We will first direct our attention to the simplest case brought about by an interference between the individual effects of stimuli in the same series. We will study the effect, which here occurs, in the accompanying diagram, which shows the facts involved in the interference of two stimuli of a series of stimuli. (Figure 53.) The curve shows the development of summation and inhibition. The single stimuli of equal intensity follow at the same intervals, so that the succeeding stimuli meet with an incomplete recovery of excitation and accordingly a decreased state of irritability. In spite of the diminution of the relative response to each stimulus the summation of excitation brings about an absolute increase of the same. At the same time the irritability decreases more and more, for after each stimulation the oxydative disintegration as well as restitution require a progressively greater time and a relative fatigue must, therefore, necessarily develop. The summation, consequently, reaches its limit very soon and then decreases progressively, for, as a result of the increase of fatigue, the oxydative decomposition which occurs at the instant of every stimulation reduces and with this the energy production becomes less and less. The system is relatively refractory for the given intensity of stimulus. Accordingly the response to stimulation falls below the threshold of perceptible response (dotted line S) and finally an equilibrium between disintegration and restitution occurs, wherein the small amount of material used at each stimulation by oxydative decomposition is again replaced before the next stimulus. In other words, the irritability is reduced at each stimulation to an amount equal to that of the recovery in the interval. If this all takes place beneath the threshold of perceptible response, the system during the continuance of the stimulation seems responseless, that is, inhibited. The inhibition consists then of a reduction of irritability below the perceptible threshold of response of the stimulus concerned. It depends upon a continued lessening of dissimilative excitation to a low level through the delay of the oxydative decomposition processes. The inhibition is according to this a relative fatigue, which is conditioned, as is true of every fatigue, by a lengthening of the refractory period following a relative deficiency of oxygen. The processes of inhibition are simply and solely an expression of a refractory period persisting as a result of dissimilatory excitating stimuli.

Accordingly the general conditions requisite for summation on the one side and inhibition on the other may be formulated as follows:

A summation may develop in a heterobolic system and by the use of submaximal stimuli. It always develops when the following stimulus is applied before there is complete recovery of excitation from the previous stimulus. The absolute increase of excitation as a result of summation is, however, limited by the diminution of irritability. By continuation of the series of stimuli the state of equilibrium between the amount of excitation and the irritability will be established on a higher or lower level. There occurs then, depending on whether the feeble persistent excitation remains above or below the level of perceptible effect, either a tonus or an inhibition.

Summation can be transformed into inhibition by the continuance of stimuli of constant intensity. The principles which underlie both processes are in no way antagonistic and indeed are not separated by distinct boundaries. The diagram here shown (Figure 53) illustrates this development of summation and inhibition. The time required for this development is in manifold ways influenced by variations of the above-stated factors which control the occurrence of interference. Thereby results an immense number of special cases which differentiate themselves in characteristic manner depending on whether an isobolic or heterobolic system is involved, depending on whether the irritability of the system, as measured by the threshold of stimulation, is high or low, depending on whether fatigability is great or small, depending upon the intensity and frequency of the stimuli, etc. Analysis of every instance shows us different combinations of the interaction of the individual factors. It is, therefore, self-evident that we cannot here analyze a greater number of these cases of summation and inhibition. I wish only to refer to a few typical examples at this time.

It is known that summation of excitation in the normal nerve does not occur. As already stated, the nerve is a system in which the “all or none law” is operative. Such isobolic systems do not summate, having no power of summation because each individual stimulus brings about a maximum response. But we have seen that the nerve, as a result of depressing factors, such as deficiency of oxygen, narcosis, fatigue, etc., which decrease its irritability, can be transformed from an isobolic into a heterobolic system. In this state the nerve possesses the capability of summating excitations. Waller,181 Boruttau,182 Boruttau and Fröhlich,183 Thörner184 and others have shown that the action current of the nerve during the application of tetanic stimulation becomes decidedly greater during a certain stage of narcosis or asphyxiation, so that the wave of negative variation is higher than when the nerve is excitated by a single induction shock. Fröhlich185 first threw light upon this subject in that he made the observation that here a principle is involved which has far-reaching importance in the phenomena occurring in the organism. He showed that as a result of fatigue, cold and narcosis, etc., the course of excitation brought about by the single stimulation undergoes retardation. These conditions within certain limits become more favorable for the production of summation, because each succeeding stimulus meets with a more incomplete recovery of excitation than the one previously applied. In consequence of this, the irritability of the system in the beginning of fatigue, or narcosis, or immediately after the application of cold, is apparently increased. This “apparent excitation,” as it was called by Fröhlich, depends, however, in reality upon a beginning depression which is evident in that the course of the individual excitations are lengthened by this means. The irritability is likewise also reduced. Reinecke186 later studied in further detail the retardation of excitation in the muscle and attributed to this the characteristic property shown in muscle in the so-called “reaction of degeneration.” Fatigue, asphyxia, cold, degeneration, in fact all factors which retard the course of excitation, are favorable to the summation of excitation, provided their influence does not exceed certain limits.

