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YALE UNIVERSITY

MRS. HEPSA ELY SILLIMAN MEMORIAL LECTURES

IRRITABILITY

SILLIMAN MEMORIAL LECTURES

PUBLISHED BY YALE UNIVERSITY PRESS

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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.

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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.

PREFACE

The lectures on irritability here published were held at the University of Yale in October, 1911. When the authorities of that University honored me by an invitation to give a course of Silliman memorial lectures, I accepted with the more pleasure as it furnished me with the opportunity of summarizing the results of numerous experimental researches carried out with the assistance of my co-workers during the course of more than two decades in the physiological laboratories of Jena, Göttingen and Bonn, to unite therewith the results obtained by other investigators and thus present a uniform exposition of the general effects and laws of stimulation in the living substance. I have long entertained this plan and this for the following reason:

The physiologist, the zoölogist, the botanist, the psychologist, the pathologist, have to deal, day in, day out, with the effects of stimulation on the living substance. No living substance exists without stimulation. In the vital manifestations of all organisms the interplay of the most varied stimuli produces an enormous and manifold variety of effects. Experimental biological science employs artificial stimulation as the most important aid in the methodic production of certain effects of stimulation. The number of researches in which special effects of stimulation are treated is endless. Nevertheless the systematic investigation of the effects of stimulation have, curiously enough, been strangely neglected. Although countless results of individual effects of stimulation have been studied, the attempt has never been made to establish a general physiology of the laws of stimulation and consider it as an independent problem. This circumstance induced me to systematically investigate the general laws of the effect of stimulation. In the fifth and sixth chapters of my book on general physiology the results of these studies are recorded for the first time. Since then, especially during our own researches on the general physiology of the nervous system, a great number of new facts of importance for the general physiology of the effects of stimulation have been obtained. All these results I have endeavored to combine and elucidate in the following lectures.

The text of the lectures in its present form was written in German in 1911. The English translation was made by my wife, with the help of our friend, Dr. Lodholz of the University of Pennsylvania, who also undertook the reading of the proofs. We wish here to thank him once again and express our deep appreciation of the great sacrifice of time and labor involved in this task. I am likewise much indebted to Dr. Julius Vészi for his assistance unstintingly given, especially in obtaining a number of curves. Finally, I wish to take this opportunity to render warmest thanks to the authorities of Yale University, and especially to President Hadley and Professor Chittenden, as well as to my special colleagues, for the hospitality and cordial reception extended to me in New Haven and for the pleasant hours I was privileged to spend in their midst.

Max Verworn.

Bonn.
Physiological Laboratory of the University.

CONTENTS

IRRITABILITY

CHAPTER I
THE HISTORY OF THE SUBJECT

Contents: Introductory. Earliest period. Francis Glisson as founder of the doctrine of irritability. Albrecht von Haller. The vitalists. Bordeu and Barthez. John Brown’s system. Johannes Müller and the specific energy of living substance. Rudolf Virchow’s doctrine of the irritability of the cell. Discovery of the inhibitory effects of stimulation. Weber, Schiff, Goltz, Setschenow, Sherrington. Claude Bernard studies on narcosis. Tropisms. Ehrenberg, Engelmann, Pfeffer, Strassburger, Stahl. Semon’s speculations on mneme.

Irritability is a general property of living substance but not exclusively so. Irritable systems also exist in inanimate nature. What characterizes living substances is not irritability as such, but an irritability of a specific type. The irritability of the living system can, therefore, not be studied alone, but as the properties of a living system are dependent upon each other, so this property must be considered with the others possessed by a living substance. In this sense irritability presents a problem of fundamental physiological importance. For if we could analyze the irritability of living substance to its essence, then the nature of life itself would be fathomed. The analysis of irritability of living substance offers us, therefore, a path to the investigation of life and herein lies the importance of the study of irritability.

I wish to follow this path toward the knowledge of the vital processes and to endeavor to show in these lectures what information the analysis of irritability and that of the effect of stimuli can give us of the mechanism of the processes in living substance. Before doing so, however, I wish to consider somewhat more in detail the question as to how we have arrived at the conception of the nature of irritability.

To the thinkers both in the field of physiology and medicine of ancient and mediæval times the conception of irritability was quite foreign. Even a comprehension of the nature of stimuli had not yet begun to crystallize from vague impressions of the various influences of different agents on the human being. Nevertheless they knew of such influences of the most varying kinds upon the human body. The ancients already possessed a materia medica, founded on the real or supposed influence of various mineral, vegetable and animal substances upon the organism. It was also known that heat and cold, light and darkness had an effect upon disease. They likewise believed in the influence of certain factors upon the health of man, which in reality have no effect whatsoever, as the stars and the magnet. But neither in ancient nor in mediæval times was the state of knowledge reached wherein generalizations were made from these agents, which had a real or supposed action upon the organism, and to combine these to a general conception of stimulation.

The conception of stimulation and irritability cannot however be separated.

The founder of the doctrine of the irritability of living substance is Francis Glisson (1597–1677), member of the Collegium Medicum in London and at the same time Professor in Cambridge. It is a fact also not altogether without interest, that Glisson at the same time was in a certain sense a forerunner of those who interpreted nature from a physical standpoint. Glisson as an anatomist and physiologist was an excellent observer and experimenter, but the most prominent trait of his character was his inclination to philosophic observation and analysis of nature. His “Tractatus de natura substantiæ energetica”[1] must, therefore, be considered as the chief work of his life. In this voluminous book Glisson develops an entire system of natural philosophy, which in accord with the character of the philosophy of that time is unfortunately of an absolutely speculative nature and which had hardly emancipated itself from the scholasticism of the preceding period of thought. When the ideas of Glisson are isolated from the wilderness of scholastic phraseology, the system is somewhat as follows. The basis of all existence, “substance,” has according to him two general properties, its “fundamental subsistence,” that is, the essence of its being, and its “energetic subsistence,” that is, the essence of its activity. To these are added the properties possessed in specific cases, that is, its “additional subsistence.” The energetic subsistence forms the basis of all life. Life is therefore present not only in organic nature, but in all nature which is characterized by the union of the general energetic subsistence with the special additional subsistence of an animal and vegetable nature. In other forms of life in nature the energetic subsistence is combined with other special forms of the additional subsistence. The universal essence of all life, that is the energetic subsistence, has only three fundamental faculties: the “appetitiva,” the “perceptiva” and the “motiva.” The modus is the result of a “perceptio,” but the “perceptio” is not thinkable unless the object has the “appetitus” to receive the external influence. Glisson’s doctrine of irritability is based on this conception, which he develops in a second work already begun before the “Tractatus de natura substantiæ,” but not finished until later and only published after his death. In this “Tractatus de ventriculo et intestinis,”[2] Glisson dwells in detail on the physiological properties of animal structures and develops for the first time his conception of irritability in the chapter “De irritabilitate fibrarum.” The “irritability” manifests itself in the appearance of the alteration of movement, which is brought about by external influences on the animal structure, for: “Motiva fibrarum facultas nisi irritabilis foret, vel, perpetuo quiesceret, vel perpetuo idem ageret.” The fundamental factor of this irritability Glisson attributes to the “perceptio,” which he distinguishes as a “perceptio naturalis, sensitiva and animalis.” The want of clearness produced here by Glisson’s artificial distinctions and mode of expression is in part removed if we endeavor to transfer his meaning into our present methods of thought. This distinction would then simply point out the different means by which the stimuli can reach the irritable structures. The “Perceptio naturalis” is that which today we should call “direct response” to stimulation, that is, the excitation of the fiber by artificial stimuli applied directly to the tissue. Glisson shows here, that the intestines and muscles in the body immediately after death and even when removed from the body can be stimulated to movement by means of corrosive fluids or cold. The “Perceptio sensitiva” is, according to Glisson, the excitation of the fibers by external stimuli which act on the intact body as a whole by way of the sensory nerves. The “Perceptio ab appetitu animali regulata” finally is the excitation by inner stimuli proceeding from the brain. The Perceptio naturalis is possessed by all parts of the body, even the fluids, the bones and the fat. All of them are irritable. But a “vitale” and a special “animal” irritability they do not possess to a perceptible degree. These forms of irritability belong only to the special parts of the body. Here, however, the distinctions made by Glisson, are quite vague and contradictory. In his “Tractatus de ventriculo et intestinis” Glisson sharply distinguishes the “sensatio” from the “perceptio.” The perceptio in itself is not a sensation, for although individual organs of the body are irritable, as they all possess a “perceptio,” they are not in themselves sensitive. The “sensatio,” the sensation, only arises when the external “perceptio” of the individual organs combine through the nerves with the internal “perceptio” of the brain. “Nisi enim percepto externa ab interna simul percipiatur, non est cognitio sensitiva completa.” Sensitivity is, therefore, a special faculty, that is only based upon irritability.

I have treated the views of Glisson somewhat in detail for on the one hand this seemed to me to be only due to the founder of the doctrine of irritability, and on the other we have here for the first time, although in somewhat vague and little worked out form, the discovery of a general property of all living substance, and its fundamental importance for the life of the organisms. One might, therefore, in a certain sense, date from Glisson the beginning of general physiology, and all the more so, because Glisson from the very first connected the irritability of the living substance through its possessing universal energy with the phenomena in nature generally, just as we do today two hundred years after, on the basis of the modern teachings of energy.

It might appear strange that a teaching of such fundamental importance as that of Glisson’s theory of irritability was not at once accepted on all sides and further developed. There were two reasons, however, which prevented this. Firstly, Glisson did not devote himself to his post of teacher at the University of Cambridge with any particular zeal and so consequently did not establish a school of his own, to further work out and develop his ideas. Secondly, his doctrines were so speculative and difficult to understand, his differentiations and definitions so artificial and labored, that it required the greatest effort to penetrate to his fundamental conceptions and so it happened that Glisson’s theory of irritability received attention only at a comparatively late date. Even then, of his speculative theories hardly more than the name “doctrine of irritability” was adopted. Since the middle of the eighteenth century this name, however, was destined to lead to excited controversies.

The first attempt to give Glisson’s expression “irritability” a more concrete meaning was made by Haller (1708–1777)[3]. Unfortunately, though, he confined this conception solely to muscles, in that he understood by the term irritability “the capability of the muscles to contract, when stimulated, as the result of vital force (vi viva).” He, therefore, applied the term “irritability” to that which we today refer to as “contractility.” On the other hand he applied the term contractility solely to a property possessed by other living and dead animal as well as vegetable matter, elasticity, that is, the capability to resume its original form after distortion. He makes a sharp distinction between “irritability,” which manifests itself by a contraction of the muscles after stimulation by its own vital force (vi viva), and the “sensitivity,” which is possessed only by the nervous system. “Sola fibra muscularis contrahitur vi viva; sentit solus nervus et quæ nervos acciperunt animales partes.” By confining the conception of irritability to a single living substance, the muscle, Haller’s theory represents a great regression in comparison to the correct fundamental thoughts of Glisson. This unfortunate use of the term of “irritability,” “contractility” and “sensitivity” has opened wide the gates to confusion and misunderstanding. This confusion was still further augmented by the fact that the vitalistic school of Montpelier confused the idea of vital force with that of irritability. In the works of Bordeu (1722–1776) these views are comparatively clear, if one bears in mind that he substitutes Glisson’s term of “irritability” with that of “sensitivity.” He assumes a “sensibilité générale” or a common property of all living structures, both solid and fluid. Besides this, each different part has according to him its “sensibilité propre.” Here in place of the clear conception of irritability we find one of more or less mythical nature possessing traces of Stahl’s “anima.” Nevertheless we observe here the idea that all living organisms possess in common a capability to respond to stimuli. Even though Bordeu’s differentiation of the “sensibilité propre” and the “sensibilité générale” is too artificial and the coexistence of both not justifiable, his discussion of the “sensibilité propre” shows that he is already on the track of the characteristics of the effect of stimuli which only later under the name of “specific energy” was clearly recognized as a fundamental property of all living substance. On the other hand the celebrated pupil of Bordeu, Barthez (1734–1806), accepted the existence of a meaningless vital principle, the “principe vitale,” governing all vital manifestations. The two forms of vital force of all living substances, the “forces sensitives” and the “forces motrices,” were according to his views manifestations of this vital principle. He differentiates the “force sensitive” into a “sensibilité avec perception” and “sensibilité sans perception,” using the term sensibility in the sense adopted by Bordeu and which today we, with Glisson, call irritability.

In this way serious thinkers of that time trifled with the words irritability, sensitivity, contractility, perception. This led to futile conceptions, which equalled the phantasies of the worst period of speculative philosophy and which in no way led to progress. Hence it is easy to understand that numerous attempts were made in those days to reconcile in some way these different conceptions. An explanation, which was the beginning of further development, came from England in the works of John Brown (1735–1788),[4] a man who was as talented as he was dissolute. Brown was an independent thinker, not without genius, whose knowledge in practice and theory, however, was limited. This combination in his mentality enabled him to observe the problems somewhat differently than through the glasses of the usual conceptions of that time. In direct opposition to his teacher Cullen (1712–1790), one of the leading minds in the medical school of Edinburgh, who considered irritability only as an effect of sensibility and pronounced the latter a specific property of the nervous system, Brown took the standpoint that all living substance, vegetable as well as animal, in contrast to lifeless matter, possessed a fundamental property which he designated as excitability, that is to say, the capability of being stimulated to specific vital manifestations through external factors or “stimuli,” in which sensitivity and indeed all mental processes as well as movement are interpreted as specific effects, which the “stimuli” produce on the irritable organs. This was an important advance and from a wilderness of trifling conceptions his observations led to a clearer knowledge of this subject. But Brown went even further. In his so-called “theory of irritation,” he has presented a whole system of responsivity to stimulation, which in the first chapters of his chief work he expounds with wonderful clearness. The fundamental principles here established must be accepted even today. The essential basis of this “theory of irritability” which he worked out especially for his doctrine of disease, and which has also played an important part in pathology, is the following: Every living, that is, excitable system, is continually influenced by stimuli. The stimuli consist of either external factors, such as heat, food, foreign matter, poisons, etc., or inner factors which result from the influence of the activity of one organ upon another. Only as a result of the continual action of stimuli is life maintained, in that the stimuli produce continual “excitement” in the irritable substance. The degree of irritability differs in various plants, animals, in different structures of the body, and even in the same individual at different times under different circumstances. The strength of the “excitement” depends on the one hand upon the degree of irritability, and on the other upon the strength of the stimulus. The irritability itself is influenced and changed by the action of the stimuli. If the stimuli are too strong and are of prolonged duration, the irritability diminishes as a result of exhaustion; if weak stimuli act during a prolonged time, the irritability increases. The healthy organism has a mean degree of irritability. Disease occurs when this state is altered by strong stimuli or by an absence of stimulation. Disease and health, therefore, differ not qualitatively but only quantitatively. It is here seen that we have the first attempt at a systematic interpretation of the effects of stimulation, and it is astonishing how sharply and successfully Brown has pointed out the foundations of this important field. He has in this way not only amply compensated for the great setback in the history of the teaching of irritability produced by the confusions of conceptions created by Haller and the vitalists, but also placed the whole of the physiology of stimulation on a firm foundation upon which it is possible to build further. Though it is true that many of his special theories, in particular those on nature and the origin of disease, are quite erroneous, still a just critic must judge work in relation to the period in which it was written, and I question if at the present day the science of medicine does not contain teachings which in a hundred years will also prove untenable.

Johannes Müller (1801–1858) then added an important stone to the building up of our knowledge of irritability. This was the clear recognition of the specific energy of living substances. We have already found the germ in Bordeu’s term “sensibilité propre” or “sensibilité particulière.” Brown was also of the opinion that different living objects possessed different types of irritability and that excitation of their special functions was not dependent upon the kind of stimulus acting upon them. Johannes Müller, grasping the idea hidden in this presentation, transformed it into a clear and fundamental conception. Already in the work written in his early years treating of optical illusions he says:[5] “It is immaterial by which means the muscle is stimulated, whether by galvanism, chemical agents, mechanical irritation, inner organic stimuli or sympathetic response from quite different organs; to every means by which it is stimulated and an effect produced, it responds by movement. Movement is, therefore, the effect and the energy of the muscle at the same time.” “Thus it is throughout with all reactions in the organisms.” “The sensory nerve, responding to any stimulus of whatever kind, has its specific energy; pressure, friction, galvanism and inner organic stimuli produce in nerves of sight that which is peculiar to them, light sensation; in the nerves of hearing, that which is peculiar to them, sound sensation; and in the nerves of touch, touch sensations. On the other hand, everything which affects a secretory organ produces change of the secretion; that which affects the muscle, movement. Galvanism is not superior to any other methods, of whatever kind, which can bring about stimulation.” And in his handbook of physiology Johannes Müller[6] formulates the law of specific energy for the sensory structures briefly in the following words: “The same external factor produces different sensations in the different senses according to the nature of each sense, namely, the sensation of the particular sensory nerves; and the reverse: the characteristic sensations peculiar to every sensory nerve can be produced by several internal and external influences.” This doctrine of the specific energy of the sense substance possesses an importance which extends far beyond the domain of the physiology of stimulation, for it forms the basis on which the whole theory of human knowledge must be built up, no matter how it may be constructed in detail.

As Johannes Müller already clearly emphasizes, it is here not the question of a law confined to the sense substance, but one that applies to all living substances. Every living substance has its “specific energy,” that is, its characteristic vital phenomena and this is produced by stimuli of the most varied kind. This doctrine received an extension of inestimable value for its future development by the great discovery of Schleiden, that the cell is the elementary building stone of the plant organism. Subsequently Schwann at the instigation of Schleiden made further investigations and found that this discovery applied also to the animal organism. Irritability having been recognized as a general property of living substance, it followed that, after the foundation of the cell doctrine, every cell must possess irritability and have its own specific energy. It now became necessary to study the manifestations of irritability of the cells in their specific form. Strange to say, this was done at an earlier date in pathology than in physiology. Indeed, since the time of Brown the study of irritability was furthered far more by pathology than by physiology. The chief reason for this is probably the great practical interest that the investigation of disease possesses, Brown having already quite correctly ascribed the existence of disease to the relations of the organism or its parts to stimuli. Rudolph Virchow then, after the establishment of the cell doctrine, arrived at the momentous conclusion, that disease must be considered as reactions of the body cells to stimuli. In his epoch-making “Cellular pathologie,”[7] he has carried out this idea in a classical manner. By irritability Virchow understands “a property of the cells, by virtue of which they are set into activity, when affected by external influences.” There are, however, various kinds of actions which can be brought about by external influences. But essentially there are three kinds. The effects produced are functional, nutritive, formative. The result of excitation, or if one will, of stimulation of a living part, can, therefore, according to circumstances, be either merely a functional process, or there can be a more or less intense nutritive activity produced without the function being necessarily at the same time activated, or finally, it is possible that a process of formative change may occur which produces new elements in greater or less numbers. Virchow touches here for the first time upon a question of extraordinary moment, the important bearings of which have only now begun to be recognized and seriously considered. We now know, for example, that the functional excitation can be separated to a certain degree from the cytoplastic excitation of the muscle. If the muscle is acted upon by functional stimuli, the excitation takes place mainly in the form of functional metabolism, nitrogen-free substances are broken down in increased quantities, whereas cytoplastic metabolism, which produces more profound alteration in the living substance, and which goes so far as to bring about a breaking down and building up of the nitrogen containing atom groups, is hardly at all increased. It would be an error, however, to look upon these different kinds of metabolism as quite independent. Considering the close correlation which all the phases of metabolism bear to each other, this idea cannot well be entertained. If, however, we question in what manner, for instance, the functional and the cytoplastic metabolism are linked together, we have a problem before us which does not belong to the past, but to the present and future. Indeed, Virchow seems already to have felt that a sharp division between the different phases and parts of functional metabolism in the cell does not exist, for he says: “It is true that it cannot be denied that, especially between the nutritive and formative processes and likewise between the functional and nutritive, intermediate gradations occur.” Still they differ essentially in their characteristic action and in the internal alterations which the stimulated part undergoes, depending on whether it functionates, nourishes itself, or is the seat of special growth. Disease consists of the influence of stimuli upon these physiological processes. The law of the specific energy of living substance is as clearly expressed in functional disease as it is in the physiological effects of stimuli. The pathological disturbance of function is purely quantitative, “nowhere is there a qualitative divergence.” The function exists or it does not exist. If it is present, it is either strengthened or weakened. This gives the three fundamental forms of disturbance: absence, weakening and strengthening of the function. No function other than the physiological, even under the greatest pathological alterations, exists in any structure of the body. “The muscle does not perceive, the nerve moves no bone, the cartilage does not think.” In this way Virchow rediscovered in the domain of pathology the law that his great teacher, Johannes Müller, had already clearly established in the field of physiology. But this law can no longer be applied to all pathological disturbances of the nutritive and formative activities of the cell. Here processes occur which do not consist of a quantitative change of the normal phenomena, but in the appearance of wholly foreign states, as in the case of amyloid degeneration or heteroplastic tumors. The question today and for the future arises, therefore, as to where the limits of the validity of the law of the specific energy of living substances are to be placed, a question closely connected with the other before mentioned, of the relations between functional and cytoplastic metabolism.

By means of cell pathology Virchow has laid the foundations upon which our modern medical attitude is built and which must remain essentially forever the basis of all future medical thought. Certain critics, lacking in appreciation of the interrelations between things and ignoring the safer and established knowledge, have considered, in view of the unfoldings of the researches on immunity and of serum therapy, that the time of cell-pathology was passed and must be replaced by the humoral-pathological teaching. These ultramodern critics, however, have here completely ignored the fact that, on the one hand, the life of our body is built up from the life of all of the contained cells, for life in our body exists only in the cells; and on the other, a fact not considered by them is that the components of the body fluids originate from vital activity of the cells either directly or indirectly. No result, indeed, of present serology can alter in the least degree the fact that every disease represents only a disturbance of the physiological processes of cell life of the organism and the harmony in their combined workings. Indeed the more recent observations of serology and chemotherapy are so little opposed to cell-pathology that they are in fact only possible when based on the latter. They are only comprehensible then from the unfoldings of cellular pathology.

Until quite recently all those effects of external factors on the living substance which consist in excitation, that is, in an increase of their specific vital processes, have always stood in the foreground of all researches and observations on irritability. It was gradually, however, more and more recognized that the depressing influence of stimuli played a great rôle in the vital process of the organism. Brown was acquainted with exhaustion produced by stimuli, and the discussion of “asthenic” diseases, in which the irritability was reduced, occupied an important place in his pathology. That, however, in the normal activities of the organism such depression or lessening of vital manifestation could result from the influence of stimulation, first became clear after the brothers Weber[8] in 1846 discovered the inhibitory effects of the galvanic stimulation of the vagus upon the heart.

