Irritability: A Physiological Analysis of the General Effect of Stimuli in Living Substance

by Max Verworn

Scheme of the simplest reflex arc from one to the other side, and from a higher to a lower level.

Finally, I wish to conclude this discussion on the origin of central inhibition and its dependence upon the strength of the stimulus by referring to a point which apparently is contradictory. We have already met with the fact that series of stimuli by their interference in the nervous system may have different effects depending upon their intensity; if this is strong, we obtain summation of excitation, if weak an inhibition. The question may be asked, how is it possible that a weak stimulus can have a different effect when it is believed that the nerve as an isobolic system responds to intensities of all gradations to the same extent, namely, with maximum excitation? If the “all or none law” is applicable, then the same intensity of excitation is always carried to the centers and yet we see that various kinds of responses follow various intensities of stimulation. Here, indeed, is a difficulty which has not as yet been explained. Naturally between the two facts there can be no contradiction. But the question arises, how are we to bring them into harmony? Two entirely different possibilities present themselves. If the various intensities of stimulation always bring about excitation of the same strength and we see in spite of this that various intensities of stimulation produce various kinds of effects, then we must think of the possibility that various intensities of stimulation bring about some other effect than that of variations in intensity in the course of the wave of excitation. In this connection variations in the time involved must be taken into consideration. One might think that strong stimuli may develop a longer wave of excitation than such of weak intensity. Gotch[199] tested these questions experimentally with completely negative results. A single strong stimulus does not result in an excitation differing in its course from that of a weak stimulus. But there is another possibility that requires testing. This was brought to light by the investigation of Thörner[200] on the fatigue of the nerve. His investigations showed that in a normal nerve in air the first typical beginning of fatigue resulting from faradic stimulation can be demonstrated in the characteristic summation of excitations. This is shown by the nerve after fifteen minutes of stimulation with faradic shocks applied for short intervals. The irritability, when tested with single induction shocks, is at the same time reduced. Thereby the amount of fatigue of the nerve, that is, the amount of the reduction of irritability, is dependent upon the strength and frequency of stimulation producing fatigue. When the nerve is stimulated with weak faradic shocks of a slow rate of frequency, there is a slight or a complete absence of the reduction of irritability. On the other hand, if the nerve is fatigued with strong faradic shocks of great frequency, the irritability falls very considerably. This shows that when the nerve is stimulated for a longer time, even under conditions favorable to the supply of oxygen, a diminution of irritability occurs and with it naturally an actual diminution of the wave of excitation, a diminution the intensity of which becomes greater as the strength of the stimulus increases. In other words, long-continued faradic stimulation converts the nerve from a system isobolic in character to that which is heterobolic in that the intensity of the excitation which is conducted differs depending upon the intensity of the stimulus. We have found other cases in the investigation of the nervous system in which, as in fatigue, an isobolic is converted into a heterobolic system. Vészi[201] has shown that the centers of the strychninized frog, which are isobolic in character, when fatigued by weak faradic stimuli can be brought to react again when the faradic stimulation is increased. According to this and other experiments of a like nature, it is beyond doubt that an isobolic system during the refractory period may assume a heterobolic character, and only after completion of the refractory period and entire recovery of the equilibrium of metabolism does the isobolic character return. This permits us to understand the characteristic properties of an isobolic system more accurately and precisely than has thus far been possible. The “all or none law” with its associated properties, such as the conductivity without decrement and the incapability of summating excitations, have in a system of this character only relative validity. They are realized only in the state of an equilibrium of metabolism. Only when the stimuli follow each other at intervals greater than the duration of the refractory period is there a response of equal extent to stimuli of all intensities which are above the threshold. During the refractory period and consequently in fatigue, asphyxia, cooling and narcosis, etc., in short, in all states in which the refractory period is prolonged this system loses its isobolic properties and becomes heterobolic. In order that there may not be a misunderstanding, we will consider more in detail the capability in this state of summation of excitations. When we refer to a summation of excitation of such a system under the influence of one of these factors, we, of course, at no time mean an increase of response beyond that of the degree of excitation which exists in an isobolic system in a normal state consequent upon the application of a single stimulus, for this degree of excitation is maximal. We refer rather to a summation which has become reduced as a result of fatigue.

