 
 greatest variety of vital manifestations, we may hope by the use 
 of comparative physiological methods, even though with diffi- 
 culty, to separate more and more the essential details of the gen- 
 eral processes of excitation. At present we are still at the very 
 beginning of this task and vast fields of unexplored regions arc 
 yet before us. But it is the unknown which has a particular fasci- 
 nation, 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 i)roduced 
 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 deli- 
 cate 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'^ it was made the object of innumerable investigations 
 and met with an interest which can only be explained by the exact- 
 ness of the methods employed. Among others Tigcrstcdt- has 
 made the most thorough study of the influence of various factors 
 on the duration of the latent period. 1 hese experiments have 
 established the fact that the duration of the latent period varies 
 according to the intensity of the stimulus, temperature, loading 
 
 1 Hclmholtz: "Messungen iiber den zcitlichen Vcrlauf der Zuckungcn animaliwhcr 
 Muskeln und die Fortpflanzungsgeschwindigkeit der Reizung in den Nervcn." .\rchiv 
 fiir Physiologic Jahrgang 1850. 
 
 2 Robert Tigcrstcdt: "Untersuchungen iiber die I^tenzdaucr der Muskeliuckung 
 in ihrer Abhangigkeit von verschiedenen Variablen." Arch. f. Physiologie Jahrgang 
 1885 Suppl. 
 
90 IRRITABILITY 
 
 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. 
 
 The facts concerning the whole latent period and its depend- 
 ence 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^ 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 proto- 
 plasm 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 altera- 
 tions, 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 sur- 
 face of the protoplasm. In view of the present findings of physi- 
 cal chemistry, objections can hardly be made to this theory of 
 Nernsfs. It is a question, however, in how far this theory, espe- 
 cially established for the electric stimuli, can be applied to other 
 
 \ Nernst: "Zur Theorie der electrischen Reizung." Nachrichten der Konigl. 
 Gesellsch. d. Wissensch. zu Gottingen. Math, physik. Klasse 1899. 
 
THE PROCESS OF EXCITATION 91 
 
 forms of stimuli and their action. It cannot he 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 pas- 
 sage of the ions, there arises the opi)ortunity f(^r the develoi)ment 
 of difference of electrical potential on both sides, and for further 
 chemical alterations in the prot()i)lasni. These observali(jns, how- 
 ever, require further experimental investigations in many fields, 
 before we are justified in extending the Ncrnst theory of the 
 manner of action of the electric stimuli to a general ex])lanation 
 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 resi)onses to an exci- 
 tating stimulus; these are the chemical alterations in the metab- 
 olism of rest in the living substance. 
 
 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 gen- 
 erally for all living systems. To begin with, it appears highly 
 probable that the various forms of vital substances in this res|>ect 
 act quite differently. It is to be regretted that, up to the present, 
 this question has not been treated from a comparative stand- 
 point. This inquiry should be extended to the greatest ix)ssible 
 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 ai)pears as a very remarkal)lc 
 fact, that nearly all stimuli produce primarily a dissimilath-c 
 excitation. We are only accjuaintcd with a primary asstmt- 
 lative 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 intro- 
 duction of foodstuffs extending over a prolonged length of time. 
 With this exception it cannot be proved that any other stimuli, 
 
92 IRRITABILITY 
 
 either especially those operative in the activity of the animal 
 organism or any of the physiological nerve impulses which regu- 
 late 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^ 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 pri- 
 marily 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. 
 
 As a result manifold effects of excitating stimulation, which 
 seemed possible at a first glance, are already considerably re- 
 stricted. The great mass of excitating stimuli produce an accel- 
 eration 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 "functionaV' 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 
 
 1 Paul Jensen: "Das Problem der trophischen Nerven." Medicinisch-naturwissen- 
 schaftliches Archiv. Bd. II, 1910. 
 
THE PROCESS OF EXCITATION 93 
 
 affected by stimulalion, consists as demonstrated in increase 
 of formation of carbon dioxide and water, and in tlie disintegra- 
 tion of the nitrogen-free groups. The innumerable observations 
 on metabohsm during the stage of tlie activity of the muscle, as 
 those of Hermann, v. Frcy, Fletcher, Joluiunson, I'huubcnj, 
 and many others on the individual nuiscle, and those by I'oit, 
 Pick and Wisliceniis, PfliUjer, Riibner, Ziiutz. Lehmann and 
 Hagemann, Bernstein and Lowy and others on the nuiscle 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 (hfferently 
 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 constit- 
 uent 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 com- 
 pletely unknown, wdiile 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 wt 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 /^articular labile state 
 of just this constituent part of functional metabolisf.i conditioned f 
 The lability of the functional portion of metabolism, excitated 
 by the stimulus, resembles the processes in the disintegration of 
 
94 IRRITABILITY 
 
 explosive combinations. Iodide of nitrogen, for instance, in a 
 manner similar to the living substance in the state of the metab- 
 olism of rest, constantly disintegrates even without the influence 
 of an impact. The disintegration is suddenly enormously in- 
 creased by the result of a jar. An explosion follows. In a like 
 manner the functional metabolism of rest is explosively exci- 
 tated 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 compari- 
 son 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 explo- 
 sive 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 sepa- 
 rated and stronger affinities are combined in the formation of 
 more complicated molecules (H-fO + 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 affini- 
 ties, are changed by transposition of nitroglycerine. For in- 
 
THE PROCESS OF EXCITATION 
 
 95 
 
 stance, the hydrogen atoms loosely coml)inc(i 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 fomicd and nitrogen 
 and oxygen set free. 
 
 
 C-H 
 
 c 
 
 I 
 
 ■H 
 ■O-H 
 
 O-Nto 
 
 o -h C 
 
 'O 
 
 
 
 = 5HO+6CO+5N +0 
 
 2 Z * 
 
 o 
 o 
 
 In the functional disintegration of living substance, the last 
 type is realized. Living substance contains loose complex com- 
 binations, and we know that functional disintegration is accom- 
 panied by the consumption of these organic combinations. In 
 the functional disintegration of muscle substance the nitrogen- 
 free groups are concerned, and we must, consequently, tirst con- 
 sider 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 con- 
 tain 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 metab- 
 olism of rest in the particular substance. Plants and micro- 
 organisms have been investigated more thoroughly in this con- 
 nection than animals. Plant physiology has demonstrated that 
 
96 IRRITABILITY 
 
 the material employed for the COo formation and with it the 
 production of energy is carbohydrate, but that, on the other hand, 
 various plant organisms and protistse also use a quantity of other 
 substances, such as fats and protein, indeed even such compara- 
 tively simple organic combinations as alcohol, formic acid and 
 methan. It may be accepted that in all these various instances 
 of excitation of the functional metabolism as a result of stimu- 
 lation, the specific respiratory material of the substance con- 
 cerned is used in greater amount in the decomposition and like- 
 wise 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, dis- 
 integrates in the living system into carbon dioxide, for it is this, 
 or a sugar of similar chemical nature, which is generally con- 
 cerned. 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, awoxydative disintegration. 
 
 In the oxydative disintegration of dextrose, taking place in 
 aerobic 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 mole- 
 cule, when subjected to oxdyative processes, is split up into sim- 
 pler molecules. In the living substance the oxydases play the 
 important role 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 aerobic disintegration of the carbohydrate mole- 
 cule, which I shall touch upon presently. If we suppose that 
 oxydases exist, which bring about primarily the oxydative disin- 
 
THE PROCESS OF EXCITATION' 97 
 
 tegration of the dextrose molecule, its first point of attack must 
 obviously be sought in the aldehyd ^ninij). Mere would l>c sit- 
 uated the activator, as it were, for the whole carbon cliain. from 
 which, as by a sjiark, the entire series of links would be ignited. 
 In an anoxydativc disintcynitioti of dextrose as observed in 
 anaerobic as well as in aerobic organisms, provided the latter have 
 an insufficient supi)ly of oxygen, the dextrose molecule, by 
 enzymic action as a result of the splitting olY of carbon dioxide, 
 is converted into substances having a comi)aratively large carlxjn 
 content. The best-known exam])le of this anoxydativc disin- 
 tegration is the formation of alcohol by fermentation in which 
 the dextrose molecule is si)lit u]) by the yeast into alcohol and 
 carbon dioxide. (C,; H^oOo = 2CoH^()H -f- 2COo.) Instead of 
 the production of alcohol and CO^ we may have other enzymic 
 actions with the formation of other carl)on-containing disintegra- 
 tion products, such as lactic acid, fatty acids, hydrogen, etc. Of 
 course in such an anoxydativc disintegration, which does not lead 
 to the formation of such simple combinations as carlxjii dioxide 
 and water, the quantity of energy set free is much less in amount 
 than in complete oxy dative decomposition, the energy production 
 of the alcohol fermentation being only 1 1 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, there- 
 fore, that the anoxydativc type of disintegration develops either 
 only where the respiratory substances are ])resent in sutVicient 
 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 temi)erature. In this respect 
 putter^ has demonstrated in the leech that at a higher tempera- 
 ture, the oxydative, at a lower, the anoxydativc, decomposition 
 predominates. These are important facts in tliat ihey show us 
 the superiority of oxydative to that of llie anoxydativc dismte- 
 gration in the cell economy. This is of particular interest when 
 we consider those organisms in wliiili great demands are made 
 
 \ A. Putter: "Dcr Stoffwechscl des Blutcgcis (Ilinulo mc(licinali» !-> I Thril. 
 
 Zeitschrift fiir allgemeine Physiologic Hd. VI. 1907. II Ttil. cbcrnla IW. VII. 1908. 
 
98 IRRITABILITY 
 
 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 res- 
 piration of oxygen is the almost exclusive source of energy 
 production. 
 
 The previously mentioned facts make it clear that in one and 
 the same form of living substance both oxydative and anoxdyative 
 decomposition processes are found, depending upon the condi- 
 tions. This does not apply merely to the individual organic 
 forms, such as the facultative anaerobic organisms, but generally 
 to all aerobic living substance. If oxygen is withdrawn from an 
 aerobic organism the disintegration does not cease in conse- 
 quence. In place of the oxydative we have anoxydative decom- 
 position. The various aerobic organisms are, however, adapted 
 in very different degrees to the possibility of an anaerobic exist- 
 ence. While the facultative anaerobic organisms can continue to 
 exist without oxygen, the homothermous animals become asphyx- 
 iated 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 aerobic organisms inva- 
 riably 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, how- 
 ever, to state that one should be very reluctant in generalization 
 of this assumption for all aerobic organisms. The types of metab- 
 olism in the different organisms are so manifold and of such 
 immense variety that we should be very careful in our general- 
 izations 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 
 
THE PROCESS OF EXCITATION' 99 
 
 temperatures, and still less to apply it to those instances in which 
 the production of energy following stimulation is suddenly in- 
 creased to great amounts. Let us suppose that the disintegration 
 process occurs in two phases, the first of which after the tyi)c of 
 the fermentation of dextrose separates the molecule into larger 
 fragments, while in the second phase these fragments are si)lit 
 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, nui-t l)e a<^ociatcd 
 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 imjxict, i)roduces 
 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 pri- 
 marily explosively breaks up the whole carbon chain, certainly 
 presents no more difficulties than the sui)position that the sim- 
 pler substances are attacked secondarily, provided sufficient oxy- 
 gen 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 casr. 
 the sudden discharge of energy in the aerobic organism set free 
 bv 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 investi- 
 gation of the state of excitation of aerobic substances on the 
 withdrawal of oxygen. Exi)erience gained by observation in this 
 respect on a great number of living substances shows that exci- 
 
Fig. 10. 
 
 Rhizoplasma kaiseri. A— Under normal conditions. 
 B— In an atmosphere of pure hydrogen. 
 
THE PROCESS OF EXCITATIOX lui 
 
 lability decreases upon ihc withdrawal of oxygen. In this con- 
 nection I should like to cite some i)articularly significant instances. 
 
 During a sojourn at the Red Sea in iSD-t-'jo 1 was able to 
 establish this dependence in the single-celled organism, the Rhizo- 
 plasma Kaiseri, a large naked orange-colored rhizojuxl. i I^'igurc 
 10, A.) Mechanical stimulation, which under normal vital con- 
 ditions 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 re|)laced 
 by a stream of hydrogen. (Figure 1<>. W.) With renewed intro- 
 duction of oxygen there is a return of the ijrotoi)la^mic movement 
 and entire recovery takes place. 
 
 This dependence of irritability upon oxygen i^ most clearly 
 demonstrated in the nerve centers. Vov tliis purpose I have 
 employed the spinal cord of the frog.' A canula is introduced 
 and fixed into the aorta of the animal and the bhjod is rej)laced 
 by a current of oxygen-free saline solution. 'I'he centers of tlic 
 spinal cord are thereby wdiolly isolated from the supply of oxy- 
 gen. The indicator for the irritability here used is retlex exci- 
 tation 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 tlic triceps. The retlex 
 may be considerably augmented by increasing the reflex excita- 
 bility of the spinal cord by poisoning the animal with strychnine. 
 On testing the reflex excitability at the beginning of the experi- 
 ment 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 fol- 
 lowing a single stimulus. Soon reflex tetanic responses are 
 merely short single contractions, whicli 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 efTect. Although by 
 
 1 Max Vcrworn: "Ermiidung ErschopfunR und Krh(ilv>n>{ tier ncrv..^,i. v t-mrcn 
 des Riickenmarks. Ein Hcitrag zur Kt-mUiiiss dor I.clK-nsvorKMUgc in den Ncuroncn." 
 Archiv. f. Anat. u. Physiologic, physiol. Al)tcil. 1900 Suppl. 
 
 The same: "Ermiidung und Erholung." In lUrliiu-r Klin. Wochcnschrift I90I. 
 
102 IRRITABILITY 
 
 increasing the intensity of stimulation brief contractions can 
 again be brought about, irritabiHty 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 satu- 
 rated 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 per- 
 fusing 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. 
 
 This same fact can be observed with equal clearness in the 
 nerve. At my suggestion H. v. Baeyer^ showed as the result of 
 investigations made in the Gottingen 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 irrita- 
 bility during asphyxiation. These observations were soon after 
 continued by Frohlichr 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 plati- 
 num 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 stimula- 
 tion required is so strong as to reach the region of the "Strom- 
 schleifengrenze." If in place of the stream of nitrogen, air or 
 pure oxygen is now allowed to flow through the chamber, the 
 
 1 H. V. Baeyer: "Das Sauerstoflfbediirfniss des Nerven." Zeitschrift f. allgemeine 
 Physiologic Bd. II, 1903. 
 
 2 Fr. W. Frohlich: "Das SauerstofFbediirfniss des Nerven." Zeitschrift f. allgem. 
 Physiologic Bd. Ill, 1904. 
 
THE PROCESS OF EXCITATION 
 
 1(»3 
 
 Fig. 11. 
 
 Arrangement for asphyxiating the nerve. A— Gasometer containing pure nitr«»g«:n. B and IT ViMili far 
 wcishing the gas. C— Ether chamber for eventual experiments with narcosis. D. Di And K CUm 
 faucets. F— Moist chamber. G— Asphyxiation chamber. H and Hi Two pairs of ckctrotScs ovci 
 which the nerve is laid. I— Nerve muscle preparation. 
 
 nerve recovers almost instantaneously. Within the space of a 
 minute its irritability has risen again to its full lici^Hit and the 
 same experiment, with the same result, can he repeated. I'inally, 
 as Fillie^ has shown, the like result is obtained wlu-n tlie nerve is 
 asphyxiated in a fluid medium. 
 
 All these facts, the number of which indeed could be increased 
 greatly for other aerobic forms, suffice to establish tlie fundamen- 
 
 1 H. Fillie: "Studien iibcr die Ersticknng dcs Ncrven in Flusigkcitcn." Zril- 
 
 schrift f. allgemeine Physiologie, Bd. \III. 1908. 
 
104 IRRITABILITY 
 
 tal importance of oxygen to the maintenance of irritability of 
 living substance. Oxygen is of greatest importance for a high 
 degree of irritability in all aerobic 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 aerobic, whereas 
 the living organisms of pronounced anaerobic 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 momen- 
 tarily acting stimulus. It is immaterial how the stimulus pro- 
 duces 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 mole- 
 cules 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 
 anaerobic organisms this decomposition takes place anoxyda- 
 tively with the cooperation of enzymic processes, and as larger 
 fragments generally result from the disintegration of the com- 
 plex molecule, the production of energy is accordingly smaller. 
 The disintegration of aerobic organisms, on the other hand, occurs 
 in the form of an oxydative splitting up of the complex mole- 
 cules 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 gen- 
 eralize 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 frag- 
 ments, followed by an oxydative splitting up of these into carbon 
 dioxide and water, can in no case as yet be justifiably applied to 
 
THE PROCESS OF EXCITATIOX 103 
 
 all conditions and all aerobic organisms. This is more or less the 
 impression which we derive of the functi(jnal excitation process 
 as seen today. 
 
 Under normal conditions the fnnctional excitation is at once 
 followed by a succession of secondary processes, the "sclf- 
 rcgulation of metabolism." Self -regulation after a functional 
 excitation is a fact demonstrated by experience. Hut in what 
 manner does it take i)lacc in detail ? 
 
 As the functional constituent members of metaboli.sm involve 
 a disintegration of the nitrogen-free atom groups, the functional 
 self-regulation must necessarily furnish in sufficient (juantity 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 w^ell known, by the food and the intake 
 of oxygen. It is of importance to the maintenance of living sub- 
 stance 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 i)roper form. 
 Indeed, the restitution of the original state follows under favor- 
 able conditions with lightning rapidity, although varying in dif- 
 ferent forms of living substance. This occurs in the nerve in 
 an extremely short time. From this it might be sui)posed that 
 the living system by accumulating a store of the necessary com- 
 pensation substances in suitable form, had made itself independ- 
 ent to a certain degree of the frequently varying sui)ply <^f 
 material obtained from the medium. 
 
 This may be held as the proper view, first with regard lu com- 
 pensation substances. The fact that living organisms can under 
 some conditions remain for a lengthened jKTiod in a state of 
 starvation, without losing their capal)ility of activity, can only 
 be explained by the presence of a great quaiuity of reserve sup- 
 plies of compensation substances. In the course of work in the 
 laboratory every physiologist has become accjuainted with the 
 fact that frogs which have been kept without food for a year, 
 although much reduced in weight, are still ca])able of some 
 muscular activity. 
 
106 
 
 IRRITABILITY 
 
 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^ has shown that the ganglion cells in the frog, in 
 which saline solution was transfused at room temperature and 
 
 Motor ganglia cells from the spinal cord of the frog. A— In normal state. 
 B— After an asphyxiation leisting 8 to 9 hours. (After Gordon Holmes.) 
 
 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 
 
 1 H. V. Baeyer: "Zur Kenntniss des Stoffwechsels in den nervosen Centren." Zeit- 
 schr. f. allgem. Physiol. Bd. I, 1902. 
 
THE PROCESS OE EXCITATION 
 
 107 
 
 responsivity. The nerves and muscles of ilie animal retain iheir 
 excitability for even a lon^^er period under the same conditions. 
 Indeed, we have histological evidence of the existence of or^^'anic 
 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.* 
 (Figure 12), or that of the granules in infusoria cells during 
 starvation.- (Eigure 13.) We assume that a certain amount of 
 
 
 .'M>^ 
 
 
 
 
 
 V' 
 
 A 
 
 Fig. 
 
 13. 
 
 
 B 
 
 ium aurelia. A— In normal state. 
 
 B 
 
 In a state of starvation 
 
 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 role, 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 
 
 1 Gustav Mann: "Histological changes induced in synipatliftic mutor and sensory 
 nerve cells by functional activity." In Jcmrn. of Anat. and Physiol. 1894. Further: 
 Gordon Holmes: "On morphological changes in exhausted Ranglion cellft." Zcit- 
 schrift f. allgem. Physiol. Ed. II, 1903. 
 
 ZlVallcngrcn: "Inanitionserscheinungen der Zdlc." Zc-it-schrift f. allgrm. Physiol. 
 Bd. I, 1902. 
 
108 IRRITABILITY 
 
 essential data for the assumption of the existence of such pro- 
 cesses which regulate the transformation of reserve substances 
 as well as its extent. Pfeffer^ 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- 
 some time ago also observed in the bacillus amylobacter an analo- 
 gous 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 mate- 
 rial. 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 suit- 
 able material for building-up processes, the extent of which is 
 controlled according to need, by the processes of self-regulation. 
 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 aerobic organisms and tis- 
 sues can exist under complete exclusion of oxygen for a longer 
 or shorter period, retaining their excitability and producing car- 
 bon dioxide, has for a long time led a great number of investi- 
 gators, 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, 
 
 1 W. Pfeffer: "Ueber die regulatorische Bildung von Diastase." In der math. phys. 
 Klasse d. Konigl. Sachs Ges. d. Wiss. zu Leipzig 1896. 
 
 2 De Bary: "Sur la fermentation de la cellulose." In Bull, de la Soc. hot. de 
 France 1879. 
 
THE PROCESS OF EXCITATION 109 
 
 as can be observed in plants and certain invertebrate animals, 
 indicates that here also there is the p(jssibility of another expla- 
 nation of these facts. V^arious attem|)ts have !)een made to solve 
 the problem if reserve oxygen is present in the cell or not. The 
 experiments of Rosenthal,^ carried out with his respiration calo- 
 rimeter, 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, lO,) 
 became lower than in ordinary air, that is, that oxygen, and that 
 indeed in considerable quantity, must be retained in the organism. 
 Nevertheless Falloisc- 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 dis- 
 puted by Durig.^ PVinterstein* also, employing the microrespira- 
 tion 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 detinite 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 con- 
 cluded 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 
 
 1 Rosenthal: "Untersuchungen iiber den respiratorischcn Stoffwcchscl." Arch. f. 
 Anat. u. Physiologic physiolog. Abt. 1902 und Suppl. 1902. 
 
 2 Falloise: "Influence de la respiration d'une atmosphere suroxygenc »ur I'tbtorp- 
 tion d'o-xygene." Traveaux du laborat. de physiol. de L. Frederic LicKe. T. VI. 
 
 ZDurig: "Ueber Aufnahme und Verbrauch von Sauerstoff bei -'Xendcrung Mrinet 
 Partialdruckes in der Alveolarluft." Arch. f. Anat. u. Physiol, physiol. Abt. 1903 
 Suppl. 
 
 4, IVinterstein : "Ueber den Mechanismus der Gcwcbeatmung." Zcitschr. f. allijcra. 
 
 Physiol. Bd. VI, 1907. 
 
110 IRRITABILITY 
 
 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^ has already emphasized, in opposition to these 
 experiments, that the respiratory quotient in recovery is no crite- 
 rion 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, there- 
 fore, 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 con- 
 vinced 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 pro- 
 duction 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 produc- 
 tion 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 re- 
 serve, 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 
 
 1 Lesser: "Die Warmeabgabe der Frosche in Luft und sauerstofffreien Medien. 
 Ein experimenteller Beweis dass die COj Production der Frosche im sauerstofffreien 
 Raum nicht auf Kosten gespeicherten Sauerstoffs geschieht." Zeitschr. f. Biologie 
 Bd. 51, 1908. 
 
THE PROCESS OF EXCITATION ill 
 
 entire carbon dioxide production during a period of many hours. 
 No conclusions can be drawn from this as to ilic conditions 
 existing in the first period of time, chrcclly after the animals 
 have been subjected to an atmosj)lierc of nitrof^cn. It is (juitc 
 possible that subsequent to the ciiange to nitrogen an oxydative 
 carbon dioxide formation may have continued in decreasing 
 degree, without this being shown in the final result. The i)rob- 
 lem of the existence of a reserve sui)ply of oxygen is in no way 
 solved by these experiments. 
 
 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 empha- 
 size, 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. Strych- 
 ninized frogs, in which the blood has been replaced by an oxygen- 
 free saline solution, lose, as I have shown, ^ their excitability com- 
 pletely 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 l)ecn 
 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 momenta- 
 rily to a very low level, for the anoxydative disintegration pro- 
 cesses are associated with an incomparably smaller production of 
 energy than those of oxydative disintegration. We sec, however, 
 that the irritability in the muscles, nerves and nerve centers of the 
 frog even after the complete withdrawal of oxygen at first re- 
 mains practically at the former height and only very gradually 
 
 \Max Verworn: "Ermudung, Ersch6pfung und Krholung der ncrvoncn Centra dc« 
 Ruchenmarks." Arch. f. Anat. u. Physiol, physiol. Abt. Suppl. 1900. 
 
112 IRRITABILITY 
 
 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. 
 
