Exactly similar conditions as those of the muscle are seen in the central nervous system. The reflex contraction of the triceps of the frog produced by stimulation of the central end of the sciatic nerve with single induction shocks demonstrates clearly as Ishikawa151 has proved in certain stages of fatigue, an increase in height and a strong relaxation which does not depend upon the fatigue of the muscle but on that of the centers. If the fatigue is greater, the height of the contraction then decreases, whereas the extension of the course of relaxation increases further. The possibility of fatigue of the muscle during these experiments was, of course, precluded by proper precautionary measures. Irritability and the course of excitation in fatigue of the centers show exactly the same alterations as developed in fatigue of the muscle. The processes of oxydative breaking down are retarded more and more with increasing fatigue, that is, fatigue is characterized by exactly the same processes as is the prolongation of the refractory period by the deficiency of oxygen, and likewise in fatigue this retardation of the oxydative disintegration processes is conditioned by the relative deficiency of oxygen. This is shown by the rôle played by oxygen in recovery after fatigue.

It was found by Hermann152 in 1867 and confirmed by Mademoiselle Joteyko153 in Richet’s laboratory, that the isolated muscle of the frog, which was completely nonirritable as the result of fatigue, does not regain irritability in an oxygen-free medium, but does so when oxygen is introduced. The previously described experiments of artificial circulation in the frog show clearly how dependent the centers are upon the oxygen supply for the restoration of irritability. In consequence of the strychnine poisoning the irritability of the centers is so enormously increased that the “all or none law” is applicable to the centers of the spinal cord under these conditions.154 These are the best conditions for the production of fatigue. One can readily demonstrate the importance of the oxygen supply for the rapidity with which irritability returns after fatigue if in the strychninized frog an artificial circulation is used, at the same time varying on one hand the amount of oxygen, on the other the activity of the centers. If a saline solution containing merely a trace of oxygen is circulated, the centers recover very slowly and incompletely after every fatigue. Subsequent to every reaction produced by a stimulus, an increasing length of time is required until irritability is so far recovered that a new stimulus can meet with response. If, however, a saline solution is circulated which has been saturated by being shaken with oxygen and is continuously in a pure atmosphere of oxygen, recovery takes place in comparison with far greater rapidity and completeness. If the supply of oxygen is ample and the stimuli act at longer intervals on the frog, irritability always is quickly restored in the periods of rest between the stimuli. With continuous stimulation of quickly succeeding stimuli, irritability is soon completely obliterated, even though an abundant oxygen supply be present, and it is not until a pause is interpolated that oxygen is capable of bringing about a recovery. By manifold variations of these experiments the connection between fatigue and the refractory period can be more and more clearly recognized. Fatigue is simply the refractory period prolonged by deficiency of oxygen. In both cases there is a diminution of irritability. In both cases this diminution is conditioned by a retardation of oxydative disintegration following every stimulation. In both cases it is the relative deficiency of oxygen which produces this delay. In both cases the oxydative decomposition can be quickened and irritability restored, that is, the refractory period lessened and fatigue removed by a sufficient supply of oxygen. The amount of oxygen which suffices to constantly maintain the specific irritability of a living system in an undisturbed metabolism of rest is not sufficient if the system is continuously functionally activated by stimulation. The refractory period increases after excitation and merges, although very gradually, finally into permanent nonirritability, that is, into complete fatigue.