On the basis of these facts it is readily understood when a level of equilibrium of lower intensity has been reached that excitation produced by weak faradic stimulation must have weaker effects than when strong stimuli are applied, for when the system assumes a heterobolic type as the result of relative fatigue weak stimuli bring about weak, and strong, stronger excitation. Consequently, during interference induced by a second series of excitations, in the first case we have the conditions favorable for inhibition, in the second for those of summation. If we also assume that this characteristic alteration of the isobolic character of the elementary nerve fibers which has been shown to occur in fatigue, as seen when continued faradic stimulation is employed, develops immediately after the beginning of stimulation then we can readily understand the various kinds of effects produced by interference observed in the reflex response following weak and strong faradic stimulation to the different nerves in spite of the fact that the nerve in the state of rest is a system isobolic in type. Experimental evidence, therefore, must be brought forward to show that faradic stimulation of short duration produces the above-mentioned alteration in the character of the system. Thörner in his experiments on the nerve stimulated it faradically at least four minutes and always found after this that excitation was reduced. After shorter intervals of stimulation Thörner made no test of the state of excitation. It is, however, highly probable that a reduction of excitation is much more quickly reached. Indeed, we are unavoidably compelled to accept the assumption that even after the first single stimulus of the faradic current, alterations of a slight degree are present which, after repeated stimulation, become constantly greater and give to the system a heterobolic character. As a result of fatigue, as we have already seen, the refractory period becomes more and more prolonged. As the individual shocks in faradic stimulation follow each other at regular intervals, a necessary consequence is that the shocks are operative before the refractory period has completely disappeared, otherwise Thörner could not have obtained fatigue produced by continued stimulation. The intervals of the individual shocks must be somewhat shorter than the duration of the refractory period, even in fatigue of a very slight degree. It is very interesting in this connection that Thörner invariably obtained positive evidences of fatigue by the application of stimuli at the rate of 10–12 per second. When the number of stimuli per second was less than this the above-mentioned result was not always obtained. From this we can easily estimate the refractory period of the nerve, which is present after reaching a state of equilibrium under certain conditions. If we assume ten stimuli per second to be the number required to produce slight fatigue when stimulation is prolonged, we can conclude that the refractory period in this state is somewhat longer than one tenth of a second. Even though Gotch in his investigations already cited placed the refractory period of the normal nerve at about .005 second, this statement is in no way contradictory to the figure which we have just given. Gotch measured simply the duration of the absolute refractory period of the normal nerve, in other words, the duration of the period in which no excitation at all could be brought about. On the contrary, my estimate, based upon the investigations of Thörner, refers to the total refractory period of the nerve, that is, to the point of complete recovery of the equilibrium of metabolism and of the specific irritability. Experimental proof of this assumption is already under way.

I have endeavored to show the elementary principles at the basis of these extremely varied interference effects and to make a few generalizations concerning the complicated conditions here concerned. It has been shown that a great number of interference effects possess characteristics in common if one takes into consideration the process occurring in the course of a single excitation. The altered state which exists in living substance until the complete disappearance of excitation is the basis upon which to explain the altered effects produced by a second stimulus. This state alters during the whole course of the first stimulus until the original equilibrium of the metabolism of rest is, by self-regulation, again reached. It is, therefore, self-evident that the second stimulus must have different effects depending upon the momentary state of the living system at the time of its application. The state of the system differs depending on the length of the interval in which the second stimulation follows the first. The most important factor is the phase of the excitation period and the reduction of irritability. The second important factor is the intensity of the second stimulus; the relation of the two with each other determines the response. But the specific properties of the given systems must also be taken into consideration. It is important to know if the living system possesses isobolic properties, that is, every intensity of stimulation produces a maximal liberation of energy, or if it possesses a heterobolic character, that is, stimuli of different strength bring about the liberation of different amounts of energy. It is further important to know the rapidity of reaction, whether the system rapidly or slowly fatigues. In all cases it depends whether the second stimulus produces a perceptible excitation or whether it occurs in the refractory period and produces no perceptible effect. Upon these factors depend the results of the interference of two rhythmic series of stimuli, whether a summation or inhibition of excitation takes place. Here is the key to the understanding of the great variety of interference effects. By determination of these various factors in a given case and their sequence, we can anticipate the nature of the interference which will follow. The complex actions brought about by the various factors, which we cannot at first clearly understand, can be at once interpreted as soon as we convert them into their elements.