 In accordance with this we must suppose that under physiologi- 
 cal conditions all those substances required to replace the disin- 
 tegrated molecules are always present in the cell in sufficient 
 quantity and suitable form to replace at once those lost by exci- 
 tation. Further, without doubt, in the organism which is always 
 aerobic, oxygen must be present in certain quantities to assure at 
 any moment oxygen replacement following oxydative disinte- 
 gration, 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 pro- 
 cess before us, the principle of which is nowadays restricted to 
 living substance. In my ''Biogen hypothesis,"^ 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 equilib- 
 rium between the quantity of foodstuffs and the quantity of a 
 hypothetical combination of living substance, the hiogen, 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, 
 
 1 Max Verworn: "Die Biogenhypothese." Jena 1903. Compare also Max Verworn: 
 Allgemeine Physiologic V. Aufl. Jena 1909. 
 
THE PROCESS OF EXCITATION 113 
 
 we have a case of an inanimate system, in which tlic amounts of 
 the reacting substances are in constant e(|uihhrium. Tlic reaction 
 following the mixture of equal amounts of alcohol and acetic acid 
 
 is as follows: 
 
 Yi Mol. C,HpH +/3 Mol. CH,C()OH 
 = yz Mol. CH3CO0C,H, + 23 Mol. II,(). 
 
 In this reaction there is an alteration only in the ah'^olute 
 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 i)lace. certain 
 quantities of substances reacting on each ollu-r are continually 
 introduced into and certain reaction i)roducts continually re- 
 moved from the living system. Secondly, the reacting mixture 
 of the living substance is not homogeneous, and at the s«'ime 
 time is more complicated than that of the inanimate example. 
 Thirdly, the sum total of the reaction is not reversible in its en- 
 tirety. The question arises, should any essential ditTcrencc 
 between metabolic self-regulation and the maintenance of chemi- 
 cal equilibrium be assumed upon this statement? I must con- 
 fess that this does not appear to me to be the case. Tlic fact 
 that organisms exist in a stream of substances by which tlieir 
 nutrition is introduced and the metabolic ])roducts removed, 
 cannot have any influence on the state of ecjuilibrium 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 eciuilihrium takes place, 
 having a higher or a lower mass level. This is also true in the 
 living substance, in growth and in atroi)hy. The ecjuilibrium 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 mix- 
 
114 IRRITABILITY 
 
 ture is concerned, it is self-evident that this Hkewise does not 
 constitute an essential difference, for we are acquainted with con- 
 ditions 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 con- 
 ceive 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 quantita- 
 tive relations of foodstuffs, following every disintegration of 
 assimilative products with removal of the decomposition products, 
 the same amount of assimilatory processes is required for build- 
 ing up. And this is just that which we observe in metabolic 
 equilibrium. Accordingly, we may look upon the metabolic equi- 
 librium 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 sub- 
 stance 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 accom- 
 plished, 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 per- 
 vious 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 ex- 
 ceeded and which is osmotically regulated by its amount of salt 
 
THE PROCESS OF EXCITATIOX 115 
 
 content. \Mien, finally, osmotic pressure wiiliin the living cell 
 and in the surrounding medium is equal, the interchange of water 
 ceases. All these processes are exi)lained by dilTusion. Self- 
 regulation takes place in this regard simply by osmotic means. 
 The conditions in respect to those decomjKjsition products con- 
 sisting in more complicated organic combinations, such as lactic 
 acid, fatty acids and nitrogen derivatives of protein disintegration, 
 are somewhat different in that the protoi)lasm surface possesses 
 the property of hindering the passage of these substances into the 
 medium. These are, as is well known, first transformed by sec- 
 ondary chemical processes into transfusable substances. In this 
 transference the oxydative decomposition with the formation of 
 simpler substances plays the most important role, so that the sub- 
 stances 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 thi> 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 protoj^lasm ? It 
 is quite impossible to prove that such an effect follows the momen- 
 tarily 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 i)ossible by fre(iuently 
 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 fre(]uently 
 recurring functional excitation. We can, therefore, assume with 
 great probability that even the momentarily acting individual 
 stimulus produces, although not perceptible per sc. lasting ctTect 
 in the cell. The functional excitation must be followed sec- 
 ondarily by an increase of the assimilative phase of the entire 
 cytoplastic metabolism. Otherw^ise the taking place of the in- 
 crease of volume of the living system following frequent excita- 
 tion of the functional constituent members of metabolism, is 
 
116 IRRITABILITY 
 
 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 rela- 
 tions between activity and the blood supply of the particular 
 tissue or organ furnish a physical interpretation for the exist- 
 ence 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 aethylacetat 
 increases if more alcohol and acetic acid are introduced to an 
 equal degree. Some time ago^ 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 Lemherger^ 
 and Ishikawa^ 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. 
 
 1 Max Verworn: "Die cellularphysiologische Grundlage des Gedachtnisses." Zeitschr. 
 f. allgem. Physiol. Bd. VI, 1907. 
 
 2 Schwarz und Leniherger : "Uber die Wirkung Kleinster Sauremengen auf die 
 Blutgefiisse." Pfliigers Arch. Bd. 141, 1911. 
 
 3 These investigations have not yet been published. 
 
THE PROCESS OF EXCITATION 117 
 
 Whether or not the same ai)i)lics to the single hving cell, if the 
 unicellular organism likewise undcrgcK's a (juantilative increase 
 by a continuous functional excitation, and if the single cell |>os- 
 sesses in itself a corresponding mechanism of self-regulation 
 similar to the cell community in the vertebrates, cannot I>c 
 answered, for concerning all these ])r()l)lems information is lack- 
 ing for the present. 
 
CHAPTER VI 
 
 CONDUCTIVITY 
 
 Contents: Only processes of excitation are conducted, not processes of 
 depression. Conduction of excitation in its two extreme instances. 
 Conduction in undififerentiated 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 con- 
 ductivity. Conduction of excitation with decrement of the nerve after 
 artificial depression of irritability by narcosis. Theory of the decre- 
 mentless 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, pro- 
 duction of certain substances, the development of Hght, 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 pos- 
 sesses 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 
 
CONDUCTIVITY 119 
 
 only primarily for the reason lliat 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 l>e 
 conducted from the part affected by the stimulus to the sur- 
 roundings. 
 
 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 experimcnlallv of 
 the fact that depression following a stimulus is invariably local- 
 ized 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 elec- 
 trodes, and another pair is applied to the nerve between the cham- 
 ber and the muscle, it is possible to subject the stretch of nerve in 
 the chamber to various agents, producing a paralyzing etTect. In 
 this way it may be exposed to an atmosphere of pure nitrogen 
 for example, or to narcosis as by ether, chloroform, carbon diox- 
 ide and other gases, to an increase in temperature or to other 
 agents, without these in any w^ay affecting the irritability of the 
 nerve stretch situated over the electrode between the chamber 
 and the muscle. The contractions of the muscle, which are pro- 
 duced 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 gangliun cell «»f a 
 motory neuron is likew^ise wholly without influence on the degree 
 of excitability of its nerve fiber, as I was able to demonstrate* 
 in the reflex inhibition of the motor neurons of the si)inal cord 
 of the dog. (Figure 14.) That which is conducted by the 
 nerves is solely the process of excitation. 
 
 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 
 
 1 Max I'crworn: "Zur Physiologic der nervoscn Hcmmungs«rschcinungcn." Arch. f. 
 
 Anat. u. Physiol, physiol. Abt. Suppl. 1900. 
 
IRRITABILITY 
 
 Fig. 14. 
 
 Contractions of the musculus extensor digitorum communis longus of the dog, brought about by rhyth- 
 mic stimulation of the nervus peroneus. The muscle is in the condition of tonic excitation which 
 proceeds from the center. The <utows indicate the point where reflex inhibition of the central tonus 
 is produced. The height of the single contraction undergoes no diminution. 
 
 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 con- 
 ductivity. Not all cell forms are suitable objects for the study of 
 conductivity. There are forms of rhizopods which are as favor- 
 able to investigation as the nerve; this is due to the fact that, 
 
CONDUCTIMTV 121 
 
 although they are often of microscopic dimensions, they ix)ssess 
 elongated fingerlike or threadlike pseudopods. 
 
 Indeed, a rhizopod cell, with its straight, elongated pseudcjpods, 
 is preeminently fitted as an object of comparison with a neuron. 
 Although the difiference 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 observa- 
 tion. 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 investi- 
 gation 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 func- 
 tion of the conductivity of excitation is particularly highly devel- 
 oped, was considered at the same time as the tyi)e 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 seriou> 
 errors, as the nerve, resulting from the high development of its 
 conductive capability, shows quite one-sided si)ecialized conditions, 
 which can by no means be transferred to other forms of living 
 substance. 
 
 A very suitable object among rhizopods for the study of con- 
 ductivity, and which is everywhere easily procured, is Difflinjia. 
 This species living in small pools has a delicate urn-sha{>ed. pear- 
 shaped or flask-shaped capsule built up of sand grains, diatomes 
 or material produced by the organism itself. hVom the oj)ening 
 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 microscoi)e. it is frequently 
 seen to extend from the opening long i)seudopods in exactly oppo- 
 site 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 i)seudopods are very readily stim- 
 ulated at any position to a desired extent by means of a sharp 
 
122 IRRITABILITY 
 
 needle, to which fat has been previously applied and subse- 
 quently 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 advan- 
 tage 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. 
 
 All these factors, the intensity with which the excitation 
 extends from the point of stimulation, the rapidity of the exten- 
 sion, 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 ex- 
 tends 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 char- 
 acteristic 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 
 
 1 Max Verworn : "Psycho-physiologische Protistenstudien. Experimentelle Unter- 
 suchungen." Jena 1889. 
 
CONDUCTIVITY 
 
 1-^3 
 
 Fig. 15. 
 
 Difflugia urceolata. A— Weak local stimulation at the end of a long extended pse 
 B — Stronger local stimulation applied to the end of a long pseudopod. 
 
 last there is complete disappearance. (Figure 1."), 15.) The 
 pseudopod has at the same time retracted to a c()nsi(leral)le 
 degree. If a still stronger stimulus is api)he(l by firm |)rcssure 
 at the end of the pseudopod the ])rocess takes ])lace witli mucli 
 greater violence. The differentiation of the ])rot()phism spreads 
 centripetally from the point of stimulation over the wliule 
 pseudopod with great rapidity, and produces a (juick retraction 
 in the same, then involves the op]>ositely dirccte<l j)scu(Ii)i)od, 
 in which it then extends more and more slowly, until, proceeding 
 in a centrifugal direction, it is at last gradually comi)leteIy oblit- 
 erated. When strong stimulation is ai)i)licd. the i)rocess occtirii 
 with such rapidity that the contraction of the pseudopod is 
 almost twdtchlike. As the rapidity of the conduction alters 
 
124 
 
 IRRITABILITY 
 
 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 
 
 Fig. 16. 
 
 Diffiugia urceolata. A— In non-stimulated condition. B— The same individual 
 locally stimulated in the middle of a long extended pseudopod. The excita- 
 tion spreads in both directions, centripetal as well as centrifugal. 
 
 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 
 
CONDUCTIVITY 
 
 125 
 
 show very clearly that in DiffluyUi ilie excitation following a 
 localized stimulus is dependent on the intensity of the stimu- 
 lus, and that according to the degree of this, the wave pro- 
 gresses in either stronger, more rai)i(l and extended, or weaker. 
 slower and more limited manner. With the greater distance 
 
 Fig. 17. 
 
 Cyphoderia margaritacea. Result of localized mechanical stimulation at the rnd 
 of a long extended pseudopod. A. H. C -three successive staitcs. 
 
 from the point of stimulation the excitation undergoes an increas- 
 ing decrement of its intensity and rapidity of conduction. Dif- 
 ferent species of Diffliigia which I have investigated. Diffluijia 
 lohostoma, nrceolata, pyriformis, have shown a complete con- 
 
126 
 
 IRRITABILITY 
 
 formity in this respect. A great number of other fresh water and 
 marine rhizopods, the pseudopods of which I have used for anal- 
 ogous 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 
 
 Fig. 18. 
 
 Cyphoderia margaritacea. Result of localized mechanical 
 stimulation in the middle of a long extended pseudopod. 
 
 favorable form is, for instance, the much smaller Cyphoderiu 
 margaritacea, which is distinguished by a somewhat higher degree 
 of excitability and rapidity of reaction.^ The long straightly 
 extended pseudopods are thinner and more threadlike than those 
 
 1 Max Verworn : "Die Bewegung der lebendigen Substanz. Eine vergleichend physi- 
 ologische Untersuchung der Contractionserscheinungen." Jena 1892. 
 
CONDUCTIX'ITV 
 
 127 
 
 of Difflnyia and show upon stinuilalion as a result of tlieir local 
 excitation a simple contraction into cluini)s of the .stimulated 
 protoplasm without the characteristic differentiation of that of 
 Difflugia. (Figure 17.) In the case of the marine rhizoi>ods, 
 
 J 
 
 f 
 
 Fig. 19. 
 
 A pseudopod of Orbitolites complanatus icf. Fi«. 7'. a In normal condition. 
 b — Severed by a cross section near the end. hf Five successive stjycs 
 of the effect, b-d— The pseudopod retracts by centripetal Huwinti of the 
 protoplasm contracted in the shape of microscopic balls and spindles. «* 
 and f The pseudopod begins to extend again. The centripetal flowintt 
 balls and spindles begin to disappear. 
 
 Orbitolites (Figure 19), Amphistcgiua, etc.. which I investij^ated 
 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. 
 
128 IRRITABILITY 
 
 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.^ 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 "unwirk- 
 same Ableitung" in the sense of Du Bois-Reymond, that is, in 
 which there is no demarcation current. When a tetanizing cur- 
 rent 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 repeat- 
 edly confirmed, shows us that the medullated nerve, under normal 
 conditions, conducts excitation without a perceptible decrement 
 of the intensity. 
 
 This specific property of a medullated nerve is in conformity 
 with the conditions in connection with the rapidity of conduc- 
 tivity. Since Helmholtz- 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.* 
 Helmholtz found the rate for motor nerves of the frog to be 
 27 meters per second, for the sensory nerves of man 60 meters, 
 
 1 Du Bois-Reymond: "Untersuchungen iiber tierische Electricitat." II Band. 1849. 
 
 2 H. Helmholtz: "Messungen iiber den zeitlichen Verlauf der Zuckung animalischer 
 Muskeln und die Fortpflanzungsgeschwindigkeit der Reizung des Nerven." Miiller's 
 Archiv. 1850. 
 
 The same: "Messungen iiber die Fortpflanzungsgeschwindigkeit der Reizung in den 
 Nerven." Zweite Reihe, Miiller's Arch. 1852. 
 
 3 Compare: Hermann: "Handbuch der Physiologie." II, 1 Leipzig 1879. 
 
CONDUCTIVITY 129 
 
 and the motor nerves of man 34 meters. Other investigators 
 have obtained quite different resuUs; Hirsch, for the sensory 
 nerves of man, 34 meters; Schclskc, for the same, •v^')-33 meters; 
 De Jaager, 26 meters; v. IVittich, 34-44 meters, and Kohlrausch. 
 56-225 meters ; v. IVittich for the motor nerves of man, 30 meters ; 
 Piper^ finally in the most recent investigations about ll'O meters 
 in the second. 
 
 These differences may be explained in a larijc measure by the 
 variety of the methods used, in part also ])y liie difference in the 
 structures. The methods employed for the study of the velocity 
 have also been used to solve the question, whetlier 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 jxiint 
 of stimulation. Here the endeavor w^as made to study the differ- 
 ence in time of the latent period, which is observed by the indi- 
 cator, when the nerve is stimulated at two points at different dis- 
 tances from the muscle, used as an indicator, or from the wires 
 leading the current to the indicator. The more recent investiga- 
 tors, as Rene Du Bois-Reymoud,- Engelmann,^ G. Weiss.* 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.) 
 
 The medullated nerve shows, therefore, under normal condi- 
 tions neither a decrement of its conductivity, nor of its irritability. 
 as the distance of the w^ave of excitation increases from that of 
 the position of stimulation ; this means, in other words, that excita- 
 tion is conducted with the same intensity with which it is started, 
 and with a constant rate throughout the entire course of the 
 nerve. 
 
 There is, nevertheless, a third point of considerable difference 
 
 1 Piper: "Ueber die Leitungsgeschwindigkcit in dcm markhaltiRcn mmschlichcn 
 Nerven." 
 
 The same: "Weitere Mitteilungen iiher die CieschwindiRkcit dcr Errrifiingalcitiing «m 
 markhaltigen menschlichen Nerven." Pfliigers .\rcb. Hd. 1J7. 190'». 
 
 2 R. Du Bois-Rcymond: "Ueber die Geschwindigkcit dcs Nervcnprincip*." Arch. 
 f. Anat. u. Physiol, physiol. Abt. Suppl. 1900. 
 
 3 Engelmauu: "Graphische Untersuchungcn ubcr die Fortpflan/nnipmrichwindir 
 keit der Nervcnerregung." Arch. f. Anat. u. Physiol, physiol. .Abt. 1901. 
 
 4 G. Weiss: "La conductibilite et rexcitabilite dcs ncrf.s." In Journ. dc Phywol. 
 et de Pathol, generale 1903. 
 
130 
 
 IRRITABILITY 
 
 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.) 
 
 between the types of conduction of excitation in the rhizopods 
 and in the nerve. Whereas in the rhizopods the rapidity of con- 
 duction is dependent upon the intensity of the stimulus, it has 
 been long known as the result of investigation by Rosenthal, 
 Briicke and Laiitenhach and at a more recent date by Gotch^ and 
 Piper,- 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^ explains this shortening of the latent period, 
 
 1 Gotch : "The submaximal electric response of nerve to a single stimulus." Journal 
 of Physiology, Vol. XXVIII, 1902. 
 
 2 Piper : Ueber die Leitungsgeschwindigkeit in den markhaltigen menschlichen 
 Nerven. Pfliigers Arch. Bd. 124, 1908, und Bd. 127, 1909. 
 
 3 Nicolai: "Ueber Ungleichformigkeiten in der Fortpflanzungsgeschwindigkeit des 
 Nervenprincips, nach Untersuchungen am marklosen Riechnerven des Hechts." Arch, 
 f. Physiologie 1905. 
 
CONDUCTIX'ITV 
 
 131 
 
 
 
 
 
 
 
 
 
 
 
 
 
 on> 
 
 
 / 
 
 
 
 V 
 
 
 
 
 
 
 
 
 O V 
 
 "^191 
 
 926 
 
 
 
 
 
 V 
 
 
 
 - 
 
 
 ^ 
 
 
 
 O/l 
 
 X -001 -002 003 OOi 005 006 OOr OOS 009 010 on 0/2 
 
 Fig. 21. 
 
 Course of the action current of the nerve. The thin line indicates the action currcat 
 produced by a weak, the thick line the action current produced by a strong stiaulu*. 
 The duration of the action current is the same in both cases. (After GotchJ 
 
 resulting from the application of strong electrical stimuli, to a 
 spreading out of the "Stromschleifen" from the i)oint of appli- 
 cation and consequently there is a shortening of the stretch of 
 nerve between the point of stimulation and tiie indicator. 
 
 This conspicuous difference in the conduction uf tlie two 
 extreme types of living substance, which we have already ob- 
 served, arouses the question as to what properties of living sub- 
 stance bring about these differences, in order to answer this 
 question, it is necessary, first of all, to make some general .state- 
 ments concerning the processes of conductivity. 
 
 As already emphasized, all living substance possesses the cajva- 
 bility of conducting excitations to a definite degree. W e may, 
 therefore, assume that the same fundamental property of con- 
 ductivity exists in all substances. A fact to be considered in tlie 
 conduction of excitation, is that the i)rimary breaking down of 
 the complex molecules at the position of stimulation act in turn 
 as exciting stimuli ui)on the neighl)()ring i)()rtion of the living 
 substance, which in turn undergoes a similar decomposition. And 
 so this process continues. This fact is evident from the observa- 
 tions on the process of excitation. Ikil the nature of the stimulus 
 
132 IRRITABILITY 
 
 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 irrita- 
 bility. The greater the irritability, that is, the greater the number 
 of molecules broken down in a unit of time and space by a stim- 
 ulus 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,^ Erb,^ Grilnhagen,^ Effron,^ 
 Hirschberg^ and G. Weiss,^ 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, 
 
 1 Schiff : "Uber die Verschiedenheit der Aufnahmsfahigkeit und Leitungsfahigkeit in 
 dem peripherischen Nervensystem." Henle u. Pfliigers Zeitschr. 1866. 
 
 2 Erb: "Zur Pathologic und pathologischen Anatomic pcripherischer Paralysen." 
 Deutsches Arch. f. Klin. Med. 1869. 
 
 3 Grunhagen: "Vcrsuche iibcr intcrmitticrende Ncrvcnrcizung." Pfliigers Archiv. 
 Bd. 6, 1872. — Funke-Griinhagen." Lehrbuch der Physiologic Bd. I, 1876. 
 
 4 Effron: "Bcitrage zur allgemeinen Nervenphysiologie." Pfliigers Arch. Bd. 36, 
 1885. 
 
 5 Hirschberg : "In welcher Beziehung stehen Leitung und Erregung der Nervenfaser 
 zu einander?" Pfliigers Arch. Bd. 39, 1886. 
 
 6 G. Weiss: "La condvictibilite et I'cxcitabilite des nerfs." Journ. de physiol. et de 
 pathol. generale. T. V. 1903. — "Influence des variations de temperature et des actions 
 mechaniques sur I'excitabilite et la conductibilite des nerfs." Ibidem. 
 
CONDUCTIVn \' 133 
 
 other investigators, such as Hcrmanu} Szpilmmm aiui I.uch- 
 singcr,- Gad,^ Piotroivski* and U'cdcuski/ have more or less 
 decidedly taken the stand that an actual separation of irritability 
 and of conductivity does not exist. Tlie ai)i)arently contradictory 
 evidence as well as the conflictini^ theoretical views have Inren 
 cleared up by Wcrigo'' DeudrinosJ NoW* and I-rohliclt.^ These 
 investigators have shown that the length of the narcotized stretch 
 of the nerve plays an important nMe in the obliteration of con- 
 ductivity. It has been found by the ai)plication of a stinnihis 
 above the narcotized stretch of nerve, that the longer this stretch 
 is, the less is the reduction of irritability which ()l)literatcs the 
 excitation wave reaching this area. I'urther: The shorter 
 the stretch, the greater must be tlie reduction in irrital)ility 
 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 inten- 
 sity 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, wdien the stretch is long enough, the wave 
 
 1 Hermann: "Handbuch der Physiologic." Bd. II. I Leipzig 1879. 
 
 2 Scpilmann titid Luchsiuger : "Zur Bezichung von LcitunRSund Errcff\ing»»cr- 
 mogen der Nervenfaser." Pfliigers Arch. Bd. 24, 1881. 
 
 3 Gad: "Ueber Trennung von Reizbarkeit und Lcitungsfahigkcit dcs Ncrvcn." 
 (Nach Versuchen des Herrn Sawyers) Arch. f. Anat. u. Physiol, physiol. .\\A. 1888. 
 
 Derselbe: "Ueber Leituiigsfahigkeit und Reizbarkeit dcs Ncrvcn in ihrcn Hczich- 
 ungen zur Langs und Querschnitts erregbarkeit." Nach Versuchen dcs Ilcrrn Piotrow- 
 ski Arch. f. Anat. und Physiol, physiol. Abt. 1889. 
 
 4 Piotrozvski : "Ueber Trennung von Reizbarkeit und Lcitungsf.ihigkcit dcs Ncrvcn." 
 Arch. f. Anat. u. Physiol, physiol. Abt. 1893. 
 
 5 IVedenski: "Die fundamentalen Eipenschaften dcs Ncrvcn unter Einwirkung 
 einiger Gifte." Pfliigers Arch. Bd. 82. 1900. 
 
 The same: "Excitation, inhibition et narcosc." Compt. rcndus du v. Confrw 
 internal, de Physiologic a Turin 1901. 
 
 6 Werigo: "Zur Fragc iiber die Bcziehungcn zwischcn Errcpharkcit nnd I-citunf»- 
 fahigkeit des Nerven." (Nach Versuchen von stud. Rajmisf. Pfliifrcrs Arch. Bd. Tt.. 
 
 1899. 
 
 7 Deiidritws: "Ueber das LeitungsvermoRen des motorischcn FroMrhncrvcn." 
 SNoH: "Ueber Erregbarkeit und Leitungsvcrmi>Kcn dcs motorischcn Ncrtrcn unlcr 
 
 dem Einfluss von Giften und Kfilte." Zcitsch. f. Allgcm. Physiol. Rd. III. 1007. 
 