Since then the inhibitory processes in nerves have been frequently investigated by Schiff (1823–1896), Goltz (1834–1901) and others, who gave us a theory concerning the same. Only a small number of inhibitory processes were known at that time, as for instance the inhibition of the croak reflex of the frog, or the inhibition of the grasp reflex during copulation of these animals through skin stimuli, and a few other cases. They regarded the inhibitory nervous processes as a special state, of which the inhibition of the heart through the vagus was the best illustration. Further, the Russian physiologist Setschenow succeeded by directly stimulating certain parts of the central nervous system, especially the optic lobes of the frog, in producing inhibition. It was, therefore, frequently assumed, as Setschenow did, that in the brain there exist special inhibitory centers, just as there are motor centers. This view was later shown to be untenable. It is only quite recently, and especially since Sherrington has shown that inhibition plays a part in all antagonistic muscle movements, that we have obtained a broad and more thorough understanding of the inhibitory processes in the life of the organism, and a physiological explanation of this important group of activities of the central nervous system. This inhibitory effect of stimulation, brought about by the involvement of the central nervous system in the normal organism, was studied side by side with the depressing effects of stimulation. Claude Bernard (1813–1878)[9] first discovered that the excitation of all living substance could be depressed or totally suspended through the influence of certain anæsthetics, such as ether or chloroform. By a series of experiments, as simple as they were convincing, the French scientist showed that irritability could be depressed in mimosa leaves, the growth of germinating plant seeds and the ferment action of yeast cells stopped, likewise the disintegration of the carbon dioxide in the cells of the green leaf, as well as the development of the egg cells, and also the movements of the animal organism and the sensations of man. By this means he recognized that not only does all living protoplasm possess irritability, but that it can also by means of certain substances be put into the condition of “anæsthesia,” a state dependent upon a change of the protoplasm, which he termed “semi-coagulation.” Finally, besides the more apparent processes of excitation and those less so, belonging to the group of inhibition and depression, in the last century the knowledge of the subject was greatly increased by the addition of another group, which recently in consequence of various reasons has met with particular interest. These being effects of stimuli on the direction of movements of motile organisms, it became more and more recognized that these curious manifestations of irritability, which appeared to have such a surprising likeness to the mysterious attraction and repulsion in the sphere of electricity and magnetism, occur universally in the vegetable as well as in the animal world. These movements are of the greatest biological importance for the obtaining of food, propagation, protection against disease, etc. Botanists have long known of the geotaxis of the roots and stems of plants, the heliotaxis of their leaves and flowers and of the thigmotaxis of their tendrils. Likewise the phototaxis of freely moving protistæ had been often observed, especially by Ehrenberg[10] of Berlin, well known for his researches on infusoria. Then Engelmann, Pfeffer, Strassburger, Stahl, and many others discovered and studied more carefully the facts concerning chemotaxis, thigmotaxis, rheotaxis, geotaxis, phototaxis, etc., of bacteria, motile spores, rhizopoda, and so on. The question arose if one should regard this singular behavior of the unicellular organisms as an expression of conscious sensations, discrimination or will. This view was as determinedly denied on the one hand as it was accepted on the other. Whilst even today certain scientists still consider the reactions of the unicellular organisms as a manifestation of conscious sensation, discrimination or will, others look upon them as unconscious reflex reactions of cell organism, taking place as purely mechanically as the spinal cord reflexes of vertebrates. This divergence of opinion would have practically no value for the development of our knowledge of irritability had not here, as in the case of the relations between the mental and physical processes in man, the view been entertained with more or less fervor, that at some stage or other in the chain of the purely physiological processes of responsivity, an intangible factor had been introduced which was considered as the essential “cause” of the peculiar reactions to stimuli. It is not here the place to enter into the question if, and in what degree, animal psychology may be a field of scientific research. Even if one looks upon conscious processes as effects of stimulation, in both lower animals and in man, in no case should one assume them to be factors of an essentially different nature, interrupting the chain of the mechanical reactions; neither should one consider the particular characteristic responses observed in unicellular organisms as effects of non-mechanical “causes.” As a result, a mysticism, in reality quite foreign to it, would be introduced into physiology. As a matter of fact the physiological investigations for the tropic reactions of stimuli, which have been carried out in great number since the end of the eighties, have shown more and more clearly that this peculiar behavior of unicellular organisms towards unilateral stimuli is produced by a comparatively simple mechanism. The analysis of this shows a difference in the intensity of the exciting or depressing effect produced by the stimulus. The stimulus exerts its influence unequally upon the specific activity of the motor elements of different parts of the surface of the cell body. This difference in response causes the axis of the freely moving organism to assume a different direction in which to move. It is compelled to move in a definite direction and so, in this field, the apparently mysterious attraction and repulsion of living organisms toward stimuli has, by means of the most simple analysis, been robbed of its mystical character.

Finally, I should like to touch briefly upon a view of the irritability of living substance which has recently been brought forward by Semon.[11] It assumes the proportions of a whole system and is proclaimed as a basis for the comprehension of organic phenomena. It originated with an idea which Hering[12] developed many years ago and which later was accepted by Haeckel,[13] namely that heredity is a species of memory of the living substance. Semon attributes to living substance, in contrast to non-living, a “Mneme.” By “Mneme” he understands the capability of living substance to assume, through the influence of a stimulus, a permanently altered condition. The latent alteration resulting from the stimulus he terms “Engramm.” These “Engramms” can later, however, not only be activated by the reapplication of the original stimulus, but also by other stimuli, so that the state of excitation once brought about by the original stimulus reappears. Semon calls the reproduction of the state of primary excitation by a later stimulus “Ekphorie.” A great number of other new word formations, such as “chronogene Engramme,” “phasogene Ekphorie,” “mnemische Homophonie,” “mnemisches Protomer” and countless others are supposed to serve for the better understanding of a series of special facts, chiefly in the domain of the processes of heredity. That which is termed “Mneme” and “Engramm” is not further analyzed. Semon expressly declines to discuss the kind of alterations in which the physical or chemical nature of an “Engramm” consists. Hence physiological analysis has not been advanced in any way by Semon’s new formation of words applied to long-known facts. With a series of new expressions the originator of the “Mneme doctrine” deceives himself, as well as a number of his readers not endowed with the critical faculty, into supposing that he has achieved a serious analysis. Of such, however, there is not a trace. As can be conceived, this way of treating the manifestations of life has met with no further attention from the physiological side. For indeed, what physiologist would consider that the fact of muscle responding by a contraction to an induction shock, or to any other stimulus, is sufficiently analyzed by the explanation that we have the “Ekphorie” of a state of excitation that was once previously produced by an original stimulus of some unknown kind, and of which the living substance of the muscle, in consequence of its “Mneme,” has retained a latent “Engramm”? Here the deep gulf is apparent which exists between the demands of a physiological analysis and the futile explanation of the mneme doctrine. Physiological investigation must reject such a manner of treating its problems.

With this the history of the doctrine of irritability enters into its present phase of development. To future research remains then the problem of further analyzing irritability, this common property of living substance, and finally rendering it into its simplest chemical and physical components. This last goal can only be approached very gradually, step by step. With the analysis of irritability we shall investigate life itself. In the following lectures it will be my endeavor to show how far, with our present knowledge, we can penetrate by this path into the great secret.

CHAPTER II
THE NATURE OF STIMULATION

Contents: Principles of scientific knowledge and research. Origin and meaning of the conception of cause. Cause and condition. Criticism of the conception of cause. The conditional point of view. Conception of cause. The conditional point of view applied to the investigation of life. Conception of vital conditions. Definition of the conception of stimulation.

The common problem of all scientific research is the investigation and formulation of natural laws. The assumption of a unity in the happenings and of existence in the world, in accordance with definite laws, forms the indispensable foundation of all scientific study and is fully justified by experience. Experience has taught us, as a result of innumerable individual observations, the existence of such an accordance, whereas in not a single instance has it been shown that this is not the case. We are thus justified in assuming without further discussion that every scientific research, every new problem which we approach, is likewise founded on this unity of occurrences in accordance with natural laws. Only on the firm basis of this assumption has scientific investigation a purpose, and every success is a new proof of this. There is an unanimity of opinion concerning this among scientific investigators in all fields.

Not such complete agreement, however, exists in regard to the question by what symbols of human thought and speech these laws can be described in part as well as in toto, so that existing laws can not only be fully and conclusively defined, but at the same time without the use of superfluous terms. According to Ernst Mach, thought is an adaptation to facts. Our speech is simply a method of expression of our thoughts and indeed the most satisfactory form we have. We must, therefore, use those symbols which are most closely adapted to facts as the most precise expression of these existing laws. What forms of expression have we?

It might appear that a discussion of this fundamental question has not a close connection with our special subject of physiology of stimulation. This, however, is not the case. Indeed, it is an irremissibly previous requirement not only for the elucidation, but also for the understanding itself in this particular field. We could not come to a clear understanding in this field without such analysis. The interpretation of the unity of being and happenings in accordance with natural laws, which today is widely accepted in the scientific world as the only exact one, implies the assumption of a “causation” according to which things are explained by the law of “cause” and “effect.” I[14] have already on various occasions taken the opportunity to criticise this view and to show the error and confusion to which it leads. I should like here to enter somewhat more in detail into the reason for this criticism. It is particularly directed against the scientific use of the term “cause” on the basis of our best-known theoretical principles. It is clear that all scientific observations and explanations are founded on experience. Can it be said that the conception of “cause” originates from experience?

We can say with absolute certainty that the conception of cause dates from prehistoric times. Its beginning reaches back to the stone age, at least to neolithic, possibly to palæolithic culture. This is demonstrated by the careful reconstruction of these prehistoric races based on a critical comparison of the remains of their culture with that of primitive races living today. The ideas of these primitive races show an inclination to an extraordinary degree to explain all happenings in the world anthropomorphously. All happenings in surrounding nature are given the same origin as the activities of man himself. To man, on this plane of phantastic religious speculation, all events in nature appear as acts of the will of invisible powers, which, having originally proceeded from the souls of dead human beings, think, feel and act exactly as he does. This anthropomorphic conception of the occurrences in the surrounding world is one of the many conclusions which ensue from the supposition of an invisible soul, which can be separated from the body. It was this conception which gave the impetus for the transition of human thought from the era of the naïvely practical to the era of the theoretical spirit in that far removed age. In this anthropomorphic transference of personal subjective impulses of will to the objectively observed events of the surrounding world, lies the origin of causal conception, which since then has been generally used as the explanation of the happenings in the world. One cannot assert that the formation of the conception of cause is purely a product of experience, but rather a result of naïve speculation. Even if a later evolution of human thought shows a continued endeavor to dismantle the conception of cause of its primitive trappings and to modernize, as it were, its outer appearance, we still find today many inner components clinging to it, which do not agree with the strict demands of critical scientific exactness, demands which must particularly be made concerning a conception which has been given such fundamental importance in theoretical knowledge.

I wish to observe here, however, that the conception of cause, even though more or less unconsciously so, is still the remains of a part of the old anthropomorphic mysticism carried over into our own times. This shows itself especially in the conception of force, which is nothing more than a form of the conception of cause. Force is the cause of movement. One has here in anthropomorphic manner transferred the action of the will of man, which produces movement of the muscles, into lifeless nature. The force of the sun attracts the earth, that of the magnet attracts iron, etc. In short, one has introduced a mysterious unknown factor instead of being content with the simple description of facts, such as Kirchhoff[15] has advanced in the field of mechanics. Although of late natural science has also dispensed more and more with conception of force as a means of explanation, it is still today not wholly done away with. That which applies to the conception of force is likewise true of the conception of cause.

Another point concerning the application of the conception of cause seems to me, however, to be of much more importance, namely that a single cause is held responsible for the taking place of a process. One endeavors to explain a process in general by seeking for its “cause.” The cause being found, the process is considered as fully accounted for. This idea is not only widely spread in everyday life, but is even found frequently in natural science, especially in biology, although here, it should be known, the processes are decidedly more complicated. The search for the “cause” of development, for the “cause” of heredity, for the “cause” of death, for the “cause” of the respiration, for the “cause” of the heart beat, for the “cause” of sleep, for the “cause” of disease, etc., was for a long time and frequently even today a characteristic of biological investigation. As if such a complicated process as development, death or disease could be explained by a single factor! In reality, one has obtained very little as a result of the analysis of a process by discovering its cause; and in addition the false impression arises that through the finding of this one factor the process has been definitely explained. It has been generally recognized in the natural sciences in recent times that no process in the world is dependent upon one single factor and attempts have been made to give this fact more consideration.

It is the custom at the present time to hold the view that every process or state is brought about by its cause, but that a series of conditions are also necessary to the production of the process. Such a view, however, which considers that two different factors existing at the same time are necessary to the accomplishment of every happening or state, namely, the cause and the conditions, leads to new difficulties, for then, upon a more exact analysis arises the question: Which is the cause and what are the conditions? It is very soon found, however, that this does not permit of any strict differentiation, as the two conceptions can not be sharply separated. This difficulty was brought to my notice with particular force during an animated discussion with a friend and colleague about twenty years ago, which I have always remembered. I had observed at that time the dependence of pseudopod formation of amœboid cells on the oxygen of the medium, and had found that the expansion phase of protoplasmic movement, that is, the extension of pseudopods, the centrifugal flowing of the protoplasm into the surrounding medium and with this the enlargement of the surface of the cell body, only takes place when oxygen is contained in the surrounding medium and never occurs in its absence. Being at that time wholly under the influence of the conception of cause, I believed that oxygen was the cause of the formation of the pseudopods. To this my friend made the objection: “Yes, I quite acknowledge the fact of the dependence of the formation of pseudopods on oxygen, but what informs me that the oxygen is really the cause? It might be simply a necessary condition.” This objection led to a long debate, which ended, however, without our being able to agree. We were not in a position to distinguish between the conception of cause and that of condition, and at that time the idea did not occur to us to emancipate ourselves from the conception of cause deeply implanted in us as a result of our training. In fact, one is greatly embarrassed if one attempts to sharply distinguish by a definition the conception of cause and that of condition. A condition is a factor on which a state or a process is dependent for its existence or its taking place. To the conception of condition belongs, besides the factor of relation, that of necessity. Every condition is necessary to the existence or taking place of this state or process. Without the condition in question the state or process does not occur. The same must be demanded for the conception of cause. No state exists, no process takes place, without its cause. The cause then has itself the specific character of a condition, it is itself a condition. Has it perhaps then some specific peculiarity in contrast to the other conditions, which would give it a prominent place? Experience teaches us that nothing, that is to say, no state or process in the world, is dependent upon a single factor alone. There are always numerous factors which bring about the state or process. Would it be possible to distinguish which of these particular conditions is of the greatest importance?

First of all, it must here be taken into consideration that the importance of a condition is not one which is capable of increase or decrease, for the simple reason that necessity, which forms an essential component of the conception of cause cannot be varied. A factor cannot be more than necessary for the existence of a state or the taking place of a process. If, however, it is less than necessary, then it is not necessary at all, and the state or process exists also without it, that is to say, the factor is not a condition. In other words: all conditions for a state or process are of equal value for its existence, as they are all necessary.

If one attempts to prove by means of concrete examples this statement obtained by purely logical deduction—a control which, considering the experimental nature of modern thought, never should be neglected even in the simplest of reasoning—it might appear that an objection could still be made against its general validity. From various instances it might be concluded that there are conditions, which as such are not absolutely necessary for a state or process, but can be replaced by other factors. An example may serve to make this clear. I pour diluted hydrochloric acid on powdered carbonate of sodium, and carbon dioxide is set free. The addition of hydrochloric acid is here a condition for the liberation of the carbon dioxide. Without the presence of the hydrochloric acid the process does not occur. Nevertheless I can substitute diluted sulphuric acid for the hydrochloric acid. Here it would appear that one condition can be replaced by another. But one must not be deceived. A closer observation soon shows that the process has not been sufficiently analyzed if we look upon the addition of hydrochloric acid as a condition for the liberation of carbon dioxide. It is not the presence of hydrochloric acid or sulphuric acid, as such, which is a condition for the process, but rather the separation of the sodium atoms from their combinations with the oxygen in the molecule of the carbonate. This reaction can occur as a partial component in very different complexes of processes. Or to quote another example, taken from the subject with which we are especially here concerned. I allow an induction shock to act on the nerve of a nerve muscle preparation of the frog. The muscle contracts. The electric stimulus is the condition for the muscle contraction. But I can substitute for the induction shock a mechanical stimulus by sudden pressure of the nerve. The muscle again contracts. The analysis again shows that the induction shock as such was not the condition for the muscle contraction, but the excitation of the nerve which it produced and which is conducted as a specific impulse to the muscle. This excitation of the nerve can, however, be induced by very different kinds of processes, namely, by all processes which possess in common the condition that they suddenly increase certain disintegration processes in the living nerve substance. Indeed, the further analysis of the whole process shows in addition that the nerve impulse as such likewise does not form a condition for the contraction of the muscle, but it first of all produces the necessary condition for the muscle contraction by suddenly greatly increasing certain chemical processes, which take place in the living substance of the resting muscle. The nerve impulse can, therefore, also be replaced by other processes, if only these contain the condition for an increase of disintegration of the muscle substance, as in the case of the direct stimulation of the curarized muscle, where the influence of nervous impulses is totally eliminated. In a further analysis of this process we should penetrate even more deeply into the differentiation of the individual constituent processes and the isolating of the special conditions on which each link in the chain is dependent.

Such an analysis then shows us the following: Every thing, every state or process, is a complex of numerous components, of which one always conditions the other in the manner that the individual conditioning components are themselves in their turn contained as constituents of other complexes and are conditioned here again by other factors. These factors in themselves as such are not directly necessary to the taking place or existing of the special component and can, therefore, be replaced by others. Closer observation shows that there is a constant interdependence between all things in the world. Every thing in the world is indirectly dependent upon every other, although often so remotely that we are not able to trace the connection. Absolute things, completely isolated and independent of others, do not exist in the world. In observing and studying complexes individually, we must not forget that we only think of them as isolated from the great eternal coherence, from which they are in reality not separated. The conception of condition, however, only then has meaning, if we refer to it in connection with the direct dependence of one factor upon another. Nevertheless if we understand by conditions those which are connected by multitudinous intermediate components, then we would render the conception of conditions useless. For if every thing in the world were the condition for every other, the conception of relation would lose its value in special states or processes. Should the conception of condition have a meaning in regard to a certain state or process, then we should only look upon that part of a complex upon which the other is directly dependent as a condition. When, however, we meet with a factor for a process or state, which can apparently be replaced by another factor, we have not carried the analysis far enough. Upon deeper penetration into the subject, it is found that the essential condition for the process, which exists, is a component common to both factors, one of which in consequence can replace the other.

It is the task of all scientific research to penetrate deeper and deeper into these relations, these connections and the order of succession of states and processes and to separate them into their individual components, and in this way gain a more thorough knowledge of the constancy of existence and happenings in the world.

This analytical process, it is true, only advances very gradually, and we must accept for the present, especially in the complex biological processes, that a whole complexity of members appear conditioned, and that a complex aggregate is a condition of the whole process. We are not yet in the position to define the special components of the constituent processes. It is only step by step that we are able to differentiate the necessary from the accessory parts in these complexes. However, we are here only concerned for the present with a purely theoretical question and we may be permitted to say: If we maintain that the conception of condition has as an integral part the element of necessity and of relation to a special thing, then there are no substituting conditions. For then every condition for a state or process is of equal value. There is no justification to give more prominence to one condition and place it in the position of being the “cause.”

If the cause is elevated, then it is done from some superficial motive. This is confirmed by a glance at the practical use of the term cause. The cases in which the cause is always at once clearly recognized and named without doubt or hesitation are those where a new factor is added to an already existing system of conditions, which bring about a process. When such a process is produced, the last added condition is considered as “cause.” A shock acts on an explosive body, the body explodes: the shock is considered the cause. An induction shock acts on a muscle, the muscle contracts; the induction shock is looked upon as the cause of the muscle contraction. To regard only the last added condition as being of especial importance to the taking place and the explanation for a process is, however, a standpoint which could satisfy only the most superficial of observers.

In a scientific investigation such methods should play no rôle. For to every careful observer it must appear quite clear from the beginning, that the previously existing conditions have as great a value for the taking place of the process and its explanation as that last added.

The induction shock would not have produced the characteristic effect had not the other conditions been already previously combined, had not certain special atoms in the molecule of the explosive combination in consequence of former processes assumed quite a peculiar labile position, had not in the evolution of the muscle in the growth and metabolism certain combinations been formed, and certain chemical processes taken place.

Therefore if I do not analyze these previously existing processes and the conditions brought about by them in the system of the explosive substances or the muscle, and simply know the condition added last, then I have learned nothing of the process itself, have explained nothing. The time of application of a new condition does not justify in any degree the assignment of a dominant position to a factor. But more: in many cases there is not a question at all of the addition of a process to an existing state, but rather of the simultaneous interference of two or more processes. Several conditions can appear at the same time. In other cases the sequence of the combination can be reversed. Which then is the cause? Has the process several causes, or has it no cause? Here one sees plainly to what absurd results it leads if time alone is used as a basis of the conception of cause. To illustrate this I return to the case of the liberation of carbon dioxide from carbonate of sodium. I place anhydrous carbonate of sodium in a beaker and add hydrochloric acid. The carbon dioxide escapes. Here the addition of hydrochloric acid would be assumed to be the cause of the freeing of the gas. Then I put hydrochloric acid in a beaker and add carbonate of sodium. The same process takes place, but now the addition of carbonate of sodium would be considered the cause for the formation of gas. Now I put both simultaneously into a beaker. Again the same process. Which was now the cause? Has the process now two or has it no cause at all? Finally I put anhydrous carbonate of sodium and hydrochloric acid in ether solution into the beaker. The formation of gas does not take place, and yet both causes for this formation of gas are present, the carbonate of sodium and the hydrochloric acid. Only when I add water to the mixture does the formation of carbon dioxide take place. Here water would be considered the cause. Hence every condition would be in succession the cause for one and the same process. Under some circumstances the same process would have several and in others no cause at all. It is scarcely necessary for further comments upon the value of the conception of cause for the scientific explanation of a state or process. If we do not seek to introduce into exact science the antiquated symbols which have become useless and belong to a primitive phase of development of human thought, there cannot be a moment’s doubt that a strict scientific analysis in whatever field of investigation it may be carried on can consist only in the study of all the conditions concerned in a state or process. If this is done, then the work of exact research is accomplished. Further problems do not exist. The use of superfluous terms or symbols for the definition of things would be in opposition to the fundamental principle, already brought forward by Kirchhoff, especially for mechanics, namely, that of formulating comprehensively and in the simplest manner the processes which take place in nature.

At first glance one might be tempted to find an incompleteness in the observation and description, when a conditional standpoint is adopted. It might be thought that conditionalism were a purely formal method of observation, and only considered the interdependence of things, but not the properties, the nature of the objects themselves. Regarded more closely, however, it is seen that this objection does not hold good. For what is a condition?

A condition is in itself a thing of quite distinct properties. The properties of a thing are, however, determined by the specific combination of conditions which characterize the thing. The conditions by which a thing, that is to say, a state or process, is determined, are identical with its being and nature; in other words, they are the thing itself. Purely formal relations without essence would be altogether an absurd fiction not in accord with reality, and which even the science of mathematics does not acknowledge, for we cannot have a conception without concrete content, just as in nature we do not find a form existing independently of a thing. Every thing is equal to the sum of all its conditions and depending upon the uniform constancy in accordance with natural laws is solely determined by its conditions. The problem of all scientific research consists wholly in the ascertaining of the conditional interdependency.

A state or process is solely determined by the sum total of its conditions. A state or process is identical with all of its conditions in totality. From this it follows that equal states or processes are always the expression of equal conditions and wherever unequal conditions exist, unequal states or processes will result; and further, a state or process is completely investigated when the entire number of its conditions is ascertained.

This fundamental statement of conditionism should be engraved over the portals to the entrance of every scientific investigation.

That there is not the least difficulty in presenting scientific observations strictly according to these principles of conditionism, and that one can perfectly well do without the causal conception in a scientific description, I have shown by a concrete example, namely, in the fifth edition of my “General Physiology.” In the whole volume the conception of cause is only mentioned in one place, where its theoretical value is criticised, elsewhere not at all, and yet I do not think that any one will miss this conception, and indeed, if their attention is not especially called to the fact, even notice the omission.

These principles of an exact conditional investigation must also guide us in the analysis of the processes of stimulation. The process of stimulation is especially apt to tempt one to employ the old conception of cause, for it belongs to that group of processes which originate from an already existing system by the addition of a new factor. An electric stimulus acts on the muscle. The muscle contracts. The stimulus is considered the cause of the contraction. But what would I explain if I were to prove that the stimulation is the cause of the contraction?

The history of physiology shows us that this subject has advanced long since far beyond the stage of being satisfied with such an explanation. Today the process would only then be fully investigated if we knew the entire number of its conditions and had traced the dependency of the individual partial constituents of the whole complex process upon one another. For this, however, it is essential that we study the conditions already existent in the entire system previous to the action of the stimulus.

That which we describe with the word life is an exceedingly complex process. If we analyze life, it is found to be composed of an immense number of separate constituent processes, each one being conditioned by the others. These constituent processes are the vital conditions. A vital process occurs, and must occur, where and when the whole sum of vital conditions is realized. It is identical with the sum total of the vital conditions. If only one condition is absent, then life does not exist. It is then expedient to reserve the expression “life” for the entire sum of the vital conditions. When we speak of the individual constituent processes as “vital processes” in the plural, we must bear in mind that in reality each is not in itself life. Only the whole complex “lives,” not an individual constituent of the same. Living substance is rather the whole system, and not a constituent part of the same, not a piece of protoplasm, not a nucleus and not a specific protein combination in the cell.