The knowledge that fatigue represents a prolonged refractory period resulting from relative deficiency of oxygen has enabled me with the aid of my coworkers to demonstrate the existence of fatigue and produce the typical symptoms experimentally for a living tissue, which up to then was considered indefatigable: I refer to the medullated nerve. After having found that the condition necessary for the production of fatigue in the nervous centers is a deficiency of oxygen, I arrived at the conclusion that fatigue could only be obtained in the medullated nerve when subjected to a deficiency of oxygen. Up to that time, however, no consumption of oxygen was known for the nerve. It was, therefore, necessary to first ascertain if the nerve possessed an oxydative metabolism. At my request, H. von Baeyer investigated these questions. After many vain attempts to obtain absolutely pure nitrogen, we finally succeeded in finding a method by which it is possible to gain nitrogen gas, which is, one might almost say, in a mathematical sense absolutely pure. It was then possible for H. von Baeyer155 to asphyxiate the nerve and subsequently to bring about complete restoration by the introduction of oxygen. It was shown that the nerve requires merely a minute quantity of oxygen and only completely asphyxiates when the last trace of oxygen is removed, and further that recovery takes place within a fraction of a minute if the oxygen is again supplied. These experiments which have been carried further by Fröhlich156 were afterwards confirmed in other laboratories,157 and form the basis for proving the existence of fatigue of the medullated nerve. Shortly after, Fröhlich158 was able to demonstrate symptoms of fatigue in the medullated nerve. He found that the refractory period of the nerve, which, as previously mentioned, Gotch and Burch fixed at about .005 second duration, was prolonged by oxygen deficiency to .1 second, so that stimuli following each other oftener than ten times per minute produced merely single initial contractions in the muscle concerned, that is, in a series of stimuli of which the intervals are less than .1 per second, only the first produces response, whereas the following occur in the refractory period, brought about by those preceding, and are, therefore, inoperative. The nerve is fatigued by the quick succession of stimuli. The normal nerve on the contrary invariably responds, as known, to an even more rapid succession of stimuli with a rhythmical excitation corresponding to the number of stimuli and which is manifest in the muscle by a tetanus. This again confirmed the identity of fatigue with the prolonged refractory period, conditioned by the relative want of oxygen. It likewise explained the conditions of the analogous behavior that Wedensky159 had observed in the narcotized nerve, but had neither recognized as manifestation of the prolonged refractory period nor as fatigue. A further advance was made by the investigations of Thörner. He placed two nerves of the same frog in a double chamber under completely identical conditions with the exception that one remained in a state of rest, whilst to the other tetanic stimuli were applied. (Figure 35.) If this took place in nitrogen, the irritability of the stimulated nerve invariably sank with much greater velocity than that of the nonstimulated, whereas after an introduction of oxygen, even when the stimulation was continuous, both again recovered. In these experiments of Thörner160 the action current and not the muscle contraction served as indicator. Here the fatigue of the medullated nerve brought about by the deficiency of oxygen during prolonged stimulation is demonstrated in the most obvious manner. (Figure 36.) Thörner161 further succeeded by a continuous stimulation of the nerve in obtaining even in atmospheric air the indications of primary fatigue. The symptoms were exactly the same as those characterizing fatigue of the muscle; the extension of the course of excitation and, as a consequence of this, the appearance of a summation of excitation produced by tetanic currents and a reduction of irritability in response to single stimuli. The form of the curve, resulting from alteration of irritability in fatigue and recovery, likewise shows complete conformity with that of the muscle. (Figure 37.) Finally Thörner162 proved that the nerve, when fatigued by continuous tetanic stimulation in nitrogen, could also partially recover in the latter if the stimulation was interrupted, whereas a complete recovery could not take place unless a supply of oxygen was introduced. (Figure 38.) This fact is in perfect accordance with the relations found by Verworn, Lipschütz, in fatigue of the nervous centers. It is the expression for the accumulation and removal of fatigue substances, the depressing effect of which Ranke163 first established for the fatigued muscle. The fact that the nerve could also partially recover in an atmosphere of nitrogen would seem to likewise contain the proof that among the fatigue substances products in the form of gas must be present. It is probable that an escape of carbon dioxide has taken place.

As a result of all these investigations, linked together in a systematic series, the proof has now been obtained that the nerve like all other living substances is fatigable. Its fatigue is solely the manifestation of a prolonged refractory period and the extension of the latter by continuous stimulation is, as in all aërobic substances, a result of relative deficiency of oxygen.

To briefly summarize in conclusion, I will repeat that just as all living systems show a refractory period after an excitation, in which irritability is reduced, all living systems are likewise capable of fatigue. Both are most intimately connected and are based fundamentally on the facts of metabolism.

An excitating stimulus disturbs the metabolic equilibrium of rest by suddenly bringing about increased decomposition of certain substances. During and directly after the breaking down, irritability is reduced in the same degree as the amount of substances required for disintegration in response to a succeeding stimulus is decreased and the quantity of the decomposition products is increased. This is the refractory period. By the metabolic self-regulation in accordance with the principle of chemical equilibrium, the original metabolic equilibrium is restored after every excitation. Irritability, therefore, increases in the same measure as this occurs, that is, in the form of a logarithmic curve, until it again reaches the specific degree of irritability of the particular system. The refractory period diminishes. If the processes of disintegration and self-regulation are delayed, either by want of substance necessary for breaking down or the accumulation of decomposition substances, the refractory period is prolonged and the response to every further stimulation decreased, that is, the system is fatigued. In all aërobic organisms the retardation of the course of excitation and self-regulation under a continuous influence of stimuli is the result of the relative want of oxygen. The processes of oxydative disintegration are prolonged and restricted by relative deficiency of oxygen and merge more and more into anoxydative decomposition. The products of incomplete oxydative and anoxydative decomposition accumulate. Both factors decrease the strength of the response after every stimulation. Thus the want of oxygen leads to reduced activity. In the anaërobic organisms the refractory period and symptoms of fatigue are, of course, produced by the relative deficiency of other substances. Fatigue in the anaërobic systems has, however, so far not been investigated. We advance very slowly, step by step, in physiology, and, as in every science, an acquirement of a new knowledge means a new problem. In this lies the inexhaustible charm of our scientific research.