 9 Fr. IV. Frdhlich: "Erregbarkeit und Leitfahigkcit «!cs Ncrvcn." Zcitschr f 
 allgem. Physiol. Bd. III. 1904. 
 
134 
 
 IRRITABILITY 
 
 of excitation is obliterated. This important fact has been fur- 
 ther estabHshed by the experiments of Boruttau and FroJilich,^ 
 in which they studied the intensity of the current of action, 
 
 +f 
 
 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 excita- 
 tion 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 pziss 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. 
 
 produced by a wave of excitation, from two points in the narco- 
 tized stretch. The wave of negative variation, brought about by 
 
 I Boruttau und Frohlich: "Erregbarkeit und Leitfahigkeit des Nerven." Zeitschrift 
 f. allgem. Physiologie Bd. IV, 1904. The same: "Electropathologische Untersuchungen 
 ueber die Veranderungen der Erregungswelle durch Schadigung des Nerven." Pfliigers 
 Arch. Bd. 105, 1904. 
 
CONDUCTIVITY 135 
 
 the excitation, gradually decreases in the narcotized stretch as 
 the electrode is further removed from the point of entrance. 
 Beside a decrement of iiitcusity, as the investigations of Vrohlich^ 
 prove, the wave of excitation shows a decrement of the velocity 
 in the narcotized stretch. And it is jjrohahle that the wave of 
 excitation extends with progressive reduction in the velocity, 
 corresponding to the decrement of intensity. The work of Koike* 
 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 accei)ted as conclusive in spite 
 of the delicate method employed. These investigations are ex- 
 tremely 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 irri- 
 tability and conductivity intelligible. It flepends entirely ui>on 
 the length of the narcotized area, and the amount of reduction 
 in irritability on the one hand, and the strength of the stimuhis 
 used for testing the irritability on the other, whether the con- 
 ductivity will disappear before the irritability or vice versa. If 
 I test the irritability in the narcotized stretch with a weak stimu- 
 lus, 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 he 
 found to be present at a time when the conductivity for the exci- 
 tation, coming from above, is already obliterated. Thi< is due 
 to the fact that the decrement in the narcotized area is already 
 great enough to bring about the complete disappearance of the 
 
 iFrohlich: "Die Verringerung di r Fortpflanziingsgcschwindigkcit dcr Ncnrrncrre- 
 gung durch Narkose und Erstickung des Ncrvcn." Zcitschrift alljicm. Phywologie Bd. 
 
 Ill, 1904. 
 
 2Izuo Koike: "Uebcr die Fortlcitung dcs ErrcKuiiKSvorKaiiRS -' -i'lcr narko* 
 
 tisierten Nervenstrecke." Zeitsch. f. Biologic Rd. 5. 1910. 
 
136 IRRITABILITY 
 
 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, there- 
 fore, 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 con- 
 ductivity is a manifestation of irritability. 
 
 The facts just mentioned have, however, a much deeper mean- 
 ing. 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 per- 
 manent injury of the nerve. We are, therefore, in the fortunate 
 position in the case of the medullated nerve of having a sub- 
 stance 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 condi- 
 tions 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 con- 
 
CONDUCTIX ITV 137 
 
 ducting excitation into a long scries, starting wiili tliose |Xisscss- 
 ing the least irritability, as we found in the rhizopuds. then tliosc 
 having greater irritability, as the smooth muscle and ganglion 
 cells, then those with still greater irritability, as the strij>ed muscle, 
 and finally those having the greatest degree of irritability, as ihc 
 medullated nerves of the warm-blooded animal. Should the 
 processes of excitation, as we saw, result from the energy pro- 
 duction 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, i)y 
 the number of molecules which are broken down in a defmitc 
 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 i)ro(luction 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 devel- 
 oped 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, pro- 
 duced 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 w^ords : an equal amount of energy is set free at every 
 cross section, which, in its turn, acts as stinuilus t»^ the next. 
 etc. Such a condition presupposes, however, in an elementary 
 fiber of the nerve, that by the conduction of the wave of excita- 
 tion from cross section to cross section, all tho-e molecules 
 capable of disintegration are broken down. If it is assumed that 
 
138 IRRITABILITY 
 
 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 
 
 0^ 0^0 o 
 
 
 ^n°nO°0 °°0°°0 Ooo°° 0^0^,0 o^ o%%''o°oO 
 y O 00° o\o /O O 0^ ^ , 0^o°o°°0°0 °, ^^O^^^O 
 
 Fig. 23. 
 
 would be entirely incomprehensible how, with the decrementless 
 extension of the excitation, individual molecules capable of break- 
 ing 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 
 
CONDUCTIVITY 139 
 
 reality and would lluis transfer the dithculty to the uliiniaie 
 fiber unit, for which a liomo^cncous 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. 
 
 This gives us occasion to return to the di.scussion of the ques- 
 tion, if living systems really exist which respond in accordance 
 with the "all or none law." The medullatcd nerve forms an 
 object particularly suited to serve as a starting point for the 
 treatment of this especially important i)roblem. The (juestion 
 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^ has 
 pointed out, as the result of experimental studies of the wave 
 of activity of the nerve, that the difference in response, follow- 
 ing the application of stimuli of varying strengths, is under- 
 standable from the fact that threshold stimuli stimulate only a 
 few of the fibers of the nerve trunk, wliereas progressively in- 
 creasing the intensity of the current involves more and more 
 fibers. There can be no doubt that this factor explains the ditler- 
 ence 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 o|>cr- 
 able stimulus produces maximal excitation, so that tlie response 
 
 1 Gotch: "The submaximal electrical response of nerve to a tingle mmulu*." 
 Journal of Physiology, Vol. XXVIII. 1902. 
 
140 IRRITABILITY 
 
 cannot be further increased. But above all, there is a series of 
 facts, which have been gained in the Gottingen 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. 
 
 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 pro- 
 duced minimal contraction in the muscle, and Frohlich^ continued 
 these observations. As a result the following very remark- 
 able 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 stimula- 
 tion 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 excita- 
 tion of different intensity, and are then conducted. Let us now 
 clearly comprehend this problem. 
 
 We have already seen that the wave of excitation meets with 
 a decrement of its intensity in the narcotized stretch, which 
 
 1 Frohlich: "Erregbarkeit und Leitfahigkeit des Nerven." Zeitschr. f. allgem. Physi- 
 ologic, Bd. Ill, 1904. 
 
COXDUCTIVITV 
 
 Fig. 24. 
 
 Curves of the changes in irritability (p) and conductivity c of a nerve under the influence of 
 
 narcosis or asphyxiation. (After Fruhlkh.i 
 
 increases in strength as the irritabiHty diniinislics. It the value 
 of the threshold is learned by stinuilatinj^ the nerve at the elec- 
 trodes centrally placed to the chamber with minimal siiimili. it 
 would necessarily follow that this weak stimulus wcuild lining 
 about a corresponding weak excitation of the individual TiIkts 
 and the wave of excitation already in the bej^inning of narcosis 
 would be obliterated, for it would meet with a decrement, the 
 result of the reduction in the irrital)ility. A wave of excita- 
 tion of minimal strength could imdcr these conditions no longer 
 reach the muscle, even in the beginning of narcosis. In spite 
 of this the excitation, even when pro<iuced with ilireshold 
 stimuli, passes through for a long time. e\ en when the irri- 
 tability in the chamber is greatly reduced, as sliown by testing 
 with the electrodes within the chamber. This is not consistent 
 with the assumption that a threshold stinuilus l)rings alw-iut tlu- 
 minimal excitation, even in the individual nerve fiber. But 
 further: with a definite decrease of irritabilitv of the narcotized 
 
142 IRRITABILITY 
 
 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 stimu- 
 lation, 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 capa- 
 bility of conduction is completely obliterated, and even the strong- 
 est 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. 
 
 In order to examine these facts once more on an extensive 
 scale, and at the same time obtain an understanding of the devel- 
 opment of the decrement in the narcotized stretch, I have re- 
 quested Dr. Lodhoh to register as many accurate curves as pos- 
 sible 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 asphyxi- 
 ated stretch; the fourth is centrally placed. (Figure 24.) As 
 
 Fig. 24. 
 
CONDUCTIVITY 143 
 
 might be expected the resuh was the same as in former investiga- 
 tions. They show however even more strikingly the abruptness 
 of the disappearance of conchicliviiy simnhaneously for the weak- 
 est and the strongest stimuli. Tlie curve produced by the centrally 
 placed electrode remains at the same lieight f(jr a considerable 
 period, then suddenly al)ruptly declines. Those of the eleclro<lcs 
 within the chamber likewise sink, at first slowly, then with in- 
 creasing rapidity in successive order corresponding to the dis- 
 tance 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 c<jmplete 
 clearness that in contrast to all those points within the atlectcd 
 stretch, where the conductivity, though already obliterated for 
 weaker stimuli, still exists for stronger, that with stimulaticjii 
 of a point towards the center above the affected stretch, con- 
 duction ceases simultaneously for all tlilYereni .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 resi)onse at a iK)int sit- 
 uated at the greatest distance from the place of exit, an eflect 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 j^oints in equal measure, 
 the fact of a weaker stimulus becoming inoi)erativc whilst a 
 stronger remains effective can only be attributed to the circum- 
 stance 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 manifesta- 
 tions of the nerves in response to stimuli api)lied centrally al)ovc 
 the chamber in the normal stretch are compared to those in 
 response to a stimulus acting on the affected stretch, dearly 
 demonstrate the totallv different effect in both cases. In stinuila- 
 
144 IRRITABILITY 
 
 tion of the centrally situated normal stretch, the wave of excita- 
 tion, which enters from here into the influenced stretch, is oblit- 
 erated at the same point simultaneously for the weakest as well as 
 for the strongest stimulus ; stimulation of the afifected stretch, the 
 wave of excitation which is set free at one point by a weak stimu- 
 lus, 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 differ- 
 ence of intensity in the conduction of excitation is not, as has 
 been assumed until now, the result of the conduction of vary- 
 ing 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 phys- 
 iology. 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 oper- 
 
CONDUCTIVITY Ij:, 
 
 ative brings about disintegration of all the material involved 
 in excitation, and consequently the i)roperty 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 decre- 
 ment 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 u\Hm one another, f(jr they arc 
 the combined expression of one and the same factor, that of the 
 high state of irritability. When the irritability is artificially re- 
 duced, then the nerve approaches more and more, dej)ending u\Hm 
 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 rhizoi)ods with their minimal 
 capability of reaction, we find innumerable gradations in groups 
 of living substances. \\ hethcr or not other forms of living sub- 
 stances 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 KcitJi Liicas^ seem to show, rccjuires further 
 investigation. 
 
 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 alx)ut 
 by the decomposition of the molecules in one region acting as a 
 stimulus and producing a disintegration of the molecules in 
 another region, etc. \\'e have already seen that the intensity is 
 dependent upon the amount of energy produced by the disinte- 
 gration of the molecules following the stimulus, that is. u\K)n the 
 amount liberated in a definite space in a definite time. The ques- 
 tion which now arises is this: What form of energy is produced 
 
 1 Keith Lucas: "On the gradation of activity in a skeletal muscle f»l>cr." Journal 
 of Physiology, Vol. IX, 1888. The same: The "all or none'* contractiont of the 
 amphibian skeletal muscIe-fiber. Journ. of Physiology. Vol. XXXVIII. 1909. 
 
146 IRRITABILITY 
 
 by the stimulus at the point of stimulation, which acts upon the 
 neighboring molecules? The conduction of excitation is a prop- 
 erty 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 mole- 
 cule 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 explo- 
 sive 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.^ 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 pro- 
 duction 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. 
 
 1 Compare Pflilger: "Ueber die physiologische Verbrennung in den lebendigen Or- 
 ganismen." In Pfliigers Archiv. Bd. 10, 1875. Further: L. Hermann: "Handbuch der 
 Physiologic, Bd. II, Allgemeine Nervenphysiologie," 1879. 
 
CONDUCTIVITY 147 
 
 of dry siil)stanccs remain. Even (»f this 25 per cent, by far 
 the largest part is apportioned to connective tissue, iur which 15 
 per cent, is certainly not i(jo hi^di a figure. Neither can the re- 
 maining 10 per cent, of dry substances be regarded as consisting 
 entirely of molecules capable of decomi)osition. For in this is 
 also included the organic reserve material of the axis cylinder pro- 
 toplasm, which is doubtless of very considerable amount. Furtiier. 
 the salts and products of disintegration, for which the estimate 
 for the sum total would i)rol)ably not be too low if we assume the 
 amount to be equal to that of the group si)ecially concerned in 
 the process of excitation. As, however, a constant metabolism 
 of rest takes place, these last molecules or atom groups arc cer- 
 tainly not at the moment of entrance of the stinudus in their 
 entirety in a condition capable of decomposition. It is (|uitc cer- 
 tain, therefore, that we are still overestimating the amount of the 
 molecules capable of disintegration, if we i)Ut them down as 5 |)er 
 cent, of the entire nerve substance. If we now supi>ose 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 mole- 
 cules 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 uix)n 
 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. How- 
 ever, 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 Pjh'njcr remove this difticulty. 
 
148 
 
 IRRITABILITY 
 
 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. 
 
 In consideration of this difficulty it seems easier to assign 
 the role of mediator of disintegration not to heat but to elec- 
 tricity. 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 impor- 
 tant conditions, which must be demanded for the form of energy, 
 acting as mediator for the conduction of disintegration from 
 cross section to cross section. 
 
 a — {H 
 A 
 
 U 
 
 3] b 
 
 Fig. 25. 
 
 Model of a "Kemleiter." 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 /—Tubes for con- 
 nection with a galvanometer, (After Hermann.) 
 
 Physiologists even at an early date, misled by the apparent like- 
 ness 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 experi- 
 mentally 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. 
 
 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 
 
 
CONDUCTIVITY 149 
 
 processes. Mattcucci, later Ilcrnumn and finallv Huruttau' have 
 endeavored to apply the results obtained when electricity is intro- 
 duced in a wire covered with a moist envelope (saline solution), 
 to the explanation of conductivity in tin- nerve. ( I'i^'ure 25 ) 
 The fact has been shown, that in sucli a model the ai)plicalion 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 2i\.) 'Yh\<, fact, in con- 
 
 Fig. 26. 
 
 Scheme of the conduction by local electric currents 
 in a "Kernleiter." (After Hermann.^ 
 
 nection with the apparent similarity in the differentiation of the 
 axial fibers and peripheral envelope in the nerve, has led Borut- 
 tau to apply the principles of conductivity in the "core model" 
 to that of the nerve. Then, however, A^cmst and Zcynrck 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 ditTerent 
 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 diflerentiation of a 
 central fibrilla and a peripheral enveloj)ing substance was appro- 
 priated. It seems to me that this factor can likewise be consid- 
 
 1 The enormously extensive literature nn this subject up to the mo»i recent date it 
 quoted in Cremer: "Die allgemeine Physiologic dcr Nervcn." In Sagtls Ilandbiirh dcr 
 Physiologic des Menschen, Bd. IV, 1909. Braunschweig. 
 
150 IRRITABILITY 
 
 ered as completely dispensable and may, therefore, be omitted; 
 thus nothing remains of the "core model explanation" of the 
 conduction of excitation in the nerve. 
 
 The results of continually increasing numbers of investigation 
 in recent times make it appear almost as a certainty that the ele- 
 mentary fibrillae in the axis cylinder are nothing else but skeletal 
 substances. IVolff,^ Verworn^ and others have first expressed 
 the view that the neurofibrillae must be looked upon as skeletal 
 fibers for the soft neuroplasm, and more recently Lenhossek^ and 
 especially Goldschmidt^ have confirmed this assumption in detail. 
 Goldschmidt has shown by extensive comparative studies of cell 
 mechanism the role played by the neurofibrillae in a physical con- 
 nection as internal skeletal formations, and has proved at the 
 same time, in complete unanimity with other investigators, their 
 continuity with other undoubted skeletal fibrillae. By this the 
 numerous combinations and speculations of Apathy and Bethe 
 concerning the part taken by the neurofibrillae 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 exci- 
 tation for all living substance. 
 
 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 
 
 1 M. Wolff : "Ueber die fibrillaren Structuren in der Leber des Frosches." Anatom. 
 Anzeiger Bd. 26, 1905. 
 
 2 Max Verworn: "Bemerkungen zum heutigen Stand der Neuronlehre." Medicin. 
 Klinik, Jahrg. IV, 1908. 
 
 3 M. V. Lenhossek: "Ueber die physiologische Bedeutung der Neurofibrillen." 
 Anatom. Anzeiger Bd. 36, 1910. 
 
 4 Richard Goldschmidt : "Das Nervensystem von Ascaris lumbricoides und megalo- 
 cephala. Ein Versuch in den Aufbau eines einfachen Nervensystems einzudringen." 
 Ill Teil. Festschrift zum 60 Geburtstage Richard Hertwigs Bd. II, 1910, Jena. 
 
CONDUCTIVITY 
 
 151 
 
 substances. This is in the way thai the two different suhitiuns, 
 separated by a semi-permeable surface, do not follow the known 
 laws of diffusion, but are altered in thai certain substances in 
 contrast to their rapidity of diffusion i)ass through the membrane 
 or are prevented from entering by the latter. This applies like- 
 wise to the two kinds of ions, which arc dissfx-iateti in diluted 
 substances. If the surface exercises a selection in the wav, 
 for instance, that the positive kations are allowed to pass througli, 
 whilst the negative anions are held back, a difference of iKjtential 
 must exist between the two. In this manner, wherever two differ- 
 ent 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 colloi- 
 dal components possesses, in common with all colloidal sub- 
 stances, on its surface the properties of semi-permeable mem- 
 branes. Between the cell and the medium, therefore, there is 
 ahvays the opportunity for the occurrence of differences of elec- 
 tric potential. But more. We likewise know that protoplasm itself 
 
 
 R 
 Fig. 27. 
 
 Scheme of the foam structure of livintf !wihstanc«. A In 
 undifferentiated protoplasm. H In fibrilbc protopUtm. 
 
■ ^ ■ " T 
 
 T-'- y" 
 
 
 ^^^Trn" 
 
 ^ssT'^:^ 
 
 Protoplasm of different cells, showing foam structures. A— Pseudopod of a marine 
 rhizopod. The protoplasm only shows foam structure at the point of stimu- 
 lation. B— Epidermic cell of lumbricus. C— Nerve fiber. D— Part of the cell 
 body of a ganglia cell. (A-C after Biifschli, D after Held.) 
 
CONDUCTIVITY 153 
 
 represents a mixture of colloid suhstances and actual solutions. 
 Frequently, if not always, living structure i)rcscnts a ni(>ri)hu- 
 logical differentiation of two tyi)es, when seen under the micro- 
 scope, in the form of a foam structure described by Biitschli. 
 (Figures 27 and 28.) If we suppose that with the disintegra- 
 tion of complex molecules, which we mu^t assume as taking place 
 in the material of the walls of ilic i)r()toplasm network, sub- 
 stances are formed which are subjected to electrolytic dissociation, 
 the anions and kations here])y liberated must be dilTused from 
 the place of their separation into the surroundings. Their dif- 
 fusion, how^ever, is restricted by the pr()to|)lasmic network. The 
 positive ions may pass through, but the negative ions may not. 
 As a result: the reticulated substance is the seat of electric dis- 
 charge, wdiich in turn gives the impact to the breaking down of 
 new molecules and with this to the occurrence of new j)otcntia! 
 differences, and so on, consequently the disintegration is extended 
 further and further through the connected masses of the proto- 
 plasmic framew^ork. 
 
 This theory, founded on facts gained entirely from investiga- 
 tion, would involve those forms of energy which play the role 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 
 W'Ould be applicable to all vital systems. It would be premature 
 to attempt to extend this assumjnion and further develop its 
 specific details, above all to make it responsible for the si>ecific 
 differences in the i)rocess 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 manifestation^, 
 as, for instance, the facts concerning the production of electricity, 
 of galvanotaxis, chemotaxis and so on. This, however, exceeds 
 the limits of the task w^e have here mapin-d out. We are con- 
 cerned here solely with the general principle on which the con- 
 ductivity of excitation in the living substrince is founded. 
 
CHAPTER VII 
 
 THE REFRACTORY PERIOD AND FATIGUE 
 
 Contents: Conception of specific irritability. Alteration of specific irri- 
 tability 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 tempera- 
 ture. Dependence on supply of oxygen. Theory of refractory period. 
 Refractory period as basis of fatigue. Fatigue as a form of asphyxia- 
 tion. Alterations of irritability and the course of excitation in fatigue. 
 Recovery from fatigue. The role 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 char- 
 acteristic 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 Milller. 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 irrita- 
 bility, 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 irri- 
 tability, must be solely determined by the specific conditions exist- 
 ing in the particular system. It follows from this that every alter- 
 ation 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 
 
THE REFRACTORY PERIOD A\I) FATKiL'E 155 
 
 system in the process of excitation, l)rings ahout 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 \)c re- 
 established. The specific irritability is, therefore, a proi>erty of 
 the living system, which, like the metabolic eciuilibrium. under- 
 goes restitution by the process of self -regulation after variation 
 produced by a stimulus of any kind. It is scarcelv necessary to 
 repeat each time that this is only ai)i)licable within the physiologi- 
 cal variations and for a limited period, during which the altera- 
 tions in development need not be considered. 
 
 These alterations of the specific irritability following an excita- 
 tion 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 ha> l>cen 
 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. lUit that this is a 
 fact of general physiological fundamental importance for the 
 wdiole field of response to stimulation in the living substance has 
 only been recognized within the last few years. 
 
 In 1876 Marey'^ found that the irritability of the heart in re- 
 sponse to artificial stimulation was greatly reduced during the 
 systole, and that recovery took place during the following dias- 
 tole. (Figure 29.) This fact was already apparent from the 
 observations made by Boivditclr and Kroticckcr.^ that by stimula- 
 tion of the isolated frog's heart with single induction sluvks. an 
 
 1 Marcy: "Des excitations artificielks du civiir.'* Travaux du lah. dc .M. Ma'ff 
 II, 1875. The same: "Des mouvcmints <|ui produit It- ctrur lors<iu'«l «"»< »oumi« i dc« 
 excitations artificielles." Comptes rcndues dc racadt-mic des micmcc* T. I-. X.WII. 
 1876. 
 
 2 Bou'ditcli: "Ueher die Kigentliiimlichkcitcn dcr Kcizbarkcit wclchc die .Mi>»kcl- 
 fasern des Ilerzens Zeigen." Arbeiten aiis drr physioloRisclini .Xnntalt iii I cipxir. 1872. 
 
 Z Kroncckcr: "Das charakteristischc Mcrkmal «Icr Hcr/miiskcH.cwcgijni:." Hcitra^r 
 zur Anatomic und Physiologic als Festgabc f. Carl I-udwig zum 15, Oct. 1874. gvwid- 
 met von seinen Schiilcrn. Leipzig 1874. 
 
156 
 
 IRRITABILITY 
 
 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.) 
 
THE REFRACTORY PERIOD AND FATIGUE 15 
 
 O I 
 
 artificial systole can only he produced with certainty wlien the 
 stimuli succeed each other at certain intervals, which must l>c the 
 longer as the strength of the stimulation is weaker. A/arry calls 
 this period of reduced irritability "f^lutsc rcfractairc" of the lieart. 
 The refractory period of the heart has been marie the subject of 
 a great number of investigations, especially by liuf/clmautt and 
 his pupils. It was llngchnann^ especially who determined more 
 exactly the duration of the course of the refractory period. Mc 
 found, namely, that irritability disap])ears immediately l>eforc 
 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 j>eriod was 
 looked upon as a special peculiarity of the heart. It was not until 
 Broca and RicJiet,^ twenty years after Marey's in\estigations, dis- 
 covered an analogous refractory period for the motor centers of 
 the cerebral cortex of the dog. Tliey first made this observation 
 on a dog affected with chorea, in which tlie choreic movements 
 rhythmically occurred in intervals of one second. They foun<l 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 re- 
 fractory period after every artificial stimulation equal to .1 
 second, so that the number of contractions brought aUnit by 
 rhythmical electrical stimulation w^ere only ten per second. h'oUow- 
 ing this, numerous other investigations of the refractory period 
 have been made on the central nervous system, /wihirdrmakt'r^ 
 and Lans have observed a refractory period in the eyelid reflex 
 of the human being which, on stimulation of the optic nerve, 
 
 1 Th. IV. Engclmann : "Beobachtungcn und Vcrsuchc am «ii|»cndicrtcn Ilcrxcti 
 III. Refractare Phase und compcnsatorischc Riihc in iJircr Hrdrutung (iir den I!cr«- 
 rhythmus." Pfliigers Arch. lUl. 59. 1895. 
 