A property of this system should receive our consideration at this point. It is a characteristic of every system in the world, namely, the fact that a system is not isolated from its surroundings. It is a deception resulting from the selective action of our sensory organs, if we consider the bodies as separated and isolated from their environment. This deception disappears upon further analysis and when we assist our organs of sense, which only respond to certain parts of the whole process, by experimental methods of investigation. Our experience then shows us that an isolated system does not exist, but that there are instead everywhere connections which extend further and further into the infinity of the world. An organism is consequently no delimitated system and the vital process cannot, therefore, be sharply separated from the processes in the medium. We cannot draw a sharp line between vital processes and say: on the right we have factors which are necessary for the maintenance of life, and on the left factors which are not necessary. The conditional connection between individual processes extends to the entire world, and likewise a great series of constituents, each influencing the others, extend from the medium into the organism. The nature of our sense perception, and consequently the knowledge derived therefrom, is such that we are obliged to arbitrarily take into consideration merely fragments from the endless interdependence of all things in the world, and so we separate the vital conditions of the organisms from their surrounding factors, as though they were independent. A conscientious theoretical analysis requires that we should never forget that in reality such an isolation does not exist. Only with the recognition of this can we distinguish for practical purposes between internal and external vital conditions. In such a differentiation the internal vital conditions which compose the living system conceived to be isolated, are the organs, the tissues, the cells, the protoplasm and the cell nucleus, and within the protoplasm and the nucleus the arrangement and quantitative relations of certain substances, such as proteins, salts, water and the thousands of special components with their interactions and continued alterations. On the other hand, the external vital conditions, which act on the periphery, are the conditions of the surrounding medium, as foodstuffs, water, oxygen, static and osmotic pressure, temperature, light, etc. But this distinction has only a practical value for the study of the organism as an independent system. Theoretically it is as impossible to make a sharp distinction between internal and external vital conditions, as to distinguish between the vital conditions generally and the more remote conditions of the environment. All these conditions form a widely branching system of factors of which one is conditioned by the other reaching continually from the interior of the vital system into the surrounding medium, so that on the periphery of the system it cannot always be said whether or not a component still belongs to life. Considering these circumstances we can roughly for the present define the conception of stimulus as follows:

A stimulus is every change in the vital conditions.

The most essential point in this definition is the relation of the conception of stimulus to that of vital conditions. These relations, however, call for a brief explanation. Here again the conditional method of observation saves us from error, for it would be wrong to place the conception of stimulus and vital conditions in contrast to one another, one excluding the other. On the other hand, this method of observation shows that the stimuli are likewise only conditions, but conditions producing certain changes in the vital system. If a stimulus acts, that is, if there is any change whatever in the vital conditions, the whole complex of life in consequence of the dependency of the constituent parts upon each other is also changed, and a new state of living substance occurs. Stimuli are, therefore, also only vital conditions, but vital conditions for new vital manifestations. The relation of one given state to another, forms an indispensable point in the understanding of vital conditions as well as that of the stimulus. The stimulus becomes a vital condition for the new state which it produces. It is only a stimulus relatively to the original state, which previously existed. The essential point, therefore, in the conception of the stimulus is that of alteration. An example will serve to make this clearer. If Amœba limax are bred in a hay infusion they appear in countless masses. Observed in water in a watch glass they show at first the well-known form of Amœba proteus with short, broad, lobate pseudopods. (Figure [1], A.) After a period of rest, however, they gradually assume the characteristic elongated limax form. (Figure [1], B.) In this shape they constantly move about. But if I add to the water only a faint trace of diluted solution of caustic potash, the amœbæ first assume the shape of a ball (Figure [1], C), and then after a time, stretch out long, pointed pseudopods, which give them the characteristic form of Amœba radiosa. I have observed them for several hours at a time. (Figure [1], D and E.) They remain permanently[16] in this form. They move in the same manner as Amœba radiosa. They draw in one pseudopod, stretch out another and float freely in the water in contrast to their limax state, in which they are always attached to some support. The long, pointed, often threadlike pseudopods, yield to every movement of the water, bending in consequence like whipcords. In this example the amœbæ under the vital conditions existing in tap water have limax form. The vital conditions undergo a change by the addition of a solution of caustic potash, which acts as a stimulus. The consequence is a reaction, in which the animal assumes radiosa form. By the action of the stimulus a new state of the living substance is produced, and remains as long as the solution of caustic potash is contained in the medium. The solution of caustic potash is, therefore, a stimulus for the state of the vital system, which is manifested in the limax form, whilst for the state of the system which shows itself in the radiosa form, it is a vital condition. If I place the amœbæ of the radiosa form once again in tap water, they assume the proteus and then the limax form. The withdrawal of the solution of caustic potash, the presence of which is a vital condition for the radiosa state, acts as a stimulus, which results in a transition of the vital system to another state. By altering the medium I can at will bring about this change of form in the same individuals. In this way one and the same factor can figure as stimulus and vital condition, according to the state of the vital system on which it acts. Whilst its addition acts as stimulus in the one state, its withdrawal acts as a stimulus in the other state, which it has produced. The same fact is shown by the well-known example of Artemia salina, which on being placed in fresh water changes into Branchipus stagnalis and, when again introduced into sea water, becomes once more Artemia salina.

Fig. 1.

These facts show clearly that some stimuli can also be considered as vital conditions. In the absence of certain stimuli, life could not exist for any length of time. In the highly differentiated cell community of the animal organism, for instance, as a result of the coexistence of the cells and the tissues, many parts have forfeited in a measure their independence. An example of this is the skeletal muscle, which, in the absence of impulses from the nervous system, reaches a low level of chemical change and energy transformation. Here the nervous impulses which act as momentary stimuli, are also in the course of time indispensable vital conditions. Without them the muscle would gradually become atrophied from inactivity. The same applies to all other tissues of our bodies. The functional stimuli are for them at the same time vital conditions. These vital conditions undergo fluctuations and interruptions but at each alteration from a given state they act as stimuli.

Stimulus is every change in the vital conditions. But is this definition complete? Are we really justified in regarding every alteration in the vital conditions as a stimulus?

In considering this question, one point must not be omitted. This is the fact that one of the chief characteristics of the vital process is, that it undergoes continuous change. A vital process involves not simply an alteration in metabolism or transformation of energy in the sense that the same chemical processes continuously reoccur in the same manner. Such a view could only be admissible for the observation of living substance during a limited period. An investigation over a long period of time shows rather that every living system alters as long as it exists, although this alteration is very gradual. The constituent processes, in short, continuously undergo metabolic change both quantitative and qualitative in nature.

If we observe the occurrences in a living system at various moments of the cycle of life, we will find that the condition differs qualitatively at each period. The progressive alteration of the system is such that every state of living substance conditions another, by which it is followed. No state can permanently exist as such. Every state is the product of the preceding, as it in turn conditions its successor. Consequently the relations of the system to the surrounding medium also undergo alteration, even when the external factors themselves in no way alter. That which today is still a vital condition, is not in consequence necessarily one tomorrow. These progressive changes exist continuously until the death of the system takes place. They characterize life. It is development, and life cannot exist without development. Death is only the last phase of development. The individual constituent processes of metabolism gradually change to such a degree that they can no longer work harmoniously together. Then the chain of processes is interrupted at one point or another. The system develops into death or, on the other hand—and this, as Weissman especially emphasizes, is realized in the case of unicellular organisms—a corrective process takes place, a process of cell division by which the original state of the cell is restored and development begins anew and in a similar manner.

Ought we to designate these constant alterations in the inner vital conditions as “stimuli”? Usage in this connection has already answered in the negative, by applying to them the word “development.” And this use is in a certain sense justified. Let us imagine an organism or any other object for the purpose of investigation as isolated from its surroundings. This conception, which we have already stated, proves untenable on closer analysis, but it, however, is based on the nature of the methods of human observation and is indispensable for practical use within certain limits. Then the inner vital conditions belong to the organism, the external to the medium. They differ in so far that the external vital conditions can exist permanently without alteration, that is, independently of the development of living systems, whilst the inner vital conditions of every living organism continuously and progressively undergo alteration. In this sense, but only in this, there is evidently a difference between the inner and outer vital conditions, which permits a separation of the two groups. But we should always bear in mind that this separation cannot be sharply defined. On the same basis we assume that the organism for purposes of study is separated from its surroundings as an independent system, which leads us in consequence to contrast the alterations in the internal with those in the external vital conditions, in which we designate the first as processes of development, the latter as stimuli. This distinction, as all differentiations and separations in nature, gives us only a practical working basis.

In this way we confine the conception of the stimulus to all alterations in the external vital conditions of a living system, considered as isolated. This view does not exclude the fact that stimuli can also occur and act within an organism. If a nervous impulse is conducted from the cerebral cortex through the pyramidal tract to a skeletal muscle, this impulse acts upon the muscle cells as a stimulus. Although the explosion of the impulse is an alteration within the body, nevertheless, as far as the muscle is concerned, it may be looked upon as an external vital condition, therefore as a stimulus. As the conception of stimulus involves the relation to a given state, it likewise involves at the same time the relation to a given living system, upon which it acts from the exterior.

What is the value then of all this theoretical discussion?

In presenting the conception of stimulation from a conditional standpoint, I desired to show what difficulties stand in the way of a theoretical isolation of a fundamental conception in the field of physiology, which indeed is used in our practical research work at every step. “Natura non facit saltus.” I wished to demonstrate that the sharp separation of the conception of stimulation, like all artificial divisions which we make in nature, must always contain an arbitrary note, as in reality isolated systems do not exist in the world. I wished to show that, for this reason, the conception of vital system, the conception of life, the conception of vital conditions are not sharply defined. I wished likewise to show that as a necessary consequence of this fact a sharp separation of the conception of stimulation, which can only be made in relation to that of vital conditions, cannot be maintained theoretically. I wished to show further that there is no sharp line of division between inner and outer vital conditions, and that we cannot, therefore, make a strictly theoretical distinction between the conception of stimulation and that of the processes of development. I wished to show that, for these reasons, we must not expect from the conception of stimulation, as we understand it, anything beyond its possibilities. But finally I wished also to show that, whilst fully conscious of and with due consideration of all these difficulties, it is possible to work out a definition of stimulation which is of great practical working value. The definition in short is: “Stimulus is every alteration in the external vital conditions.”

This definition gives to the conception of stimulation its most complete, that is to say, its generally applicable and simplest form. The great importance from a methodical standpoint of this definition of stimulation for the research of life is evident. Our whole experimental natural science always employs for investigation of any state or process the same method: the state or process to be observed is studied under systematically altered conditions. By stimulating the living substance it is brought under changed external conditions. A systematic employment of stimulus is, therefore, the experimental means for the research of life.

CHAPTER III
THE CHARACTERISTICS OF STIMULI

Contents: The quality of the stimulus. Positive and negative alterations of the factors which act as vital conditions. Extent of the alteration in vital conditions or intensity of the stimulus. Threshold stimuli, sub-threshold, submaximal, maximal and supermaximal intensities of stimulus. Relations between the intensity of stimulus and the amount of response. The Weber and Fechner law. All or none law. Time relations of the course of the stimulus. Form of individual stimulus. Absolute and relative rapidity in the course of the stimulus. Duration of the stimulus after reaching its highest point. Adaptation to persistent stimuli. Series of individual stimuli. Rhythmical stimuli. The Nernst law.

We have found that stimuli are alterations in the external vital conditions and that the irritability of living substance consists in the capability to respond to stimuli by changes of the vital processes. It now behooves us in the interest of experimental research to investigate the relations between the nature of the alterations in the external vital conditions on the one hand, and that of the alterations of the vital process on the other; that is to say, to systematically study the effects of stimulation on the living organism. For this purpose it is above all necessary to become acquainted with the almost countless numbers of alterations which take place in the external vital conditions of an organism, and to create a systematic scheme of stimulation which differentiates and presents in comprehensive order those various elementary factors which, among the innumerable varieties of stimuli, would prove effectual. For this purpose it is necessary to select the various factors which are involved in an alteration of the external vital conditions.

The first of these factors is the quality of the stimulus. The external vital conditions are, in short, a series of chemical factors, such as foodstuffs, water and oxygen; the presence of a certain temperature; the existence of a certain light intensity; the existence of a definite static pressure; and finally the presence of an equal osmotic pressure. The stimulus according to its quality can be differentiated into chemical, thermal, photic, mechanical and osmotic varieties. To these must be added other forms of stimuli not ordinarily operative, for instance, many uncommon chemicals, and certain kinds of rays. The form of stimulation, par excellence, which has acquired the greatest importance for the experimental investigation of life, is electricity. In its manifold forms it permits, as no other, of such fine gradations of intensity and duration that it has become in the hand of the physiologist an invaluable means of research.

Alterations in those factors which act as vital conditions compose the great mass of physiological stimuli which act continuously on every living organism. The first point to be considered in every alteration is its direction. The alterations produced by stimuli may be of two different kinds, either positive or negative. The quantity of foodstuffs, water or oxygen, in the surrounding medium, can undergo an increase or diminution; as may the temperature, intensity of light, the atmospheric and osmotic pressure. The strength of the electric current, which may be applied, can also be regulated. In accordance with the definition of stimulation already referred to, we must consider these alterations, whether negative or positive, as forms of stimulation. Now the question arises: Is this point of view justifiable? Should one also consider, for example, the lessening or total removal of a vital condition as a stimulus? Should one consider the removal of water or oxygen, cooling or darkening, as a stimulus? It has, in point of fact, been occasionally attempted not to regard these negative deviations as forms of stimuli. These observers permitted themselves to be led by the dogma, that only that which produces an excitation, that is, an increase of the processes in the living substance, should be regarded as a stimulus. Such a limitation of the conception of stimuli would only result from the one-sided consideration of an all too limited circle of facts. Considered from the point of view which results from a broader range of experience, this narrow view becomes untenable.

In the first place it does not follow that only positive fluctuations of a factor, acting as a vital condition, result in excitation in the existing vital processes. The withdrawal of water produces a diametrically opposite effect. A muscle, from which water has been removed, if exposed to dry air or placed in a hypertonic salt solution, shows violent excitation, which manifests itself in great increase of irritability and development of fibrillary contractions. The breaking of a constant current which has for a long time flowed through a nerve or muscle also elicits a momentary excitation. Further, the abrupt removal of light may also bring about stimulation. To cite an example from the physiology of the single cell, I should like to call to your attention the interesting observations of Engelmann[17] on the Bacterium photometricum, of which he was the discoverer. When the field containing these organisms is suddenly darkened, all the individuals contained in the drop immediately dart forward for some distance, at the same time, as is usually the case, quickly rotating around their own axis, and then after a moment of immobility, swim on quickly in another direction. An analogous responsivity has also been shown by other single cell organisms, as has been pointed out by several observers and especially by Jennings.[18] In all these cases the excitation was produced by a lessening or total withdrawal of the factors which act as vital conditions; and even those who take the standpoint that only such factors are to be considered as stimuli which produce an exciting effect, are compelled to regard these alterations as stimuli, in spite of the fact that they are negative variations of external vital conditions.

But further, the restriction of the term stimulation to those alterations which increase the course of the changes in the living substance involves the observer in still greater contradictions. It can easily be shown that one and the same factor in one and the same form of living substance has now an exciting, now a depressing effect on the vital processes. This fact can be readily demonstrated[19] by means of the infusoria Colpidium colpoda, which can be grown without difficulty in a hay infusion. A number of individuals in a drop of fluid may be placed in a warm stage and observed under the microscope; one then sees that at room temperature they swim about by moving their ciliary processes at a definite rate. Now if the temperature is raised to about 35° C., the ciliary movement becomes enormously increased. The infusoria swim madly through the field of vision. They are in a state of violent excitement. The increase has, therefore, acted as a strong, exciting stimulus. But if one allows the temperature to further increase only a few degrees the ciliary movements are suddenly greatly retarded. The infusoria now swim sluggishly through the field of vision and finally remain stationary. In this case the increase in the temperature has had a depressing effect. If the infusoria are not quickly removed, the depression is followed by death. Should the increase in temperature be regarded in the first instance as a stimulus, and not as such in the second, in which the temperature rises only a few degrees higher? Here the change in the vital conditions concerned is in both instances positive. In all cases of overstimulation we are confronted by the same question. Nevertheless it is not at all necessary to refer to such strong or even life-endangering stimuli for the observation of these conditions. In this connection I would like to cite an even more striking instance and which is of special interest for the understanding of the phenomena in nerve centers. If the posterior spinal roots of a Rana temporara are severed, and the eighth root stimulated with a faradic current, whilst the musculus Gastrocnemius of the same side is connected with a writing lever, one obtains, as Vészi[20] has found, at the moment of the beginning of stimulation a contraction of the muscle. The faradic stimulus has, therefore, produced an excitation reflexly. If instead of the eighth the ninth posterior root is stimulated, the result obtained is also an excitation of the muscle. In this case, however, the excitation in the form of a tetanic contraction lasts for some time, provided that the stimulation is not at once stopped. If now during tetanic stimulation of the ninth root the eighth is at the same time stimulated, with a strength of current equal to that which previously brought about contraction of the muscle, instead of an increase and a strengthening of contraction there is, on the contrary, an inhibition which continues throughout the time during the stimulation of the eighth root. If the stimulation of the eighth root is discontinued, the tetanic response of the ninth root reappears. If, on the other hand, the faradic stimulation of the ninth root is interrupted and the eighth root now again stimulated, one obtains once more, as in the beginning, with each stimulation a contraction of the muscle. This fact is illustrated by the accompanying tracings. (Figure [2].) In this investigation undertaken in the Göttingen laboratory it was further shown that a faradic current of the same strength and the same frequency had at one time an augmenting, at another an inhibitory effect, and these effects could be produced alternately at will. Should the faradic current at one time be called a stimulus, at another not? It is here clearly shown to what absurd consequences it leads if the conception of stimulation is limited solely to the cases in which an external factor has an exciting effect; and yet an immense number of instances of a like nature could be cited to show the untenability of this view.

Fig. 2.

Lower thick line shows duration of stimulation of 9th root; upper thick line that of 8th root.

It follows from this, that it is altogether impracticable to define the stimulus itself in relation to the nature of the effects which the stimulus has upon the substances in the living system. One can only appreciate the nature of stimulation in relation to the vital conditions and without considering the nature of the action of the stimuli on the living substance. It is true that every stimulus is followed by an alteration in living processes, but this is to be expected when one clearly understands the nature of vital conditions. A stimulus is in all cases an alteration in vital conditions and, in that each of the vital conditions is necessary for the continuance of life, it follows of necessity that every alteration in the vital conditions, so intimately connected with the living processes, will also be followed by an alteration in the processes occurring in the living system. In short, response is produced. Nevertheless, a definite alteration of an external vital condition, depending upon the state of other vital conditions, that is, according to the state of living substance at the moment, can produce quite opposite effects. Although it may appear expedient to include in the conception of stimulation in given instances, distinctions between stimuli according to the nature of their effects upon the living substance, in all cases the conception must under all circumstances be so formulated that it comprises all alterations in the external vital conditions, either positive or negative, that is to say, an increase or decrease, an augmentation or diminution in those factors, acting as vital conditions.

Besides the quality there is another highly important factor to be considered in the study of every alteration in the living process, namely, its amount. The chemical concentration of the medium, temperature, amount of light, the static and osmotic pressure may undergo more or less variation. The electric stimulus can rise from zero to great intensity and from great intensity can fall to zero. The extent of the alteration determines the intensity of the stimulus. In relation to the intensity, a differentiation of stimulation has been introduced, which is not dependent upon the absolute intensity of the stimulus, that is, upon the extent of the alterations in the external vital conditions, but the intensity of the response that can be observed. One refers frequently to threshold stimulation, to stimulation beneath the threshold, to submaximal, maximal and supermaximal stimulation. Such a classification is in many ways very valuable. It is not only of practical value for the establishment of definite intensities of stimulation, but also for the study of the state of irritability in the living organisms.

The threshold of stimulation furnishes roughly a standard for the degree of irritability of a living system. The threshold value of a stimulus is then that degree of intensity which is just sufficient to bring about a perceptible response. The threshold of stimulation is low, that is, the irritability is great, when the intensity of the threshold stimulus is small; the threshold is high, that is, the irritability of a system is small, if the intensity of the threshold stimulus is great. All intensities of stimuli beneath the threshold are sub-threshold stimuli. Here a point must not be overlooked, which in older physiology did not generally meet with sufficient attention. From the fact that the sub-threshold stimuli produce no apparent effects, the wrong deduction must not be made, that they have no effect whatsoever. The conception of the threshold of stimulation originated in the field of muscle physiology and that of the special senses. Here the indicator of the response is, on the one hand, contraction of the muscles, and on the other, conscious sensation. There was a great temptation to consider the stimulus altogether ineffectual, if it produced no conscious sensation or no contraction of the muscle. Today with our finer and more sensitive indicators for the study of the alterations in the living substance, we know in reality that sub-threshold stimuli, which produce no apparent effect in the living substance, can have an effect in reality.

I will call your attention later to the fact that these sub-threshold stimuli play a very important rôle under certain conditions in the activities of the central nervous system. It only depends upon the sensitivity of our special senses, or the indicators used for this purpose, as to whether the alterations can be observed or not. The conception of the threshold of stimulation, therefore, has meaning only when used in relation to a certain indicator. The threshold of the same living system may be different for different indicators. When we use the term threshold we must necessarily know the indicator employed in its determination. The threshold stimulus produces only barely perceptible effects. The amount of response in most living substances increases with the intensity to a certain limit. If this limit is reached, that is, if the response is maximal, the stimulus of the weakest strength necessary to produce this result is termed the maximal stimulus, whereas all intensities lying between the threshold and the maximal stimulus are termed submaximal stimuli. If the intensity of the stimulus is increased above that of the maximal, the response, as in the case of the muscle, does not increase, and therefore one could say that all intensities above the maximal could also be called maximal stimuli.

In realty, however, the response to stimuli of different intensities is never equal, even though it may appear so, when measured by an indicator, as for instance, the height of the maximal muscle contractions. This is clearly shown, for example, when the electrical stimulus is increased far beyond that intensity which is necessary to produce maximal effect. Injury is thereby produced, which is manifested, for instance, in the muscle contraction by the nature of its course and also by its height. One is, therefore, justified in a certain sense in calling the intensities of the stimulus, which are above the value which barely produces maximal contraction, “supermaximal stimuli,” notwithstanding this is logically far from being a happy expression. The term “maximal stimulus,” then, is limited to the intensity of the stimulus which just produces a maximal effect. I wish to point out this distinction between maximal and supermaximal stimulus, as there is often a lack of clearness in the use of these terms.

In that the nomenclature of intensity of stimulation is based upon the intensity of response, the question arises as to the relation between the intensity of stimulus and the amount of response. It is well known that this question has met in one special field of physiology with a very detailed and comprehensive treatment. I allude to the teaching concerning sensation. Ernst Heinrich Weber[21] first called attention to the relation between increase in sensation and that of the stimulus in the case of the sense of touch. His observations, which have been formulated into “Weber’s law,” have been the object of animated discussion. A presentation of this law is the following: “The amount of pressure necessary to produce a perceptible increase of sensation always bears the same ratio to the amount of the stimulus already applied.”

If in accordance with Ziehen[22] we designate the relative increase in pressure to that already applied, which is necessary to produce a perceptible increase in sensation, as the threshold of relative differentiation, we can formulate the law in the simplest way thus: The relative threshold of differentiation is constant. Fechner,[23] who indeed attempted to apply this law, applicable to the sense of pressure, to all the other special senses, has given us a mathematical formula, based on the assumption that the just perceptible increase of sensation has the same value at all levels. By this assumption he was able to establish for the first time a relation between the intensity of sensation and that of stimulus, for it follows that “the sensation increases in intensity in arithmetical progression, whereas the intensity of the stimulus increases in geometrical progression.” From this Fechner has worked out a psychophysical formula, which today is generally termed the Fechner law. This is the law: The intensity of sensation varies with the logarithm of the intensity of the stimulus.

