It was found by _Hermann_[152] in 1867 and confirmed by Mademoiselle _Joteyko_[153] 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