 2 Broca ct Riclict : "Pt-riode rcfractairc dans Ics centres nerveiix." Comple» rmdut 
 de I'academie des sciences 1897. Further Hichcl : "l..i vibration nenreu«c." RcTue 
 
 scientific Dec. 1899. 
 
 3 Zzcaardemakcr unci Lans: "Uebcr das Stadium rclativer fnerrrfUrVcil aU 
 Ursache des intcrmitticrcnden Charakters dcs LidschlaKrcrtcxe*." CenlralbUll Ittf 
 Physiol. XIII, 1899. 
 
158 IRRITABILITY 
 
 amounts to about .5-1 second; on the stimulation of the trige- 
 minus produced by blowing on the cornea on the other hand, 
 it is somewhat shorter, less than .25 seconds. Zwaardemaker^ 
 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 Verwornr for the reflexes in 
 the spinal cord of the strychninized frog. Dodge^ found a refrac- 
 tory period in the knee jerk reflex of man. Gotch and Burch* 
 showed, by two induction shocks following each other in quick 
 succession, a refractory period of the nerve, which is char- 
 acterized 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^ 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^ 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 
 
 1 Zwaardemaker : "Sur une phase refractaire du reflex deglutition." Arch, inter- 
 national de physiologic Vol. I, 1900. 
 
 2 Max Verworn: "Zur Kenntniss der physiologischen Wirkungen des Strychnins." 
 Arch. f. Anat. u. Physiol, physiol. Abth., 1900. "Ermiidung Erschopfung und Erholung 
 der nervosen Centra des Riickenmarks." Ibidem, 1900. "Die Biogenhypothese." 
 Jena 1903. "Die Vorgange in den Elementen des Nervensystems." Zeitsch. f. allgem. 
 Physiologie Bd. VI, 1907. 
 
 Z 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. 
 
 4 Gotch and Burch: "The electrical response of nerve to two stimuli." Journ. of 
 Physiology, Vol. XXIV, 1899. 
 
 5 Florence Buchanan: "The electrical response of muscle in different kinds of per- 
 sistent contraction." Journ. of Physiology, Vol. XXVII, 1901-1902. 
 
 6 Keith Lucas: "On the refractory period of muscle and nerve." Journ. of Physiol- 
 ogy, Vol. XXXIX, 1909-1910. 
 
THE REFRACTORY PERIOD AND FATIGUE 159 
 
 of varied duration and then rcp;-istcrcd the action currents by 
 means of the capillary electrometer. lie then found that the 
 second stimulus was ineffective for about .< )().') seconds after tlic 
 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 a|>- 
 proaches the first in point of time. ( iM^ure 'M).) Massart^ anci 
 Jennings- likewise observed the existence of a refractory i>erio<l 
 for the myoids of unicellular organisms brought about liy mechan- 
 ical stimuli. Massart attributes this cessation of reaction to 
 stimuli following each other at certain intervals, to fatigue, an 
 explanation which has been disputed by J cunings as the result of 
 his investigations made on Stentor and X'orticella. Jennings looks 
 upon the behavior of the infusoria rather as an "adaptation" to 
 the stimulus. Putter was the first to see in this the existence of 
 a refractory period. His experiments on Spirostomun ambigiuim 
 in 1900 showed a refractory period in the reaction to rhythmical 
 mechanical stimuli. I wish to state, however, that these observa- 
 tions of Putter have not as yet been published. Thus the exist- 
 ence of a refractory period has even today been proved for a 
 whole series of very different kinds of substances. 
 
 We will now examine the alterations of irritability which are 
 perceptible during the refractory period to comi)lete restitution of 
 the specific irritability of the particular system, and endeavor by 
 the analysis of their special conditions to render them comi)re- 
 hensible 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 readied 
 its highest point, that is, shortly before the begiiming of the dias- 
 tole. 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 dis- 
 
 1 Massart: Annales de I'lnstitut Pasteur 1901. 
 
 2 Jennings: "Studies on reactions to stimuli in unicellular org»niKnt." IX. 
 American Journal of Physiology. 1902. 
 
t I I I ■ ■ I I ' I ■ ■ ■ ' ' ' ' I I I I I I I I 1 1 1 I I I I I 1 
 
 5: ' I ! I I ri I I I I 1 I I I 1 1 Ml I I I I I I I I I I j I I I I 
 SEC 'OJ ^2 03 
 
 A 
 
 ' 'I I I I I I I I I I I I I I I I 1 I I 1 I I I I I I I 
 
 03- 
 
 02- 
 
 01- 
 
 i 
 
 SEC. 
 
 I M I ri I I I I I I'l I I I I M I I I I 
 01 OZ 
 
' ' ' ' ' 1 1 1 1 1 1 1 1 1 1 1 ■ 1 1 1 , 1 1 1 , 1 . , 1 1 , , , , 
 
 ^J- 
 
 I ' I I I I I I [ I I I' l I I r 'l I I I I I I I I I I I I I I I I 
 SEC. 02 OZ 03 
 
 '''''■' I I ■'' I ■ I I I I I ■■ I I ■ I I 1 I I I 1 I » 
 
 Fifl. 30. 
 
 Curve of action current of the musculut <uir1<>riu» cxcitatrJ by two mic- 
 cessive stimuli iSt. 1 and St. 2'. The effect of the u-mnJ fttimiihit 
 is the less and the latent ix'rioJ is the lontfer the more giiKkly the 
 first stimulus is followed by the second. 'Keith I. mas 
 
162 IRRITABILITY 
 
 integration produced by the stimulus and is restored by the meta- 
 boHc 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 indi- 
 vidual components involved. This amount of energy is deter- 
 mined 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 stimu- 
 lus 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 consider- 
 ation, to which the "all or none law" is applicable, as, for instance, 
 the heart at the moment of the beginning of excitation, irrita- 
 bility 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 disin- 
 tegrating 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 
 
TIIK RKFRACTMRV PFRIOD AXD FATUiUE 103 
 
 these are self-evident facts wliicli are in accordance with tlic con- 
 ception we have here developed of tlie course of the process of 
 excitation and its physical nature. Rut anoiluT iniiMjriant {Kjini 
 is evolved from llic ohservations we liave made of the nature of 
 the process of self-regulation. The i)rocess of self-regulation is 
 founded on the same princii)le as that which governs the taking 
 place of all chemical efjuilihriuni. for mctaholic equilihrium is 
 merely a special kind of a chemical ecjuilihrium. The <levelop- 
 ment of a chemical equilihrium hetween reading suhstances and 
 reaction i)roducts has, as known, a characteristic course in regard 
 to its duration. If the rai)idity willi which the e(|uilil)riuni is 
 reached is expressed hy a curve in which the ahscissa represents 
 the time, while the ordinates signify the numl)er of contacts of 
 the interacting molecules, the rapidity of reaction is altered with 
 the approach to the equilil^rium in the form of a logarithmic 
 curve; that is, the approach to the state of e(|uilihrium. wliich is 
 represented hy ordinate value zero, takes place at first very rap- 
 idly, then with more and more decreasing speed, for with llic 
 decrease of the number of reacting molecules an(i the increase 
 of the amount of products of reaction, the contact of the inter- 
 acting molecules and w'ith this the opi)ortuniiy fur the reaction 
 occurs less and less frequently. Although the self -regulation 
 of metabolic equilibrium is by no means such a simple pro- 
 cess as, for instance, that of the well-kncnvn exam|)le of the 
 forming of ethylester from acetic acid and a-thyl alcohol, we have 
 still in every case to deal with the taking place of a chemical 
 mass equilibrium. Hence the progress to the metabolic equilib- 
 rium must likewise correspond with a logarithmic curve, i.e.. resti- 
 tution after a disturbance of the e(|uilil)rium 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 diOiculty that, when the tests are 
 applied which are necessary to determine the restitution at dif- 
 ferent intervals, with each testing stimulus irritability is each 
 time reduced. Hence the construction of the restitution curve 
 
164 IRRITABILITY 
 
 can only be achieved by indirect means, and we must content our- 
 selves 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^ 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 grad- 
 ually regain their maximum. The exact periods of time for the 
 course of the return of irritability for the heart have unfortu- 
 nately not been so far ascertained. On the other hand, the inves- 
 tigations of Ishikawa- 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 indi- 
 cator 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 ex- 
 tended duration and only regains its normal value in the same 
 degree as restitution takes place. By a great number of pains- 
 taking experiments Ishikawa ascertained the duration of the 
 reflex time at intervals of thirty seconds to one minute, and ob- 
 tained 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 ex- 
 actly determined in the near future. But even at the pres- 
 ent we are fully justified in describing the form of restitution 
 curve as a logarithmic in type. Therefore, a relative refractory 
 
 1 Bowditch, 1. c. 
 
 2 Hidetsurumaru Ishikawa: "Ueber die scheinbare Bahnung." Zeitschrift f. allgem. 
 Physiologic Bd. XI, 1910. 
 
THE REFRACTORY PERIOD AXD FATTGUR 163 
 
 period must be present in every mclalxjlic sclf-rcKu!atiuii after 
 an excitation, durinjj^ which stron^a-r stiiniih produce rcsjKjnsc, 
 while weaker are still without result. This is a fact whidi, as wc 
 shall see later, is of fundamental importance for the compre- 
 hension of the various kinds of interference resjxjnses to stimuli. 
 
 From the information here p^ainecl on the nature and origin 
 of the refractory period the conclusion nuist inevitably Ik* 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 i)roper conditions a refractory i)eri(Ml can \)C 
 demonstrated for every living (organism, h'very living system 
 possessing irritability undergoes a period of reduce<l irritability 
 at the time of and subsequent to every excitation, for cvcr>' 
 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 comi)lete restitution cannot break down 
 the same quantity of molecules as would l)e the case after the 
 establishment of complete restitution, that i>. the res|)onsc is 
 weaker, the irritability is decreased. The refractory i>eriod during 
 and subsequent to excitation is as much a general i)roi>erty 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 jK-riod 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 i)eriod is still of compara- 
 tively recent date and that few physiologists are in the habit of 
 connecting special observations with general i)hysiological con- 
 ceptions, but also for the reason that some investigators have 
 vainly tried to find a refractory i)erio(l in certain forms of living 
 substance. Langcndorff and Wmtcrstcm.' for instance, have not 
 succeeded in proving a refractory period for the si)inal cord of 
 the frog. Langcndorff stinudated the central sciatic stump 
 
 1 Langcndorff u. JVintcrstcin : "IkitraRC zur Rcncxlchrc " IMn^rrr*. Arrh. Bd. 127. 
 
 1909. 
 
166 IRRITABILITY 
 
 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 per- 
 ceptible in an increase of the contraction or with greater inter- 
 vals 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, Frohlich^ and especially Vessi^ 
 have incontestably proved the existence of relative refractory 
 periods in the normal spinal cord. 
 
 If the existence of the refractory period is based on the fact 
 that during the time of and subsequent to an excitation the quan- 
 tity 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 fac- 
 tors 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 physiologi- 
 cal 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 
 
 1 Fr. W. Frohlich: "Beitrage zur Analyse der Reflexfunction des Riickenmarks 
 mit besonderer Beriicksichtigung von Tonus, Bahnung und Hemmung." Zeitschrift f. 
 allgem. Physiologic Bd. IX, 1909. 
 
 2 Julius Veszi: "Der einfachste Reflexbogen im Riickenmark." Zeitschr. f. allgem. 
 Physiologic Bd. XI, 1910. 
 
THE REFRACTORY PERIOD ANT) FATKiUE 167 
 
 that the duration of the refractory jicriod is influenced in like 
 manner by temperature. Indeed, Kroncckcr^ found some time ago 
 that in the isolated frog's heart a much more fretjuent rhythm of 
 stimulation is efTeclivc at a hij^her than at a lower temjKTaturc. 
 When the heart is stimulated at a lemi)erature of 11-1'.*° C. with 
 twelve rhythmical induction shocks in the second, every stinnilus 
 is operative and i)roduces a systole, if a stimulus of the same 
 frequency is used at a temperature of 5° C, the heart resiK>nds 
 merely to every second stimulus. This shows that the refractory 
 period is of longer duration at a lower than at a higher temi)cra- 
 ture. 
 
 A factor of particular interest is the su])j)ly of oxygen, for we 
 know its fundamental imj^ortance in all aerobic organism'^ in the 
 breaking down of the living substance. The life of these organ- 
 isms is primarily dependent upon the supply of oxygen from 
 without. Organic reserve substances for restitution after dis- 
 integration 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. Never- 
 theless it is not the absolute quantity but the relative amount of 
 oxygen in relation to the momentary reciuirement which is of 
 importance. For instance, the quantity of oxygen present may 
 completely suffice for the oxydative disintegration in tiie metab- 
 olism of rest or at lower temperature, whereas the same amount 
 would be much too small to meet the demand increased by exci- 
 tation or at higher temperature. In the latter case "a relative 
 deficiency of oxygen' occurs. I have introduced the term "rela- 
 tive deficiency of oxygen'"- for I have found that a numlnrr 
 of authors by neglecting the relations of the availal)le oxygen 
 to that which is required at the moment have been led to false 
 conclusions. There is no living object so preeminently titled 
 to demonstrate in such a striking maimer the de|K'ndence of 
 
 1 H. Kroncckcr: "Das charakteristisclic .Mcrkmal dcr Hcrximi^kclNrwce-.tns " 
 Beitrape ziir Anatomic iind Physiologic als KcstRabc <'^'i 1 n-lwig xum 1^ Oc!..l<r 
 1874 gewidmet. Leipzig 1874. 
 
 2 Max Verworn: "Allgcmcinc Physiologic." V. Auflagc. Jma 1909. 
 
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THE REFRACTORY PERIOD AND FATIGUE 1G'» 
 
 the duration of the refractory period upon the supply of oxy- 
 gen as the spinal cord centers of the frofj, \yhen ihcir irri- 
 tability has been increased to the inaxinuun hy strychnine.* 
 Various observers, such as Lorcii, Hucluitujn, II. z'ott Hacyrr and 
 others, investigated the action current by the cai)illary electrom- 
 eter. 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 imjmlses to equal ten per second at rf>om 
 temperature. In short, in the freshly strychninized frog the dura- 
 tion of the refractory period is about .1 second. I'.y means of the 
 method of artificial circulation already mentioned a deficiency of 
 oxygen can readily be brought about. It ha- been demonstraleil 
 that the rhythmic in contrast to the contiiuKjus method of intro- 
 duction of circulatory fluid is superior in that the former repro- 
 duces more closely the natural conditions of the circulation of 
 the blood and renders the smallest capillaries more |)enncablc. 
 In consequence T have recently constructed a small appliance for 
 artificial circulation, which accomi)lishes this in a manner as 
 simple as it is complete. ( Figure -U.) The fluid flo\ys from a ves- 
 sel, E, provided with an outlet tube through a thin rubber tul>c 
 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. I), produced by a 
 metronom, B. The pressure of the circulating fluid can Ik readily 
 changed at will by varying the level of the vessel and the fre- 
 quency of the pulse by the rhythm of the metronom. which makes 
 and breaks the current to the electromagnet.- In this way it is 
 possible to artificially replace the normal circulation with satis- 
 factory exactitude and substitute for the blood, circulating in the 
 vessels of the frog, any desired fluid. If the entire cjuantity 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 api>o.irs after 
 
 1 Max Verworn: "Ermiidung ErschopfuMR iiiul Erholung dcr ncrvo«cn I mir* dc« 
 Riickenmarks." Arch. f. .\nat. u. Physiol, physiol. .M)t. Suppl. l">00. Thr Mine: 
 ErmuduiiK und ErholuiiK. Ik-rliiur Klin. Wochcnschrift 1901. 
 
 2 As I have not yet described this method elsewhere the above figure will ntfioe 
 for demonstration. 
 
IRRITABILITY 
 
 B 
 
 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. 
 
 the lapse of a few seconds. (Figure 32, A.) If the artificial cir- 
 culation 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 with- 
 out interest for the understanding of the question of reserve sub- 
 
THE REFRACTOKN' IM-KloD AM) I-ATIGUE 1:1 
 
 stances. If we assume tliat at the moment wlicn tlic entire amount 
 of blood is removed from the vascular system, no oxygen remains 
 in the cells of the spinal cord and nuiscle, then disintepraiion of 
 the living substance could from lliis instant take |)lace exclu- 
 sively anoxydatively, and there would l)e no further oxydativc 
 breaking down into carbon dioxide and water. The energy pro- 
 duction compared in ecjual numljcr of molecules, taking the 
 figures of Lesser for the fermentation of sugar, would a|»proxi- 
 mately amount to about ;3.8 jx^r cent, of that of the energy pro- 
 duction in the oxydative disintegration of dextrose into carUm 
 dioxide and water. In reality, however, tlie tetanic convulsions 
 are at first exactly as violent as in the frog with a normal circu- 
 lation. There simply remains the assumptic^n. therefore, that 
 either the disintegration as soon as it becomes a;ioxydative in- 
 volves relatively greater number of molecules than would be the 
 case if it were oxydative in nature, or to suj)pose that even 
 after the complete disi)lacement of the bhxjd a certain, though 
 relatively small, amount of oxygen is present in the cells which 
 for a short time suffices for the taking i)lacc of oxydative disin- 
 tegration and wnth 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 i)r()l)ability than 
 the first. To return, however, from this observation to a further 
 consideration of the animal we are studying, we sec how tlic 
 complete tetanic convulsions in the refractory period which we 
 assumed to be .1 second are gradually transformed into incom- 
 plete tetanus. After a time the tetanic convulsions become shorter 
 after each stimulus { iMgure 32, H ) and permit us to distingmsh 
 their individual movements, even though the latter at first succect! 
 each other still very rapidly. Oradually this incomplete tetanic 
 convulsion assumes the form of a short series of iiulividual con- 
 tractions, distinctlv scj^arated from each other and soon a stage is 
 reached in which each reaction to a i)erii)hcral stimulus consists 
 merelv in a single contraction. ( iMgure ;*>'i. 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 succeed- 
 
172 IRRITABILITY 
 
 ing each other at intervals of less than a second are without effect. 
 It is possible at this stage, as Tiedemann^ 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 w^ith a wanting lever. It is then found that w^hen 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 opera- 
 tive and all those succeeding ineffectual, if the stimuli follow each 
 other at shorter intervals. The refractory period becomes, how- 
 ever, more and more prolonged. The rhythm of the stimulus 
 
 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. 
 
 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, 
 
 1 Tiedemann: "Untersuchungen iiber das absolute Refractaerstadium und die 
 Hemmungsvorgaenge im Riickenmark des Strychninfrosches." Zeitschrift f. allgem. 
 Physiologic Bd. X, 1910. 
 
THE REFRACTORY PERIOD AXD FATIGUE 173 
 
 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 perio<i is, in the 
 absence of oxygen, more and ni(jre prolonged until eventually a 
 prolonged state of nonirritability is developed, can he better 
 followed by observing the experiment than when dcscrilxrd 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 satu- 
 rated with oxygen is circulated in tlie 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 perioti 
 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 sh(jrtened with a renewed 
 supply. 
 
 I have described this experiment somewhat in detail as it con- 
 tains facts which are the key for the comprehension of a general 
 physiological process of paramount imi)ortance. I refer to 
 fatigue. The refractory period and fatigue are inseparably con- 
 nected, 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 ditTerentiate somewhat more in 
 detail the factors wiiich bring about the prolongation of the 
 refractory period in deficiency of oxygen. 
 
 If we first turn our attention to the normal refracitjry j>eriod 
 wdiich 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 resj)onse is. as wc 
 have seen, determined by the time involved in the metalK)lic 
 decomposition and recovery. P)Oth these i)rocesses recjuire time 
 and until their completion the quantity of substance demanded 
 for the oxydative disintegration is decreased in a given space. 
 and every stimulus nui.st conseciuently be followed by a weaker 
 response. Our conceptions of the physical details of these pro- 
 
174 IRRITABILITY 
 
 cesses depend essentially upon the question, if the oxydative dis- 
 integration itself in the given living system occurs in one single 
 phase, in that the oxygen is the activator for the oxydative split- 
 ting 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 pro- 
 duced 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 increas- 
 ing 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 stimu- 
 lus 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 break- 
 ing down, the smaller is the degree of irritability, the weaker the 
 response and the slower the return of irritability after every 
 
THE REFRACTORY PERIOD AND FATIGUE 175 
 
 stimulus. In other words, witli the increasing deficiency of 
 oxygen, the response is not merely reduced for every slimulus, 
 but the duration of the refractory period is likewise progressively 
 prolonged until finally with an ahsolute want of oxygen, constant 
 and complete depression takes i)lace. In the genesis of this pro- 
 cess another factor, however, has the same effect. 
 
 While with a sufticient supply of oxygen disintegration leads 
 to the formation of carbon dioxide and water, therefore to end 
 products, v^hich can quickly and easily be removed by diflusion, 
 the want of oxygen produces complex products of incomplete 
 combustion and finally of anoxydative deconijwsition, such as 
 lactic acid, fatty acids and even more complex substances in con- 
 stantly increasing quantities. These products permeate the protf>- 
 plasmic surfaces with great difficulty, if at all. and as they cannot 
 subsequently be oxydatively split up, constantly accunuilate. 
 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 strych- 
 nine, 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 w^as again started, a 
 certain degree of recovery took place within one or more minutes. 
 The stimuli were once more effective and i)roduccd a numl>er 
 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 incom- 
 plete tetanic convulsions was never again obtained, whereas by 
 the introduction of oxygen comi)lete recovery could at once l)C 
 brought about. If, however, the circulation with oxygcn-frcc 
 saline solution w^as continued, irritability gradually decreased. 
 The refractory periods after the individual stimuli became longer, 
 
176 IRRITABILITY 
 
 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. Lipschiits^ to repeat the experiments, taking the 
 utmost possible precaution in respect to the absolute exclusion of 
 oxygen. Lipschiitz 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 solu- 
 tion sets free an amount of iodide from iodide of potassium corre- 
 sponding to that of the consumed oxygen. These experiments 
 of Lipschiitz 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 depress- 
 ing asphyxiation substances by artificial circulation. Moreover 
 Fillip has previously succeeded in the laboratory at Gottingen in 
 obtaining by the same methods a corresponding result for the 
 nerve. In both cases the experiments are extremely compli- 
 cated 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 disintegra- 
 tion. It is not possible to give any detailed account as to the part 
 taken by accumulating asphyxiation substances in the prolonga- 
 tion 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 de- 
 pression resulting from the deficiency of oxygen. We can merely 
 
 1 Alexander Lipschiita: "Ermiidung vmd Erholung des Riickenmarks." Zeitschr. 
 f. allgem. Physiologic Bd. VIII, 1908. 
 
 2 Fillie : "Studien iiber die Erstickung und Erholung des Nerven in Fliissigkeiten." 
 Zeitschr, f. allgem. Physiologic Bd, VIII, 1908. 
 
THE REFRACTORY PERIOD AXD FATIGUE 1 
 
 1 1 
 
 say, the individual alterations produced by the want of oxygen, 
 that is, the restriction and retardatic.n of the oxydativc disinte- 
 gration, the corresponding increase of the anoxydative deconiiKj- 
 sition and the accumulation of the products of incomj)letc oxyda- 
 tion and anoxydative breaking down have the same influence in 
 that they decrease the strength of the response and retard the 
 rapidity of the decomposition ])rocess. These are the general 
 effects perceptible in the refractory period by the deficiency of 
 oxygen. 
 
 The establishment of these facts of the dependence of the re- 
 fractory period upon oxygen are of the utmost imi>ortance for 
 the genesis of fatigue, for the state of fatigue in all aerobic organ- 
 isms 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 l>eforc 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 com- 
 plete paralysis was brought about in the frog by the introduction 
 of an oxygen-free saline solution was ascertained and conii)ared 
 with the period which elapsed before complete paralysis took 
 place, when the same solution saturated with oxygen was used. 
 
 Although the previously described ex])eriments on the strych- 
 ninized 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 stimu- 
 lated 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 ai)pears directly after the first 
 contraction and becomes more and more noticeable after every 
 
178 IRRITABILITY 
 
 succeeding one. With the isolated apex preparation of the 
 frog's heart an effect is produced which Bowditch^ has termed 
 the "Treppe" and Tiegel/ Minof 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. Frohlich'^ 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^ 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 sub- 
 stance 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^ already has shown, becomes continu- 
 ously 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 insufBcient for this to occur. There 
 
 1 Bowditch : "Ueber die Eigenthiimlichkeiten der Reizbarkeit, welche die Muskel- 
 fasern des Herzens zeigen." Arbeiten aus der physiologischen Anstalt zu Leipzig VI 
 Jahrgang 1871, Leipzig 1872. 
 