Soon the Weber as well as the Fechner law had been extended over the whole field of sensation and stimulation. In this connection Preyer[24] has formulated his “myophysical law,” which states that there is the same relation between strength of stimulus and the intensity of response of the muscle as is laid down by the Fechner law for stimulation and sensation. Pfeffer[25] has found that Weber’s law applied also to the relations of the chemotaxis of bacteria, to the intensity of the chemical stimulus, and likewise the attempt has been made to show that all living substances respond in the manner laid down by the Weber-Fechner law. Unfortunately the innumerable investigations in this field have shown more and more clearly that it is not possible to formulate a general mathematical law, which strictly fixes the relations of the intensity of the stimulus and the intensity of response. Even in the field of the physiology of the special senses many voices have opposed the general application of the Weber and the Fechner law. Lotze, G. Meissner, Dohrn, Hering, Biedermann and Löwitt, Funke and numerous other investigators have already demonstrated for some decades, partly by means of critical inquiry, partly by experimentation, that these laws are not strictly valid. Above all these experiments have shown that logarithmic relations are not tenable and likewise are not applicable to very strong stimuli. The assumption made by Fechner, that is, the acceptance that all barely perceptible increases of sensation have an equal value, has been set aside as incorrect, and with this his mathematical formulation within those boundaries of intensity of the stimulus, in which the Weber law has proven itself valid, must also be abandoned. That which we can say today with certainty concerning the relation between the intensity of stimulus and the amount of response is as follows: A law generally applicable to the relation between the strength of the stimulus and the amount of response cannot be mathematically formulated. For a great number of living systems the rule which holds for the intensity of stimulation within certain boundaries is the following: With increase of the intensity of stimulation the response at first increases rapidly and later more and more slowly.

This rule of course only applies within the boundaries of the intensity between the threshold of stimulation and maximal stimulus. The interval, however, between these intensities varies considerably in different living substances. In this connection there are several forms of living substance which call for our special attention. In these the surprising condition seems to exist, that the interval between the threshold and the maximal stimulus is zero; that is, every stimulus which acts at all always produces a maximal response. Bowditch[26] first observed this behavior in the frog’s heart and this has also been confirmed by Kronecker.[27] The induction current produces, as Bowditch says, either a contraction or nothing. If the former, it is the strongest contraction which can be produced by an induction shock at the given time. Here for the first time a constancy of response was discovered which has been termed the all or none law. McWilliams[28] has later verified the same fact for the mammalian heart. Gotch[29] has also arrived at the same conclusion in connection with the nerve. He states that “the comparison of submaximal with maximal responses shows that although there is an obvious difference in the amount of E. M. F., there is little or no difference between such time relations as the moment of commencement, the moment of culmination of E. M. F. and the rate at which E. M. F. disappears.” Further: “the rate of propagation of the excitatory wave is the same whether this is maximal or submaximal.” He likewise assumes that the “all or none law” is applicable to the constituent fibers, and that the variations in the strength of response with weak and strong stimulation are brought about in the first instance by stimulation of a few, in the latter by a greater number of fibers in the nerve trunk. The same conclusion has been reached by Keith Lucas[30] for the single cross-striated fiber of the skeletal muscle, founded on the fact that by direct stimulation of a bundle of curarized muscle fibers, the contraction only increases inconstantly and not regularly with the increasing intensity of the stimulus. This is only comprehensible if one takes into consideration that, with the increasing intensity of the stimulus, a greater and greater number of fibers are stimulated. Keith Lucas[31] came to the same conclusion in the case of the muscle stimulated indirectly through the nerve. He, therefore, sees, because of the nature of the response of the single muscle cell, no difference between heart muscle and skeletal muscle. The “all or none law” applies to the individual muscle cells of both kinds. The difference between the heart and skeletal muscle, according to him, lies in the fact that in the heart the individual muscle cells in their totality stand together as conductors of excitation, whereas in the skeletal muscle the individual muscle fibers are separated, as far as conduction of excitation is concerned, by the sarcolemma. Finally, the recent investigations of Vészi[32] with strychnine poisoned ganglia cells of the posterior horns of the spinal cord, have made it appear probable that “the all or none law” can be applied likewise to the individual ganglion cell. He draws this conclusion not only from the fact that all reflex contractions of a muscle of a strychninized frog are maximal, whether they are produced by weak or strong stimuli, but also especially because of the loss in the strychninized spinal cord of the capacity of the summation of irritability. The normal spinal cord does not reflexly respond at all to weak single stimuli, but responds to equally weak faradic stimulation very readily. Therefore, the threshold lies very high for the individual induction shock and very low for faradic shocks. But these differences are equalized in the strychninized frog. This seems intelligible, when we assume that the strychninized cell responds to every stimulus, to which it responds at all, to the maximal extent which is permitted at that moment by its stored up energy, otherwise the excitation would necessarily be summated by faradic stimulation.

Such are the instances to which one has up to the present applied the “all or none law.” The question if, as a matter of fact, such a condition has ever been realized in any living substance has until now found no final answer. Most authors, who accept the validity of the “all or none law” for certain living substances, do so with a certain reserve and speak only of the possibility or probability of such behavior. The subject has, however, as will be shown later, a great and even vital interest in another direction. For this reason I should prefer to postpone the treatment of the same to a later occasion. Here I wish simply to say, that if the “all or none law” is valid in a strict sense for certain structures, then there exists no general constancy of the relations of the intensity of the stimulation and the amount of response, applicable to all living organisms.

We will now return from this digression concerning the relations between the intensity of the stimulus and the response, to the further characterization of the properties of the stimulus. Besides the quality, the direction and the intensity of every alteration in vital conditions, an equally important factor is the duration of the alteration. The time relations, under which a deviation of the external vital conditions takes place, present immense and manifold variations in nature. In many cases the change is very complicated, as for instance, the alteration of the static pressure or the temperature under the influence of air or water currents, the osmotic pressure or chemical factors in diffusion currents, and the light intensity produced by the movement of clouds. These very irregular alterations have practically little interest for us. Here we are concerned rather with the differentiation of the time alterations of the processes of the simplest fundamental types, which are of importance in studying the course of the reaction. For it is of such simple elements that the complicated and irregular alterations of the above-mentioned kinds are composed.

The simplest form of an individual change in the external vital conditions would be a regular and constant alteration of intensity which can be graphically represented as a straight line, wherein the intensities are the ordinates and the time the abscissa. (Figure [3], A.) A regularly rising pressure would, for instance, represent a stimulus in its simplest form. But such forms of stimuli are only very rare in nature and are also experimentally very difficult to produce. It is, for example, not easy to give the electrical stimulus, so much used for experimental purposes, this form. Fleichl and v. Kries have only accomplished this by means of complicated apparatus. The usual form of the individual stimulus is not a straight line, but a logarithmic curve. (Figure [3], B.) The alteration hardly ever progresses with equal rapidity from its beginning until it reaches its highest point, but as a rule, with decreasing rapidity. This is the usual course of alterations of concentration, also of chemical and osmotic stimuli, of changes of temperature and of electric stimulation.

Fig. 3.

The rapidity of alterations in vital conditions has quite an important influence on the development of the response to stimulation. It is well known that if a constant current, which reaches its highest intensity rapidly, is permitted to act upon a muscle, the effect differs from that following the application of a current of the same intensity but in which this is reached very slowly. In the first case there is a sudden strong twitch, in the second none at all. In spite of this there can be no doubt whatever of the current in the last case being effective. That the muscle is also excited when the current is slowly increased is shown by the contracture, which grows more and more plainly perceptible with the increasing intensity of the current and in higher intensities by the so-called Porret’s phenomenon, which consists in a curious wave-like movement of the muscle-substance. In reference to the rapidity of the alterations in the factors which act as stimuli, the behavior varies greatly. Many stimuli because of their nature never have a steep ascent or descent of intensity, as, for instance, alterations in the concentrations of soluble substances, that is, chemical or osmotic stimuli; likewise temperature variations may be mentioned. They always act relatively slowly. On the contrary there are forms of stimuli which have now a rapid, now a slow, ascent or descent of their intensity, such as the photic and mechanical stimuli. Finally, there are other stimuli that nearly always show a very abrupt change of intensity, such as the electrical form.

The most important factor to be considered in producing the response to variations of intensity, is not the absolute rapidity, but rather the relative rapidity; that is, the rapidity in relation to the characteristic rapidity of reaction of the particular living substance concerned. The rapidity of the reaction to stimuli is very different in various forms of living substance. On the one hand, we have forms reacting very quickly, as the nerve and the striated muscle; on the other, those which respond very slowly, such as a great number of unicellular organisms. Between these are a great number of living substances which, as far as the rapidity of the reaction is concerned, occupy intermediate positions of every varying degree. It is clear that the adequate stimuli for slowly reacting substances must be those having also a slow change of intensity; for quickly reacting, those having a rapid change of intensity.[33] If a nerve muscle preparation is simulated with the single induction shock, the “break” as well as the “make” shock has effect. But even here a difference is noticeable. The “make” shock has a weaker effect than the “break” shock. This difference is due to the difference of abruptness in its course, which when the current is made is less than that of opening, for, when the current is made, the ascent of the primary current is retarded by the extra current flowing in the opposite direction, whereas, when broken, with the fall of the intensity of the primary current, the extra current in the primary coil flows in the same direction. In consequence of this there is a perceptible difference in the rapidity of the alteration of the “make” and “break” shocks. (Figure [4.])

Fig. 4.

Course of induction shocks. 1 and 2 make and break of the primary current. 1₁ and 2₁ make and break induction shocks. (After Hermann.)

Now slowly reacting forms of living substance, such as certain foraminifera, in which the extended pseudopods are stimulated with single induction shocks, the break as well as the make shocks are wholly without effect, as both take place far too quickly for the slow responsivity of these organisms. I have made such observations on various forms of foraminifera of the Red Sea, on Orbitolites, Amphistegina and others. The movement of granules in the pseudopods is not influenced by the induction shocks in the least. It also continues without interruption when the pseudopods are extended. Even with the strongest induction shocks at my disposal I could not induce them to contract; the faradic current, also, the intensity of which I found quite unbearable, remained utterly without effect.[34] These two extreme cases, the nerve and the foraminifera, show plainly that the effect of a stimulus is not produced by the absolute rapidity of the increase of intensity, but is solely influenced by the relative rapidity of the same.

Fig. 5.

A further point for consideration in the duration of an alteration in a vital condition in producing a stimulant action is the length of time the stimulus remains after reaching its highest point. In the forms of stimuli occurring in nature the duration of the alteration after reaching its highest level can vary considerably. The stimulus may remain indefinitely at a certain level, when this is once reached. (Figure [5], A.) The alteration likewise persists. This would be the case, for instance, with the changes of concentration in the transfer of an organism from fresh into sea water. The alteration can also, however, immediately after attaining its highest level, return, so that the original state is at once reestablished. (Figure [5], B and C.) Here it is a case of a quick deviation in the external vital conditions. A sudden jar would be a case in point. Between these two extremes we have all variations in the duration of all natural and experimental forms of single stimuli.

Now we arrive at the question: Has a prolonged stimulation really a prolonged effect? This question might seem superfluous, as from a conditional standpoint it is self-evident that every alteration in any one of the conditions of a system is followed by an alteration in the system. But this very question played an important rôle in older physiology and led to prolonged discussions for the reason that a special case was taken into consideration in this connection, which at that time was not clearly understood. Du Bois-Reymond,[35] as a result of his investigations on the nerve muscle preparation of the frog, formulated a law of nerve excitation, according to which it is not the absolute value of the intensity of the constant current which produces an excitation of the nerve and contraction of its muscle, but an alteration of the intensity from one moment to another. The more rapidly these changes are produced, the greater is the excitation. His arguments were based upon the fact that a contraction can only take place on the “making” or “breaking,” or by rapidly strengthening or weakening the constant current; it is possible to subject a nerve muscle preparation to a current of considerable strength without a muscle contraction resulting, provided it is slowly increased. One might be disposed to conclude from this that the constant current, when showing no fluctuations, has no stimulating effect whatsoever. Should this observation be carried even further and the attempt made to extend it into a general law of excitation by assuming that the effects of stimulation are only produced by variations in the intensity, not by its continued duration, one would commit the error of judging the occurrence of a stimulus only by the unsatisfactory criterion of an abrupt muscle contraction. Today we know with positiveness that a continued effect also exists during the uninterrupted flowing of a constant current in nerve or muscle, though much weaker, however, than in the case of the excitations produced by sudden fluctuations of the intensity. This is shown in the nerve by an altered excitability, which continues at the poles during the whole duration of the current. In the region of the anode the excitability is diminished, in that of the cathode it is increased. An excitation can also be demonstrated which extends from the cathode through the nerve, which can easily be detected by sufficiently delicate methods. Among other effects of prolonged stimulation is that of cathodal contracture, which remains localized in the region of the cathode and which excitation persists as long as the current continues. This permanent excitation can be particularly well observed in the single cells of the rhizopods. If a constant current is allowed to flow through an Actinosphærium,[36] the straight, smooth, ray-shaped pseudopods of the cell body at the moment of “making,” show evidence of contraction by being drawn in, particularly those directed towards the anodic and in less degree also those towards the cathodic pole. This excitation, greatest at the time of “making” of the current, though diminishing rapidly in intensity during its continuance, remains, however, to a less degree, and leads to a progressive disintegration of the protoplasm on the side towards the anode, which lasts until the current is again broken. (Figure [6].) Thus even though there can be no doubt, on the one hand, that the effect of stimulation, which appears at the moment of the entrance, is to produce alterations, which develop very rapidly, and that by a continuation of this state there is a more or less rapid fall to a low level; on the other hand, it is just as certain that the alterations in the living system persist throughout the duration of the changed external conditions, or to put it more concisely: the effect of the stimulus never wholly disappears unless the changes in the external vital conditions return to their original state.

Fig. 6.

Actinosphaerium eichhornii. Four stages showing the progressive influence of a constant current. Protoplasmic disintegration at the side toward the anode.

But more, an effect of the stimulus cannot indeed take place without a certain duration of stimulation, which is related in its turn to the rapidity of reaction of particular living system. This can be much more readily observed in more slowly reacting substances. Fick[37] first proved this fact on the muscle of the Anodonta. I have also been able to demonstrate the same fact in the slowly reacting sea rhizopods[38] by the use of the constant current. When Orbitolites is stimulated with a constant current lasting approximately the tenth of a second, no response is seen in its extended pseudopods, which are directed towards the poles. The same is the case if the induction current is employed. Only when the constant current of the uniform strength lasts approximately .05 seconds, a barely perceptible response occurs, manifested by the sudden stoppage of the centrifugal flowing of granules in the anodic pseudopods, which, however, after the lapse of one to three seconds continues again unaltered. Should the duration of the constant current be still further prolonged, typical symptoms of contraction are seen being manifested by a heaping up of the protoplasm in the pseudopods in the form of spindles and balls, whilst the protoplasm flows in a centripetal direction towards the central cell body. (Figure [7].)

Two effects can be realized by the alteration in the living system as the result of prolonged stimulation. Either a new state of equilibrium is established by the prolonged action, or sooner or later death develops. In considering both results, however, we will ignore for the present the fact that every living system in the absence of such prolonged stimulation is always in a state of change, i.e., development. Only with this restriction can an equilibrium of the living system be spoken of.

Fig. 7.

Orbitolites complanatus. A—Before stimulation. B—Under influence of a constant current.

It is sometimes the case that under the influence of a stimulus a new equilibrium is developed, which may remain as long as the stimulus persists. This most frequently occurs as a result of weak stimuli. That which is usually termed “individual adaptation” belongs in this category. Likewise some of the natural and artificial immunizations may also be included. The continued stimulation in such cases of adaptation as we learned before in the example of Amœba limax and radiosa or Branchipus stagnalis and Artemia salina becomes a vital condition for the living substance in its new state.

The other result, namely, that of death ensuing sooner or later, is most frequently produced by stronger stimulation. Through the effect of the prolonged stimulation, the change in the living system is so great that all harmonious interaction of the various processes of life become after a time impossible. The disturbance of this equilibrium after a longer or shorter time becomes so great that life ceases. By far the greater number of all diseases furnish examples of this kind. Disease is nothing else but reaction to stimulation. Should a constant stimulus persist and if the development of a new equilibrium of this system is not established, the result is premature death.

In most cases, as, for instance, the nerve impulses which move toward an organ, or better still the electrical stimuli as used for experimental purposes, it is not a question of a permanent but of a temporary alteration in the external vital conditions. The stimulus starts, then ceases after a longer or shorter period. In this way there is added to the deviation at the start also the alteration at its termination. The latter takes place with different degrees of rapidity, in a manner analogous to that of the initial alteration, and can bring about response. With this the curve of the duration of the course of the stimulus becomes somewhat more complicated and in consequence a like effect is observed in the response. The “making,” duration and “breaking” of the constant current furnishes the example of this type. The “making” of the current being a quick alteration calls forth a strong and sudden excitation (in the muscle contraction); the continuation of the current maintains weak excitation of equal intensity (in the muscle a continued contraction) and the “breaking,” being a sudden alteration, is followed again by a stronger excitation (in the muscle a contraction). The duration of the change can, however, be so short that its intensity does not remain at two periods of time at the same height, but instead the ascent of the intensity is immediately followed by its descent to zero. Induction shocks of short duration, the duration of which have been observed more in detail especially by Grützner,[39] offer typical examples. Here a single effect of the stimulus results from the rise and fall of the intensity curve. Hence the induction shocks as momentary stimuli are universally used for experimental purposes.

In contrast to the single stimuli, which find their ideal in induction shocks, another form of stimulation should receive our attention, namely, the series of stimuli which produce a rhythmical alteration of vital conditions. These show among their complex combination of simultaneous and successive actions of their single stimuli relatively the simplest and most easily understood regularity in their effects. They are of particular interest, because they develop in the normal physiological happenings of the animal body in the form of rhythmical intermittent impulses of the nervous system.

Here again it is self-evident that with regard to the course of response, we must first consider the character of the single stimulus of the series, and this must be done from all those standpoints already here discussed. However, a new factor is met with here, that is, the frequency of the single stimuli of the series, or that which has the same meaning, the duration of the intervals between them. This is a feature upon which the result of stimulation depends in a very high degree. But here, too, however, it is not a case of the absolute frequency of the single stimulus, but simply of the relative frequency in regard to the rapidity of reaction of the particular living system. I should like to remark here that it is of greatest importance whether the interval between the two single stimuli of the series is sufficiently long or not to allow the living system time to completely recover from the effect of the preceding stimulus. In the cases, for instance, where we have recovery, we have the same rhythm of stimulation as that of response. When recovery does not occur, interferences of the response are developed, which are of great physiological importance, with the analysis of which we shall later on find occasion to occupy ourselves in detail. The physiological example for these stimuli is the rhythmical discharge of impulses of the nerve centers; the physical method, which is most widely used for experiments, is the faradic current.

It is apparent that the question of frequency must again be combined with all those factors previously discussed in connection with the single stimulus. In consequence another complication arises and with this another point must be taken into consideration, namely, the fact that the duration of the single stimulus in a series undergoes alteration by increasing frequency beyond a certain limit. Beyond this limit the duration of the single stimulus must become less and less. As the result of the fact that stimulation is, as we have seen, dependent on the duration of stimulus, it is evident that, depending upon the rapidity of response of the living system, sooner or later the rhythmical stimulation must become ineffectual. Nevertheless, this effect of shortening the duration of the single stimulus can be compensated by a corresponding increase of its intensity. In this connection Nernst[40] showed a very simple relation for induction currents of higher frequency of interruption, which furnishes a law according to which such a compensation takes place. In conjunction with Barratt he found, namely, that the intensity must increase proportionately to the square root of the number of single stimuli if the threshold value of the stimulus is to be maintained, that is, I : √m = const., in which I is the intensity of the current and m the frequency of interruptions. The limits of the validity of this law cannot at present be conclusively established.

This exhausts the small number of elementary factors concerned in the course of the stimulation, and which are of importance in considering its effect. The combination of the different varieties of these single factors, that is, the nature, the direction, the intensity, the rapidity, the duration and number of alterations in the external vital conditions of the organism produce the enormous variety of effects of stimulation which we observe in the living world.

CHAPTER IV
THE GENERAL EFFECT OF STIMULATION

Contents: Various examples of the effects of stimulation. Metabolism of rest and metabolism of stimulation. Metabolic equilibrium. Disturbances of equilibrium by stimuli. Quantitative and qualitative alterations of the metabolism of rest under the influence of stimuli. Excitation and depression. Specific energy of living substance. Qualitative alterations of the specific metabolism and their relations to pathology. Functional and cytoplastic stimuli. Relations of the cytoplastic effects of stimuli to the functional. Hypertrophy of activity and atrophy of inactivity. Metabolic alterations during growth of the cell. Primary and secondary effects of stimulation. Scheme of effects of stimulation.

In the foregoing lectures we have had occasion to touch more or less often on the subject of the effects of the stimuli. This was the case, however, only when it appeared necessary to obtain a systematic knowledge of the stimuli and the differentiation of the individual factors. We will now proceed to consider the effect of stimulation in a more systematic manner. The conditional method of observation, however, will remain our guide.

We have already pointed out the relations between the conception of stimulation and that of vital conditions, now we will consider that of the effect of stimulation with that of vital processes. Nevertheless, the effect of stimulation being a manifestation of the vital process is not, therefore, in opposition to the latter as such. Hence the question presents itself as to the connections between vital process and the effect of stimulation.

When we study the motile flagellate infusorium Peranema swimming undisturbed in water, we observe that the swimming movements are absolutely regular in character. The elongated cell body remains unaltered in shape. The long flagellum is extended in a perfectly straight line in the axis of the body and only the extreme end lashes with regularity through the water (Figure [8], A). There is majestic grace in this perfect uniformity of motion. The picture suddenly alters the moment the Peranema is influenced by the slightest jar. The whole flagellum at once executes a few violent movements (Figure [8], B), the body draws together, soon stretches itself again and swims immediately after, in another direction, with the same majestic calm as before.

Fig. 8.

Peranema. A—Swimming in non-stimulated condition. B—Mechanically stimulated at the end of the flagellum.

Another instance. A number of fertilized eggs of the sea urchin are placed in a watch glass in sea water. The temperature of the water should correspond with the mean temperature in which the animals live in the sea, averaging about 15° C. The eggs begin to form grooves and to develop slowly by progressive division. In another glass we observe a second sample of fertilized eggs of the same kind and under the same conditions, but in this case we increase the temperature to 25° C. The increased temperature brings about a decided increase of segmentation and the same stage of development is reached in less than half the time. The increased temperature, therefore, increases the development. Further we take a third sample of the same urchin eggs in a watch glass with sea water of 15° C. and add a little sea water mixed with ether. The development of the eggs now comes to a standstill. The narcotic has produced an inhibition of development.

To quote another instance. Bacterium phosphorescens having been bred upon a putrid fish are exposed in the culture fluid to the air. In the dark the bacteria give forth a phosphorescent light. Then the culture fluid containing the bacteria is put into a glass receptacle, which can be rendered air-tight and all oxygen excluded. After a short time the light formation ceases completely. The absence of oxygen has here had a depressing effect and it is only after air has been again introduced that light is once more produced.

Lastly, an example from the group of mammals may be cited. The metabolism of a dog in complete rest is examined for a prolonged length of time and we ascertain the values of the oxygen consumption, the carbon dioxide production, and the nitrogen elimination in the urine. Under the same nutritive conditions the animal is then allowed to work from time to time in a treadmill. During these working periods impulses of excitation are continually conducted to the muscles from the nervous system. It is now found that under the influence of the constantly recurring stimuli the quantity of nitrogen in the urine has only very slightly augmented, whereas the consumption of oxygen and the production of carbon dioxide has markedly increased.

What conclusions can be drawn from these instances of response to stimuli, of which any number could still be quoted? They show us, first of all, that a state or process existing under given conditions, is altered by the influence of the stimulus. This is a fact, however, which could be expected from the beginning and is self-evident, for stimuli are alterations in the vital conditions, and when these are altered the state of the system or the happenings thereof must also alter. The question with which we are here more closely concerned, however, is a somewhat more detailed characterization of the state or process itself, as well as that of alterations produced by the influence of the stimulus. The instances of response to stimuli already cited furnish us with information in both kinds.

In all these examples, the living processes occur with equal constancy and unaltered rapidity, provided a stimulus is not operative. Here, however, the gradual alterations, the result of development, must not be overlooked. An excellent example of this is seen in the eggs of sea urchin, where the development is readily perceptible. In all these instances, however, the condition is immediately changed by the influence of the stimulus. The previous state of constancy in the vital process is disturbed. The rapidity of its course is changed, being either increased or decreased, and the specific vital manifestations concerned are, therefore, augmented or diminished. We will now study the vital process with the methods of chemical investigation and consider the problem from the standpoint of metabolism. It may be noted here, that other methods, such as the transformation of energy or changes of form of the living system, would serve equally well as indicators for this purpose. In every instance there is a uniformity of the processes; the difference, however, is in the nature of the indicators and the terms used. The methods and the terms used in chemical investigation and description reach proportionately much deeper than those employed when the transformation, energy or the variations of form of the organisms are studied, and permit of the finest differentiation of the processes. The atomistic terminology is, for this reason, preëminently fitted for the description of vital processes. When we study the vital process metabolically, we can, as shown in the above-mentioned instance, divide the processes into a metabolism of stimulation in contradistinction to a metabolism of rest.