CHAPTER IX
THE PROCESSES OF DEPRESSION

Contents: Necessity of cellular physiological analysis of toxic depressions by pharmacology. Apparent variety of processes of depression. Depression of oxydative disintegration as the most extended principle in the processes of depression. Asphyxiation, fatigue, heat depression, as a consequence of restriction of oxydative disintegration. Narcosis. Theories of narcosis. The alteration of specific irritability and conductivity in narcosis. Depression of oxydative processes in narcosis. Asphyxiation of living substance when oxygen is present during narcosis. Persistence of anoxydative disintegration in narcosis. Increase of the same by stimuli. Depression by narcosis as a form of acute asphyxiation. Hypothesis on the mechanism of depression of oxygen exchange by narcotics. Possibility of combining the facts with the observations of Meyer and Overton.

The processes of excitation of all the effects of stimulation are those which have invariably claimed place in the interest of physiologists. The study of the processes of depression, on the other hand, has remained more or less in the background. This is readily understood when it is considered how much more apparent the processes of excitation are than those of depression. Nevertheless, these latter possess no less importance for the course of vital phenomena than those of excitation. Without depression no excitation can take place in the vital activity of the organism, for, as we have seen, every excitation is secondarily followed by a refractory period. To this must be added the great number of primary depressions, directly brought about by the most varied stimuli, such as cold, want of oxygen, poisons, etc., without the presence of a preceding excitation. Thus it is essential that the processes of depression should be studied with no less interest than those of excitation, and it is much to be desired that the former should receive a more detailed analysis than has up to now been the case. Even as it is, extensive material has been obtained for the analysis of this group of reactions. With the closer study of the process of excitation the facts in connection with the refractory period and fatigue make it necessary that the processes of depression be taken into consideration. Toxicology and pharmacology likewise furnish innumerable effects of depression produced by poisons and drugs. Unfortunately the investigation of these reactions has been in the main purely superficial. This arises from the recency of the development of these sciences. Even later than physiology they are only now beginning to extend their investigations, directed up to the present to the grosser organic reactions, to the cellular analysis of the effects of poisons. How rarely we find instances in which the effect of some drug is studied at the point of attack and systematically followed to the specific cell form, and its primary excitating or depressing effect on this or that constituent process of the metabolic activities ascertained. And how great, on the other hand, is the number of “medicines” making their appearance each year in pharmacology of which nothing further is known than a few secondary effects on the action of the heart, the blood pressure, the secretion and excretion and on some other outwardly perceptible organic actions! This deplorable condition of present-day pharmacology must be ascribed to the regrettable circumstances that pharmacological research is only in a very small degree the result of careful investigations, carried out by biologically and chemically trained pharmacologists, but is for the most part undertaken at the instigation of chemical manufacturers. This eager haste to obtain superficially practical results has lessened in great degree the interest in the close and painstaking theoretical analysis of reaction to poisons. Thus it happens that, in spite of the numberless examples of the depressing effects of poisons discovered by pharmacologists, it is only in rare instances that the physical nature of these processes is more closely studied. Therefore, investigation in pharmacology and toxicology in so far as they are carried out in a purely scientific spirit and not influenced by the desire for merely superficial results, may find here a wide field of research work, rich in future promise. It is from such investigation that we may expect an abundance of material for the closer analysis of the processes of depression. For the present, however, we must restrict ourselves to the consideration of some individual cases which have been studied somewhat more in detail by physiologists.