 2 Tiegel: "L^eber den Einfluss einiger willkiirlichen Veranderungen auf die 
 Zuckungshohe des untermaximal gereizten Muskels." Arbeiten aus der physiol. 
 Anst. zu Leipzig X Jahrgang 1875, Leipzig 1876. 
 
 ZMinot: "Experiments on tetanus." Journ. of Anat. and Physiol. Vol. XII. 
 
 4 Fr. W. Frohlich: "Ueber die scheinbare Steigerung der Leistungsfahigkeit des 
 quergestreiften Muskels im Beginn der Ermiidung. (Muskel Treppe), der Kohlen- 
 saurewirkung und der Wirkung anderer Narcotica (Aether, Alkohol)." Zeitschr. £. 
 allgem. Physiologic Bd. V, 1905. 
 
 5 Frederic S. Lee: "The cause of the Treppe." Americ. Journ. of Physiol. Vol. 
 XVIII. 1907. 
 
 6 Alexander Rollet: "Ueber die Veranderlichkeit des Zuckungsverlaufs quer- 
 gestreifter Muskeln bei fortgesetzter periodischer Erregung und bei der Erholung 
 nach derselben." Pfliigers Arch. Bd. 64, 1896. 
 
180 IRRITABILITY 
 
 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 oxyda- 
 tive decomposition in the fatigued muscle is increasingly pro- 
 longed. 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. 
 
 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} 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. Irri- 
 tability 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 charac- 
 terized 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 pro- 
 cesses is conditioned by the relative deficiency of oxygen. This 
 is shown by the role played by oxygen in recovery after fatigue. 
 
 1 Hidetsurumaru Ishikawa: "Ueber die scheinbare Bahnung." Zeitsclir. f. allgem. 
 Physiologic Bd. XI, 1910. 
 
THE REFRACTORY PERIOD AND FATKiL'E 181 
 
 It was found by Hermann^ in 18(17 and confirnicd by Mademoi- 
 selle Jotcyko'^ in Richct's laboratory, that the isolated nuisclc of 
 the frog, which was c()nii)lL'tely nonirritable as the result of 
 fatigue, does not regain irritability in an oxygcn-frcc medium, 
 but does so when oxygen is introduced. The i)reviously de- 
 scribed experiments of artificial circulation in the frog show 
 clearly how dependent the centers are upon the oxygen suj)ply 
 for the restoration of irritability. In consequence of the strych- 
 nine poisoning the irritability of the centers is so enormously 
 increased that the *'all or none law" is aj)plicable to the centers of 
 the spinal cord under these conditions.^ These are the l>cst condi- 
 tions for the production of fatigue. One can readily demonstrate 
 the importance of the oxygen supply for the ra{)idity 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 ])r()(luced by a stinuilus, 
 an increasing length of time is required until irritability is so far 
 recovered that a new stimulus can meet with response. If. how- 
 ever, a saline solution is circulated which has been saturated l)y 
 being shaken with oxygen and is continuously in a ])urc atmos- 
 phere of oxygen, recovery takes ])lace in comj)arison with far 
 greater rapidity and completeness. If the supi)ly of oxygen is 
 ample and the stimuli act at longer intervals on the frog, irri- 
 tability always is quickly restored in the i)erio(ls of rest l>etween 
 the stimuli. With continuous stimulation of quickly succeeding 
 stimuli, irritability is soon completely obliterated, even th«»ugh 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 
 
 \ Hermann: "Untersiichungcn iil.cr tk-n StotTwcchscl -Irr Mnskcln •unrchcnd T.-m 
 
 Gaswechsel dersclben." Berlin 1867. 
 
 2Jotcyko: "La fatigue et la respiration elcmentaire du muscle." Pan* iv 
 i Julius Veszi: "Zur Frage des .Mies oder Nichts ('.c»etie» beim Strychn. 
 
 Zeitschr. fur allgem. Physiologic Bd. XII. 1911. 
 
182 IRRITABILITY 
 
 clearly recognized. Fatigue is simply the refractory period pro- 
 longed by deficiency of oxygen. In both cases there is a diminu- 
 tion 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 decompo- 
 sition can be quickened and irritability restored, that is, the refrac- 
 tory period lessened and fatigue removed by a sufficient supply of 
 oxygen. The amount of oxygen which suffices to constantly main- 
 tain 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. 
 
 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 sub- 
 jected to a deficiency of oxygen. Up to that time, however, no 
 consumption of oxygen was known for the nerve. It was, there- 
 fore, necessary to first ascertain if the nerve possessed an oxyda- 
 tive 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'^ 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 
 
 1 Hidetsurutnaru Ishikawa: "Ueber die scheinbare Bahnung." Zeitschr. f. allgem. 
 Physiologic Bd. Ill, 1904. 
 
THE REFRACTORY PERIOD ANT) FATIGUE 183 
 
 oxygen and only completely asi)hyxiales 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 hy ProhlicIO were 
 afterwards confirmed in other laboratories.- and form the basis 
 for proving the existence of fatigue of the medullated nerve. 
 Shortly after, Frohlich^ was able to demonstrate symptoms of 
 fatigue in the medullated ner\e. 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 arc, 
 therefore, inoperative. The nerve is fatigued by the (juick suc- 
 cession of stimuli. The normal nerve on the contrary invarial)ly 
 responds, as knowni, 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 re- 
 fractory period, conditioned by the relative want of oxygen. It 
 likewise explained the conditions of the analogous behavior that 
 Wedensky^ had observed in the narcotized nerve, but had neither 
 
 \ Fr. W. Frohlich: "Das Sauerstoffbedurfniss des Ncrvcn." Zeitscbr. f. allfrtn. 
 
 Physiologic Bd. Ill, 1904. 
 
 2 K. H. Baas: "Zur Frage nach dem SauerstofThcdiirfniss dcs Fro»chncnren." 
 
 Pflugers Arch. Bd. 103, 1904. 
 
 K. Prick: "Die Abhangigkeit der Erregbarkcit dcs i»criphcri»chcn Ncnrrn vom 
 Sauerstoff." Inaugural Dissertation vorgelegt dcr mcdicinischcn Facullat der I'niTcr*. 
 Berlin (Aus dem physiologischen Institut dcr Univcrs.). Berlin 1904. 
 
 Uchtomsky und Dcrnoff: "Zur Frage nach dem SaucrstofT»)cdiJrfniM dcr Ncrvcti " 
 Travaux du laboratoire de Physiologic a I'univcrsitc dc St. Prtrf -ihotirK II .\niirc 
 
 1907. 
 
 3 Fr. W. Frohlich: "Die Ermiidung dcs markhaltigen Ncrvcn." ZcHKrhr. f. »IIgrm. 
 
 Physiologic Bd. Ill, 1904. 
 
 AlVedensky: "Die fundamcntalen Eigcnschaftcu dts .Ncrvcn untcr Kinwirkung 
 
 einiger Cifte." Pflugers Arch. Bd. 82, 1900. 
 
 The same: "Erregung, Hcmmung und Narkosc." In the name pUc*. Bd. 100. 
 
 1903. 
 
184 
 
 IRRITABILITY 
 
 recognized as manifestation of the prolonged refractory period 
 nor as fatigue. A further advance was made by the investigations 
 of Thorner. He placed two nerves of the same frog in a double 
 chamber under completely identical conditions with the excep- 
 tion that one remained in a state of rest, whilst to the other 
 tetanic stimuli were applied. (Figure 35.) If this took place in 
 
 ji 
 
 
 TX 
 
 "T VBSI8 
 
 Fig. 35. 
 
 Double glass chamber for comparative experiments on 
 fatigue of the nerve in n). A and B— Wires of 
 the electrodes. (After Thorner.) 
 
 nitrogen, the irritability of the stimulated nerve invariably sank 
 with much greater velocity than that of the nonstimulated, where- 
 as after an introduction of oxygen, even when the stimulation was 
 continuous, both again recovered. In these experiments of 
 
THE REFRACTORY PERIOD AND FATIGUE 185 
 
 Thorner' the action current and not the nuiscle contraction served 
 as indicator. Here the fatigue of the nicihillaled nerve brought 
 about by the deficiency of oxygen during prolonged stimulation 
 is demonstrated in the most obvious manner. (Figure 36.) 
 
 2 
 
 
 
 
 
 
 
 
 <^ 
 
 ^ 
 
 
 ■ 
 
 
 
 r — 
 
 
 
 \ 
 
 — 
 
 ... 
 
 .,- 
 
 — 
 
 ._. 
 
 "'' 
 
 / 
 
 
 ^ 
 
 S 
 
 ^ — 
 
 -- 
 
 ^ ^ 
 
 n-' 
 
 "7 
 
 fi 
 
 
 \ 
 
 
 
 
 
 
 / 
 
 
 
 
 X 
 
 V 
 
 
 
 
 
 \ 
 
 --H 
 
 ^ 
 
 "K 
 
 
 } 
 
 
 
 
 
 
 \ 
 
 k 
 
 / 
 
 1 
 
 
 
 
 
 
 ^ 
 
 r 
 
 1 — 
 
 
 
 
 
 
 tN 
 
 J 
 
 0.5 
 
 
 — «. 
 
 "itu 
 
 kst 
 
 ^JT 
 
 _^ 
 
 ^au 
 
 KTii 
 
 
 -^ 
 
 "tic 
 
 r— ) — ' 
 kstojf- 
 
 1 
 
 _Sausrst 
 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 0.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ^ 
 
 V 
 
 ;. 
 
 V 
 
 I 
 
 V 
 
 ; 
 
 v 
 
 i 
 
 
 3 
 
 v 
 
 S^ 
 
 Xr 
 
 41 
 
 Fig. 36. 
 Curve of action current of two nerves, one of which is stimu- 
 lated (plain line I whilst the other remains at rest di>tted 
 linei. After decrease of irritability of the stimulated nerve 
 in nitrogen, oxygen is introduced into the chamber and 
 irrritability increases again. Then the previously resting 
 nerve is stimulated in nitrogen and the stimulated nerve 
 remains at rest. (After Thorner.) 
 
 Thorner- further succeeded by a continuous stimulation of the 
 nerve in obtaining even in atmospheric air the indications of pri- 
 mary 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 re- 
 duction 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 Thorner proved that tlie nerve, 
 when fatigued by continuous tetanic stimulation in nitrogen, 
 could also partially recover in the latter if the stimulation was 
 
 iTIwrticr: "Die Ermiidung des markhaltigen Nervcn." Zcitschr. f. aliKfni i'n)»i- 
 ologie Bd. VIII, 1908. 
 
 2 Thorner: "Weitere Untersuchungen ijber die Krmiidung dcs markhaltigrn Nerren. 
 Die Ermiidung in Luft und die scheinharc ErrcgharkcitMtcigcrung." Zrilachr. f. 
 allgcm. Physioiogie Hd. X, 1910. 
 
 3 Thorner: "Weitere Untersuchungen iihcr die Krmudung dr» markhalligrn Nervcn 
 Die Ermiidung und Erholung unter Ausschluss von SaucrstofT." Zeittchr. (. tllgcm 
 Physioiogie Bd. X. 1910. 
 
186 IRRITABILITY 
 
 ■Maaa 
 
 \ 
 
 *_ 
 
 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 Thomer.) 
 
 y 
 / 
 / 
 / 
 / 
 / 
 / 
 t 
 I 
 I 
 I 
 I 
 
 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 Thomer.) 
 
 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 Ver- 
 worn, Lipschiitz, in fatigue of the nervous centers. It is the 
 expression for the accumulation and removal of fatigue sub- 
 stances, the depressing effect of which Ranke'^ first established 
 for the fatigued muscle. The fact that the nerve could also par- 
 tially recover in an atmosphere of nitrogen would seem to like- 
 wise 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. 
 
 1 Ranke: "Untersuchungen tiber die chemischen Bedingungen der Ermiidung des 
 Muskels." Arch. f. Anat. u. Physiol. 1863 u. 1864. 
 
THE REFRACTORY PERIOD AXlJ FATIGUE 187 
 
 As a result of all these investigations, linked together in a 5)3- 
 tematic series, the proof has now been obtained that ilie nerve 
 like all other living substances is fatigable. its fatigue is solely 
 the manifestation of a prolonged refractory period and the exten- 
 sion of the latter by continuous stinuilation is. as in all aerobic 
 substances, a result of relative deficiency of oxygen. 
 
 WO 
 
 CL 
 
 200 
 
 300 
 
 kOO 
 
 Stick stuff' 
 
 Scuwr staff 
 
 o5« 
 
 w 
 
 Fig. 38 
 
 30 
 
 tfO 
 
 50 
 
 rv 
 
 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. ' AUcr 
 Thorner.) 
 
 To briefly summarize in conclusion, I will rej)eai that just as 
 all living systems show a refractory j)erio(l 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 increa.sed decomi)osition of cer- 
 tain substances. During and directly after the breaking down, 
 irritability is reduced in the same degree as the amount of siil>- 
 stances required for disintegration in response to a succeeding 
 stimulus is decreased and the (juantity of the decomposition 
 
188 IRRITABILITY 
 
 products is increased. This is the refractory period. By the 
 metaboHc 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 
 aerobic 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 dis- 
 integration are prolonged and restricted by relative deficiency of 
 oxygen and merge more and more into anoxydative decomposi- 
 tion. 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 anaerobic organisms the refrac- 
 tory period and symptoms of fatigue are, of course, produced by 
 the relative deficiency of other substances. Fatigue in the 
 anaerobic 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 prob- 
 lem. In this lies the inexhaustible charm of our scientific 
 research. 
 
CHAPTER \III 
 INTERFERENCE OF EXCITATION'S 
 
 Contents: Examples of effects of interference of stimuli in unicellular 
 organisms. Interference of galvanic and thermic stimuli in Para- 
 mecia. Interference of galvanic and thermic stimuli and narc«ilics. 
 Interference of galvanic and mechanical stimuli. Interference of gal- 
 vanotaxis and thigmotaxis in Paramecia and hypotrii infusoria. Real 
 or homotop interference, apparent or hcterotop 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. Inter- 
 ference 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 i)eriod. 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. Peculiari- 
 ties of the nerve fibers. Conversion of the nerve by relative fatigue 
 from an isobolic into a heterobolic system. 
 
 Until now the mechanism of the .'tingle excitation has received 
 the major portion of our attention. It was iu)t initil we reached 
 the subject of the origin of fatigue that we became acijuaintetl 
 with the effects of repeated stimulation. Here we fi)und a case 
 of interference of individual excitations. lUit fatigue is dimply 
 a special instance of such interference, for tlic subject of inter- 
 ference action occupies a much greater field. 
 
 Every cell of the larger organisms, and more esi>ccially the 
 single celled organisms, is subjected to manifold stinuili. It is 
 
190 
 
 IRRITABILITY 
 
 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 inter- 
 fering 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. 
 
 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 elec- 
 trodes and allow a constant current of about .2 milliampere to 
 flow through, it will be seen that the infusoria at room tempera- 
 ture 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 
 
INTERFKRRNCE OF KXCITATIOXS 191 
 
 to the galvanic is increased In- the thernial stimulation. This 
 summation of excitation is readily understood on the hasis of the 
 laws conccrninn^ the eilect of tcnii)crature upon the velocity of 
 chemical change established by ra;/'/ 1 1 off. If. however,' the 
 Paramecia are in a 1 i)cr cent, alcoholic solution, then, as was 
 shown by Nagai,' the rai)i(lity of movement following' jjalvanic 
 stimulation is decidedly reduced. The interference effect Inrtween 
 the galvanic and chemical stimulati(jn is. because of the depressing 
 effect of the latter, likewise readilv understood. 
 
 Fig. 40. 
 Thigmota.xis of Paramaecium aurelia. i .After Jennings. ' 
 
 Greater difficulty meets us, however, in the following instance. 
 The forward movements of the Paramecia follow in conse(|uence 
 of the fact that the individual cilia of the body lash more ])ower- 
 fully backward than forward. If now the Paramecia, while 
 moving forward, meet with a resisting body, they withdraw side- 
 ways 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 ])ortion 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, arc mnrc or less inhibited. I Figure 
 40.) The degree of inhibition brought about by this weak 
 mechanical stimulation may vary considerably. .\t times the cilia 
 
 1 Nagai: "Der Einfluss vcrschiedcner Narcotica. (lasc und Salzc auf die Schwi 
 geschwindigkcit von Paramecium." Zeitschr. f. allgcm. Physiologic Bd. VI. 1907. 
 
192 
 
 IRRITABILITY 
 
 of the whole body suddenly cease their movement. (Figure 41, 
 A.) At other times, this cessation is Hmited 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 
 
 B 
 
 Fig. 41. 
 Thigmotaxis of Paramaecium aurelia. 
 
 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. 
 
 However, the strength of the inhibitory effect of a weak con- 
 tact stimulus upon another excitation is best appreciated when 
 
INTERFERENCE OF EXCITATIONS 193 
 
 positive thigiiiotaxis is interfered with by the effect of a tliernuil 
 or galvanic stimulus. Joinings^ and especially Putter- have, at 
 my request, more thoroughly investigated my original observa- 
 tions and have given us a complete analysis of these interesting 
 interference effects. If the freely swimming Paramecia are sub- 
 jected 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 rcacii their maxi- 
 mal. If now the same experiment is repealed with Paramecia 
 vv^hich have in consequence of thigmotaxis lixed themselves to 
 particles of slime, the temperature may be increased to 30** C. 
 without an observable effect. The infus(»ria remain througliout 
 in contact with the resistance. Only when the tem])erature is 
 37° C. do they release their contact and move violently through 
 the water. If a drop containing Paramecia is i)laced 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 j^articles of slime. When 
 a constant current of about .2 of a milliam])ere is passed through, 
 it is observed that the freely swimming individuals hasten 
 towards the cathode. Those attached to objects, on the con- 
 trary, do not respond in this manner to the electrical current. 
 (Figure 42.) The intensity of the current can be greatly in- 
 creased without bringing about detachment of the individuals 
 from their position of fixation. The typical intlucnce of the 
 strong current upon the movement of the cilia of the thigmotacti- 
 cally fixed individuals can be clearly seen. Xevertheless. 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. Xot until 
 the current becomes very strong is the excitation thereby pro- 
 duced sufficient to bring about a separation of the infusoria, 
 whereupon they immediately swim toward the cathode. In this 
 
 1 Herbert S. Jennings: "Studies on reactions to stimuli in uniccllul.ir .- - 
 I. Reactions to chemical, osmotic and mechanical stimuli io ih«- cili.itc 
 
 Journal of Physiology, Vol. XXI. 189 F. , . , 
 
 2 putter: "Studien iiber Thigmotaxis bci Protistcn." .\rch. i. .\nat. und I hywol- 
 
 ogie, physiol. Abt. Suppl. 1900. 
 
194 
 
 IRRITABILITY 
 
 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. 
 
 Fig. 42. 
 
 Interference of galvanotaxis and thigmotaxis in Paramaecium aurelia. The 
 individuals which are thigmotactically attached to sHme particles 
 remain at rest while the freely swimming individuals move toward the 
 cathodic pole. 
 
 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 swim- 
 ming, contribute the propelling force. The perioral cilia also 
 
INTERFERENCE OF EXCITATIONS 
 
 195 
 
 form the elements which hring al)out a screw-like movement on 
 the axis. They further ])ossess several cilia, which jiermit a re- 
 bounding of the organism, and fmally certain forms have anal- 
 cilia, which probably serve as breaks and lu steer the organism. 
 (Figure 43.) Their usual mode of locomotion is that of creep- 
 ing, moving by means of the cilia on the ventral surface. These 
 movements dei)en(l upon the positive thigmota.xis of the cilia of 
 locomotion. At the same time there is inhibition of the cilia on 
 
 A B 
 
 Fig. 43. 
 
 Hypotrichous infusoria. A— Stylonychia. B— Urostyla. 
 
 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 dilTerently to the galvanic cur- 
 rent, depending on whether they are swimming or in a fixed 
 position. If one places a drop of water with numerous L'rostyla 
 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 
 
196 
 
 IRRITABILITY 
 
 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 indi- 
 
 irifftrriri — '""- 71 
 
 Fig. 44. 
 
 Urostyla grandis. Interference of galvanotaxis and thigmotaxis. The 
 freely swimming individuals move towards the cathode (left side). 
 The creeping individuals move in tranverse direction. 
 
 viduals 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 Putter,^ the explanation being based upon an 
 
 1 Putter: 1. c. 
 
INTERFERENCE OF EXCITATIONS 197 
 
 accurate investigation of the mechanism of cihary activity. The 
 galvanotactic swimming toward the cathode is explained by the 
 same principle as that applicable to all galvanotaxis.' As a result 
 of the excitation produced by the anode, the cell body must 
 assume a position wherein the 1)()rder cilia, whicli are of greatest 
 importance in swimming, are e(iually stimulated on both sides 
 of that part of the body directed toward the anode. It is only 
 in this position that forward swimming is i)ossil)le. for as a result 
 of ^^//symmetrical excitation of the border cilia a turning must at 
 once occur, which automatically brings al)out a resumi)tion of the 
 position of the long axis. The perioral cilia bring about the 
 screws-like movement around the axis during swimming. It fol- 
 lows 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 aljout the assumption of 
 the position of the axis, above described. The ])erioral cilia dur- 
 ing 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. 
 
 These, then, are a few examples of the interference action of 
 various stimuli on the single cell. They show us in part fairly 
 
 \ Max I'erworn: "Allgemeine Physiologic." V Aufl. Jena 1909. 
 
198 IRRITABILITY 
 
 simple, and in part very complex states. It now behooves us to 
 obtain a general understanding of interference action, to learn 
 the fundamental lazvs 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 wdiich 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 
 the fact that the location of attack is the same. The constant 
 current acts upon a portion of the infusorium, which also re- 
 sponds 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 me- 
 chanical 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 com- 
 ponents. This heterotopic interference is of particular impor- 
 tance in the bringing about of the movements of the living system. 
 
INTKRFEREXCK OF KXCITATIOXS 109 
 
 The locomotion of the animal and especially the direction is 
 in part a manifestation of heterotoi)ic interference of response. 
 At the same time, however, especially in the coordinated move- 
 ments of nervous ori^^in, the h()motoi)ic interference also plays 
 an important role and, not rarely, is combined with heterotopic 
 interference. 
 
 Although the j)hysical analysis of heterotopic interference is 
 extremely attractive, we must, however. temi)orarily set aside its 
 consideration, for at this point the (juestion arises as to what 
 happens when there is interference of two stimuli at the same 
 point. In the heterotoi)ic interference the etYect of each stimulus 
 is the same as if it w^ere applied singly. In the homotopic inter- 
 ference the interfering effects of stimulation intUience 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 inhibi- 
 tion, so important in the functionation of the nervous system, 
 and wdiich has presented the greatest difticulties to j^hysiological 
 investigators until the last few years. That a stimulus bringing 
 about excitation in a ganglion cell can l)e inhibited by another 
 exciting stimulus, or that the develo])ment of excitation in a 
 ganglion cell may be prevented by another exciting stimulus can- 
 not be easily understood. The ])roblem as to how two iiUerfering 
 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 princijiles of inhibi- 
 tory processes was close on the track of being a correct one. 
 but was subsequently abandoned by its originator. Schiff^ 
 (1858) has endeavored to explain this inhibition as a manifes- 
 
 1 M. Schiff: "r,elirl)iich dcr Physiologic des Menschen." H.i. I, I.ahr 1858. 
 
200 IRRITABILITY 
 
 tation 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 Ershopfungstheorie," 
 he renounced the idea as untenable. 
 
 Among other investigations, which since this time have been 
 made to explain the mechanism of inhibition, those of Gaskell,^ 
 Hering- and Meltzer^ have received widest consideration. These 
 theories are built upon the existence of the two phases of metab- 
 olism, and assume that inhibition, in contradistinction to dissimi- 
 latory 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 sub- 
 stance, seems very plausible, and I have accepted this even in my 
 address on excitation and depression before the Frankfurter 
 Naturforscher Versammlung.^ 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 reduc- 
 tion 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 investiga- 
 tion, 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 
 
 1 Gaskell: "On the innervation of the heart with especial reference to the heart of 
 the tortoise." Journ. of Physiology, Vol. IV, 1884. 
 
 2 Ewald Hering: "Zur Theorie der Vorgange in der lebendigen Substanz." Lotos 
 IX. Prag 1888. 
 
 ZMeltzer: "Inhibition." New York Medical Journal, 1899. 
 