The comprehension of the metabolism of rest demands a closer consideration. On closer observation we must say that this much-used conception is merely an abstraction nowhere realized in a strict sense. In truth, there is nowhere in nature a metabolism of rest. No cell exists which in a mathematical sense remains for even two successive moments under absolutely the same external conditions. If we imagine a single living cell of the simplest kind living in a fluid nutritive medium, and if we suppose its body and surroundings so magnified that the single molecules and atoms were respectively of the size of cannon and rifle balls, the boundary between cell and medium would represent a battlefield, on which a heavy bombardment is constantly taking place. The rain of shot of food and oxygen molecules penetrating into the cell from the medium, would produce an explosion in the existing ammunition depots, now at one point, now at another, creating great breaches through which new masses of shot would reach the interior. The fragments of these exploding molecules would be flung out here and there into the medium and would stem, now at this, now at that point the besieging masses of shot. In this wild confusion on the whole boundary line between cell and medium there can be no question of rest or even equilibrium at any point. The human mind, superior to the material world as we may deem it, is yet always dependent upon the results of experience, and even in its highest flights cannot become wholly emancipated from the concrete objects. For this reason it is of great purport to conceive processes whose dimensions cannot be observed even microscopically, as enlarged and transformed to that method of expression most familiar to the human mind, namely, in the field of optical presentation. This method is of great help in aiding our understanding, and likewise here, even in the resting state, the cell is constantly exposed to local effects of stimulation, now at one point, now at the other. The conception of the metabolism of rest is, therefore, in a strict sense fiction.

Nevertheless, the conception of the metabolism of rest as an abstraction can be of value provided always that it is strictly and definitely limited. It must, for instance, not be applied to short periods of time. The continued local and temporary responses to stimulation constitute a mean value which, although composed of numberless small sub-threshold responses, we can still call a metabolism of rest. Weak stimuli have, however, as already seen, the property, provided their influence is constant, of effecting an adaptation to the stimulus on the part of the living organism, so that the stimulus becomes a vital condition for this state of the organism. Hence the continued existence of a vital process resulting from the constant action of stimulation is made possible. That which we are in the habit of calling metabolism of rest, would, therefore, be metabolism of stimulation, but one that is characterized by a constantly existing metabolic equilibrium.

This “equilibrium of metabolism” distinguishes the metabolism of rest from that form which is developed in response to temporary stimulation, in that every temporary stimulation has the effect that it disturbs the existing metabolic equilibrium for a longer or shorter time. This disturbance of the equilibrium of metabolism can in contrast to the metabolism of rest be termed “metabolism of stimulation.” In this, but only in this sense, can these two conceptions be placed in opposition and used to characterize the processes in the living organism. The conception of the metabolism of stimulation must always stand in relation to that of an equilibrium of metabolism characterized by a constantly existing metabolism of rest, just as the conception of stimulus can likewise only be defined relatively to that of vital conditions.

Nevertheless, the conception of the equilibrium of metabolism requires a somewhat more accurate definition before we can feel justified in using this term. Definitions are always trite, nevertheless they are the basis of all our thinking and a definite understanding is impossible unless we first clearly fix their contents. The history of theology and philosophy even to the most recent times furnishes a long line of instances in which the most eminent minds, for the want of fixed definitions of the conceptions which they made use of, failed to find a mutual basis for their ideas. Without a sharp definition every conception is a mere word, which each individual, according to his personal experiences and views, endows with a different meaning. To such conceptions we may apply Mephisto’s ironical comment to his pupil:

“Mit Worten lässt sich trefflich streiten,
Mit Worten ein System bereiten.”

The natural sciences, if they are to retain their reputation for exactness and precision, require the strictest and clearest definitions of all conceptions. If we seek to penetrate more deeply into the varied happenings in concrete conditions, we must reconcile ourselves to dry pedantic definitions. In the case of that of the equilibrium of metabolism indeed we have before us one of the most important conceptions in physiology.

The justification to speak of an equilibrium of metabolism arises from investigations of metabolism in mammals. The classical experiments of the previous century, as is well known, have shown that in the adult mammal receiving a necessary quantity of nourishment and in a state of rest, the intake and outgo of the constituent elements are the same. The carbon, hydrogen, nitrogen, oxygen, sulphur, phosphorus, etc., taken in during a lengthened period in the form of food and respired air, appear again in equal quantity, in other combinations, in the products of excretion of the organisms. Calorimetric experiments likewise show an equilibrium of the consumption and elimination of energy. If there thus exists an equilibrium of metabolism for the whole cell community, it is clear that the same must also apply to the individual cell, that is, for all living substance. The quantitative relations of the foodstuffs taken in, and the excreted metabolic products given off, are, however, merely a standard of the metabolism. We know that the former are used to build up new living substance and that the latter represent the result of disintegration of that previously existing living substance; for we find, as in the case of the plant, complicated protein combinations, which are built up from comparatively simple constituents of the food and are again broken down into comparatively simple substances. And so the building up and breaking down processes form the two great processes of metabolism, which with Hering[41] we can briefly call “assimilation” and “dissimilation.” In the terms assimilation and dissimilation are comprised the sum of all processes of construction and disintegration in the living organism. It is apparent that equilibrium of metabolism occurs when assimilation and dissimilation are equal. The formula A : D, that is, the relation of the sum of all assimilation to the sum of that of all dissimilative processes, is a factor of fundamental importance in the study of the course of the vital processes, for upon its value depends individual vital manifestation, and, in fact, the continuation of life. I have, therefore, designated the formula A = D “Biotonus.” The equilibrium of metabolism would then be characterized by the biotonus[42] of a living organism being equal to one. This would be the metabolism of rest of a system, whilst its metabolism of stimulation would consist in an alteration of the biotonus. But is this state of living substance strictly speaking ever realized?

In considering the nature of the equilibrium of metabolism one factor has been disregarded which must be taken into account at every point; this is growth. Growth changes, although varying more or less, are never absent during the life of the organism. An equilibrium of metabolism never exists in a strictly mathematical sense, and here again we are working with a conception which is faulty, because it is an abstraction, originating from experience with rather too restricted boundaries. But an error of which one is aware is not dangerous. In mathematics we also consciously reckon with errors, without the result being altered. In the before mentioned cases the equilibrium of metabolism was maintained, because the investigations involved only a short time in an adult mammal. In the adult mammal the growth processes occur very slowly, so that alterations within a relatively short time are not demonstrated.

If it were possible to subject the adult mammal to metabolic or calorimetric experiments, extending for years, it would be found that the intake would be qualitatively and quantitatively different at the end of the investigation and that the same would apply to the outgo. In the growing egg cell this takes place with much more rapidity. In the organism which rapidly grows, it can be seen at once that the quantity of the outgo of the products of disintegration cannot be equal to that of the intake of foodstuffs. If biotonus were equal to one, the organism could not grow. Equilibrium of metabolism can only be understood when we take into consideration a period of time in which the alterations in growth take place with such imperceptible slowness that the resultant error is inconsiderably minute. This period of time is of greatly varying length in different living organisms and this fact must be taken into account in every living form. Only with this restriction can we justify the use of the term “equilibrium of metabolism.” Then, however, its use is of great value.

The metabolism of stimulation is then a disturbance of the metabolism of rest, that is, a disturbance of the equilibrium of metabolism through the effect of stimuli.

The question here follows: Is there a constancy of this interruption of the equilibrium of rest produced by the stimulus which can be formulated into a general law? To begin with, the number of possible responses are greater than the variety of forms of living substance, for every living organism with its specific properties can undergo alteration in its metabolism in various directions. Thereby results an infinite number of manifold reactions to stimuli. However, in answer to the question, in which direction the change in the specific metabolism of rest in response to a stimulus takes place, we find a comparatively simple scheme of general reaction. All phenomena can change in their rapidity as well as in their nature. That is quantitatively and qualitatively. In this way the specific vital process of an organism can be altered by the stimulus, on the one hand, in its rapidity; on the other, in the manner of its action.

The majority of all temporary responses to stimuli consist in alterations of rapidity of the vital process, and form either a quickening or retardation of its course. The former is manifested in a strengthening or an increase, the latter in a decrease or repression of the specific action of the living organism. The stimuli have the same effect as in the case of the catalysers in chemical processes. According to Ostwald’s[43] well-known definition of catalysis a catalyser is a substance which, without appearing in the final product of a chemical reaction, alters its rapidity. This group of reactions can, therefore, be referred to as “catalytic stimulation and response.” When the response consists in increase, we speak, in a physiological sense, of an excitation, and when there is decrease in the vital processes, we speak of a depression.

The conception of excitation and depression are purely empirical. They are terms for real things, referring, in fact, simply to alterations in rapidity of life process, which can be as readily observed as the process itself. I wish to lay particular stress on this fact, for the reason that Cremer[44] has recently made the extraordinary statement that I have introduced hypothetical processes into the definition of the conception of excitation. I have always considered excitation as merely an increase or change of intensity of the specific actions of a living system, and as such is an established process without a trace of the hypothetical element.[45] If, however, the excitation process is to be regarded as something absolute, as a mysterious state sui generis, which is entirely independent and totally unlike the metabolism of rest, then, of course, it would appear utterly incomprehensible and would be without purpose. As an absolute process excitation is merely a meaningless word. Excitation and depression are relative conceptions and can only acquire meaning when the process which is excitated or depressed is more closely defined. This is the specific vital process of a given organism, and the two conceptions only have meaning in relation to it. The conception of the vital process, however, is one directly gained from experience. However complex or difficult to analyze the process may be, it still is as little hypothetical as that of the combustion of carbon into carbon dioxide, or the revolving of the earth around the sun. It can be looked upon as something positive and real. Quite another question is the manner in which we are to consider the mechanism of the vital process. In analyzing this mechanism we cannot, at least in the present state of our knowledge, entirely dispense with hypothesis. But these hypotheses are in no way involved in the definition of the process of excitation. If we look upon every excitation or depression produced by a stimulus as an alteration in rapidity in the specific vital process of a given organism, we are thereby expressing the same fact which Johannes Müller has termed “specific energy.” We give, however, the doctrine of specific energy a more general application in so far as it comprehends not only the increase but likewise the decrease of activity in response to stimuli. Johannes Müller’s doctrine of specific energy of the living substance at all times has been the subject of most animated discussion. When I refer here to the specific energy of living substance, it is with the knowledge that Johannes Müller did not use this expression of “living substance” in this connection. He was already acquainted, however, as we have seen, with the fact of the existence of the specific energy of all living structures. For appertaining to the muscle he says: “This is universal in all organic reaction.” The reason why the doctrine of sense energy has become of importance in the discussion of the specific energy of the living substance, is in consequence of the theoretical interest, resulting from its connection with the nature of the specific energy of our sense substances. The controversies on this subject are still far from settled.[46] Indeed, according to the special philosophical standpoint taken by an observer, the existence of a specific energy of the senses is acknowledged or disputed. For any one acquainted with the general physiological reaction to stimuli, such a discussion is wholly without purport. The sense substances have as a matter of course in common with all living substances their specific energy, that is, the influence of stimuli can produce an increase or decrease of their specific vital processes. “Specific energy” of “sense substance” in this sense is like that of all other living substances, a fact. In that the psychical capability of these sense substances, in which we include not only the peripheral, but also the central portion, are dependent upon their specific vital processes, it must be self-evident that the excitation and the suppression of sense sensation can be brought about by adequate and inadequate stimuli, no matter what one may think of the relations between physical and psychical phenomena.

The only debatable question is that concerning the limits of the validity of the doctrine of the specific energy of living substances. This question will involve our attention when we have analyzed somewhat more closely the happenings in the living substance taking place under the influence of stimuli. We will, therefore, return later on to a more detailed consideration of the last question. Nevertheless, we will here refer to a fact which, upon a superficial observation, seems to restrict the validity of the conception of the specific energy of living substance.

In contrast to those reactions to stimuli, which consist merely in the changes of a rapidity of the specific vital process, are another group of reactions in which the influence of stimuli leads to qualitative alterations in the specific vital process. In these instances, the influence of the stimulus directs the metabolism of rest into new channels, so that chemical processes occur in the cell, which under ordinary circumstances do not take place. This group of reactions, which I wish to term “metamorphic stimulation and response,” are chiefly observed where weak stimuli act continuously upon the living substance. These are essentially weak chemical stimuli, which last for a prolonged period or frequently reoccur in the life of the cell community. Examples of this are found in the continual ingestion of alcohol and other poisons by the human being, or in the formation of metabolic products of bacteria, etc. The majority of chronic diseases belong to this group of reactions; disease being simply response to stimulation. Disease is life under altered vital conditions and altered vital conditions are stimuli. This simple and self-evident fact shows the immense importance which the knowledge of the general laws of the physiology of stimulation has for pathology. The pathologist, who does not wish to confine his observations to a purely superficial symptomatology or a merely histological morphology, must seek above all to penetrate as deeply as possible into the nature of the general reactions to stimulation in the living organism. It is the essential point which meets him everywhere. In spite of their great interest for pathology, however, it is just these qualitative alterations of the normal vital process produced by continuous stimulation which have up to now been least analyzed. In this field we expect much from pathological investigation which alone has the immense amount of material at its command. This will take place only when pathology adds to the almost exclusively histological direction of investigation, that also of experimental physiology. It is true that the problems of the qualitative alterations of a vital process by chronic stimulation are much more complicated than those of the rapid responses to temporary stimuli, consisting simply in mere alterations of rapidity of the specific vital process. An understanding of the nature of the former can only be expected when a deeper knowledge of the latter is gained, for, as will be seen presently, there is the closest relation between the two groups.

The reactions to catalytic stimuli of short duration, which produce merely an alteration of rapidity in the specific phenomena of a living organism, show on a closer analysis the interesting fact, that it is not always the entire metabolic processes of the cell which are perceptibly quickened, but that only certain constituent processes of the same are affected by the action of excitation. This is the more noticeable, as, considering the close correlation which all the individual links of the chain of metabolism bear to each other, it is to be expected that the alteration in rapidity of one would be followed at once by a corresponding change in all the others. An example of the case in question, in which a special constituent process may be predominately affected, is that of the specific activity of a muscle which is repeatedly stimulated by nervous impulses. Since the classical investigation of Fick and Wislicenus[47] on themselves, and of Voit[48] on the dog, we know that the nitrogen metabolism is practically unaltered by the functional use of the muscle and there is a remarkable increase only in the breaking down of the nitrogen-free groups of the living substance. Sufficient importance has not as yet been attached to this knowledge. This fact not only has a particular interest for the much-discussed question of the source of muscle energy, but also affords a deeper insight into the metabolic activity of the living substance. It shows us that we must not imagine a purely linear linking of the individual constituent metabolic processes, but rather, at least at certain points, a branching formation, the individual members spreading in various directions. An alteration in an individual member can occur without an immediate change in the other branches. This would not be the case if there were only a linear connection of the constituent processes, for the breaking of a single member of the chain would be followed by a change in all the following members.

It shows us, further, that certain branches are more labile than others. In the case referred to here, the branches of this system, which bring about the nitrogen metabolism, are relatively firm and stable, the branches, which are disturbed by the stimulus producing functional activity of the muscle, are particularly labile. I should like in passing to call here your attention to the fact that as is well known, Ehrlich,[49] in another field involving other conditions and other experiences and considerations, has arrived in analogous manner at his “side chain theory.” In order to have an expression for those stimuli which involve rapid alteration of the labile constituent processes and which are connected with the specific action of the particular organism, I have called them “functional stimuli,” and contrasted with them the “cytoplastic stimuli.” In the latter the alterations produced include all the constituent processes extending even to the stable processes of nitrogen changes, and sometimes extend to complete disintegration and rebuilding of living substance.[50] To the first group belong all adequate stimuli within certain limits of duration and intensity, and the greater part of inadequate stimuli of brief duration so long as they do not exceed a certain intensity. To the latter group belong in general all the stronger adequate and inadequate stimuli of prolonged duration; such as extreme temperature, the stronger electric currents, constant alteration in the supply of food, water, oxygen, the prolonged or stronger influence of extraneous chemical matter, etc.

Considering the close correlation of the individual part processes it would appear very strange, however, if a single one of these could undergo an alteration of its rapidity without the course of the rest of the processes being in the least influenced. One cannot comprehend such absolute independence of a process brought about by functional stimulation from all the other constituent processes, particularly when this is of prolonged duration and involves to a considerable extent the alterations in rapidity, for the individual constituent processes are dependent in a high degree upon the quantity of the particular chemical substances of which the living system is composed. The cycle of the individual constituent processes of this system is determined in the most delicate manner in its rapidity and extent, by the relative quantities of the individual substances. Associated with an alteration in the rapidity of an individual constituent process, there would also be a relative alteration quantitatively of the substances. And with the increase in the quantity of the disintegration products, and also the increase of the substances for their replacement, there would result, during this time, an alteration in the amount of interaction of the molecules of the other constituent processes, so that these processes secondarily suffer an alteration in rapidity which is perceptible after long continued involvement of the functional part of metabolism.

In fact, in the previously mentioned case of the functional stimulation of the muscle, the proof has been furnished that a long-continued increase of the functional metabolism is followed, although to a less extent, by an increase in the entire cytoplastic metabolism. Argutinski showed this on himself in 1890 in Pflüger’s laboratory. He found, namely, that after the exertion of a long walk in a hilly district, a considerable increase of nitrogen excretion in the urine took place, which extended over the succeeding two or three days. This increase of the nitrogen metabolism in its totality is not nearly as great as that of the breaking down of nitrogen-free substances, but it is, nevertheless, present and shows us that functional metabolism cannot experience a lasting excitation without being followed by secondary results in the entire cytoplastic metabolism. This fact is even more strikingly illustrated in the alteration of the entire volume of a living organism as produced by the lengthened duration of functional stimulation. It has been long known, that the muscle as the result of frequent functional excitation by means of adequate nerve impulses, that is, prolonged activity, is considerably increased in size, whereas in the absence of such it loses more and more in volume. A hypertrophy of activity, produced by functional stimuli, and the atrophy of inactivity, the result of the discontinuance of the functional excitation, is universal and can be observed in the various tissues of our body. We see it, for example, in the glands; we see it in the skin and we see it in the elements of the nervous system. Berger,[51] for instance, established the fact that the ganglion cells of the optic lobe in the cerebrum of newborn dogs only reach their full development when functionally excitated by adequate light stimuli (Figure [9], B), coming from the eye, whereas they remain in the embryonic state when these light stimuli are eliminated. (Figure [9], A.) The cytoplastic increase of volume of the neurons under the influence of functional stimuli is a fact of fundamental importance for the entire happenings of the nervous system and forms the physiological basis for reinforcement of reflexes, which, in its turn, is essential for all acts of memory and intelligence. For the increase in volume of the ganglion cell body is, when functionally activated, accompanied at the same time by an increase of specific capabilities and the intensity of discharge. Its excitation impulses can, therefore, be conducted through a greater number of neurons, with which it is connected, than would be the case if development of the volume of the ganglion cell increased to a less extent.

Fig. 9.

A—Undeveloped ganglia cells in the optic lobe of a dog, the eyes of which have been sewn up immediately after birth. B—Fully developed ganglia cells in the same region of a normal dog of the same age. (After Berger.)

The increase in volume under the influence of stimuli further shows the relation between the group of those solely catalytic effects of stimulation consisting in mere alterations of rapidity of the specific vital process, and that of the metamorphotic effects of stimulation, which manifest themselves in qualitative alterations of the vital process. Simple observation shows us that a qualitative change of individual constituent processes must necessarily result from the increase of volume of a cell, and that considering the close correlation of all the individual processes a profound alteration of the entire metabolism must be produced. I have already at another place[52,] [53] treated these conditions more in detail and will, therefore, only briefly refer to them here. If we study the growth of a ball-shaped cell, we find that the surface then increases as a square, and the volume as the cube. It therefore follows that, by progressive volume increase, the conditions for the interchange of substance with the surrounding medium must become more and more unfavorable for those cell portions situated in the interior, whereas those at the exterior are at much greater advantage. This must lead to a constantly increasing difference of the rapidity of the metabolic processes between the peripheral and central portions. Accordingly, the intricate interworkings of the individual constituent processes, the rapidity of action of all which is intimately connected, are, therefore, followed by corresponding alterations in the entire metabolism. Sooner or later a stage is reached in which the individual constituent processes become so limited that certain metabolic products, which previously were broken down as soon as formed, can be no longer eliminated and remain in the cell acting as foreign bodies. In this way the relative quantity of the individual cell substances become more and more altered, and as the course of chemical processes occurs in accordance with the law of mass action, the whole metabolism is directed into another channel, so that finally new constituent processes take place, which were formerly not possible. These in their turn produce deep-seated alterations of the relations of the cell to its surrounding medium, etc. Hence this mere increase of volume of the cell in growth forms the source of an infinite mass of alterations in the activities of cell metabolism, which we briefly term its “development,” and which by constant progression, leads either to a process of cell division, and with this to a correction of existing disorder, or finally to irreparable disturbances ending in death. In this way an inseparable relation exists between increase of volume and the development of living substance. We have seen, however, that the catalytic reactions of stimulation, which at first only produce an alteration of rapidity of the individual constituent processes, if of prolonged duration or of frequent recurrence, secondarily effect a change of volume of the entire living organism. One can, therefore, hardly reject the conclusion that seeing the close interworkings of the individual part process of metabolism, every change of rapidity of a single member, if of prolonged duration or of frequent occurrence, must finally lead to qualitative alterations of the entire metabolism. In consequence there results an important dependence between catalytic stimulation and metamorphic reaction. Indeed, it is not unlikely that the metamorphic reactions, which are especially seen in the continued effect of weak stimuli, result from alterations of rapidity, which the individual members of the vital processes have primarily undergone from this influence.

It is perhaps expedient to cite a concrete instance in illustration. A simple example is furnished by asphyxiation. If oxygen is withdrawn from any living organism, the result is a depression of its oxydation processes. Here there is primarily only a change in rapidity, especially a retardation of oxydation processes. The metabolism, however, proceeds, the disintegration of living substance continues, although at a slower rate, but produces an accumulation of other products. Whereas formerly during the existence of a sufficient supply of oxygen an oxydative disintegration of nitrogen-free groups into carbon dioxide and water took place, both of which could easily be eliminated from the cell, the anaërobic disintegration furnishes only complex products, having a higher carbon content, such as lactic acid, fatty acids, aceton, etc. These, being more difficult to excrete from the cell, accumulate. These asphyxiation products have in their turn a depressing effect and so on. In this way the whole metabolism is forced into a wrong course. The accumulation of fat in those tissue-cells with an insufficient blood supply, as we have seen in the case of the fat metamorphosis, is doubtless brought about in the same manner by relative oxygen insufficiency. The fatty acids accumulate as products of an incomplete combustion and combine with glycerine to form neutral fats. In like manner it may be that the accumulation of amyloid substance in amyloid metamorphosis, of lime salts in arteriosclerosis, etc., is produced by a primary depression of the individual constituent processes of the particular cells.

The relation here described, of the catalytic stimuli to the production of the metamorphic processes, leads us to the distinctions between primary and secondary effects of stimulation. Should the general fact be established, which has up to now only been pointed out in individual cases, that all the metamorphic processes are merely secondary results of primary alterations in rapidity of individual metabolic constituent processes, then the primary reactions of every stimulus would consist purely in the excitation or depression of the directly concerned constituent. Whether or not, as may be assumed, this primary effect of stimulation applies to all stimuli, is a question which only the future can answer.

The metamorphic processes are not, however, the only secondary effects of stimulation. The influence of long-continued excitation of the functional constituent processes upon the entire cytoplastic metabolism can be looked upon as a secondary response. Therefore, they may be considered as a secondary effect of stimulation which, in contrast to this primary excitation, may be called the secondary excitation.

Further: While the secondary excitation and metamorphic processes are generally produced by the continued existing effects of weak stimulation, we also observe as the result of a stimulus of short duration or frequently repeated at brief intervals, but otherwise not exceeding the physiological limits of intensity, a secondary effect, which plays a very important part in the activity of the organism. I refer to fatigue. Here a secondary depression is developed in connection with the primary excitation, for fatigue of a living organism must be characterized as a depression of activity. This case shows that we have to distinguish between a primary depression, as for example, produced by temperature reduction, withdrawal of food, deficiency of oxygen, etc., which occurs as a direct effect of stimulation, and secondary depression, which as in fatigue is an indirect result of primary excitation.

