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

by Max Verworn

In contradistinction to this case, we have the examples of the interference of thigmotaxis and galvanotaxis in the hypotrichous infusoria. Here the effect of interference, the characteristic position of the axis of the cell body, is brought about by the fact that the galvanic stimulus affects different elements than the mechanical. The turning of a creeping Stylonychia or Urostyla, when the current is closed, in which the anterior portion of the body was previously directed towards the anode, results from excitation of the perioral cilia from the anodic pole. The mechanical stimulation, on the contrary, exerts its effect upon the locomotion and border cilia. Only when there is a turning of the anterior portion of the body towards the anode, would the galvanic stimulus affect also the anterior locomotion cilia and thereby counteract turning towards the anode. Therefore, we have before us in this case of the assuming of a characteristic position of the axis of the cell body the expression of an apparent, or, as I prefer to express it, a “heterotopic interference,” in which the two stimuli do not actually interfere in their action, but rather influence the final result, in that the condition for the state of the system in its totality is dependent upon its individual components. This heterotopic interference is of particular importance in the bringing about of the movements of the living system. The locomotion of the animal and especially the direction is in part a manifestation of heterotopic interference of response. At the same time, however, especially in the coördinated movements of nervous origin, the homotopic interference also plays an important rôle and, not rarely, is combined with heterotopic interference.

Although the physical analysis of heterotopic interference is extremely attractive, we must, however, temporarily set aside its consideration, for at this point the question arises as to what happens when there is interference of two stimuli at the same point. In the heterotopic interference the effect of each stimulus is the same as if it were applied singly. In the homotopic interference the interfering effects of stimulation influence each other.

The above examples of homotopic interference introduce us to the two principal types of these manifold kinds of interference effects; the excitation brought about by galvanic stimulation is summated by the excitation produced by temperature. The other type consists of an inhibition of one effect of stimulation brought about by another. The depression produced by alcohol on the Paramecia weakens the excitation of the galvanic current. These examples of the two principal types of interference effects are quite simple; nevertheless, in other cases, the conditions are very complex. This is especially true in the field of nervous inhibition, so important in the functionation of the nervous system, and which has presented the greatest difficulties to physiological investigators until the last few years. That a stimulus bringing about excitation in a ganglion cell can be inhibited by another exciting stimulus, or that the development of excitation in a ganglion cell may be prevented by another exciting stimulus cannot be easily understood. The problem as to how two interfering excitations can bring about inhibition is one that has received many explanations. An interesting incident in the history of physiology is that the first explanation of the principles of inhibitory processes was close on the track of being a correct one, but was subsequently abandoned by its originator. Schiff[169] (1858) has endeavored to explain this inhibition as a manifestation of fatigue, and this idea he defended with the greatest tenacity for a long time, until finally, twenty-five years after, in a treatise which he called “Abschied von der Ershöpfungstheorie,” he renounced the idea as untenable.