 4 Max Verworn : "Erregung und Lahmung. Vortrag gehalten in der allgemeinen 
 Sitz. der Gesellsch." Deutsch. Naturf. u. Aerzte zu Frankfurt a. M. 1896. Verb. d. 
 Ges. Deutsch. Nat. u. Aerzte 1896. 
 
INTERFERENCE OF EXCITATIONS 201 
 
 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 imi)ossible 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 func- 
 tional energy production as an expression of an antagonistic pro- 
 cess to that of dissimilatory excitation. In this respect the 
 G ask ell-He ring hypothesis of inhibition rests upon a firm founrla- 
 tion. 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 antag- 
 onism need not involve the two types of metabolism, it may 
 depend upon variations of one type. When, therefore, the hy- 
 pothesis that inhibition is brought about by assimilatory excita- 
 tion 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 con- 
 ditions could not be produced experimentally wherein dissimi- 
 latory depression could bring about inhibitory processes in the 
 nervous system. The most essential requirement was, that dis- 
 similatory depression should quickly develop and pass away witli 
 like rapidity, for inhibition of the nervous system sets in momen- 
 tarily and disappears again momentarily. Another important 
 requisite is, that both interference stimuli arc individually capable 
 of producing dissimilatory excitation, for the inhibitory processes 
 of the nervous type may be assumed to be the result of dissimi- 
 latory excitation which j)ro(luce by their interference inhibition, 
 for the nerve fibers, as already stated, are capable of c(Miducting 
 only dissimilatory excitation to the responding organ. As I 
 studied the problem in this manner, it became clear to mc that all 
 
202 
 
 IRRITABILITY 
 
 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 some- 
 what 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 
 
 Fig. 45. 
 Lower line indicates stimuli. 
 
 reactions rapidly decrease until a stage is reached wherein the 
 succeeding stimuli are completely inoperative. (Figure 45.)^ 
 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 
 
 1 Max Verworn: "Zur Kenntniss der physiologischen Wirkungen des Strychnins." 
 Arch. f. Anat. u. Physiol, physiolog. Abth. 1900. The same: "Ermiidung, Erschopfung 
 und Erbolung." Ibidem Suppl. 1900. 
 
INTERFERENCE OF EXCITATION'S 
 
 203 
 
 central end of the cut sciatic nerve. Oxygen is witlidrawn in the 
 manner already referred to. At the ])ro])cr stage of oxygen 
 deficiency, rhythmic induction shocks ai)i)licd 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 nuiscles of the posterior extremity on 
 the opposite side following each individual stimulus. If, how- 
 ever, 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 
 
 Fig. 46. 
 
 Reflex inhibition in the strychninized frog. Lx)wer line indicates seconds, upper line stimuli. 
 When stimulation with single shocks at longer intervals is applied, each sinjjie stimu- 
 lus 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. 
 
 very beginning, being brought about by the first stimulus, whereas 
 the subsequent stimuli are ineffective, the nuiscles remaining at 
 rest during their entire application. (Figure 46.) Ticdcmanu^ 
 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 ]iroceeding. In 
 
 1 Tiedemann: "Untersuchungen iiber das absolute Rcfractarstadium und die 
 Hemmungsvorgange im Riickcnmark des Strychninfroschcs." Zeitschr. f. allgcm. 
 Physiologic Bd. X, 1910. 
 
204 IRRITABILITY 
 
 consequence there is a strong reduction of irritability and re- 
 action is absent. That is, the centers during appHcation 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 mechan- 
 isms 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 
 Frohlich to fatigue of the nerve itself, were in principle of the 
 same nature as the central inhibitions themselves. Frohlich,^ by 
 his analysis of the observations of Richet, Liichsinger, 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 pro- 
 cesses 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 role in the inhibition of the nervous cen- 
 ters. Thus, the relations of the processes of inhibition to the 
 refractory period, once established, their entire field, up to then 
 
 \ Fr. W. Frohlich: "Die Analyse der an der Krebsschere auftretenden Hemmun- 
 gen." Zeitschr. f. allgem. Physiologie Bd. VII, 1907. The same: "Der Mechanismus 
 der nervosen Hemmungsvorgange." Medizin. naturwiss. Arch. Bd. I, 1907. The 
 same: "Beitrage zur Analyse der Reflexf unction des Riickenmarks mit besonderer 
 Berucksichtigung von Tonus, Bahnung und Hemmung." Zeitschr. f. allgem. 
 Physiologie Bd. IX, 1909. The same: "Experimentelle Studien am Nervensystem der 
 Mollusken 12. Summation und scheinbane Bahnvuig, Tonus, Hemmung und 
 Rhythmus am Nervensystem von Aplysia limacina." Zeitschr. f. allgem. Physiol. Bd. 
 XI, 1910. 
 
INTERFERENCE OF EXCITATIONS 205 
 
 shrouded in darkness, has gradually in the course of years been 
 completely elucidated. 
 
 Before going back to the cases of inhibition and explaining 
 them by this general principle, it is necessary tiiat we penetrate 
 more deeply into the details of the characteristic course of the 
 refractory period. ]*>y this means we will tind tiie conditions 
 which universally determijie the interference in the efTccts of 
 stimulation. 
 
 First of all, it is self-evident that the occurrence of interference 
 of stimulation in a living system can only take i)lace when the 
 succeeding stimulus is ai)plied before the etTects 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 metal)- 
 olism, 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 tyi)e wherein the first 
 stimulation produces depression, whereas the second has an excit- 
 ing 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 eft'ect on the threshold de- 
 termined. As shown by Baeycr it is found that with increasing 
 asphyxia the threshold of stimulation for induction shocks be- 
 comes 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 irri- 
 tability has a logarithmic form. During the continuation of the 
 depressing stimulus, i.e., the want of oxygen, the exciting stimulus 
 has less and less eft"ect. If oxygen is again brought in contact 
 with the nerve, irritability immediately returns to its original 
 
206 IRRITABILITY 
 
 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 inter- 
 ference 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 suppres- 
 sion, 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 pre- 
 suppose what may happen under certain given conditions with- 
 out first making the necessary experiments. The strength of 
 scientific investigation depends upon the fact that every deduc- 
 tion, 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 inter- 
 ference 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 differ- 
 ent. 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 
 aerobic 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 
 
INTERFERENCE OF EXCITATIONS 
 
 207 
 
 of occurrence. The disintegration, determined by energy pro- 
 duction, reaches a maximum suddenly, then diminishes, at tirst 
 rapidly, then more and more slowly until the zero point is reached. 
 In an analogous manner the irritability abruj)tly reaches a mini- 
 mum, then increases rai)i(lly, 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 
 
 Fig. 47. 
 
 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 irri- 
 tability. 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 cciuilibrium re- 
 established. 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 stinuilus is 
 operative during the course of the first. 
 
 It is from the beginning apparent that the resix)nse 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 stinuilus. In the 
 following diagram the intensity of the existing threshold value is 
 
208 
 
 IRRITABILITY 
 
 fixed for convenience as ordinates beneath the abscissa. If, for 
 example, at the time point x, a stimulus of weak intensity Ri acts, 
 this stimulus being under the existing threshold, produces no 
 perceptible effect. (Figure 48.) If now instead of a weak stimu- 
 lus, one of stronger intensity acts at the time point x, this stimulus 
 
 Fig. 48. 
 
 Fig. 49. 
 
 will produce an appreciable response. (Figure 49.) If the sec- 
 ond stimulus is of the same strength as the first, this second stimu- 
 lus 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 excita- 
 tion still existing as the result of the first stimulus can produce 
 an absolute increase of the height above that of the abscissa. 
 
INTERFERENCE OF EXCITATIONS 
 
 209 
 
 Here then we see the possibiHty of an increase of response 
 resulting from summation. Accorthngly the increase of disin- 
 tegration must occur simultaneously with a diminution of irri- 
 tability 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 i)ro- 
 duced by the first stimulus acting ujjon an unexcitatcd system is, 
 however, connected with another condition. The above e.\ami)le 
 refers to systems in whicli weak stinuili bring about weak re- 
 sponse and strong stimuli .strong response, that is. the resj^onse 
 is capable of increase. In systems in which the "all or none 
 
 Fig. 50. 
 
 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 exi)res- 
 sion rather than by a long sentence, we will call the first a 
 ''heteroholic system," the latter in which the "all or none law" is 
 operative an "isobolic systc)}i." The former term expresses 
 various degrees of discharge dei)ending 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 cai)able of summa- 
 tion. The response to the second stimulus of e(|ual intensity 
 cannot be greater than that of the first, it may be ecjual to the 
 first (Figure 50) or be less in extent, but it can never be greater 
 
210 
 
 IRRITABILITY 
 
 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; never- 
 theless a weak eft'ect does occur, as is shown by succeeding re- 
 actions. This effect is manifested by a sub-threshold disinte- 
 gration and a corresponding slight reduction of irritability. 
 (Figure 51.) The presence of such a sub-threshold effect is 
 
 Fig. 51. 
 
 Effect of sub-threshold stimuli, o— Level of the ideal threshold, 
 s— Level of the threshold of perceptible effect. 
 
 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, 
 
LNTERFERENCE OF EXCITATIOXS 
 
 211 
 
 secondly, upon the momentary amuunt of irritability which exists 
 just at the time when the second stimulus produces its effects. 
 It is, therefore, clear that the response produced hy interference 
 must also alter with the momentary deforce of irritability in a 
 manner analogous with variations of the intensity of the second 
 stimulus. One nuist, therefore, know the factors which control 
 the momentary degree of excitation. 
 
 The first factor to be considered is the moment of time in which 
 the second stimulus is ai)plied, that is, the interval between the 
 first and the second stimulus. If, for example, a weak second 
 stimulus follows very cjuickly after the first, the stimulus will 
 bring about no response, as the system at the time of its appli- 
 cation is in a relative refractory period. (Figure IS.) The 
 stimulus is, therefore, under the threshold, [f, however, a stinui- 
 lus of the same strength is applied somewhat later, when the irri- 
 tability 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 
 
 Fig. 52. 
 
 existing, is summated. (Figure 52.) But further, ii is not a 
 question of the absolute interval between the stimuli. I)ut rather 
 to the relative interval to the specific rapidity of the reaction of 
 the living substance under consideration. There arc living sub- 
 stances, as we have seen, in which the refractory perio<l is un- 
 usually short, as, for instance, the nerve. There are other sub- 
 
212 IRRITABILITY 
 
 stances wherein this period lasts a considerable time after stimu- 
 lation, 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 like- 
 wise 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 pro- 
 longed 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 prolonga- 
 tion 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^ upon the refractory period 
 of the heart, and more recently has been the subject of study 
 by Samojloff,^ Keith Lucas^ and Gotch^ in the muscle and 
 nerve. These, then, are the essential factors which bring about 
 interference, and although there are special details which deserve 
 
 1 Marey : "Des excitations artificielles du coeur." Trav. du lab. de M. Marey II, 
 1875. The same: "Des mouvements que produit le coeur lorsqu'il est soumis a des 
 excitations artificielles." Compt. rend, de I'acad. des sciences T. LXXXVII, 1876. 
 
 2 Samojloff : "Actionsstrome bei summierten Muskelzuckungen." Arch. f. Physio- 
 logic Suppl. 1908. The same: "Uber die Actionsstromkurve des quergestreiften 
 Muskels bei zwei rasch aufeinanderfolgenden Reizen." Zentralblatt f. Physiol. 1910. 
 
 3 Keith Lucas: "On the refractory period of muscle and nerve." Journ. of Physiol- 
 ogy, XXXIX, 1909-10. The same: "On the recovery of muscle and nerve after the 
 passage of a propagated disturbance." Ibid. XXXXI, 1910-11. 
 
 4Gotch: "The delay of the electrical response of nerve to a second stimulus." 
 Journ. of Physiology, XXXX, 1910. 
 
INTERFERENCE OF EXCITATIONS 
 
 213 
 
 more close analysis, nevertheless, we are in a position to attribute 
 to them the origins of summation and inhibitory processes, wliich 
 occur in all living systems, especially the nervous system. 
 
 For the analysis of summation and the inhibitory processes 
 which occur in the i)hysiologically active organisms or wiiich are 
 experimentally produced, a very imi)ortant point should be ob- 
 served, that is, the fact that the stimuli which bring about these 
 phenomena are practically always a scries of single stimuli. The 
 nerve impulses, for example, consist of a shorter or a longer 
 series of single discharges which follow each other in raj)i(l 
 rhythmic sequence. Here, then, we have the conditions neces- 
 sary 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 huo series. 
 
 \ 
 
 / 
 
 ( / 
 
 [ / 
 
 \ J 
 
 
 ,,-'"' 
 
 ,^-"' 
 
 -■-",. 
 
 ' 
 
 
 T--; 
 
 --;■;;.■. 
 
 ■....-• 
 
 
 
 
 V 
 
 / 
 
 w 
 
 \ r 
 
 \ / 
 
 \ } 
 
 \ / 
 
 \ / 
 
 V / 
 
 \ / 
 
 \ / 
 
 •s-' / 
 
 \' /■ 
 
 V / 
 
 »^ / 
 
 V /- 
 
 ; >^ 
 
 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 wdll first direct our attention to the simi)lest case brought 
 about by an interference between the individual effects of stimuli 
 in the same series. \\'e will study the effect, which here occurs, 
 in the accompanying diagram, which shows the facts involved in 
 the interference of tzvo stimuli of a scries of stimuli. ( h'igure 
 53.) The curve shows the development of summation and inhi- 
 bition. The single stimuli of equal intensity follow at the same 
 intervals, so that the succeeding stimuli meet with an incomplete 
 
214 IRRITABILITY 
 
 recovery of excitation and accordingly a decreased state of irri- 
 tability. 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 stim- 
 ulation 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 re- 
 duced at each stimulation to an amount equal to that of the 
 recovery in the interval. If this all takes place beneath the thresh- 
 old of perceptible response, the system during the contin- 
 uance 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 follow- 
 
INTERFERENCE OF EXCITATION'S 215 
 
 ing stimulus is applied before there is complete recovery of exci- 
 tation from the previous stimulus. The absolute increase of 
 excitation as a result of summation is, however, limited by the 
 diminution of irritability. Hy continuation of the series of stimuli 
 the state of ecjuilibrium between the amount of excitation and 
 the irritability will be established on a hi^dicr or hnver 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 inhibiticjn by the continu- 
 ance of stimuli of constant intensity. The i)rinciples which under- 
 lie 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 inhi- 
 bition. The time required for this development is in manifold 
 ways influenced by variations of the above-stated factors which 
 control the occurrence of interference. There) )y 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 irri- 
 tability of the system, as measured by the threshold of stimula- 
 tion, 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, v^uch isobolic systems do not 
 summate, having no power of summation because each individual 
 stimulus brings about a maximum response. lUit 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 capal)ilily of summat- 
 
216 IRRITABILITY 
 
 ing excitations. Waller,^ Boruttau,- Boruttan and Frohlich,^ 
 Thorner^ and others have shown that the action current of the 
 nerve during the appHcation of tetanic stimulation becomes decid- 
 edly 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. Frohlich^ first 
 threw light upon this subject in that he made the observation 
 that here a principle is involved which has far-reaching impor- 
 tance 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 succeed- 
 ing stimulus meets with a more incomplete recovery of excitation 
 than the one previously applied. In consequence of this, the irri- 
 tability 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 Frohlich, 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^ 
 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 
 
 1 Waller: "Observations on isolated nerve." Croonian Lecture, Philosophical 
 transactions. 1897. 
 
 2 Boruttau: "Die Actionsstrome und die Theorie der Nervenleitung." Pfliigers Arch. 
 Bd. 84, 1901. 
 
 3 Boruttau und Frohlich: "Electropathologische Untersuchungen. Ueber die 
 Aenderung der Erregungswelle durch Schadigung des Nerven." Pflugers Arch. Bd. 
 105, 1904. 
 
 4 Thorner: "Die Ermijdung des markhaltigen Nerven." Zeitschr. f. allgem. Physi- 
 ologic Bd. VIII, 1908, und Bd. X, 1910. 
 
 5 Fr. IV. Frohlich : "Ueber die scheinbare Steigerung der Leistungsfahigkeit des 
 quergestreiften Muskels im Beginn der Ermiidung (Muskeltreppe), der Kohlensaure- 
 wirkung und Wirkung anderer Narkotica (Aether, Alkohol)." Zeitschr. f. allgem. 
 Physiologie Bd. V, 1905. The same: "Das Princip der scheinbaren Erregbarkeits- 
 steigerung." Zeitschr. f. allgem. Physiologie Bd. IX, 1909. 
 
 6 Fr. Reinecke: "Ueber die Entartungsreaction und eine Reihe mit ihr verwandter 
 Reactionen." Zeitschr. f. allgem. Physiologie Bd. VIII, 1908. 
 
INTERFERENCE OF EXCFrXTK )XS 
 
 2ir 
 
 course of excitation, are favorable to the summation of excitation, 
 provided their iiitluence does not exceed certain limits. 
 
 Although the nerve as an isoholic system can only he rendered 
 capable of exhibiting summation when artificially influenced, 
 there are other forms of li\ing substance which normally are 
 systems with a slow course (jf excitation, in which excitation 
 may be summated, for this type possesses at the same time a 
 heterobolic character. Vuv example, a single mechanical exci- 
 tation elicits a hardly perceptible response in Amivba, Actino- 
 splucrium, Orbitolitcs. When it is perce])til)le at all, there occurs 
 a short interruption of the centrifugal uKJvement of the proto- 
 plasm. After a i)ause the movement of the ])rotoj)lasm and the 
 stretching out of the pseudopods again return. Ihu if the 
 organism is agitated one or more minutes by rhythmically shak- 
 ing the edge of the slide by a special device, as a result of the 
 summation of weak excitations there occurs a comi)lete drawing 
 in of the pseudopods and the anKcbre become bell-shajied.' The 
 ganglion cells also possess a great cai)ability for summation. W'e 
 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. 
 
 Fig. 54. 
 
 Development of tonus by interference of sub-threshold stimuli. 
 
 S— Level of the threshold of perceptible cflect. 
 
 The summation of sub-threshold excitation to a certain height 
 oflers very favorable conditions for the development of tonus. 
 (Figure 54.) This fact has been established for many kinds of 
 centers (cardio-inhibitory center, vasomotor ceiUer, etc.). During 
 the continuance of a scries of stimuli, as we have already seen, 
 an equilibrium between disintegration and replacement soon takes 
 
 I Max Verworn: Psychophysiologischc Protistcnstudieii. Expcrimcntclle I'ntcr- 
 suchungen." Jena 1889. 
 
 The same: "Die physiologische lUdeutung dcs Zcllkcrns," Fllugers Arch. Bd. 51. 
 
 1892. 
 
218 IRRITABILITY 
 
 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 Thorner^ on the fatigue of medullated 
 nerves in air. This investigator showed that during continued 
 tetanic stimulation of the nerv^e, 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 Thor- 
 ner 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 per- 
 ceptible 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. Frohlich^ 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 inter- 
 ference dare not be overlooked in the genesis of muscle tonus. 
 If it is true, as appears from the investigations of Keith Lucas,^ 
 
 1 Tlwrner : "Weitere Untersuchungen uber die Ermiidung des markhaltigen Nerven. 
 Die Ermiidung in Luft." Zeitschr. f. allgem. Physiologic Bd. X, 1910. 
 
 2 Fr. IV. Frohlich: "Ueber die scheinbare Steigerung," etc. Zeitschr. f. allgem. 
 Physiol. Bd. V, 1905. 
 
 3 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. 
 
INTERFERENCE OE EXCITA'l loXS 219 
 
 that the "all or none law" ai)i)lies 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 bein^' the case, 
 the tonic shortening of striated muscle can only be exi)lained as 
 an expression of a heterotopic interference. 
 
 If we assume that the suiumation of sub-threshold stimulation, 
 by increasing excitation, brings about a state of e(iuilibrium from 
 below, as it were, so also inhibition may be assumed to be the 
 reverse, the level of cquilil)rium being reached from above, as it 
 were, by decrease of the primary excitation from strtjng >tinuila- 
 tion. This is expressed in our general scheme of the develop- 
 ment 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 e(|uilibrium 
 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 experi- 
 ments for understanding of the theory of inhibition. If we stinui- 
 late a sensory nerve of a strychninized frog, in which the refrac- 
 tory period is already lengthened, with rhythmic single induction 
 shocks of slow frequency, the muscle arranged to make a graj)hic 
 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 41), pages 202, 2<»;}). For 
 the succeeding stimuli the centers remain inhibited, because eacli 
 succeeding stimulus occurs in the refractory ])eriod of the former. 
 The origin of this inhibition shows us with particular clearness 
 how excitation ])roduce(l 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 ecjui- 
 librium is reached which is maintained by the following stimuli. 
 That a single stimulus is not entirely without cfTcct ujkmi thi^ 
 state of equilibrium follows from the fact that during the con- 
 tinuation of the stinmlus a recovery to the i)oint of observable 
 
220 IRRITABILITY 
 
 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 betzveen excita- 
 tion 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 ele- 
 mentary conditions are at the basis of an understanding of com- 
 plicated interference effects which arise zvhen tzvo series of stim- 
 uli 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 condi- 
 tions 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 inhi- 
 bition, as the general scheme (Figure 55) has shown us. Depend- 
 ing upon the special combination of the factors involved in inter- 
 
INTERFERF.XCE OF FXCITATIOXS 
 
 221 
 
 ferencc. we may have a summation of the exciting eflfect of each 
 series of stimuh or an inhibition of one series hy the exciting 
 effects of the other series. If ilie frecjuency of I)oth series is 
 essentially different, we may have here the cuiuiitions for periodi- 
 cally increasing and decreasing excitations. Nevertheless these 
 conditions have not been systematically analyzed and exi)erimcn- 
 tally studied. 
 
 s - 
 
 
 
 
 
 ■ ;^ 
 
 
 a 
 
 V 
 
 X 
 
 A. 
 
 1 
 
 r' 
 
 b' 
 
 ♦ ^ » . 
 
 ■ '• K ■ ' K \ 
 
 '. < « '< \ \ '. 
 
 • • 
 
 
 H 
 
 FiS. 55. 
 
 Interference of two series of stimuli. A Effect of the one scries 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 scries. 
 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 ditlerent 
 tracks affect the same ganglia i)lays a very important role. It 
 is this to which Sherrington^ has alluded as "ihc princ'xplc 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 princii)le has 
 a broad application in the phenomena of association in the cere- 
 bral cortex. The simpler and, therefore, the most easily under- 
 stood cases are, however, in the spinal cord. The motor neurons 
 of the anterior horns of the spinal cord are the junction of a 
 
 \ Sherrington : "Ueber das Zusammcnwirkcn dcr RucWcnmarksrcflcxc und di* 
 Princip der gemeinsamen Strecke." Ergebnissc dcr Physiologie. Jahr. IV. l^^OS. 
 
222 IRRITABILITY 
 
 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 Sherring- 
 ton, 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, excel- 
 lent opportunities for the experimental investigation of the inter- 
 ference 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 Sherring- 
 ton'^ and his coworkers on the dog, and Frohlich,- Veszi,^ Tiede- 
 mann'^ and Satake^ on the frog. 
 
 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 suffi- 
 cient to bring about perceptible effect. If both stimuli were 
 simultaneously operative, an increase in the response was ob- 
 served. 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 
 
 1 Sherrington: "The integrative action of the nervous system." New York 1906. 
 
 2 Fr. W. Frohlich: "Der Mechanismus der nervosen Hemmungsvorgange." Med. 
 Natur. Arch. Bd. I, 1907. The same: "Beitrage zur Analyse der Reflexfunction des 
 Riickenmarks, etc." Zeitschr. f. allgem. Physiologie Bd. IX, 1909. The same: "Das 
 Princip der scheinbaren Erregbarkeitssteigerung." Ibid. 
 
 3 Julius Vessi: "Der einfachste Refiexbogen im Riickenmark." Zeitschr. fur allgem. 
 Physiol. Bd. IX, 1910. 
 
 4 Tiedemann : "Untersuchungen iiber das absolvite Ref ractarstadium und die 
 Hemmungsvorgange im Riickenmark des Strychninfrosches." Zeitschr. f. allgem. 
 Physiologie Bd. X, 1910. 
 
 5 Satake: The researches are not yet published. 
 
INTERFERENCE OF EXCITATIONS 
 
 223 
 
 real and apparent ''Bahnungen." On account of this lack of clear- 
 ness in the meaning of the term "Bahniing." I wish to discard its 
 use as it is not at all essential. We will si)eak simply of a summa- 
 tion of excitation, for here it is sinij)!)' a question of summation 
 of two excitations of the motor cells of the si)inal cord. 
 