After the cessation of a briefly catalytic stimulus, not exceeding the physiological limit of intensity, another secondary result is observed, which is of the greatest importance for the continued existence of the living substance. The catalytic stimulus brings about a disturbance of the equilibrium of metabolism, which after cessation of the stimulus is reestablished by the living substance. In other words: recovery takes place. This fundamental principle has been known for a long time as the result of observation. If a skeletal muscle of our body has been activated for a prolonged period by nerve impulses, until it has become completely fatigued and incapable of work, a recovery takes place on the cessation of these impulses and the muscle is again capable of action. Likewise, as the result of strong mental activity during the day, we are mentally fatigued in the evening; recovery, however, occurs during the night, which results from the removal of the source of activity. The next morning finds us refreshed. This restitution occurs in every cell, and the return of its former capability of action, which had disappeared under the influence of stimulation, shows that compensation has taken place of the metabolism of rest, disturbed by the effects of the stimulus. Hering[54] has aptly termed this restitution as “the internal self-regulation of metabolism.” All recovery after disease is based on this self-regulation. The physician simply provides, by means of therapy, for the possibility of its taking place. Healing itself is brought about by the organism. “Natura sanat, medicus curat.”

Finally, a third kind of secondary effect of stimulation claims our interest. This is the secondary extension of the result of stimulation from the part of a living organism directly and primarily affected by the stimulus, to the surrounding structures. All living substance has the capability of conducting an excitation, which is produced locally through a catalytic stimulus, to a neighboring part, not directly affected by the stimulus. It finds its highest development in the nerve, but in no living structure is it completely absent. This capability has been frequently termed “conductivity of stimulation.” It is more precise, however, to speak of conductivity of excitation, for it is not the primary influencing external stimulus which is conducted in the living substance, but the excitation which it has produced. I have intentionally considered only the excitating effects of stimulation, and not those of the depressing reactions, as only excitations, not depressions, are conducted by the living substance. These questions, however, demand a closer analysis. Here we were concerned only with a survey of the general effects of stimulation. If I, therefore, once more summarize the results which have been gained, this is most clearly demonstrated by the following scheme:

Primary Effects of Stimulation

Excitation  Depression
Functional  Cytoplastic  Functional

Secondary Effects of Stimulation

Secondary excitation  Secondary depression
Conduction of excitation, Metamorphic processes, Self-regulation of metabolism

This, however, is simply a scheme, like all other schemes, having for its purpose a superficial survey of the subject.

It brings to some extent order into the overwhelming mass of manifold effects of stimulation but tells us nothing of the mechanism and genesis. Our further task must, therefore, be a more thorough analysis of this field.

CHAPTER V
THE ANALYSIS OF THE PROCESS OF EXCITATION

Contents: Indicators for the investigation of the process of excitation. Latent period. The question of the existence of assimilatory excitations. Dissimilatory excitations. Excitations of the partial components of functional metabolism. Production of energy in the chemical splitting up processes. Oxydative and anoxydative disintegration. Theory of oxydative disintegration. Dependence of irritability on oxygen. Experiments on unicellular organisms, nerve centers and nerve fibers. Restitution after disintegration by metabolic self-regulation. Organic reserve supplies of the cell. The question of a reserve supply of oxygen of the cell. Metabolic self-regulation as a form of the law of mass effect, and metabolic equilibrium as a condition of chemical equilibrium. Functional hypertrophy.

If it is true that all primary effects of stimulation consist either in an excitation or depression of the metabolism, and that all other effects of stimulation secondarily follow this primary alteration of the metabolism of rest, then every thorough analysis of the mechanics of reaction must have its beginning in the investigation of these primary processes. I desire to adopt this method here and will analyze somewhat further the primary process of excitation and its immediate and remote sequences. This will be followed later by the analysis of the process of primary depression and its results.

The investigation of the more obscure processes in the living substance places us in a difficult position, for their details cannot be observed by the unaided senses. That which we can perceive is merely the grosser vital action, consisting of a complex combination of the individual processes, the total result of a multitude of different components. For this reason the conception of excitation can only be established by observations based upon the combined vital actions, which are produced by the effect of stimulation upon the complex system. In the beginning, the process of excitation was studied exclusively on the muscle and nervous system. A physical factor served as indicator, such as muscle contraction or production of electricity. These showed, besides the direct and primary effect of stimulation, the secondary process of conductivity. Even graphic registration is merely an expression of the phenomena composed of a great mass of individual elements. The visible course of the phenomena, as shown, for instance, by the latent period by the ascent and descent of the curve of contraction, represents as it were a reflected picture of the actual excitation processes similar to an object seen in a distorting mirror; the first and the last parts of the process are not even perceptible. Later, when organ physiology was extended into a cell physiology the processes of excitation were studied in numerous simple organisms, such as the plant cell, the rhizopoda, the infusoria, etc. Later, in this way, by the use of comparative methods many essential facts were discovered. However, even the single cell, in spite of its minuteness, is, compared with the size of a molecule, a gigantic system, and it would be a grave error if we should consider this system even in its simplest aspect as homogeneous. In order, therefore, to analyze the vital activities in the cell, cell physiology must endeavor to penetrate into molecular conditions. For this purpose the indicators employed must be essentially of a chemical nature, capable of magnifying the processes of molecular dimension to such a degree that we are enabled to base conclusions upon these not otherwise directly perceptible phenomena. To obtain a sufficient magnification we must necessarily place somewhat larger quantities of living substance under observation and apply a stimulus of such frequency or length of duration that the chemical alterations as a result of excitation are so increased as to be plainly perceptible with the aid of our chemical indicators. Unfortunately, we do not possess specific chemical indicators for every individual molecular constituent process of the cell and so cannot dispose with the help of indicators of the combined happenings in a greater quantity of living substance. It remains for us to obtain data concerning the cycle of excitation processes in the living substances by the aid of the combined employment of the most varied kinds of physical as well as chemical indicators. If we use the most varied types of living substance of widely differing properties, showing us the greatest variety of vital manifestations, we may hope by the use of comparative physiological methods, even though with difficulty, to separate more and more the essential details of the general processes of excitation. At present we are still at the very beginning of this task and vast fields of unexplored regions are yet before us. But it is the unknown which has a particular fascination, especially if we succeed from time to time in making new advances.

If we suppose a living system in a state of metabolism of rest influenced by an instantaneously excitating stimulus, the entire course of excitation extends from the first alteration produced by the stimulation until the complete restitution of the metabolic equilibrium, and we will, therefore, differentiate individually the successive stages of this whole process.

The very beginning of the chain of alterations produced by the excitating stimulus cannot be studied by any indicator. The changes must first reach a certain dimension by conduction from the point of stimulation before they influence even the most delicate indicators. The application of the stimulus is, therefore, followed at first by a measurable “latent period,” in which the living substance remains apparently at rest. This latent period has been particularly studied in muscle. After its discovery by Helmholtz[55] it was made the object of innumerable investigations and met with an interest which can only be explained by the exactness of the methods employed. Among others Tigerstedt[56] has made the most thorough study of the influence of various factors on the duration of the latent period. These experiments have established the fact that the duration of the latent period varies according to the intensity of the stimulus, temperature, loading or fatigue. This is apparent when it is understood that the amount of the alterations produced by the stimulus must ascend from the value zero to a certain height before the changes are perceptible, and that under various conditions this amount is, on the one hand, attained in different lengths of time and, on the other, must reach a varying amount before it is perceptible by means of the indicator.

The facts concerning the whole latent period and its dependence on various factors would be incomprehensible if it were assumed that no alterations whatever take place during the latent period although the stimulus is already operative. In reality, the alterations following a stimulus occur with imperceptible rapidity in the form of a molecular interchange, and the latent period is simply an expression of the fact that the primary alterations, being limited in nature, are not registered by our indicators.

The question first arises, In what do these first imperceptible alterations consist? Nernst[57] has evolved the theory for electric stimulus, that the primary effect produced by the electric current is an alteration in the ion concentration on the surface of the living substance. In fact, we know that the surfaces of all protoplasm possess the property of semi-permeable membranes and that changes in the concentration of ions invariably occur when an electric current flows through two electrolytes separated by a semi-permeable membrane, in which the anions and cations have a different rapidity of movement. It is apparent, therefore, that such an alteration in the ion concentration must be followed by further chemical processes in the living substance. According to the theory of Nernst the first impetus for all further alterations, which the electrical stimulus brings about in the metabolism of rest, is the alteration in the concentration of the ions on both sides of the semi-permeable membrane, which represents the surface of the protoplasm. In view of the present findings of physical chemistry, objections can hardly be made to this theory of Nernst’s. It is a question, however, in how far this theory, especially established for the electric stimuli, can be applied to other forms of stimuli and their action. It cannot be denied that the degree of dissociation of an electrolyte can be altered by very different factors, such as heat, light, chemical processes, etc., and in that the surfaces of the protoplasm, acting as semi-permeable membranes, bring about a selective action on the passage of the ions, there arises the opportunity for the development of difference of electrical potential on both sides, and for further chemical alterations in the protoplasm. These observations, however, require further experimental investigations in many fields, before we are justified in extending the Nernst theory of the manner of action of the electric stimuli to a general explanation of the primary alterations produced by all stimuli in the living substance. For the present we must confine our observations to those alterations which are known to be responses to an excitating stimulus; these are the chemical alterations in the metabolism of rest in the living substance.

If it is asked, which members of the entire metabolic chain are increased primarily by the stimulating excitation of a vital system, we should not be able to answer this question generally for all living systems. To begin with, it appears highly probable that the various forms of vital substances in this respect act quite differently. It is to be regretted that, up to the present, this question has not been treated from a comparative standpoint. This inquiry should be extended to the greatest possible number of organisms. Still there is enough material at hand, obtained from the muscles, glands, ganglion cells, nerve fibers and plants, to show that the complexity is by no means so great as one might at first assume.

In considering the two stages of metabolism, assimilation and dissimilation, in their entirety, it appears as a very remarkable fact, that nearly all stimuli produce primarily a dissimilative excitation. We are only acquainted with a primary assimilative excitation, that is, an augmentation of the building up processes, in short, the formation of living substance, occurring as a primary result of stimulation, following increased introduction of foodstuffs extending over a prolonged length of time. With this exception it cannot be proved that any other stimuli, either especially those operative in the activity of the animal organism or any of the physiological nerve impulses which regulate the actions of the different organs and tissues, bring about primarily an assimilative excitation, which leads to an increase of new formation of living substance. The much-discussed teaching of the existence of the trophic nerves has not given us a single case in which there was positive proof that a nerve impulse brought about a primarily assimilative excitation. I have endeavored for nearly fifteen years to discover such a case. My efforts have been, however, without avail. In the most recent critical review by Jensen[58] on the subject of the trophic nerves, the same conclusion is reached although certain facts, as, for instance, the excitation of assimilative processes in the green plant cell, produced by light, seems at the first glance to clearly demonstrate a primary excitation of the building up processes resulting from a stimulation. Nevertheless closer observation invariably shows that these conditions are much more complicated and that primarily assimilative excitating reaction of the stimulus cannot be conclusively shown. There remains, therefore, as a primary assimilative excitating stimulus only the increased introduction of nutrition in a living organism. This excitating effect on the assimilative portion of metabolism is, as we shall see later, a simple manifestation of the law of mass action.

As a result manifold effects of excitating stimulation, which seemed possible at a first glance, are already considerably restricted. The great mass of excitating stimuli produce an acceleration of the dissimilative processes of the metabolic chain. But here our former observations have already shown that certain constituent processes are especially responsive and very readily increase as a result of the most varied adequate and inadequate stimuli. These are the “functional” members of metabolism. These members are particularly labile, so that they are always affected by every influence to which the system is subjected in the form of a stimulus. The functional portion of metabolism of the muscle, which is particularly labile and is always primarily affected by stimulation, consists as demonstrated in increase of formation of carbon dioxide and water, and in the disintegration of the nitrogen-free groups. The innumerable observations on metabolism during the stage of the activity of the muscle, as those of Hermann, v. Frey, Fletcher, Johannson, Thunberg, and many others on the individual muscle, and those by Voit, Fick and Wislicenus, Pflüger, Rubner, Zuntz, Lehmann and Hagemann, Bernstein and Löwy and others on the muscle of the entire organisms, have sufficiently proved this fact. However, we should not apply in detail the conditions existing in the muscle to all living substance. Comparative methods show us, rather, that the functional portion of metabolism is very differently involved in various forms of living substance. The formation of carbon dioxide and water is constant in nearly all forms of living substance. We must, however, exclude certain micro-organisms, which have adapted themselves to unusual vital conditions. Further, there appear in some forms manifold special constituent processes consisting in a disintegration of living substance which are in part converted into very complex combinations. In the gland cells this type is represented in an especially high degree. Here the functional disintegration leads to excretion of proteins, glycoproteins, nucleoproteins, cholic acid, enzymes of various kinds, all of which are complex and at the same time nitrogenous organic combinations. This fact must not be lost sight of. The origin of these special members, however, for the present is completely unknown, while on the other hand, it is self-evident that the general and constant constituents of the process of excitation must claim a first place in our interest. It is just at this point, therefore, that we must endeavor to penetrate somewhat more deeply into the mechanism of the excitation process and analyze in greater detail the acceleration of the functional constituent parts of metabolism produced by the stimulus bringing about the formation of carbon dioxide and water.

The question arises: By what means is the particular labile state of just this constituent part of functional metabolism conditioned? The lability of the functional portion of metabolism, excitated by the stimulus, resembles the processes in the disintegration of explosive combinations. Iodide of nitrogen, for instance, in a manner similar to the living substance in the state of the metabolism of rest, constantly disintegrates even without the influence of an impact. The disintegration is suddenly enormously increased by the result of a jar. An explosion follows. In a like manner the functional metabolism of rest is explosively excitated by the stimulus, the transformation of the energy involved likewise bears a similar relation.

In both instances the transformation of energy, constant in the resting state, is by the impact of the stimulus suddenly increased. The dynamic method of investigation of the excitation process with its physical indicators, forms, therefore, in many respects an excellent addition to the chemical analysis. A development, that is, exothermic formation, of energy can only occur in a chemical process when the chemical affinities which are to be combined are stronger than those which have been separated. When this process is brought about by a simple impact, the energy value of which bears no relation to that of the quantity of energy in the process itself and which occurs with explosive rapidity, then it can be simply a question of a liberation process, that is, a process by which the impact brought about a conversion of latent chemical energy into that of kinetic energy. The comparison of the functional excitation process with that of an explosion does not, therefore, consist in a merely superficial analogy, but is founded on the same dynamic principles.

When we study the chemical process which occurs in the explosive transformation of potential into kinetic energy we find two types of chemical processes. The first type includes the synthetic processes. For this, the synthesis of water from explosive gas may serve as a simple example. Here the weaker affinities in comparatively simple molecules (H + H and O + O) are separated and stronger affinities are combined in the formation of more complicated molecules (H + O + H). The second type represents the process of cleavage. As example for the latter, the explosive disintegration of nitroglycerine may be quoted. Here the atoms, held together in a complex molecule by weaker affinities, are changed by transposition of nitroglycerine. For instance, the hydrogen atoms loosely combined with carbon enter into strong combinations with oxygen and the oxygen loosely combined with the nitrogen enters into strong combination with carbon, so that water and carbon dioxide are formed and nitrogen and oxygen set free.

In the functional disintegration of living substance, the last type is realized. Living substance contains loose complex combinations, and we know that functional disintegration is accompanied by the consumption of these organic combinations. In the functional disintegration of muscle substance the nitrogen-free groups are concerned, and we must, consequently, first consider the carbohydrates. However, without further study we should not generalize from that which is true in the case of muscle. There are other forms of living substances which contain different combinations, which disintegrate as a result of the contact of a stimulus and yield carbon dioxide. A clue as to which combinations in individual cases undergo disintegration as a result of excitating stimulation, is furnished by the metabolism of rest in the particular substance. Plants and micro-organisms have been investigated more thoroughly in this connection than animals. Plant physiology has demonstrated that the material employed for the CO₂ formation and with it the production of energy is carbohydrate, but that, on the other hand, various plant organisms and protistæ also use a quantity of other substances, such as fats and protein, indeed even such comparatively simple organic combinations as alcohol, formic acid and methane. It may be accepted that in all these various instances of excitation of the functional metabolism as a result of stimulation, the specific respiratory material of the substance concerned is used in greater amount in the decomposition and likewise invariably yields carbon dioxide.

The point of most essential interest for the analysis of the excitation processes is, above all, the mechanism of the organic combustion and the associated energy production. Here we may base our observations on the disintegration of carbohydrates, which is most extensive in the animal as well as in the vegetable kingdom. We may now ask how dextrose, for instance, disintegrates in the living system into carbon dioxide, for it is this, or a sugar of similar chemical nature, which is generally concerned. Plant physiology, which here, as in many other respects, is in advance of animal physiology, has indicated two ways by which this can be accomplished in the living substance. One is oxydative, the other, anoxydative disintegration.

In the oxydative disintegration of dextrose, taking place in aërobic organisms, if sufficient quantities of oxygen are present, there occurs a splitting up of the carbohydrate molecule, as a result of the introduction of oxygen, into simpler substances and finally into carbon dioxide and water, just as the dextrose molecule, when subjected to oxydative processes, is split up into simpler molecules. In the living substance the oxydases play the important rôle of oxygen carriers. It cannot be denied, however, that up to now no carbohydrate splitting oxydases have been obtained from living substance. This, of course, does not prove its nonexistence. But this deserves consideration in connection with an assumption very widely spread among plant physiologists in regard to the aërobic disintegration of the carbohydrate molecule, which I shall touch upon presently. If we suppose that oxydases exist, which bring about primarily the oxydative disintegration of the dextrose molecule, its first point of attack must obviously be sought in the aldehyde group. Here would be situated the activator, as it were, for the whole carbon chain, from which, as by a spark, the entire series of links would be ignited.

In an anoxydative disintegration of dextrose as observed in anaërobic as well as in aërobic organisms, provided the latter have an insufficient supply of oxygen, the dextrose molecule, by enzymic action as a result of the splitting off of carbon dioxide, is converted into substances having a comparatively large carbon content. The best-known example of this anoxydative disintegration is the formation of alcohol by fermentation in which the dextrose molecule is split up by the yeast into alcohol and carbon dioxide. (C₆H₁₂O₆ = 2C₂H₅OH + 2CO₂.) Instead of the production of alcohol and CO₂ we may have other enzymic actions with the formation of other carbon-containing disintegration products, such as lactic acid, fatty acids, hydrogen, etc. Of course in such an anoxydative disintegration, which does not lead to the formation of such simple combinations as carbon dioxide and water, the quantity of energy set free is much less in amount than in complete oxydative decomposition, the energy production of the alcohol fermentation being only 11 per cent of the latter. In order to produce the same amount of energy as in the former, a much greater number of molecules is required. We find, therefore, that the anoxydative type of disintegration develops either only where the respiratory substances are present in sufficient amounts, as for instance, in the case of yeast cells, existing in nutritive solutions rich in sugar; or where the chemical and energy transformations occur only to a limited extent, as, for example, in the presence of low temperature. In this respect Pütter[59] has demonstrated in the leech that at a higher temperature, the oxydative, at a lower, the anoxydative, decomposition predominates. These are important facts in that they show us the superiority of oxydative to that of the anoxydative disintegration in the cell economy. This is of particular interest when we consider those organisms in which great demands are made upon the capability of movement, above all, in homothermous forms, the metabolism of which takes place on a continuously high level. For this reason, in homothermous animals the respiration of oxygen is the almost exclusive source of energy production.

The previously mentioned facts make it clear that in one and the same form of living substance both oxydative and anoxydative decomposition processes are found, depending upon the conditions. This does not apply merely to the individual organic forms, such as the facultative anaërobic organisms, but generally to all aërobic living substance. If oxygen is withdrawn from an aërobic organism the disintegration does not cease in consequence. In place of the oxydative we have anoxydative decomposition. The various aërobic organisms are, however, adapted in very different degrees to the possibility of an anaërobic existence. While the facultative anaërobic organisms can continue to exist without oxygen, the homothermous animals become asphyxiated in a very short time in the absence of oxygen, in that they are poisoned by the products of the anoxydative decomposition, which are eliminated with much more difficulty than carbon dioxide and water. The fact, however, that disintegration also continues in an anoxydative form, if oxygen is withdrawn, has given rise to the thought, which has been accepted especially by plant physiologists with great readiness, that the decomposition of organic respiratory substances of the aërobic organisms invariably takes place in two stages; in that the dextrose molecule—to again use this as an example—is split up first by an enzyme into larger fragments, which then in the second stage of the process undergo combustion to the formation of carbon dioxide and water. Such a possibility cannot be repudiated. I wish, however, to state that one should be very reluctant in generalization of this assumption for all aërobic organisms. The types of metabolism in the different organisms are so manifold and of such immense variety that we should be very careful in our generalizations before being in possession of material extending over a great number of groups of organisms. Above all, it does not seem justifiable to also accept this type for life existing at higher temperatures, and still less to apply it to those instances in which the production of energy following stimulation is suddenly increased to great amounts. Let us suppose that the disintegration process occurs in two phases, the first of which after the type of the fermentation of dextrose separates the molecule into larger fragments, while in the second phase these fragments are split up through oxydation into the formation of carbon dioxide and water. We can then say with certainty that in the first stage only a comparatively small amount of energy production occurs, for energy production by enzymic processes of this kind is never great; the second phase, on the other hand, must be associated with a very considerable energy production, for by the addition of oxygen and the formation of carbon dioxide and water the strongest affinities possible are combined. With this assumption in certain cases, as, for instance, in the sudden production of energy in muscle contraction, which necessarily occurs in the purely oxydative phase of the whole process, the view is forced upon us, that, in these cases, the entrance of oxygen into the molecule from the very beginning, even the first impact, produces oxydative decomposition of the whole molecule. The view that, in the reactions of warm-blooded animals, which occur with great rapidity and considerable energy production, the oxygen primarily explosively breaks up the whole carbon chain, certainly presents no more difficulties than the supposition that the simpler substances are attacked secondarily, provided sufficient oxygen be present. This method would be obviously the simplest. This is, however, mere speculation and a definite decision between the two possibilities cannot be made at present. However, whether the process takes place in two phases, an anoxydative and an oxydative, or simply in an oxydative phase, in any case, the sudden discharge of energy in the aërobic organism set free by the stimulus, is brought about by the addition of oxygen.

This is a highly important fact and as such requires the most thorough confirmation, and is best accomplished by the investigation of the state of excitation of aërobic substances on the withdrawal of oxygen. Experience gained by observation in this respect on a great number of living substances shows that excitability decreases upon the withdrawal of oxygen. In this connection I should like to cite some particularly significant instances.

Fig. 10.

Rhizoplasma kaiseri. A—Under normal conditions. B—In an atmosphere of pure hydrogen.

During a sojourn at the Red Sea in 1894–95 I was able to establish this dependence in the single-celled organism, the Rhizoplasma Kaiseri, a large naked orange-colored rhizopod. (Figure [10], A.) Mechanical stimulation, which under normal vital conditions of these organisms brings about contraction in the long-branched pseudopods, becomes ineffective with a cessation of the movement of protoplasm, when oxygen is removed and is replaced by a stream of hydrogen. (Figure [10], B.) With renewed introduction of oxygen there is a return of the protoplasmic movement and entire recovery takes place.