Among other investigations, which since this time have been made to explain the mechanism of inhibition, those of Gaskell,[170] Hering[171] and Meltzer[172] have received widest consideration. These theories are built upon the existence of the two phases of metabolism, and assume that inhibition, in contradistinction to dissimilatory excitation processes, depends upon an increase of the assimilative processes. The principal evidence which Gaskell advances is that when the vagus nerve of the tortoise heart, a typical inhibitory nerve, is stimulated, a positive variation of the demarcation current of the heart muscle occurs, whereas when a motor nerve of a skeleton muscle is stimulated the attached muscle shows a negative variation of the demarcation current. I must confess that this explanation of inhibitory processes, from the standpoint of an interpretation of processes in the living substance, seems very plausible, and I have accepted this even in my address on excitation and depression before the Frankfurter Naturforscher Versammlung.[173] I have since then endeavored to obtain experimental evidence to substantiate this theory, in that I attempted to prove that increase of the assimilatory processes brought about by stimulation would be associated with a reduction of the specific irritability. For this purpose I have sought for such cases in which a stimulus primarily and momentarily increases assimilative processes in a system in a state of metabolic equilibrium. I was disappointed, when, after years of investigation, I could not find such cases. There is only one kind of stimulus of which we can say with positiveness that it primarily increases the assimilative processes, that is, increased supply of food. But here the increase in the processes of assimilation never occurs momentarily, and indeed this increase is so extremely slight that it can only be demonstrated over a long course of time. These totally negative results of my investigation had awakened strong doubts concerning the assimilation hypothesis of inhibition. Above all, this explanation seemed to me to be impossible for the nervous system. I searched, therefore, for another explanation for the processes of inhibition in the nervous system. If the increase of energy production resulting from the application of a stimulus is dependent upon an excitation of a dissimilative nature, then one is justified to look upon the reduction of functional energy production as an expression of an antagonistic process to that of dissimilatory excitation. In this respect the Gaskell-Hering hypothesis of inhibition rests upon a firm foundation. When, however, this hypothesis assumes an antagonism between dissimilatory and assimilatory excitation, then it must not be overlooked that a second antagonism is possible between dissimilatory excitation and dissimilatory depression. The antagonism need not involve the two types of metabolism, it may depend upon variations of one type. When, therefore, the hypothesis that inhibition is brought about by assimilatory excitation meets with insuperable difficulties, the possibility should be considered if it is not more likely dependent upon dissimilatory depression. These reflections induced me to investigate if conditions could not be produced experimentally wherein dissimilatory depression could bring about inhibitory processes in the nervous system. The most essential requirement was, that dissimilatory depression should quickly develop and pass away with like rapidity, for inhibition of the nervous system sets in momentarily and disappears again momentarily. Another important requisite is, that both interference stimuli are individually capable of producing dissimilatory excitation, for the inhibitory processes of the nervous type may be assumed to be the result of dissimilatory excitation which produce by their interference inhibition, for the nerve fibers, as already stated, are capable of conducting only dissimilatory excitation to the responding organ. As I studied the problem in this manner, it became clear to me that all the conditions necessary for the genesis of inhibition are realized in the existence of the refractory period, and that I had already produced inhibition by prolonging the refractory period, by oxygen withdrawal, in the strychninized frog. If we take a strychninized frog in which the refractory period has been somewhat prolonged by oxygen withdrawal, so that the reaction is simply a short reflex contraction, and rhythmically stimulate the skin, a reaction is only obtained with the first few stimuli, which reactions rapidly decrease until a stage is reached wherein the succeeding stimuli are completely inoperative. (Figure [45].)[174] This inhibition is demonstrated even more clearly by the following experiment. Contractions of the triceps muscle of a strychninized frog are recorded which reflexly follow from stimulation of the central end of the cut sciatic nerve. Oxygen is withdrawn in the manner already referred to. At the proper stage of oxygen deficiency, rhythmic induction shocks applied to the central end of the nerve, the interval between the individual stimuli of which being longer than the duration of the refractory period, elicit reflex contractions of the muscles of the posterior extremity on the opposite side following each individual stimulus. If, however, in the same stage the central end of the nerve is stimulated with induction shocks at intervals briefer than the duration of the refractory period, a contraction is only observed during the very beginning, being brought about by the first stimulus, whereas the subsequent stimuli are ineffective, the muscles remaining at rest during their entire application. (Figure [46].) Tiedemann[175] at a later date continued these observations and analyzed them more in detail. In all these experiments, therefore, there is an interference of the frequent stimulus, because each succeeding stimulus occurs in the refractory period of the proceeding. In consequence there is a strong reduction of irritability and reaction is absent. That is, the centers during application of the frequent current are inhibited. If cessation of stimulation by frequent shocks takes place, stimulation by slowly succeeding individual shocks becomes effective again in a few seconds. This is the simplest example of the process of inhibition and by it I was led to seek in the refractory period the key of the mechanisms of the process of inhibition. This principle once recognized, further material for the more detailed working out and extension of the theory was gathered from the experiences already gained during the course of the preceding years in the researches on fatigue and the refractory period in the nerve. Here it became apparent that the processes resembling inhibition discovered by Schiff in the nerve preparation and which were studied anew at a later date by Wedenski, F. B. Hofmann and Amaja and in part attributed by Hofmann to fatigue of the nerve endings, by Fröhlich to fatigue of the nerve itself, were in principle of the same nature as the central inhibitions themselves. Fröhlich,[176] by his analysis of the observations of Richet, Luchsinger, Fick, Biedermann and Piotrowski on inhibition in the claw of the crab, then showed that inhibition can be influenced by the alteration of the intensity of the stimulus as well as its frequency. In a series of experimental researches he could then demonstrate that the widely extended antagonistic inhibitions and other special processes of inhibitions in the centers could on the basis of the same principle be physiologically explained. Here the supposition was confirmed that the development of a relative refractory period plays a very important rôle in the inhibition of the nervous centers. Thus, the relations of the processes of inhibition to the refractory period, once established, their entire field, up to then shrouded in darkness, has gradually in the course of years been completely elucidated.

Fig. 45.

Lower line indicates stimuli.

Fig. 46.

Reflex inhibition in the strychninized frog. Lower line indicates seconds, upper line stimuli. When stimulation with single shocks at longer intervals is applied, each single stimulus is effective. When faradic stimulation is used, only the first stimulus is operative, and during the further continuance of stimulation inhibition takes place in the spinal cord.