 -» 
 
 ~v 
 
 r\rArt-ir\rArArAr\r-\i 
 
 If 
 
 s 
 
 -^ 
 
 T 
 
 J L 
 
 iiMnrtwmi 
 
 H 
 
 AruW'dVlrtrts^ rUljAnrtrv 
 
 Fig. 56. 
 
 B 
 
 Summation of two excitations in the rabbit. The one proceeds from the paw. the other frf)m 
 the motor sphere of the cerebral cortex. S Time in seconds. Pf Stimulation of the paw. 
 //—Stimulation of the motor sphere. Af— Contractions of the abductor poilicis. '.\fter 
 Exner.) 
 
 M 
 
 S 
 
 Frohlich 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. 
 
 On the other hand, the conditions for the production of inhibi- 
 tion 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 frecjuency. .\ 
 relative fatigue of the motor ganglion cells for weak stimuli 
 rapidly occurs, and there develops a state of equilil)rium beneath 
 that of the threshold of perceptible effect throughout the con- 
 tinuation of stimulation. Veszi succeeded in isolating these types 
 of summation and inhibition in the spinal cord. His method con- 
 sisted 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 i>oste- 
 
224 
 
 IRRITABILITY 
 
 rior root is then stimulated, tetanus is also produced but of some- 
 what 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 
 
 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. 
 
INTERFERENCE OF EXCITATIONS 
 
 225 
 
 is stimulated with weak shocks, one can ol)tain an increase of the 
 tetanus of short (kiration followed by inhibition. Here, as the 
 result of interference, we have an instance of inhibition with pri- 
 mary tetanus. (Figure 58.) W hen the tenth root is stimulated 
 
 B 
 
 Fig. 58. 
 
 with very weak shocks, inhibition of the tetanus produced simul- 
 taneously 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 untcnability of 
 the Gaskcll-Hcrimj hypothesis, that inhibitory i)roccsscs result 
 from assimilatory excitation. It would be impossible to under- 
 stand how two dissimilatory exciting stimuli, by their simulta- 
 neous action, could l)ring about assimilatory e\(Mtntion. When 
 
226 IRRITABILITY 
 
 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 
 
 Fig. 59. 
 
 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,^ who recognized their importance in the functional 
 processes of the nervous system, can be explained, as Frohlich 
 showed, upon this principle of inhibition resulting from weakened 
 excitation. On the basis of numerous investigations in the 
 
 1 Sherrington: "Experimental note on two movements of the eye." Journ. of Physi- 
 ology XVII, 1895. The same: "On the reciprocal Innervation of antagonistic mus- 
 cles." Proceed, of the Royal Soc, 1897. 
 
INTERFERENCE OF EXCITATIONS 
 
 227 
 
 Gottingen laboratory as well as lluit of PxHin' \vc have come to 
 look upon the reflex arc in the spinal cor^l as consisting of the 
 following elements: a neurone in the -i)inal ^anglicjn. a neurone 
 in the posterior horn and a motor neurone in the aiUerior horn. 
 This is the most direct route between the i)oint of stinuilation 
 and that of the responding organ of a unilateral retk-x. ( I-'igurc 
 60.) It is known that the excitation becomes weaker in passing 
 
 Fig. 60. 
 
 Scheme of the simplest unilateral reflex arc of the spinal cord 
 
 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 stimu- 
 
 l Max J'eru'orn: "Die einfachstcii RcflcxwrRf im Kuckcnmark." Zentralbl«(( t. 
 Physiologic Bd. XXIII. Ticdemann : "I'litcrsuchutiKcn ubcr da> absolute Rcfractar- 
 stadium und die IIcmmuiiKsvorgaiiKC im Kuckcnmark dc» StrychninfrojMrhc*.*' Zcil»chr. 
 f. allgem. Physiologic Bd. X. 1910. Julius I'^ssi: "I)er cinfachste Rcflcxbogcn im 
 Riickenmark." Zeitschr. f. allgem. Physiologic Bd. XI. NIO. Oii»iim<i "rcl»rr die 
 asphyktische Lahmung des Riickcnmarks strychninisiertcr Fro»chc." 7-"* hr. (. 
 allgem. I'hysiol. Bd. XII, 1911. Satakc: Not yet published. 
 
228 
 
 IRRITABILITY 
 
 lus 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 
 
 Fig. 61. 
 
 Scheme of the simplest reflex arc from one to the other side, and 
 from a higher to a lower level. 
 
 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 Veszi 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 excita- 
 tion. It is, therefore, understandable that reflex excitation of a 
 
INTERFERENCE OF EXCITATIONS 229 
 
 muscle under normal conditions of irrilabililv has an inhibitory 
 effect on its anta^^onist. 
 
 Finally, I wish to conclude this discussion on tlic origin of 
 central inhibition and its dependence ui)on the strength of the 
 stimulus by referring to a |)oint which apparently is contradic- 
 tory. We have already met with the fart that series of stimuli 
 by their interference in tlie nervous system may have different 
 effects depending upon their intensity; if this is strong, we obtain 
 summation of excitation, if weak an inh.ibition. The question 
 may be asked, how is it i){)ssil)le that a weak stimulus can have 
 a different effect when it is believed that the nerve as an isol>olic 
 system responds to intensities of all gradations to the same extent, 
 namely, w^ith 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 resiH:)nses 
 follow various intensities of stinuilation. Here, indeed, is a 
 difficulty which has not as yet been explained. Naturally between 
 the two facts there can be no contradiction, liut the question 
 arises, how are we to bring them into harmony? Two entirely 
 different possibilities present themselves. If the various inten- 
 sities 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 stinuilation bring 
 about some other effect than that of variations in intensity 
 in the course of the w^ave of excitation. In this comiection 
 variations in the time involved nuist be taken into consideration. 
 One might think that strong stimuli may develop a longer wave 
 of excitation than such of zucak intensity. Cotcli^ tested tliesc 
 questions experimentally with comi)letely negative results. A single 
 strong stimulus does not result in an excitation ditTering in its 
 course from that of a weak stimulus. But there is another possi- 
 bility that requires testing. This was brought to light !)y the 
 investigation of Thorucr- on the fatigue of the nerve. His invcs- 
 
 iGotch: "The submaximal electrical rcsi)onsc of nerve to • tiriKlr »»inmhi« '* 
 Journ. of Physiology, Vol. XXVIII. 1902. 
 
 • 2 Thorner: "Wcitere UntersuchtinRen iibcr die ErmrnlunK de» markhalligen Ncrrcn: 
 Die Ermvidung in Luft." etc. Zeitschr. f. allRem. Physiologie Bd. X. 1910. 
 
230 IRRITABILITY 
 
 tigations 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 reduc- 
 tion 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 stimu- 
 lated 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 diminu- 
 tion 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. Veszi^ 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 iso- 
 bolic system during the refractory period may assume a hetero- 
 bolic character, and only after completion of the refractory period 
 and entire recovery of the equilibrium of metabolism does the iso- 
 bolic character return. This permits us to understand the charac- 
 teristic properties of an isobolic system more accurately and pre- 
 cisely than has thus far been possible. The "all or none law" 
 
 1 Vessi: "Zur Frage des Alles oder Nichtsgetzes beim Strychninfrosche." Zeitschr. 
 f. allgem. Physiologic Bd. XII, 1911. 
 
INTERFERENCE OF EXCITATIONS 231 
 
 with its associated i)roi)crtics, such as the conductivity without 
 decrement and tlie incapahility of summatin^' excitations, have 
 in a system of this character only relative valichty. Tlicy arc 
 realized only in the state ui an ecjuilihrium of nietabolism. Only 
 when the stimuli follow each other at interval^ greater than the 
 duration of the refractory period is there a resi>onsc of equal 
 extent to stimuli of all intensities which are above the threshold. 
 During the refractory i)eriod and conse^juently in fatipue, 
 asphyxia, cooling and narcosis, etc., in short, in all states in which 
 the refractory period is ])rolonged this system loses its isoholic 
 properties and becomes heterobolic. In order that there may not 
 be a misunderstanding, we will consider more in detail the capa- 
 bility in this state of summation of excitations. When we refer 
 to a summation of excitation of such a .system under tiie intUiencc 
 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 uiK)n the aj)pli- 
 cation of a single stimulus, for this degree of excitation is maxi- 
 mal. We refer rather to a summation which has become reduced 
 as a result of fatigue. 
 
 On the basis of these facts it is readily understood when a icvcl 
 of equilibrium of lower intensity has been reached that excita- 
 tion produced by weak faradic stimulation must have weaker 
 effects than when strong stimuli are api)licd. for when the system 
 assumes a heterobolic type as the result of relative fatigue weak 
 stimuli bring about weak, and strong, stronger excitation. Conse- 
 quently, during interference induced by a second series of excita- 
 tions, in the first case we have the conditions favorable for inhi- 
 bition, 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 wc can 
 readily understand the various kinds of effects produced by inter- 
 ference observed in the retlcx response following weak and strong 
 faradic stimulation to the ditTerenl nerves in spite of the fact that 
 the nerve in the state of rest is a svstem isobolic in tyjK!. Kx|>cri- 
 
232 IRRITABILITY 
 
 mental 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. Thorncr 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 Thorner 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 disap- 
 peared, otherwise Thorner could not have obtained fatigue pro- 
 duced by continued stimulation. The intervals of the individual 
 shocks must be somewhat shorter than the duration of the refrac- 
 tory period, even in fatigue of a very slight degree. It is very 
 interesting in this connection that Thorner 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 equilib- 
 rium 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 dura- 
 tion of the period in which no excitation at all could be brought 
 
INTERFERENCE OF EXCITATIONS '^33 
 
 about. On the contrary, my estimate, based upon tlic invcstij^a- 
 tions of Thorncr, refers to the totnl refraelory |)crioc! of the 
 nerve, that is, to the point of complete recovery of the e(|uihbrium 
 of metabohsm and of tlie specific irrital)ihiy. Experimental pr(K)f 
 of this assuniptiun is already under way. 
 
 I have endeavored to show the elemenuiry principles at uie 
 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 interfer- 
 ence efifects possess characteristics in common if one takes into 
 consideration the process occurring in the cour>e of a single 
 excitation. The altered state which exists in living substance 
 until the complete disappearance of excitation is the basis ujKDn 
 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 eciuilibrium of the luetabolism of rest is, by self- 
 regulation, again reached. It is. therefore, self-evident that the 
 second stimulus must have different etYects depending uiK)n the 
 momentary state of the living system at the tiiue of its ai)plica- 
 tion. 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. I'ut the specific prop- 
 erties of the given systems must also be taken into consideratit)n. 
 It is important to know if the living system possesses isolH)lic 
 properties, that is, every intensity of stinuilation produces a 
 maximal liberation of energy, or if it possesses a heterol>olic 
 character, that is, stinuili of different strength bring al)OUt the 
 liberation of different amounts of energy. It is further imjKir- 
 tant to know the rapidity of reaction, whether the sy.stem rapidly 
 or slowly fatigues. In all cases it dei)ends whether the second 
 stimulus produces a perceptible excitation or whether it occurs 
 in the refractory period and jjroduces no i)erceptible effect. I'jK^n 
 these factors dei)end the results of the interference of two 
 rhythmic series of stinudi. whether a summation or inhibition of 
 
234 IRRITABILITY 
 
 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 IM<()CKSSRS ol- I)!:i'RF.SSTO\ 
 
 Contents: Necessity of cellular pliysioIoKical analysis of toxic depres- 
 sions by pharmacology- Apparent variety of prcnresses of detiression. 
 Depression of oxydative disintCKration as the most cxtcnde^l principle 
 in the processes of depression. Asphyxiation, fatigue, heal depres- 
 sion, as a consequence of restriction of oxydative disintcKration. 
 Narcosis. Theories of narcosis. The alteration of specific irritability 
 and conductivity in narcosis. Depression of oxydative processes in 
 narcosis. Asphyxiation of livin^^ substance when oxygen is present 
 during narcosis. Persistence of ant)xydative disintegration in nar- 
 cosis. Increase of the same by stimuli. Depression by narcosis as 
 a form of acute asphyxiation. Hypothesis on the mechanism of 
 depression of oxygen exchange i)y narcotics. Possibility of com- 
 bining the facts with the observations of Meyer and Overton. 
 
 The processes of excitation of all the effects of stinuihilion arc 
 those which have invariably claimed place in the inlere>t of phys- 
 iologists. The study of the i)rocesses of depression, on the other 
 hand, has remained more or less in the background. Tliis is 
 readily understood when it is considered how much more apparent 
 the processes of excitation are than those of dei)ression. Never- 
 theless, these latter possess no less imi)ortance for the course 
 of vital phenomena than those of excitation. Without dei)res- 
 sion no excitation can take i)lace in the vital activity of the org:ui- 
 ism, for, as we have seen, every excitation is secondarily ft>l- 
 lowed by a refractory period. To this must be added the great 
 number of primary depressions, directly brought about by ll)e 
 most varied stimuli, such as cold, want of oxygen, poisons, etc., 
 without the presence of a jireceding excitation. Thus it is essen- 
 tial that the processes of (le])ression sliould 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, b'ven as it is. extensive material has 
 
236 IRRITABILITY 
 
 been obtained for the analysis of this group of reactions. With 
 the closer study of the process of excitation the facts in connec- 
 tion 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. Unfortu- 
 nately the investigation of these reactions has been in the main 
 purely superficial. This arises from the recency of the devel- 
 opment 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 sys- 
 tematically 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 appear- 
 ance 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 manu- 
 facturers. 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 depress- 
 ing 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 super- 
 ficial results, may find here a wide field of research work, rich 
 in future promise. It is from such investigation that we may 
 
THE PROCESSES OF DEPRESSION 237 
 
 expect an abundance of material for the closer analysis of the 
 processes of depression. For ihc j)rcsent. however, we nui^l 
 restrict ourselves to the consideration of some individual cases 
 which have been studied somewhat more in detail by physiolo- 
 gists. 
 
 Simple reflection shows the possibility that depression, tlial is. 
 the retardation of the n(jrinal vital i)roccsses, can be broujjhi 
 about in various ways. As on the one hand the normal metab- 
 olism of rest is composed of very numercnis chemical constituent 
 processes, and on the other hand the closest inlerde|>cndciicc 
 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 cl(x"k 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 |)rocesses of 
 depression result from the primary etTect of one or a few con- 
 stituent members. A primary simultaneous depression of all or 
 at least of numerous constituent processes of the entire metab- 
 olism may only be assumed as ])ossil)le, resulting from decrea.se 
 of temperature within certain limits. lUu e\cn in the case of 
 ''cold depression" it is not probable, owing to the great etTect of 
 every alteration in the relations of masses in the cell, that depres- 
 sion is solely the manifestation oi a uniform retardation of all 
 individual constituent metabolic processes. If. therefore, the 
 greater part of the processes of depression are brought al)OUt by 
 the primary effects of an individual constituent i)rrK*ess. then the 
 possibility must be admitted that any com])onent of the chain can 
 by the means of some specific external intUience form the starting 
 point for a depression. The iunni)cr 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 luight lead one to 
 expect. Even though future investigation will certainlv nnt do 
 
238 IRRITABILITY 
 
 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 stimuH, from 
 which their depressing effects proceed. Here the highly interest- 
 ing 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 anaerobic 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 role to that of the oxydative 
 in aerobic systems. Our investigations must, therefore, be re- 
 stricted to the world of aerobic organisms. Here we have seen 
 that the different stimuli which produce an excitating effect in- 
 variably 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 
 aerobic organism, oxydative disintegration is gradually found to 
 be more and more decreased and further breaking down takes 
 place a?ioxydatively, 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 excita- 
 tion takes place, which, in turn, is likewise manifested by the 
 
THE PKOCRSSES OF DEPRKSSIOX 239 
 
 restriction of the perccptiljle response to stinuilaiion. In the 
 same degree in whicli oxydative disintegration l>cc(iines less, 
 o/zoxydative breaking down i)r(»dncts are accunnilated. The 
 accumulation of these products likewise plays a part in the |)ro- 
 duction of depression and increases the decrement in the con- 
 duction of excitation. 1 he decrease of cnerg)' prfwluction by 
 decline of the oxydative dccomj)osition. as well as the accumu- 
 lation of anoxydative lireaking down products, therefore, simi- 
 larly 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 (jxygen and leads to 
 the dei)ression of asphyxiation. It can readily be observed in 
 the most varied kinds of aerobic organisms in rhizo|)ods and 
 infusoria, in i)lant and ganglion cells, but fmds its most complete 
 demonstration in the nerves. Here these jirocesses can l)c 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 diflerenl in nature. 
 
 We have previously become accjuainted with such a ca.se and 
 studied it in detail. This is the state of fatiijuc. I^itiguc is a 
 typical state of depression, that is, a state in which the vital pro- 
 cess is retarded and irritability in response to stinmli corre- 
 spondingly decreased. Fatigue is, however. a< 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 consecjuence the previously cited 
 sequence of processes takes ])lace. A "dej^ression 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 stinmli gradually merges into 
 depression as the amount of oxygen at disposal, even if augmented 
 in the intact organism by the increa.sed bUxKl su|)|)ly. for instance, 
 is still insufficient to meet the demand made by the increased 
 oxygen consumption as a re.sult of continuous functional activity. 
 
240 IRRITABILITY 
 
 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 mani- 
 festations 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 pro- 
 cess 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 infu- 
 soria 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 depres- 
 sion produced by heat, developed in different organisms at various 
 heights of temperature, requires a closer analysis. This depres- 
 sion 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 albu- 
 men coagulates, vital activity is permanently obliterated. Depres- 
 sion 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^ by his investigations on the central 
 nervous system of frogs and on medusae. He found that when 
 placed in a heated chamber in a temperature of 33-40° 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, simi- 
 
 1 H. Winterstein: "Ueber die Wirkung der Warme auf den Biotonus der Nerven- 
 zentren." Zeitschr. f. allgem. Physiol. Bd. I, 1902. The same: "Warmelahmung tmd 
 Narkose." Ibid. 
 
THE PROCESSKS OE DEPRESSION 241 
 
 lar to tliosc characteristic oi strychnine innsoninj^. \*cry soon, 
 however, this state of lii^Hi excitation is followcil by one of de- 
 pression, in wliich no resjjonse to stinuih can be obtained. The 
 animal remains entirely motionless in any position in which it is 
 placed, in the same manner as a froj^' \vhn<e nerve centers have 
 been completely exhansted by strenuous activity. ( )n the !)asis of 
 our knowledge of the role i)laye(l 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 assumi)tion ha-- been most strikingly confinned 
 by the investigations of W'intcrstcm. li has been demonstrated 
 that recovery of the animal in a slate of heat dej)ression cannot 
 be obtained by mere cooling, but is only brought alK>ut when at 
 the same time a renewed oxygen supply is provided. I**or instance, 
 a frog is dei)ressed 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 batli artificial 
 circulation is now ap])lied in the i)reviously described manner with 
 an oxygen-free saline solution at 'Mf C, so that tlic blood is dis- 
 placed and thus the renewed oxygen sup])ly to the nervous centers 
 prevented. The animal can now be cooled and the warm sahne 
 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 
 w'wh tetanic contractions of the whole body. \\\ modifying these 
 methods of investigation to a certain extent Houdy^ has confimied 
 these results to the fullest extent. Later Wiiitrrstriu by quanti- 
 tative determinations of oxygen consumption on medusa* showed 
 that at 30-35° C, at which temperature heat dei)ression sets in. 
 the consum])tion of oxygen shows an increase of ab<»ut tliree and 
 a half times compared to that in a temperature of 11-12* C. 
 These facts show that we have in heat depression a prcK^ess which. 
 as far as its genesis is concerned. i< conipletelv anal(»gous to tliat 
 
 1 Oskar Bondy: "UntcrsuclnuiRcn iihcr dir SanrrM..»Tauf»|»cichcrung in dco Ner- 
 vcnzentren." Zeitschr. f. allpi-m. Physiol. R<J. II. 1904. 
 
242 IRRITABILITY 
 
 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, decom- 
 position must become more and more anoxydative and the well- 
 known series of processes is developed, which find their expres- 
 sion in depression. 
 
 In another direction likewise heat depression is of special 
 interest, that is, in regard to the theory of nature of the pro- 
 cesses in the living substance. According to the van't Hoff law 
 we may assume that every individual constituent metabolic pro- 
 cess, 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 in- 
 creased 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 
 
THE PROCESSES OE DEPRESSION 243 
 
 those parts in wliicli oxyj^aMi is directly reciiiired, is increased by 
 whatever means, the oxychitive processes would l>c the first to fail 
 and it must be from tliis point that tlie disturbance of the hamionv 
 in the interacting^ of tlie in(h\ idual metaboHc processes proceeds. 
 This principle which we here sec manifested in its simplest ionw 
 in the eftect of lemi)erature on oxyj^'en exchange in the f«)rm of 
 a disturbance in the correlations of the individual constituenl 
 processes based on an alteration of the mass relation and the 
 rapidity of reactions of individual members is, lunvever, not 
 merely restricted to elTects 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 nieta)>olic 
 processes, for it is ai)plicable to all nutrition and to all growth. 
 and forms one of the most important factors which intUience the 
 process of development, that is, the gradual "metachronic" altera- 
 tions in metabolism to wh.ich all living systems are subjected as 
 long as life endures. 
 
 A very extensive grouj) of depression processes is produced 
 by the action of chemical stimuli, .\mong these the processes 
 to which we apply the collective term of "narcosis" must claim 
 our special interest. As is well known, an enormous numlnrr of 
 substances of very diflerent chemical nature. sucJi as carl>on 
 dioxide, alcohol, ether, chloroform, chloral hydrate, etc., exist. 
 which, possessing the ])roperty of i)roducing cessation of the 
 vital activities in all living systems, after withdrawal of their 
 application, if it has not been too i)rol()nged or intense. jK-nnit 
 a complete restoration to normal vitality. These are the tjcnrrai 
 narcotics. Besides these there are a series of substances which 
 have a depressing effect only ui)on certain forms of living su!>- 
 stance, and which we may, therefore, term sf'ccial narcotics. As. 
 however, the particular nature of depression following the 
 ai)plication of chemical substances has hitherto Uxn closely 
 studied only in a very few instances, we arc not. at present, in a 
 position to sharply defme the limitations of the conception of 
 narcosis, a conception which originally had hardly any further 
 meaning than the production of unconsciousness by chenncal 
 means. Tn the following discussion, therefore, we shall d.--^! 
 
244 IRRITABILITY 
 
 merely with narcosis produced by the well-known general nar- 
 cotics, 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^ in his studies on narcosis. 
 
 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 ex- 
 plain from the first, can even today not be arrived at. Such a 
 theory would require the ascertainment of all primary and sec- 
 ondary alterations produced by the narcotic in the course of nor- 
 mal vital activity. For this, however, a number of minute details 
 are still lacking. Nevertheless, the careful and detailed investiga- 
 tions 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 deduc- 
 tions 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 zvith 
 a corresponding decrement of the extent of excitation. The chief 
 feature of all narcotized systems is, that in slight narcosis exci- 
 
 \ E, Overton: "Studien iiber die Narkose, zugleich ein Beitrag zur allgemeinen 
 Pharmakologie." Jena 1901. 
 
TIIF. PRDCKSSES OF DEPRESSION' 245 
 
 tating stimuli produce a greatly weakened excitation, and that 
 in deep narcosis no ])ercei)til)lc response is obtained. This can 
 readily be ascertained in the various forms of living substance. 
 According to the previous observations on the inseparable rela- 
 tions between conduction of excitation and irritability, it is self- 
 evident that with decrease of irritability there must Ik? a corre- 
 sponding decrease in the cai)ability of the conduction of excita- 
 tion from the ])oint of stimulation. This decrease in conduc- 
 tivity must, therefore, be the greater the more irritability is re- 
 duced ; that is, the deeper the narcosis, the greater must 1)C the 
 decrement undergone by the wave of excitation in its extension 
 from the point of stimulation. These facts can \)c obser\'cd in 
 the highest perfection in the nerve, and have, as we have seen, 
 been demonstrated by the investigations of ll'critjo. Dcndrinos, 
 Noll, Boruttau and Frohlicli.^ V\H)n deei)er analysis of this pro- 
 cess of depression, the next task for the investigator nuist !)c the 
 ascertainment of the special components of the metabolic activity, 
 which are depressed as a result of the narcotic. 
 