This dependence of irritability upon oxygen is most clearly demonstrated in the nerve centers. For this purpose I have employed the spinal cord of the frog.[60] A canula is introduced and fixed into the aorta of the animal and the blood is replaced by a current of oxygen-free saline solution. The centers of the spinal cord are thereby wholly isolated from the supply of oxygen. The indicator for the irritability here used is reflex excitation from the skin to the gastrocnemius, or better, stimulation of the central stump of the sciatic nerve with single induction shocks, bringing about reflex response of the triceps. The reflex may be considerably augmented by increasing the reflex excitability of the spinal cord by poisoning the animal with strychnine. On testing the reflex excitability at the beginning of the experiment it will be found that the reaction to each individual stimulus consists, in consequence of the strychnine poisoning, of a long-continued maximal tetanus. The longer the deficiency of oxygen continues, the briefer become the tetanic reflex contractions following a single stimulus. Soon reflex tetanic responses are merely short single contractions, which decrease more and more with the continuance of oxygen deficiency. Finally, the same stimuli which previously produced strong tetanic contractions of long duration are altogether without effect. Although by increasing the intensity of stimulation brief contractions can again be brought about, irritability decreases more and more, until at last even the strongest stimuli remain without result. If the oxygen-free saline solution is now replaced by one saturated with oxygen, or blood of the ox, rendered arterial, the excitability returns within a few minutes and soon reaches the maximal height which it possessed under the influence of the strychnine poison. Even the weakest single stimuli now again produce tetanus. The same process reoccurs, if the fluid used for transfusion containing oxygen is again replaced by an oxygen-free saline solution. In this way, by repeated change of the perfusing fluid, we can demonstrate in the most positive manner this alteration in irritability, the result of the alternate presence and removal of oxygen. This is perhaps the best example of the close dependence of irritability on oxygen.

This same fact can be observed with equal clearness in the nerve. At my suggestion H. v. Baeyer[61] showed as the result of investigations made in the Göttingen laboratory the dependence of irritability of the nerve upon oxygen for the first time. By employing as the method the ascertainment of the threshold of stimulation I then made a closer study of the alterations in irritability during asphyxiation. These observations were soon after continued by Fröhlich.[62] The method is as follows: the nerve of a nerve-muscle preparation of the frog is drawn through a glass chamber which is made completely air-tight and containing platinum electrodes. The air in the chamber is then displaced by a stream of pure nitrogen. (Figure [11].) On testing that part of the nerve situated within the glass chamber with single break induction shocks it can be observed that its irritability, measured by the threshold of stimulation for muscle contraction, decreases more and more, until after the lapse of some hours, the stimulation required is so strong as to reach the region of the “Stromschleifengrenze.” If in place of the stream of nitrogen, air or pure oxygen is now allowed to flow through the chamber, the nerve recovers almost instantaneously. Within the space of a minute its irritability has risen again to its full height and the same experiment, with the same result, can be repeated. Finally, as Fillié[63] has shown, the like result is obtained when the nerve is asphyxiated in a fluid medium.

Fig. 11.

Arrangement for asphyxiating the nerve. A—Gasometer containing pure nitrogen. B and B₁—Vessels for washing the gas. C—Ether chamber for eventual experiments with narcosis. D, D₁ and E—Glass faucets. F—Moist chamber. G—Asphyxiation chamber. H and H₁—Two pairs of electrodes over which the nerve is laid. I—Nerve muscle preparation.

All these facts, the number of which indeed could be increased greatly for other aërobic forms, suffice to establish the fundamental importance of oxygen to the maintenance of irritability of living substance. Oxygen is of greatest importance for a high degree of irritability in all aërobic organisms. All living systems which are characterized by a great capability of activity and evince strong responses under the influence of stimulation, such as the vertebrates and insects, are necessarily aërobic, whereas the living organisms of pronounced anaërobic character, as some bacteria, yeast cells, parasitic organisms, etc., manifest on the average much less capability of activity.

Finally, to briefly summarize the foregoing, the following picture presents itself of disintegration produced by a momentarily acting stimulus. It is immaterial how the stimulus produces an excitating effect in the given case, whether through changes in the ion concentration of the living system, by increase of intramolecular atomic movement or in any other manner, it invariably accelerates the disintegration of the complex molecules concerned in functional metabolism, the nature of which varies in the special cases. In the great majority of instances nitrogen-free organic combinations serve as material for the functional constituent members of metabolic processes. In the anaërobic organisms this decomposition takes place anoxydatively with the coöperation of enzymic processes, and as larger fragments generally result from the disintegration of the complex molecule, the production of energy is accordingly smaller. The disintegration of aërobic organisms, on the other hand, occurs in the form of an oxydative splitting up of the complex molecules into carbon dioxide and water so that the production of energy attains a high value. The details concerning the manner in which the individual stages of this decomposition take place and the interactions by which its end products are reached is at present beyond our knowledge. It would be a mistake to generalize in this connection from the behavior of certain groups of organisms. The assumption that under certain conditions the disintegration occurs in two phases, the splitting up resulting from enzymic action of the complex molecule into larger fragments, followed by an oxydative splitting up of these into carbon dioxide and water, can in no case as yet be justifiably applied to all conditions and all aërobic organisms. This is more or less the impression which we derive of the functional excitation process as seen today.

Under normal conditions the functional excitation is at once followed by a succession of secondary processes, the “self-regulation of metabolism.” Self-regulation after a functional excitation is a fact demonstrated by experience. But in what manner does it take place in detail?

As the functional constituent members of metabolism involve a disintegration of the nitrogen-free atom groups, the functional self-regulation must necessarily furnish in sufficient quantity and in proper form the carbon, hydrogen and oxygen atoms, which have been removed in the production of carbon dioxide and water. This is accomplished, as is well known, by the food and the intake of oxygen. It is of importance to the maintenance of living substance that after every functional activity it is as soon as possible again capable of reaction. Therefore, it is absolutely necessary that this material is in the proper place, where building up is essential, and is at the same time constantly in proper form. Indeed, the restitution of the original state follows under favorable conditions with lightning rapidity, although varying in different forms of living substance. This occurs in the nerve in an extremely short time. From this it might be supposed that the living system by accumulating a store of the necessary compensation substances in suitable form, had made itself independent to a certain degree of the frequently varying supply of material obtained from the medium.

This may be held as the proper view, first with regard to compensation substances. The fact that living organisms can under some conditions remain for a lengthened period in a state of starvation, without losing their capability of activity, can only be explained by the presence of a great quantity of reserve supplies of compensation substances. In the course of work in the laboratory every physiologist has become acquainted with the fact that frogs which have been kept without food for a year, although much reduced in weight, are still capable of some muscular activity.

Fig. 12.

Motor ganglia cells from the spinal cord of the frog. A—In normal state. B—After an asphyxiation lasting 8 to 9 hours. (After Gordon Holmes.)

Fig. 13

Paramecium aurelia. A—In normal state. B—In a state of starvation.

Organs and tissue, which are cut off from all food supply through the blood and lymph, may remain active for many hours. H. v. Baeyer[64] has shown that the ganglion cells in the frog, in which saline solution was transfused at room temperature and containing no trace of organic substances and where irritability has been increased to the maximal by means of strychnine, were capable of strenuous work for nine or ten hours before losing responsivity. The nerves and muscles of the animal retain their excitability for even a longer period under the same conditions. Indeed, we have histological evidence of the existence of organic reserve material in the various cells in the form of embedded bodies in the protoplasm. As for instance the disappearance of the Nissl granules in the ganglion cells following great activity,[65] (Figure [12]), or that of the granules in infusoria cells during starvation.[66] (Figure [13].) We assume that a certain amount of organic foodstuffs in a state properly prepared is present in the cell. As the amount of these prepared substances is consumed, new quantities of stores, having undergone various preparatory processes, among which the enzymic actions may be considered to play a chief rôle, are brought into that form in which they appear suited to fill the gap produced by disintegration. Plant physiologists in particular have here again furnished us with some essential data for the assumption of the existence of such processes which regulate the transformation of reserve substances as well as its extent. Pfeffer[67] has found in several fungi and bacteria that there exists a compensation between the diastatic breaking down of the carbohydrates stored as reserve material and the quantity of dextrose introduced. He further found that the more the reserve substance is split up into dextrose the less of the latter is introduced from without and vice versa. De Bary[68] some time ago also observed in the bacillus amylobacter an analogous relation between the enzymatic cellular digestion and the quantity of dextrose introduced with the food. An equilibrium, therefore, exists between the required amount of dextrose and the extent of enzymic splitting up processes of the reserve material. A great number of similar processes have been observed. Even though the details of the whole preparatory assimilative processes are beyond our knowledge we can still say with certainty that, on the one hand, everywhere great quantities of organic reserve substances are always present in the cell, and on the other, that these substances are subjected to a transformation into suitable material for building-up processes, the extent of which is controlled according to need, by the processes of self-regulation.

Entirely different is the question if the cell also possesses a reserve store of oxygen. In this respect views have widely differed, and even today no conformity of opinions has been arrived at. The fact that many purely aërobic organisms and tissues can exist under complete exclusion of oxygen for a longer or shorter period, retaining their excitability and producing carbon dioxide, has for a long time led a great number of investigators, such as Liebig, Matteucci, Engelmann, Pettenkofer and Voit, Claude Bernard, Verworn, H. v. Baeyer and others, to the supposition that a reserve store of oxygen must exist in the living substance which maintains its excitability for a time. More recent information, however, of the transition of the oxydative to the anoxydative disintegration under a deficiency of oxygen, as can be observed in plants and certain invertebrate animals, indicates that here also there is the possibility of another explanation of these facts. Various attempts have been made to solve the problem if reserve oxygen is present in the cell or not. The experiments of Rosenthal,[69] carried out with his respiration calorimeter, seemed to point directly to an oxygen reserve in the organism of the mammal. He observed that during respiration in an atmosphere rich in oxygen the respiratory quotient (CO₂ : O₂) became lower than in ordinary air, that is, that oxygen, and that indeed in considerable quantity, must be retained in the organism. Nevertheless Falloise[70] found that when rabbits, which had been kept in an atmosphere containing 80 per cent of oxygen, were asphyxiated, the time necessary to produce death was no longer than in animals which had been kept previously in ordinary air. The correctness of the observations of Rosenthal have been disputed by Durig.[71] Winterstein[72] also, employing the microrespiration methods of Thunberg upon the spinal cord of the frog, believed that he had found proof that an oxygen reserve cannot take place. He reasoned thus: If the cells of the spinal cord contain reserve oxygen, which is used up when pure nitrogen only is breathed, then it necessarily follows that after reintroduction of oxygen, following asphyxiation, a definite quantity must be stored up again as reserve. In consequence, the respiratory quotient following the intake of oxygen after asphyxiation should be smaller than when the animal is in air. He found, however, that the respiratory quotient does not essentially change and concluded from this that storage of oxygen does not take place. In these experiments, however, there exists no certain indicator as to the state of the spinal cord during asphyxiation and recovery in the given case. The spinal cord may be severely injured and even undergo degeneration during asphyxiation, and the recovery following the reintroduction of oxygen may be either incomplete or nil, without there being a method for its determination. Apart from this, Lesser[73] has already emphasized, in opposition to these experiments, that the respiratory quotient in recovery is no criterion to guide us. It is immaterial whether during asphyxiation oxygen respiration occurs following a reserve supply, or that an anoxydative formation of carbon dioxide has taken place, for in both instances the respiratory quotient would be less after asphyxiation when there is again an oxygen supply. It is, therefore, quite impossible to decide the question by the employment of this method. For this reason Lesser has attempted to solve the problem by means of quite another method, and was convinced that he had refuted finally the belief in the existence of reserve oxygen. His method consists in the employment of the Bunsen ice calorimeter, by which he determines the heat production of frogs, kept first in air, then in nitrogen, and at the end of each experiment ascertaining the amount of output of carbon dioxide, respectively in air and nitrogen. He found that the quantity of heat, calculated in terms of 100 grms. body weight per hour, produced in nitrogen was considerably less than that under corresponding conditions in air, but that the production of carbon dioxide, on the other hand, during the first hours in nitrogen was doubled in amount, as compared to that in air. From this he concludes that the carbon dioxide formation in nitrogen must be different from that in air, as it is associated with a reduced heat production. In other words, carbon dioxide formation, while the animal is in a nitrogen atmosphere, does not have its origin in oxydative processes at the cost of stored up oxygen. I regret that I am unable to accept these arguments as conclusive evidence against the assumption of an oxygen reserve, as this question cannot be decided by the use of such methods. Lesser does not measure the amount of carbon dioxide until the end of his experiments, that is, he learns merely the entire carbon dioxide production during a period of many hours. No conclusions can be drawn from this as to the conditions existing in the first period of time, directly after the animals have been subjected to an atmosphere of nitrogen. It is quite possible that subsequent to the change to nitrogen an oxydative carbon dioxide formation may have continued in decreasing degree, without this being shown in the final result. The problem of the existence of a reserve supply of oxygen is in no way solved by these experiments.

In assuming the presence of a reserve supply of oxygen in the cell we must above all entertain no false conception as to its amount. This must be, as I have often had occasion to emphasize, exceedingly small and in no way comparable with the great masses of organic reserve substances contained in the cell. The assumption, especially for the nerve centers of the frog, that the excitability remains after complete exclusion of oxygen must be looked upon as demonstrating a reserve supply of oxygen, would oblige one to suppose the presence of such a small store of oxygen that it would be completely exhausted by continued activity in room temperature within ten to twenty-five minutes. Strychninized frogs, in which the blood has been replaced by an oxygen-free saline solution, lose, as I have shown,[74] their excitability completely within ten to twenty-five minutes after the blood has been displaced. Nevertheless the assumption of the existence of a small oxygen supply in the cell can hardly be evaded. It must not be imagined that the moment the blood of the frog has been replaced with an oxygen-free solution, there is not a trace of oxygen left in the organism. Were such the case, the irritability, if measured by the extent of the response, would sink momentarily to a very low level, for the anoxydative disintegration processes are associated with an incomparably smaller production of energy than those of oxydative disintegration. We see, however, that the irritability in the muscles, nerves and nerve centers of the frog even after the complete withdrawal of oxygen at first remains practically at the former height and only very gradually decreases. Above all it would seem to me to be in the interest of the preservation of the organism and especially of those parts in which there is a high energy production and particularly those substances in which energy production predominates, that the material necessary for its formation is always at its disposal in sufficient quantity. Otherwise the capability of action of the organism would be impaired at every moment or at least suffer great fluctuations.

In accordance with this we must suppose that under physiological conditions all those substances required to replace the disintegrated molecules are always present in the cell in sufficient quantity and suitable form to replace at once those lost by excitation. Further, without doubt, in the organism which is always aërobic, oxygen must be present in certain quantities to assure at any moment oxygen replacement following oxydative disintegration, to guarantee sufficient amount for succeeding stimulation.

A further question arises: How is it that the material lost in disintegration is always replaced in just sufficient quantity to establish the metabolic equilibrium? In short, how are we to understand in a mechanical sense the self-regulation of metabolism?

In the preservation of metabolic equilibrium, we have a process before us, the principle of which is nowadays restricted to living substance. In my “Biogen hypothesis,”[75] I have associated the self-regulation of metabolism with the chemical equilibrium in interreacting masses. I have considered the metabolic self-regulation as the expression of the formation of a mass equilibrium between the quantity of foodstuffs and the quantity of a hypothetical combination of living substance, the biogen, which continuously disintegrates and builds up again of its own accord. In fact, however, we have in the chemical equilibrium of reacting mixtures in the non-living world, a principle which is completely analogous to the self-regulation in living substance. The chemical facts are, indeed, well known. If we take the classical example of the formation of ethylacetat from acetic acid and alcohol, we have a case of an inanimate system, in which the amounts of the reacting substances are in constant equilibrium. The reaction following the mixture of equal amounts of alcohol and acetic acid is as follows:

¹⁄₃ Mol. C₂H₅OH + ¹⁄₃ Mol. CH₃COOH
= ²⁄₃ Mol. CH₃COOC₂H₅ + ²⁄₃ Mol. H₂O.

In this reaction there is an alteration only in the absolute quantity of the individual constituents but never in the relative amount. In the living system we have a completely analogous instance, which apart from its course differs from the inanimate example merely in the following points: In the first place, certain quantities of substances reacting on each other are continually introduced into and certain reaction products continually removed from the living system. Secondly, the reacting mixture of the living substance is not homogeneous, and at the same time is more complicated than that of the inanimate example. Thirdly, the sum total of the reaction is not reversible in its entirety. The question arises, should any essential difference between metabolic self-regulation and the maintenance of chemical equilibrium be assumed upon this statement? I must confess that this does not appear to me to be the case. The fact that organisms exist in a stream of substances by which their nutrition is introduced and the metabolic products removed, cannot have any influence on the state of equilibrium so long as the conditions are again and again replaced in the same manner. The equilibrium can only be influenced when the introduction of foodstuffs or the output of metabolic products is changed in value. Then they occur as the inanimate example, when various amounts of material are brought together. A new equilibrium takes place, having a higher or a lower mass level. This is also true in the living substance, in growth and in atrophy. The equilibrium is disturbed as happens in the inanimate reacting mixture, where different quantities of reacting substances are brought together. In both instances we have in principle a conformity of behavior of the inanimate and the living system. Secondly, as far as the greater complexity and inhomogeneity of the living reacting mixture is concerned, it is self-evident that this likewise does not constitute an essential difference, for we are acquainted with conditions of equilibrium in chemical reactions possessing a number of members and in inhomogeneous mixtures. Finally, the fact that the reaction in the living system is not totally reversible, forms no barrier to the assumption in principle of metabolic self-regulation as a chemical equilibrium. It is quite possible to conceive of a chemical equilibrium in a reacting mixture, of which only certain constituent processes are reversible, without the totality of the reactions as a whole being necessarily so. Let us assume, by way of example, that the assimilative processes of the metabolic chain are reversible, then under constant quantitative relations of foodstuffs, following every disintegration of assimilative products with removal of the decomposition products, the same amount of assimilatory processes is required for building up. And this is just that which we observe in metabolic equilibrium. Accordingly, we may look upon the metabolic equilibrium as a special, although a very highly complicated, instance of chemical equilibrium, and we may explain the metabolic self-regulation following a dissimilative excitation of the same, by those principles on which the rebuilding of chemical equilibrium is founded. It is true that the special details of this process can be differentiated in only that degree in which it is possible to penetrate at all into the details of metabolism of the given cell form. In this, as is well known, the advance is extremely slow.

The rebuilding process following decomposition of living substance in response to an excitating stimulus consists not merely in compensation for the decomposed atom groups but also in the removal of disintegration products. This removal can be accomplished, in so far as simple chemical substances such as carbon dioxide and water are concerned, by diffusion. Observations have shown that the semi-permeable protoplasm surface is pervious to water and carbon dioxide. The latter can, therefore, depending upon the amount of concentration, be eliminated from the living substance. Output of water likewise takes place in so far as the specific water content of the living substance is exceeded and which is osmotically regulated by its amount of salt content. When, finally, osmotic pressure within the living cell and in the surrounding medium is equal, the interchange of water ceases. All these processes are explained by diffusion. Self-regulation takes place in this regard simply by osmotic means. The conditions in respect to those decomposition products consisting in more complicated organic combinations, such as lactic acid, fatty acids and nitrogen derivatives of protein disintegration, are somewhat different in that the protoplasm surface possesses the property of hindering the passage of these substances into the medium. These are, as is well known, first transformed by secondary chemical processes into transfusable substances. In this transference the oxydative decomposition with the formation of simpler substances plays the most important rôle, so that the substances thereby formed, namely, carbon dioxide, water and ammonia, are osmotically eliminated as the result of the selective permeability of the surface of the protoplasm. In this way the living cell rids itself of the useless products of metabolism.

Finally, the question remains, is the original state, as it existed before the influence of the stimulus, really completely recovered by metabolic self-regulation, or does even individual excitation of brief duration produce a continued change in the protoplasm? It is quite impossible to prove that such an effect follows the momentarily acting single stimulus, if stimulation has not exceeded the physiological limits of intensity. Should it exist, it must be imperceptible. Nevertheless, it ought to be possible by frequently repeated application of the stimulus to increase this which is imperceptible to an extent in which it is perceptible. This is, indeed, the case and is manifested as we have already seen in the increase of the volume of living substance by frequently recurring functional excitation. We can, therefore, assume with great probability that even the momentarily acting individual stimulus produces, although not perceptible per se, lasting effect in the cell. The functional excitation must be followed secondarily by an increase of the assimilative phase of the entire cytoplastic metabolism. Otherwise the taking place of the increase of volume of the living system following frequent excitation of the functional constituent members of metabolism, is unintelligible. But how are we to interpret these secondary results from a physical standpoint? First of all, it must be stated that we do not know of such hypertrophy following activity in unicellular organisms, but only in the tissues and organs of multi-cellular forms, in muscles, nerve cells, glands, etc. In the cell community of the vertebrates, however, the studies on the relations between activity and the blood supply of the particular tissue or organ furnish a physical interpretation for the existence of the functional hypertrophy. The active portions show a dilation of the blood vessels, therefore an increased supply of blood and consequently an increase in the circulation of lymph. In other words: the supply of nourishment to the individual cell and the removal of the metabolic products in a unit of time is increased. The preceding discussion of the dependence of the conditions of equilibrium upon the quantitative relations of the reacting substances makes it clear that under these conditions a metabolic equilibrium on a higher quantitative level must occur; that is, the living substance must increase in amount just as in the inanimate example the absolute amount of the æthylacetat increases if more alcohol and acetic acid are introduced to an equal degree. Some time ago[76] I expressed the opinion that the increase of the blood supply in a functionally active organ must be based on a physical self-regulation, which takes place as a result of the fact that metabolic products of the tissue cells influence the cells of the vessel walls in that part, so that the vessels dilate and more lymph is formed. In the meantime this has been proved to be indeed the case. Schwarz und Lemberger[77] and Ishikawa[78] have shown that especially the weak acids, which are produced in larger amount as a result of strong activity of the cells, bring about vessels’ dilation. By the demonstration of this highly important process of self-regulation the last link has been added for the physical understanding of the hypertrophy of activity of the tissue cells by continued functional excitation. Whether or not the same applies to the single living cell, if the unicellular organism likewise undergoes a quantitative increase by a continuous functional excitation, and if the single cell possesses in itself a corresponding mechanism of self-regulation similar to the cell community in the vertebrates, cannot be answered, for concerning all these problems information is lacking for the present.

CHAPTER VI
CONDUCTIVITY

Contents: Only processes of excitation are conducted, not processes of depression. Conduction of excitation in its two extreme instances. Conduction in undifferentiated pseudopod protoplasm of rhizopoda. Conduction of excitation with decrement of intensity and rapidity. Conduction of excitation in the nerve. Rapidity of conduction of excitation without decrement. Relation between irritability and conductivity. Conduction of excitation with decrement of the nerve after artificial depression of irritability by narcosis. Theory of the decrementless conduction of the normal nerve. Proof of the validity of the “all or none law” in the medullated nerve. Theory of the process of the conductivity of excitation. Theory of core model (Kernleiter). Electrochemical theory of conduction based on the properties of semi-permeable surfaces.

When the response to a stimulus is studied in a living system, whether it be a single cell, a tissue, or a complex organism, the indicator used, either that of movement, current of action, production of certain substances, the development of light, of heat or the alteration of form, is the result of two distinct processes. The first of these is primary excitation, brought about by the stimulus at a local point, and the second is an extension of the excitation to the surrounding tissue. We are not in a position to experimentally bring about a response to stimulation, in which the primary excitation occurs and not the secondary process, that of conductivity. All living substance contains this property, although to a very different degree, as all living substance possesses irritability, and this presents the condition not only for the taking place of the process of excitation but also that of its conduction.

If I here speak only specifically of the conduction of excitation instead of the conductivity of response to stimulation this is not only primarily for the reason that we intend especially to analyze the conductivity of excitation on this occasion, but also because no other effects of stimulation except those of excitation can be conducted from the part affected by the stimulus to the surroundings.

Although considered on theoretical grounds it appears more or less improbable that depression is extended from the place of its origin, it is very easy to convince one’s self experimentally of the fact that depression following a stimulus is invariably localized to that portion directly affected by the stimulus. The nerve furnishes a very favorable object for this purpose. If a nerve muscle preparation of the frog is made and introduced in the glass chamber previously described containing platinum electrodes, and another pair is applied to the nerve between the chamber and the muscle, it is possible to subject the stretch of nerve in the chamber to various agents, producing a paralyzing effect. In this way it may be exposed to an atmosphere of pure nitrogen for example, or to narcosis as by ether, chloroform, carbon dioxide and other gases, to an increase in temperature or to other agents, without these in any way affecting the irritability of the nerve stretch situated over the electrode between the chamber and the muscle. The contractions of the muscle, which are produced by stimulation of the periphery region of the nerve with stimuli of a definite strength, remain unaltered, even when the asphyxiated stretch of nerve in the chamber is already completely degenerated. The central depression of a ganglion cell of a motory neuron is likewise wholly without influence on the degree of excitability of its nerve fiber, as I was able to demonstrate[79] in the reflex inhibition of the motor neurons of the spinal cord of the dog. (Figure [14].) That which is conducted by the nerves is solely the process of excitation.