Simple reflection shows the possibility that depression, that is, the retardation of the normal vital processes, can be brought about in various ways. As on the one hand the normal metabolism of rest is composed of very numerous chemical constituent processes, and on the other hand the closest interdependence exists between these individual constituent processes, it follows that every factor which increases or retards even one of these must secondarily influence the course of the entire activity. Hence a wide range of possibilities exists for the processes of depression. As the complicated works of a clock can, by the stopping of a single moving part, be brought to a standstill, so in like manner the metabolic activity can be depressed by very different constituent members. In spite of this we have every reason to assume that the greater number of all processes of depression result from the primary effect of one or a few constituent members. A primary simultaneous depression of all or at least of numerous constituent processes of the entire metabolism may only be assumed as possible, resulting from decrease of temperature within certain limits. But even in the case of “cold depression” it is not probable, owing to the great effect of every alteration in the relations of masses in the cell, that depression is solely the manifestation of a uniform retardation of all individual constituent metabolic processes. If, therefore, the greater part of the processes of depression are brought about by the primary effects of an individual constituent process, then the possibility must be admitted that any component of the chain can by the means of some specific external influence form the starting point for a depression. The number of the various kinds of processes of depression would be, therefore, enormous. The knowledge obtained up to the present shows, however, that this variety is not quite as great as the above facts might lead one to expect. Even though future investigation will certainly not do away with the assumption of the existence of the most manifold physical types of depression, the analysis of a few processes which have been studied up to now demonstrates the singular fact that a number of these which are brought about by quite different external factors, are based on an absolute uniformity of their mechanism. As we have previously seen, a certain constituent of the metabolic chain can be excitated primarily by very different kinds of stimuli. In like manner there exists in metabolic activity a certain point of predilection for different kinds of stimuli, from which their depressing effects proceed. Here the highly interesting fact is shown that this point of predilection, which represents that of the most frequent attack, is the same for excitating as for depressing stimuli. These are the oxydative processes. As our knowledge of the reactions to stimuli in anaërobic organisms is still almost nil it is not possible at present to ascertain which component in the metabolism of these organisms, adapted to life without oxygen, plays an analogous rôle to that of the oxydative in aërobic systems. Our investigations must, therefore, be restricted to the world of aërobic organisms. Here we have seen that the different stimuli which produce an excitating effect invariably increase the oxydative disintegration of the living system and we now find that these constituent processes of metabolism likewise form a point from which depressing responses to stimuli very readily proceed.

The prototype of this group of processes of depression in which this is manifested in a most striking manner, is that of a simple asphyxiation by the withdrawal of the oxygen supply from the exterior. If the supply of oxygen is withheld from an aërobic organism, oxydative disintegration is gradually found to be more and more decreased and further breaking down takes place anoxydatively, as oxydative decomposition forms the chief source of energy production, and energy production consequently undergoes a gradual decrease. Excitating stimuli, therefore, meet with less response than when a sufficient supply of oxygen is present, that is, irritability is diminished. As a result of this decrease, a corresponding decrement in the extension of excitation takes place, which, in turn, is likewise manifested by the restriction of the perceptible response to stimulation. In the same degree in which oxydative disintegration becomes less, anoxydative breaking down products are accumulated. The accumulation of these products likewise plays a part in the production of depression and increases the decrement in the conduction of excitation. The decrease of energy production by decline of the oxydative decomposition, as well as the accumulation of anoxydative breaking down products, therefore, similarly reduce irritability; that is, their effect is depressing. This whole series of processes, which we have previously considered in detail, takes place on the withdrawal of oxygen and leads to the depression of asphyxiation. It can readily be observed in the most varied kinds of aërobic organisms in rhizopods and infusoria, in plant and ganglion cells, but finds its most complete demonstration in the nerves. Here these processes can be easily produced with any rapidity desired, accordingly as a relative or absolute want of oxygen is brought about. These same typical results are likewise shown in numerous processes in which the external conditions are quite different in nature.

We have previously become acquainted with such a case and studied it in detail. This is the state of fatigue. Fatigue is a typical state of depression, that is, a state in which the vital process is retarded and irritability in response to stimuli correspondingly decreased. Fatigue is, however, as we have found, the result of a relative deficiency of oxygen. The amount of oxygen at disposal is not sufficient to allow of disintegration, increased by constant functional activity oxydatively taking place, to develop to its full extent. In consequence the previously cited sequence of processes takes place. A “depression of activity” is produced. Fatigue is true asphyxiation and it is here evident that depression proceeds from the same constituent processes of metabolism as excitation, brought about by a single stimulus. Excitation produced by constant stimuli gradually merges into depression as the amount of oxygen at disposal, even if augmented in the intact organism by the increased blood supply, for instance, is still insufficient to meet the demand made by the increased oxygen consumption as a result of continuous functional activity.