 As a consequence of the result of my investigations on fatigue, 
 the idea occurred to me to test if possibly oxygen exchange like- 
 wise undergoes depression during narcosis. The sj>inal cord 
 centers of the frog, which had served me in ascertaining the role 
 played by oxygen in the Ijringing about of the depression of 
 activity, appeared likewise a favorable object for this investi- 
 gation. Indeed, the cjuestion if consumjjtion of oxygen takes 
 place during narcosis, could be experimentally deiermined 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 si)inal 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 recjuirement of the centers 
 
 1 I have previously on another occasion briefly communtcaled the * 
 
 from the investigations ma<le at the Cottinffcn 1:' - • ■ '■ tiv c<>« ; 
 
 C(.mpare: Max / VrTi^-rn .• "Ucbcr Narkosr." 1 > m. W. t. 1909. 
 
246 IRRITABILITY 
 
 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 re- 
 place the oxygen-free saline solution containing alcohol by blood 
 rich in oxygen, containing alcohol in an amount sufficient to con- 
 tinue 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 dis- 
 posal 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 strych- 
 ninized 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 con- 
 sumed 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 indi- 
 cator 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} 
 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 notwith- 
 standing 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 
 
 \ H. Winterstein: "Zur Kenntniss der Narkose." Zeitschr. fur allgem. Physiol. 
 Bd. I, 1902. 
 
THE PROCESSES OE DEPRESSION 247 
 
 at once. During narcosis, therefore, the centers, in spxte of thcxr 
 great requirement of oxygen, lose their capability of oxydative 
 splitting up and consumption of oxygen. 
 
 After tile nielliods for aspliyxialion of ihc nene had U-cn 
 worked out and perfected the wi^li arose Hkewisc to carry out 
 for these structures an analo^'ous scries of experiments to that 
 employed for llic centers and based on the same chain of reason- 
 ing. These investigations have the advantage of essentially 
 simpler conditions. After having convinced myself l)y exixrri- 
 ments, that the results on the nerve were in coini)lcte conformity 
 with those on the spinal cord, at my suggestion I-rohlich' re|H'aled 
 and continued these experiments on a more extended scdlc. 
 A nerve was asphyxiated by the previously described method. 
 This is accomplished in the simijlcst manner by the ojH:ning 
 or closing of stop cocks in the api)aratus I have employc<l 
 which permit of pure nitrogen, or nitrogen witli ether, and tiiially 
 also oxygen with ether or ])ure oxygen !)cing conducted at will 
 through the glass chamber. If the nerve was so far depres.scd 
 in pure nitrogen that conductivity became obliterated for alK)Ut 
 two cm. of the asi)hyxiated stretch, it was then narcotized in 
 nitrogen. Following this oxygen with ether was supj)licd for a 
 time. Then the oxygen-ether mixture was displaced by one of 
 nitrogen and ether and finally by pure nitrogen. I-!ven 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. Tlic results of these investigations 
 are, therefore, com])letely in harmony with those undertaken by 
 Winterstein on the nervous centers. They were later likewise 
 entirely confirmed by similar exj)eriments of Ueaton.' .\\\ these 
 investigations furnished the proof ///(// in narcosis, living sub- 
 stance, not7vithstandi)ig eroi the greatest oxygen deficiency, is 
 not capable of producing oxydation, neither can consumption of 
 oxygen take place, ivith ivhich. after cessation of the luirrntix, 
 oxydative splitting up can be carried out. 
 
 1 Fr. IV. Frohlich: "Zur Kenntniss dcr Narkosc de« Nervcn." Zcil»chr. f. all| 
 Physiol. Bd. Ill, 1904. 
 
 2 Trevor B. Hcaton: "Zur Kenntniss dcr Narko»«r." Zritschr. f. allgrm. PhftioL 
 
 Bo. 1910. 
 
248 IRRITABILITY 
 
 Recently Warburg'^ has likewise found an oxydative depression 
 during narcosis in the eggs of the sea urchin and in the red cor- 
 puscles of geese, and the same fact has lately been also demon- 
 strated by Joannovics und Pick- for the oxydative activity of the 
 liver cells of the dog. 
 
 This fundamental establishment of the fact that narcosis pre- 
 vents 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 pro- 
 cesses. 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 nar- 
 cosis, they must then take place in the same way as in the with- 
 drawal 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 nar- 
 cosis, 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 exper- 
 iments have been made by Bondy^ with the apparatus constructed 
 
 1 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 Blutkorperchen." Zeitschr. f. physiol. 
 Chemie Bd. 69, 1910. 
 
 2 Joannovics und Pick: "Intravitale Oxydationshemmung in der Leber durch Nar- 
 kotica." Pfliigers Arch. Bd. 140, 1911. 
 
 3 Bondy: "Untersuchungen iiber die Sauerstoffspeicherung in den Nervencentren." 
 Zeitschr. f. allgem. Physiol. Bd. Ill, 1904. 
 
THE PROCESSES OF DEPRESSION 249 
 
 for this puri)ose l)y Haijlioni: Two frojrs iiiidcr uinlorm comli- 
 tions of temperature were sul)niiite<i to artificial circulation, the 
 one merely witli an oxyj^en-frec fluid, the other with the same. 
 but with the addition of .") j)er cent, of alcohol. In order to render 
 the least trace of irritability |)erce|)tible, resi>onsivily was in- 
 creased in jjoth animals by the employment of strychnine. It 
 then appeared that, on the averap^e. irritability was obliterated \\\ 
 the narcotized frog in about the same time as in the animal 
 simi)ly asphyxiated. These experiments were controlled bv intro- 
 ducing at tlieir conclusion a saline solution containing oxygen 
 into both frogs and by ascertaining the degree of recovery. In 
 like manner Frohliclr has established the same fact for the nerve. 
 The period of asi)hyxiation for the nerve in a nitrogen-ether 
 mixture is approximately the same as in pure nitrogen. Analo- 
 gous exi)criments have been carried out in am<eb.'c by Ishika'ca^ 
 Here also it has been shown that living substance l)ecomes 
 asphyxiated in narcosis and can hnally recover only when oxygen 
 is supplied. In more than a hundred exi)eriments Ishikan'a has, 
 however, obtained the uniform rouit tliat anurba? asphyxiate 
 rather sooner in narcosis than in i)ure nitrogen. The most strik- 
 ing experiments are those which Hcatoti* 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 <ie- 
 scribed, and laid the central stumi)s projecting from the chanil>cr 
 over a pair of platinum electrodes, while the stretch within was 
 likewdse placed on platinum electrodes. The nniscles 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 chaml>er was 
 then subjected to a pure nitrogen current, that in the otlwr merely 
 to one of pure air with ether, in order to test the degree of 
 
 1 Baglioni: "Bczichungcnzwislicn physiolonisclicr Wirkung und chcmi»<:hcr Conui 
 tution." Zeitschr. f. allgcm. Physiologic Bd. III. 1904. 
 
 2 Fr. ll\ Frohlich: "Zur Kcnntniss dcr Narko»c dc» Nervcn." Zeitschr. f. lilffrm. 
 Physiologic B<1. III. l'>04. 
 
 3 The experiments of Ishikaua have not as yet been pii' ' " 
 
 4 Trevors B. Hcaton: "7.ut Kcnntniss dcr Narkosc." /. <■ *tl*fm Phirwol- 
 ogie Bd. X, 1910. 
 
250 IRRITABILITY 
 
 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 capa- 
 bility of conduction returning with every test. However, re- 
 covery showed itself as less and less complete. Finally irrita- 
 bility had sunk so low that the capability of conduction disap- 
 peared entirely. At the end of the experiment as control, nitro- 
 gen was displaced by air in the two chambers and in both nerves 
 recovery took place. 
 
 In both cases recovery could only be brought about by an intro- 
 duction of oxygen. From the sum of all these experiments it 
 results that during narcosis in air the nerve, even when a suffi- 
 ciency 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 investiga- 
 tions furnish two important facts for the theory of narcosis. 
 First, that in narcosis living substance becomes asphyxiated not- 
 withstanding the presence of an ample oxygen supply, and 
 secondly, that asphyxiation occurs in the same time, or some- 
 what 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 nar- 
 cosis as anoxydative disintegration. In narcosis, therefore, 
 asphyxiation takes place zvith approximately the same or a some- 
 what 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 mam- 
 mals during prolonged anaesthesia 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.^ If, as has been shown by 
 
 1 For the very extensive literature on this subject see Reicher: "Chemisch- 
 experimentelle Studien zur Kenntniss der Narkose." Zeitschr. f. klinische Medicin 
 Bd. 65, 1908. 
 
THE PROCESSES OF DEPRESSION 251 
 
 the foregoing experiineiits, tlic f)rocesses of disintegration can 
 continue to anoxydatively take place during narcosis, the prob- 
 lem arises, if this anoxydative l)reaking down can be further 
 increased by excitating stimuli. This question has been answered 
 likewise by means of exj)eriments on the nerve made by Heaton,* 
 The two sciatic nerves of the same frr>g were drawn through 
 a double glass chamber of the f(jrm i)rcvi()Usly dc^cril)cd so that 
 each nerve lay on an electrode and with the central stump pro- 
 truding out of the chamber hanging likewise over an clectro<le. 
 As in the former instances the muscle contraction of the shank 
 again served as indicator. I'.oth nerve-^ 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 stunij) of the one nerve was continuously stimulated 
 with faradic shocks during a prolonged period, while the other 
 nerve remained at rest, h'inally. 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 nuich greater decrease 
 than that of the nonstimulated. The control made by introiluc- 
 tion of air demonstrated that both nerves recovered in an oxygen 
 supply. There ca)i, therefore, be no doubt, by comparative exper- 
 iments zve find, that durinq narcosis anoxydatirc disintegration 
 can be still further i)icreased by the action of stimuli. 
 
 In view of this knowledge of the intbicncc of narcotics on 
 oxygen exchange it nia\ be considered as a tirmly established 
 fact, that a process of dej^ression is developed during narcosis, 
 which can be classified with the large group of depressions, re- 
 sulting from deficiency of oxygen. This is followed by the imix^r- 
 tant problem, is it possible to attribute the whole scries of altera- 
 tions, produced by the narcotic, solely to this one factor? In other 
 words, is narcosis the result of acute suppression of the oxyda- 
 
 tive 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 
 
 1 Heaton : 1. c. 
 
252 IRRITABILITY 
 
 of suppression of the oxydative processes. Indeed, the disap- 
 pearance of the perceptible vital activities, the decrease of 
 irritability, the restriction of the conduction of excitation, the con- 
 tinuance of an anoxydative breaking down, the recovery on ces- 
 sation 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 investi- 
 gate 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 strych- 
 nine, 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 
 
Till-: PROCESSES OI- DI-PRESSION ::o.i 
 
 by typical strycliniiK- tetanus. If a nerve is f)lacc(l in a gas cham- 
 ber throivc:b which a mixture of nitroj^'cn and ether is allowed to 
 flow until irritability is ^^reatly decreased, and is then displaced 
 by pure nitro^^en. irritability increases more or less completely 
 according to the time which has passed from the !>eginning of 
 asphyxiation. This investigation proves that living substance, 
 even after the (leei)est narcotic depression, may recover on ces- 
 sation of the narcosis, although in an entirely oxygen- free medium. 
 Frohlich, Botidy and Heat on, by the methods of their ex|)cri- 
 ments above described, have |)roved this fact in a great numU-r 
 of instances. On the other hand. Ishikaica could not obscn'C 
 a pronounced recovery in ani<eb.'e from narcosis in pure nitrogen. 
 But it is possible that here the difference is |)crhaps merely 
 quantitative. 
 
 What position should be taken in the face of these facts? Docs 
 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? r)n closer 
 view, it will be found that this difViculty is merely apj)arent. In 
 reality it is quite possible to bring these facts into harmony with 
 the assumption that narcosis consists in a suj)|)ression of these 
 processes. If one proceeds from the sui)position that living sub- 
 stance 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 sui)pression 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 i»rimary 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 comj^lete elimination of the 
 oxygen supi)ly from without would make it necessary to assume 
 the processes occurring in narcosis are entirely <lifferent in nature. 
 The explanation that narcosis is the result of sui>i>ression of the 
 
354 IRRITABILITY 
 
 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.^ 
 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- 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 with- 
 drawal 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 con- 
 stitute 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 as- 
 sumes 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 Frohlich^ in which he compared the time required for asphyx- 
 iation to take place in the nerves, when, on the one hand, the frogs 
 had been kept several days previous to the experiment in tempera- 
 
 1 Compare lecture V; lecture VII. 
 
 2 The investigations have not yet been published. 
 
 ZFr. W. Frohlich: "Das Sauerstofifbediirfniss des Nerven." Zeitschr. f. allgem. 
 Physiol. Bd. Ill, 1904. 
 
THE PROCESSES OF DEPKi:SSK)N 
 
 '^ob 
 
 tiire of 14-40° C, and on the otlicr. in one merely a few degrees 
 above zero, lie found tliat llie nerves of the cooled froffs re- 
 quired on an averaj^'e twice or three times as long for their irri- 
 tability to sink to tlie same degree as those of the heated frog. 
 although (hiring the experiment the same tem|K-rature was pre 
 in both. It was also sliown tliat the aspliyxiation |)eri<Ml was pro- 
 longed up to a certain limit, depending uj>on 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 ner>'e 
 than in high temperatures. hVom the standf)oint that from the 
 monient of withdrawal of oxygen from without, disintegration 
 likewise takes place exclusivelv anoxvdalivelv, these facts would 
 be completely incomprehensible. When, however, the assum|>- 
 tion is made, and this would ai)i)ear to me as inevitable, that living 
 substance contains in itself a certain even though a very sligfii 
 quantity of oxygen, which in low tcmi)erature is greater, in a 
 high temperature less, the recovery from narcosis, when oxygen 
 is withheld, is not at all surprising. The comparatively rapi<l 
 setting in of depression in narcosis finds a simple explanation in 
 the violent manner in which the oxydative breaking down, not- 
 withstanding the presence of oxygen, is suddenly suppressed by 
 the flooding by the narcotic. Finally, this view receives unl«M»ke<l- 
 for support by a group of facts which at the first glance would 
 appear to bear no relation whatever to the j)rtKess of narcosis. 
 
 In a series of investigations on the mechanism of movement in 
 naked protoplasm,^ I have pointed out the role played by oxygen 
 in the genesis of the aiiKxhoid protoplasm movement. We can 
 distinguish two antagonistic i)hases in the movement of am^rlioid 
 cells, the expansion phase and the contraction phase. The first 
 consists in an increase, the latter in a diminution of the surf 
 the mass remaining the same. The expansion phase is manifesie<i 
 
 \ Max Verworn: "Die physiologische Bcdcutimic dc» Zcllkeruk." Itlu*rf» Aich. 
 
 Bd. 51. 1891. 
 
 The same: "Hie BcweguiiR dcr IcbendiRcn Sul.»lan». Fine vcrtlrifhrod i4ir«<»»<>- 
 gische Untersuchur.R dcr Contraction»cr»chcinungcn." Jena 1892. 
 
 The same: ".Mlgemeinc Physiologic." V AnflaKc. Jena 1909. In V - 
 the same theory of the contraction movements with •ome new corrro:-"* , r-. r ■ 
 
256 IRRITABILITY 
 
 in the stretching out of the pseudopods by a centrifugal outflow- 
 ing of the protoplasm into the surrounding medium, the contrac- 
 tion 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 amoeboid movement is an expression of de- 
 crease, 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 amoeboid 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 nar- 
 cotized 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 
 amoebae 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 amoebae 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 amoebae 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 
 
THE PROCRSSRS OR DRPRl-.SSK )\ 
 
 
 strctcliin^r out of the i)scu(l()i)(,(ls then U-gins anew, provided the 
 narcosis has not been loo deep or too prolonged. 
 
 C^ 
 
 n 
 
 n 
 
 B 
 
 Fifi. 62. 
 Amoeba Umax. A In normal state, li Narcotiicti hy rthrr. 
 
 Til the face of all this evidence there can he nideed no further 
 barrier to the assumption that the syinj)tonis in narcosis are a 
 result of a suppression of the oxydative i)rocesse.«i. Neverthe- 
 less, I would not at present venture to maintain that tlu* entrauvt- 
 of the narcotic into livinj^ substance produces no alterations what- 
 ever, except just this oxydative supi)ression. lH)r the fircscnl 
 it seems to me that the possibility is in no way prechide<l tlut 
 
258 
 
 IRRITABILITY 
 
 the same process, which is expressed in the oxydative suppres- 
 sion, is connected with other alterations in the Hving 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 nar- 
 cotics brings about destruction of the living system with great 
 
 Fig. 63. 
 Rhizoplasma Kaiseri. Effect of chloroform. 
 
 rapidity. Here the alterations in the optical properties of the 
 cell are of such magnitude that the changes are directly percep- 
 tible under the microscope. Bin^'^ has observed such alterations 
 in the nerve cell and looked upon them as coagulation. In uni- 
 cellular organisms these optical alterations can readily be fol- 
 lowed. If amoebae, sea rhizopods or infusoria are narcotized 
 with stronger doses of ether or chloroform, the protoplasm be- 
 
 1 Bins: "Vorlesungen uber Pharmakologie fur Aerzte und Studierende." II Aufl. 
 Berlin 1891. 
 
THE PROCESSES OF DK PRI.SSION t59 
 
 comes opaque and granulated, it a|»i)cars darker than fonncrly 
 and in many cases disi)lays a yellowish brtiwii color in trans- 
 mitted light. Cells altered in this way no longer recover afler 
 removal of the narcotic. These intense and rapidly appearing 
 alterations of protoplasm resulting from the application of 
 stronger doses of the narcotic can scarcely Ik: explained as 
 the result of a mere decrease of the oxydative prcK-esses. 1 
 would seem to consist rather, as suggested hy lUttz, as coag\: 
 in an alteration of the state of certain com|K)nents of living 
 stance. Whether these alterations arc already present in a corre- 
 spondingly 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 alx)Ut the indi- 
 vidual symptoms of the foriuer. are (juestions the deci*»ion of 
 which must be left to future investigations, llober^ indec<i 
 makes such an alteration of the colloidal state of the : 
 basis of a theory of narcosis, liut such assumptions are s 
 more than speculations, lliis is one of the joints in which our 
 present knowdedge is lacking. 
 
 Even if we restrict ourselves to the actually established altera- 
 tions produced by the narcotic in living substance, new problems 
 present themselves, the investigation of which recjuircs funhcr 
 effort. Above all, the question arises as to the finer mechanism of 
 oxydative depression. In what manner does the narcotic ni 
 cule, entering into the living substance. su|)pre.ss the oxy<lalivc 
 processes? Here there are very dilVerent possibilities to Ikt 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 loads u«i into the 
 domain of hypothesis. But without hy|>olhesis there can Ikt no 
 progress in knowledge. In all branches of scientific re^icarch. 
 working hypotheses are required for the obtainmcnt of new fact*. 
 
 On closer reflection, there are chiefly three |>ossibiIitic«i. which. 
 
 1 Hbber: "Bcitragc zur physikalischcn Chcmie dcr Krrrciing und .! w " 
 
 Pfliigcrs Arch. HH. 120. 1907. The vimc: "I>.c ; ' ' slisc h chrfm.chrn \ , »c 4« 
 Erregung." Sammclrcfcrat. Zcitschr. f. allgcm. ' ' HJ X. I'lO 
 
260 IRRITABILITY 
 
 considered from the standpoint of our present knowledge of the 
 processes in Hving substance, offer an explanation of the oxyda- 
 tive 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 Biirker} 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. Biirker 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 sub- 
 stance 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 nar- 
 cotics, as, for instance, carbon dioxide, this method of a depres- 
 sion of the oxydative processes would have no bearing whatever. 
 
 1 Biirker: "Eine neue Theorie der Narkose." Miinchener Med. Wochenschrift, 
 1910. 
 
TiiF. i'R()c'i':ssi-:s of 1)1-.i>ki:ssion 
 
 This is ratlier to be looked for in llie effects of oxydativc 
 
 sion of the aldehydes, which U'arhunf has recently observed and 
 
 investigated. Here, however, it is not a trtie nnrrn«;i< which is 
 
 concerned. 
 
 A second possihilitv of a ^u|>l)re^^l(.n ot oxvdauon woiibl \tc 
 the fixation of the molecules of the oxydable substattcfs by chemi- 
 cal or f'hysical cotnhinations in that they would lose their 
 hility of oxydative disintegration. Such a su|)|h- 
 however, likewise contain hnt few elements of pr«. ..».;. it . A- 
 has been shown, an anoxydative breaking down continues during 
 narcosis, wliich. and this we may assume with certainly, fumifthcn 
 verv different i)r()ducts in great varietv. These anoxvdalivc dis- 
 integration i)roducts, as recovery on the cessation of na- 
 shows, are removed during recovery by oxydation. If the 
 of the narcotic consisted in the prevention in spite of the pr< 
 of oxygen of the oxydation by combination, it would Ikt : 
 sary to assume that the narcotic was lK)und to a mass of ctnn- 
 pletely heterogeneous substances, a conclusion we >«h(m!f1 f*:nd 
 difficult to entertain. 
 
 If, however, depression of the oxydative processes js tuundcd 
 neither on the seizure of oxygen by the narcotic nor the fixation 
 of oxvdable substances bv the former, there remains the : 
 bility that the narcotic suppresses the transmission of oxyijeti to 
 these points of consumption. We assume that the oxygen trans- 
 mission to those points where its consumi>tion takes place is car- 
 ried out by si)ecial substances, the existence of which lias l>cen 
 established in the most varied vegetable and animal cell forms. 
 Unfortunately we only know the^e oxygen-carrying substances 
 by their effects. ( )f their chemical constitution we have no 
 knowledge, but we usually assume that the transmission of ov 
 gen occurs in tlie .same manner as in catalytic priH ' »n 
 
 another occasion I have previously exj)ressed the 
 that the narcotic sui)pres.scs oxydation by pnulucing wv 
 of the groups acting as oxygen carriers to carry out this U\ 
 
 1 IVarhurg: "Ucbcr BccinrtussnnB dcr Saucrtloffathmung. II 
 Bezichung zvir Constitution." Zcitschr. f. ; ' 
 
 2 Max I'crxvorn: "L'cbcr Narkosr." !>> ' '». 
 
262 IRRITABILITY 
 
 tion. 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 like- 
 wise, as careful investigation has shown, be in complete harmony 
 with all knowledge obtained up to the present of the process of 
 narcosis. 
 
 Here is the point where the interesting observations of Hans 
 Meyer'^ and Overton^ 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 Over- 
 ton have quite independently of each other made the same obser- 
 vation, 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 distri- 
 bution 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 
 
 1 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. 
 
 2 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 iiber die Narkose 
 zugleich ein Beitrag zur allgemeinen Pharmakologie." Jena 1901. 
 
THE PROCESSES OE PEPRESSU^V 263 
 
 connection of the law established hy .\feycr and Overt, ,. .s iih ihc 
 nature of narcosis. 
 
 The depressing effect of the narcotic would ihcn consist m 
 producing incapa!)ility of the lipoids transmitting oxygen to act 
 as carriers of the same, and it is, tlKTcfore. self-evident that the 
 effect of the narcotic would be the stronger the more readily it 
 found entrance into the lii)oids. It is i)crhaps not without interest 
 that in similar manner Mansfcld^ 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 c 
 sequence of their accunnilalion in the lipoids, the narcotic; bring 
 about asphyxiation by physically obstructing the transii. -i 
 of the oxygen from the outer medium thrcjugh 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 nuist again emphasize, 
 on purely hypothetical ground. 
 
 In consideration of these observations wc may jKrrhaps est ' 
 lish the following hypothesis of the effect of the oxydativc sup- 
 pression of narcotics: The narcotics obstruct, either by absor]': 
 or loose chemical combination the oxygen carriers of the cell and 
 render them incapable to activate the molecular oxygen. In con- 
 sequence, oxydation of the oxydable substances cannot take place 
 and disintegration occurs of an a«oxydative form. The cell 
 asphyxiates. 
 
 In conclusion I wish to warn again.st erroneous assui 
 that all oxydative depressions by chemical substances are MJr- 
 cosis and that the mechanism is the .same. It is true that a num- 
 ber of chemical substances depress the j^rocesscs of oxydation. 
 But the latter can be brought about in very varying ways I 
 would like to mention the effect of oxydative depression ^-: 
 aldehydes. To this Warbunf has added hydrocyanic acid, 
 
 1 Mattsfcld: "Narkosc und SaucrstoffmanRcl." Prtintcr* Arch. Bd. I?«. I 
 
 2 Warburg: "Ucber BccinfluMiinR dcr Saucrsloffalmunt. II ^' 
 Beziehung zur Constitution." Zcitwrhrift f. phyiiol. Chemie Bd. 71. 1911. 
 
264 IRRITABILITY 
 
 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 con- 
 stituents 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. 
 
 
H 
 
 !