It is our task to analyze in detail the conditions involved in the conduction of excitation in order to obtain a deeper insight into the physics of this process. A comparative survey of a series of various types of living substance shows us that they differ in respect to the conduction of excitation in the following points: In regard to the rapidity with which the excitation is conducted, the extent of the area over which it spreads, and the intensity with which it extends. These conditions may be best illustrated by citing two extreme examples. The one is formed by the rhizopods, the other by the nerve fibers. Between these two extremes we have manifold gradations in the conditions of conductivity. Not all cell forms are suitable objects for the study of conductivity. There are forms of rhizopods which are as favorable to investigation as the nerve; this is due to the fact that, although they are often of microscopic dimensions, they possess elongated fingerlike or threadlike pseudopods.

Fig. 14.

Contractions of the musculus extensor digitorum communis longus of the dog, brought about by rhythmic stimulation of the nervus peroneus. The muscle is in the condition of tonic excitation which proceeds from the center. The arrows indicate the point where reflex inhibition of the central tonus is produced. The height of the single contraction undergoes no diminution.

Indeed, a rhizopod cell, with its straight, elongated pseudopods, is preëminently fitted as an object of comparison with a neuron. Although the difference in respect to the individual points is so far-reaching, still, based on their outward morphological similarity various physiological parallels in both are forced on our observation. A comparison of the rhizopod cell with the neuron can consequently guard us from many erroneous generalizations which we might be inclined to deduce from a one-sided investigation of the nerve. This is especially the case in regard to the conductivity of excitation, which was formerly studied almost exclusively on the nerve and only occasionally on the muscle, which offers similar conditions. The nerve, in which the function of the conductivity of excitation is particularly highly developed, was considered at the same time as the type in which this process could be most readily analyzed, and from which it was believed general information of the process of the conductivity of excitation could first be gained. This view has led to serious errors, as the nerve, resulting from the high development of its conductive capability, shows quite one-sided specialized conditions, which can by no means be transferred to other forms of living substance.

A very suitable object among rhizopods for the study of conductivity, and which is everywhere easily procured, is Difflugia. This species living in small pools has a delicate urn-shaped, pear-shaped or flask-shaped capsule built up of sand grains, diatomes or material produced by the organism itself. From the opening the protoplasm extends often to a considerable length its finger-shaped hyaline pseudopods. When Difflugia is placed in a flat dish in water and observed under the microscope, it is frequently seen to extend from the opening long pseudopods in exactly opposite directions, which reach for a considerable distance on the bottom. These offer particularly favorable conditions for the study of the conduction of excitation. When this animal is placed under a microscope, the pseudopods are very readily stimulated at any position to a desired extent by means of a sharp needle, to which fat has been previously applied and subsequently the excess removed. The extension of the response from one point toward the other can then be followed with great ease. The pseudopod of the rhizopod has the great advantage over the nerve that its excitation can be directly observed. The excitation following weaker stimulation is manifested by a wrinkling of the previously completely smooth surface; stronger stimulation produces differentiation of the hyaline protoplasm to a strongly refractive strand in the axis and a turbid myelinlike mass at the periphery, the pseudopod at the same time retracting toward the central cell body. In spite of all these occurrences being of microscopic dimensions, still with some practice it is quite possible to experiment on them under the microscope. In this way I found it comparatively simple to study the fundamental principles of conductivity.[80]

Fig. 15.

Difflugia urceolata. A—Weak local stimulation at the end of a long extended pseudopod. B—Stronger local stimulation applied to the end of a long pseudopod.

Fig. 16.

Difflugia urceolata. A—In non-stimulated condition. B—The same individual locally stimulated in the middle of a long extended pseudopod. The excitation spreads in both directions, centripetal as well as centrifugal.

All these factors, the intensity with which the excitation extends from the point of stimulation, the rapidity of the extension, and finally the area over which conduction takes place, are manifestations of the intensity of stimulus, and as such alter with these in corresponding manner. If the end of a pseudopod is barely touched and thereby weakly stimulated, the response is restricted to a slight wrinkling of the surface, which slowly extends to the immediate neighborhood, whilst the more distant parts of the pseudopod are not affected at all by the excitation. (Figure [15], A.) On a stronger stimulation of the pseudopod by slight pressure, the response is likewise stronger, and the characteristic differentiation of the protoplasm, consisting in the strongly refractive strand in the axis and the turbid myelinlike outer mass, appears at the point of stimulation. From here a peculiar alteration spreads gradually further over the pseudopod, in that first upon its smooth surface a few myelinlike droplets are seen, which become larger and with the development of the strand in the axis, dissolve into a wrinkled mass on the surface. The further this process extends from the point of stimulation, the weaker it becomes and the more slowly it proceeds, until at last there is complete disappearance. (Figure [15], B.) The pseudopod has at the same time retracted to a considerable degree. If a still stronger stimulus is applied by firm pressure at the end of the pseudopod the process takes place with much greater violence. The differentiation of the protoplasm spreads centripetally from the point of stimulation over the whole pseudopod with great rapidity, and produces a quick retraction in the same, then involves the oppositely directed pseudopod, in which it then extends more and more slowly, until, proceeding in a centrifugal direction, it is at last gradually completely obliterated. When strong stimulation is applied, the process occurs with such rapidity that the contraction of the pseudopod is almost twitchlike. As the rapidity of the conduction alters within a wide limit according to the strength of the stimulus and the distance from the point of stimulation, it is self-evident that no constant figure can be stated. To give a general idea of the rapidity, they might be estimated according to observations I have made with second watch and ocular-micrometer as from within a slight fraction to that of a millimeter in the second. When a very long extended pseudopod is locally stimulated in the middle, the response spreads from the point affected in both directions diminishing in intensity and rapidity. The excitation extends equally in all directions. (Figure [16].) These facts show very clearly that in Difflugia the excitation following a localized stimulus is dependent on the intensity of the stimulus, and that according to the degree of this, the wave progresses in either stronger, more rapid and extended, or weaker, slower and more limited manner. With the greater distance from the point of stimulation the excitation undergoes an increasing decrement of its intensity and rapidity of conduction. Different species of Difflugia which I have investigated, Difflugia lobostoma, urceolata, pyriformis, have shown a complete conformity in this respect. A great number of other fresh water and marine rhizopods, the pseudopods of which I have used for analogous experiments, although differing in the manner of reaction in regard to the extent and rapidity of the course of excitation, manifest exactly the same fundamental principles. A very favorable form is, for instance, the much smaller Cyphoderia margaritacea, which is distinguished by a somewhat higher degree of excitability and rapidity of reaction.[81] The long straightly extended pseudopods are thinner and more threadlike than those of Difflugia and show upon stimulation as a result of their local excitation a simple contraction into clumps of the stimulated protoplasm without the characteristic differentiation of that of Difflugia. (Figure [17].) In the case of the marine rhizopods, Orbitolites (Figure [19]), Amphistegina, etc., which I investigated at the Red Sea, the conduction of excitation takes place also as in Difflugia with a decrement of intensity and rapidity becoming larger with the distance from the point of stimulation until the wave of excitation is obliterated.

Fig. 17.

Cyphoderia margaritacea. Result of localized mechanical stimulation at the end of a long extended pseudopod. A, B, C—three successive stages.

Fig. 18.

Cyphoderia margaritacea. Result of localized mechanical stimulation in the middle of a long extended pseudopod.

Fig. 19.

A pseudopod of Orbitolites complanatus (cf. Fig. [7]). a—In normal condition. b—Severed by a cross section near the end. b-f—Five successive stages of the effect. b-d—The pseudopod retracts by centripetal flowing of the protoplasm contracted in the shape of microscopic balls and spindles. e and f—The pseudopod begins to extend again. The centripetal flowing balls and spindles begin to disappear.

A sharp contrast to this type is formed by the other extreme as represented by that of the medullated nerve. As an indicator of the course of excitation we will take the action current in an isolated nerve of the frog. If this is stimulated at one end, we can test the intensity of the conducted excitation by leading off the action current from two points at varying distances from the one influenced by the stimulus. Since the classical discovery of Du Bois-Reymond of the action current of the nerve, we know that in the fresh medullated nerve, if observed under favorable experimental conditions, no decrement of intensity of excitation during its course from the point of stimulation along the length of the nerve can be demonstrated.[82] If unpolarizable electrodes are applied to a nerve in such a position that they are equidistant from the cross section and are connected with apparatus for testing the current, it will be found that there exists an “unwirksame Ableitung” in the sense of Du Bois-Reymond, that is, in which there is no demarcation current. When a tetanizing current is applied to one end of the nerve, no difference of potential between the two nonpolarizable electrodes is observed, which indeed would be the case if excitation with its current of action would have a decrement on its way from one to the other point of leading off the current. This fact, which has been repeatedly confirmed, shows us that the medullated nerve, under normal conditions, conducts excitation without a perceptible decrement of the intensity.

This specific property of a medullated nerve is in conformity with the conditions in connection with the rapidity of conductivity. Since Helmholtz[83] has devised the method for measuring the rapidity of conduction in the nerve, this investigator himself and numerous others have studied the rate in different nerves.[84] Helmholtz found the rate for motor nerves of the frog to be 27 meters per second, for the sensory nerves of man 60 meters, and the motor nerves of man 34 meters. Other investigators have obtained quite different results; Hirsch, for the sensory nerves of man, 34 meters; Schelske, for the same, 25–33 meters; De Jaager, 26 meters; v. Wittich, 34–44 meters, and Kohlrausch, 56–225 meters; v. Wittich for the motor nerves of man, 30 meters; Piper[85] finally in the most recent investigations about 120 meters in the second.

These differences may be explained in a large measure by the variety of the methods used, in part also by the difference in the structures. The methods employed for the study of the velocity have also been used to solve the question, whether the velocity of the excitation wave in its course over the nerve meets with a decrement as it moves further and further away from the point of stimulation. Here the endeavor was made to study the difference in time of the latent period, which is observed by the indicator, when the nerve is stimulated at two points at different distances from the muscle, used as an indicator, or from the wires leading the current to the indicator. The more recent investigators, as René Du Bois-Reymond,[86] Engelmann,[87] G. Weiss,[88] have arrived at the same conclusion, that the rate of conductivity in the medullated nerve under normal conditions is the same at all distances from the point of stimulation. (Figure [20].)

The medullated nerve shows, therefore, under normal conditions neither a decrement of its conductivity, nor of its irritability, as the distance of the wave of excitation increases from that of the position of stimulation; this means, in other words, that excitation is conducted with the same intensity with which it is started, and with a constant rate throughout the entire course of the nerve.

Fig. 20.

Curves of muscle contraction obtained by stimulation of 3 and 4 points situated at equal distances from each other on the sciatic nerve of the frog. The increase of length of the nerve stretch corresponds with an equal increase of the latent period of contraction. From this follows, that the rapidity of the wave of excitation is the same at all points of the entire length of the nerve. (After Engelmann.)

There is, nevertheless, a third point of considerable difference between the types of conduction of excitation in the rhizopods and in the nerve. Whereas in the rhizopods the rapidity of conduction is dependent upon the intensity of the stimulus, it has been long known as the result of investigation by Rosenthal, Brücke and Lautenbach and at a more recent date by Gotch[89] and Piper,[90] that in the nerve of the frog, as well as in man, the velocity is not dependent upon the intensity of stimulation. (Figure [21].) Contrary results have been obtained by a few early observers wherein the latent period was shorter when the stimulation was strong. Nicolai[91] explains this shortening of the latent period, resulting from the application of strong electrical stimuli, to a spreading out of the “Stromschleifen” from the point of application and consequently there is a shortening of the stretch of nerve between the point of stimulation and the indicator.

Fig. 21.

Course of the action current of the nerve. The thin line indicates the action current produced by a weak, the thick line the action current produced by a strong stimulus. The duration of the action current is the same in both cases. (After Gotch.)

This conspicuous difference in the conduction of the two extreme types of living substance, which we have already observed, arouses the question as to what properties of living substance bring about these differences. In order to answer this question, it is necessary, first of all, to make some general statements concerning the processes of conductivity.

As already emphasized, all living substance possesses the capability of conducting excitations to a definite degree. We may, therefore, assume that the same fundamental property of conductivity exists in all substances. A fact to be considered in the conduction of excitation, is that the primary breaking down of the complex molecules at the position of stimulation act in turn as exciting stimuli upon the neighboring portion of the living substance, which in turn undergoes a similar decomposition. And so this process continues. This fact is evident from the observations on the process of excitation. But the nature of the stimulus which produces the breaking down of the complex molecules upon the surrounding molecules is a problem which can only be studied later. Here only one point will be mentioned in advance concerning the intensity of the stimulus. It is apparent from the experiments on the rhizopods, that the greater the intensity of the stimulus the more extensive must be the breaking down of the living substance. A stronger primary stimulation must also secondarily produce a stronger stimulus in the neighborhood. In other words: the conduction of excitation is a function of irritability. The greater the irritability, that is, the greater the number of molecules broken down in a unit of time and space by a stimulus of a certain intensity, the greater also is the conductivity of the living system, that is, the stronger, the more rapidly and the further excitation is extended. Conductivity of excitation is, therefore, unthinkable without irritability. Both are inseparably connected. The conclusion forced upon us by this chain of reasoning admits of no argument. Nevertheless the endeavor has been made, because of certain evidence at hand, to show that the property of conductivity could exist without irritability. A number of authors, such as Schiff,[92] Erb,[93] Grünhagen,[94] Effron,[95] Hirschberg[96] and G. Weiss,[97] have observed the fact that in spite of a more or less strong decrease of excitability of a stretch of nerve, stimuli applied above this stretch can still produce a conduction of excitation through the affected part. They have concluded from this that it is possible to separate the conductivity from irritability. Erb and G. Weiss have even gone so far as to directly express the opinion that capability of conduction and irritability involve two different histological elements. In contrast to this, other investigators, such as Hermann,[98] Szpilmann and Luchsinger,[99] Gad,[100] Piotrowski[101] and Wedenski,[102] have more or less decidedly taken the stand that an actual separation of irritability and of conductivity does not exist. The apparently contradictory evidence as well as the conflicting theoretical views have been cleared up by Werigo,[103] Dendrinos,[104] Noll[105] and Fröhlich.[106] These investigators have shown that the length of the narcotized stretch of the nerve plays an important rôle in the obliteration of conductivity. It has been found by the application of a stimulus above the narcotized stretch of nerve, that the longer this stretch is, the less is the reduction of irritability which obliterates the excitation wave reaching this area. Further: The shorter the stretch, the greater must be the reduction in irritability before this result is brought about. (Figure [22].) In other words, the conductivity in the narcotized nerve is dependent upon the length and the irritability of the narcotized stretch. From this observation the important fact is evolved, that the wave of excitation meets with a decrement of its intensity in the narcotized area. This decrement becomes larger as the wave progresses through the involved stretch. Further it is progressively increased as the amount of the irritability is reduced. Finally, when the stretch is long enough, the wave of excitation is obliterated. This important fact has been further established by the experiments of Boruttau and Fröhlich,[107] in which they studied the intensity of the current of action, produced by a wave of excitation, from two points in the narcotized stretch. The wave of negative variation, brought about by the excitation, gradually decreases in the narcotized stretch as the electrode is further removed from the point of entrance. Beside a decrement of intensity, as the investigations of Fröhlich[108] prove, the wave of excitation shows a decrement of the velocity in the narcotized stretch. And it is probable that the wave of excitation extends with progressive reduction in the velocity, corresponding to the decrement of intensity. The work of Koike[109] under the direction of Garten, in which the conclusion arrived at is that the reduction in the velocity is the same throughout the narcotized area, should not be accepted as conclusive in spite of the delicate method employed. These investigations are extremely difficult, being in the field of the most delicate of present-day methods. The decrement, which the wave of excitation meets with in its progress in the narcotized stretch, makes the conflicting testimony concerning the apparent separation of irritability and conductivity intelligible. It depends entirely upon the length of the narcotized area, and the amount of reduction in irritability on the one hand, and the strength of the stimulus used for testing the irritability on the other, whether the conductivity will disappear before the irritability or vice versa. If I test the irritability in the narcotized stretch with a weak stimulus, just slightly above the threshold, then by slight reduction in the irritability complete absence of response occurs, when the same stimulus is applied. This occurs at a time when excitation reaches the narcotized area from above and meets with a decrement so slight that it can pass through the whole narcotized stretch, that is, when the narcotized stretch is short enough. If I test the irritability of the narcotized area with a strong stimulus, far above that of the threshold, irritability will be found to be present at a time when the conductivity for the excitation, coming from above, is already obliterated. This is due to the fact that the decrement in the narcotized area is already great enough to bring about the complete disappearance of the wave of excitation coming from above. This, of course, only occurs provided the length of the narcotized stretch is great enough. The separation of conductivity and irritability is, therefore, only an apparent one. In reality, the facts obtained from experimentation indicate that with the reduction of irritability the decrement of the wave of excitation increases, whilst the shorter the stretch, the smaller is the decrement. This shows that conductivity is a manifestation of irritability.

Fig. 22.

Scheme of the decrement of the excitation wave in the narcotized stretch of a nerve. A—The narcotized stretch (indicated by the cross section of the chamber) is 30 mm. long. The ordinates of the dotted lines indicate the amount of the decrement. If the decrement is slight (upper dotted line), the excitation wave passes the narcotized stretch and increases again on entering the normal stretch. If the decrement is great (lower dotted line), the excitation wave is obliterated towards the end of the narcotized stretch and the muscle remains at rest. B—The narcotized stretch is 15 mm. long. The decrement is slight. The excitation wave can therefore pass into the normal stretch and here increase again. C—The narcotized stretch is 15 mm. long. The decrement is great. The excitation wave is obliterated, therefore, in the narcotized stretch, and the muscle remains at rest.

The facts just mentioned have, however, a much deeper meaning. They show us that it is possible by means of narcosis to convert an extreme type of a living system, with decrementless conductivity, into another extreme type of living substance, in which excitation in its progress meets with a strong decrement, like that seen in the rhizopods. The same results may also be obtained by asphyxiation and other forms of temporary and permanent injury of the nerve. We are, therefore, in the fortunate position in the case of the medullated nerve of having a substance to study, which, depending upon conditions which are under our control, may become a type in which conductivity occurs with or without the presence of a decrement. We can likewise reduce the irritability to various degrees, producing all intermediate gradations between the two extremes. This latter is particularly valuable in that it permits us to study the conditions in one and the same substance necessary to bring about the various peculiarities of conductivity. The great differences in the conductivity of excitation are conditioned by variations in the degree of irritability. If the irritability of the nerve is at the normal level the wave of excitation progresses to the end of the nerve without manifesting a decrement of its intensity or rapidity.

If the level of irritability of the intact nerve is artificially reduced, the wave of excitation meets with a greater decrement and reduces in velocity, and in fact disappears the more quickly in the stretch of nerve, as the reduction in irritability is increased. These three factors, irritability, intensity and velocity of the progress of the wave of excitation, are inseparable. All living substances may be grouped according to their capability of conducting excitation into a long series, starting with those possessing the least irritability, as we found in the rhizopods, then those having greater irritability, as the smooth muscle and ganglion cells, then those with still greater irritability, as the striped muscle, and finally those having the greatest degree of irritability, as the medullated nerves of the warm-blooded animal. Should the processes of excitation, as we saw, result from the energy production following the disintegration of the labile molecules of the living substance, then the degree of irritability is determined by the chemical constitution of the disintegrating molecules, by the number of molecules which are broken down in a definite space and a given time, and by the nature of the disintegration itself. All of these individual components, if we observe the problem from the physical standpoint, are manifested by the quantity of energy production. The higher the irritability of a living system, the greater is the amount of energy production in a given time and space which the stimulus produces. This has particular interest from the standpoint of the extreme cases of medullated nerves of the vertebrates with their most highly developed conductivity, and which will be analyzed in somewhat greater detail. How are we to explain their decrementless conductivity? When we study the decrement of the excitation wave in the series of living substances, before alluded to, we see that this reduces with a progressive increase of irritability. Consequently the extreme irritability of the nerve is a manifestation of its decrementless conductivity. If we study the course of a process of excitation and its conduction in its molecular details, the fact of the decrementless conduction indicates that in excitation, produced by a stimulus, the same number of specific molecules capable of disintegration are broken down in the same manner at every following cross section, as at the point of stimulation; or in other words: an equal amount of energy is set free at every cross section, which, in its turn, acts as stimulus to the next, etc. Such a condition presupposes, however, in an elementary fiber of the nerve, that by the conduction of the wave of excitation from cross section to cross section, all those molecules capable of disintegration are broken down. If it is assumed that the entire number of molecules capable of disintegration do not break down, but only a certain per cent. of the same, then it would not be possible to conceive of a molecular structure of the nerve in which this would take place without decrement of the wave of excitation. With the assumption of a generally homogeneous molecular structure (Figure [23], a) of the elementary fibers it would be entirely incomprehensible how, with the decrementless extension of the excitation, individual molecules capable of breaking down could escape disintegration. If, on the contrary, the molecular structure is not homogeneous it only is possible to explain a conduction, on each cross section of which an equal per cent. of irritable molecules break down, by the hypothesis that the irritable molecules are in their turn ordered in fiber-shaped series (Figure [23], b) within the elementary fiber and are thus protected to a certain degree from one another and from transverse conduction of excitation. This hypothesis would, therefore, only mean that the elementary fiber is not such in reality and would thus transfer the difficulty to the ultimate fiber unit, for which a homogeneous molecular structure would have to be presumed. In short, whatever may be the assumption on which molecular structure of elementary fibers is based, the fact of the decrementless conduction peremptorily demands, from the physical standpoint, that from cross section to cross section the entire number of irritable molecules are broken down. This conclusion is highly important, for it indicates very clearly that the “all or none law” is applicable to the nerve.

Fig. 23.

This gives us occasion to return to the discussion of the question, if living systems really exist which respond in accordance with the “all or none law.” The medullated nerve forms an object particularly suited to serve as a starting point for the treatment of this especially important problem. The question arises in this connection, if the validity of this law for the nerve can be tested by other means.

At first it would seem as if the application of the “all or none law” to the nerve were in contradiction to the well-known fact that a weak stimulation of the nerve produces a weak, a strong stimulation, a strong response. In this connection Gotch[110] has pointed out, as the result of experimental studies of the wave of activity of the nerve, that the difference in response, following the application of stimuli of varying strengths, is understandable from the fact that threshold stimuli stimulate only a few of the fibers of the nerve trunk, whereas progressively increasing the intensity of the current involves more and more fibers. There can be no doubt that this factor explains the difference in the strength of the response. Therefore, in reality we do not find here a contradiction of the “all or none law.” On the other hand, the fact that the nerve, in contradistinction to many other forms of living substance, the ganglion cell, for example, upon a weak stimulation does not show the phenomena of summation, even when the stimuli follow each other in a rapid succession, indicates very strongly that the weakest operable stimulus produces maximal excitation, so that the response cannot be further increased. But above all, there is a series of facts, which have been gained in the Göttingen laboratory, which demonstrate apparently without doubt the validity of the “all or none law” for the medullated nerve. These observations I wish now to consider in greater detail.

If a nerve of a nerve muscle preparation is drawn through a specially devised glass chamber so that the middle portion can be narcotized or asphyxiated and the nerve so arranged that it rests upon a pair of electrodes in the chamber and upon a second pair without the chamber and centrally located, then the nerve can be narcotized or asphyxiated and thereby the alterations in the irritability as well as the conductivity can be followed. In order to obtain as distinct a picture of this alteration as possible, I tested continuously the threshold of stimulation, which just produced minimal contraction in the muscle, and Fröhlich[111] continued these observations. As a result the following very remarkable conditions were observed. During the increase of the depth of narcosis or asphyxia the irritability sinks more and more with regularity. The conductivity remains unaltered for a long time, as the strength of the threshold stimulus is not changed until irritability has fallen to a definite point. When this is reached, conductivity disappears. (Figure [24].) The most important point in this connection, however, is, that the conductivity disappears simultaneously and practically momentarily for the excitation produced by both weak and strong stimuli. When the stimulation at the electrode placed centrally to the chamber does not bring about response for threshold stimuli, maximal stimuli at the same time also become inoperative. This is a very interesting point, the importance of which has not until now been recognized. This fact is not in harmony with the view held until now, that in the nerve fiber different strengths of stimuli bring about excitation of different intensity, and are then conducted. Let us now clearly comprehend this problem.