Although the nerve as an isobolic system can only be rendered capable of exhibiting summation when artificially influenced, there are other forms of living substance which normally are systems with a slow course of excitation, in which excitation may be summated, for this type possesses at the same time a heterobolic character. For example, a single mechanical excitation elicits a hardly perceptible response in Amœba, Actinosphærium, Orbitolites. When it is perceptible at all, there occurs a short interruption of the centrifugal movement of the protoplasm. After a pause the movement of the protoplasm and the stretching out of the pseudopods again return. But if the organism is agitated one or more minutes by rhythmically shaking the edge of the slide by a special device, as a result of the summation of weak excitations there occurs a complete drawing in of the pseudopods and the amœbæ become bell-shaped.187 The ganglion cells also possess a great capability for summation. We have already alluded to the fact that single induction shocks below that of the threshold produce no evident effect, whereas when rapidly repeated, summation occurs with reflex reaction.

The summation of sub-threshold excitation to a certain height offers very favorable conditions for the development of tonus. (Figure 54.) This fact has been established for many kinds of centers (cardio-inhibitory center, vasomotor center, etc.). During the continuance of a series of stimuli, as we have already seen, an equilibrium between disintegration and replacement soon takes place. The level of this state of equilibrium depends upon the relative intensity of the stimuli. It is lower in the case of strong and higher in that of weak stimuli. This fact becomes apparent from the researches of Thörner188 on the fatigue of medullated nerves in air. This investigator showed that during continued tetanic stimulation of the nerve, the irritability fell to a certain level, at which it remained so long as stimulation persisted. The irritability decreased to a new level when the strength of the stimulus was increased. These interesting experiments of Thörner show that the level reached when stimulation is continued is higher as the intensity is weaker. It is, therefore, clear that this level in summation of stimulation beneath the threshold can be above that of the threshold of perceptible response, that is, a perceptible tonic excitation may result. In the genesis of tonus in the muscle, there is another point to be taken into consideration. Here we have a combination of a heterotopic interference with a homotopic interference, for the total shortening of the muscle is brought about in part by several contraction waves which occur at various points at the same time and which follow each other, therefore have a heterotopic sequence. If we consider a long stretch of muscle, to one end of which a stimulus is applied, it will be found that the contraction wave moves throughout the entire length. If after a certain interval of time a second stimulus is applied, the resultant wave moves along the muscle but does not necessarily homotopically interfere with the first. In short, there are two waves of contraction occurring coincidently in the muscle, the muscle is now more strongly contracted. Fröhlich189 has made the fact intelligible by this means that tetanic shortening of a muscle is greater than that of maximal shortening which can be produced by strong single stimulation. This heterotopic interference dare not be overlooked in the genesis of muscle tonus. If it is true, as appears from the investigations of Keith Lucas,190 that the “all or none law” applies to striated muscle, then an increase of the contraction from homotopic summation cannot occur, because an isobolic system cannot show an increase of its already maximal excitation by summation. Such being the case, the tonic shortening of striated muscle can only be explained as an expression of a heterotopic interference.

If we assume that the summation of sub-threshold stimulation, by increasing excitation, brings about a state of equilibrium from below, as it were, so also inhibition may be assumed to be the reverse, the level of equilibrium being reached from above, as it were, by decrease of the primary excitation from strong stimulation. This is expressed in our general scheme of the development of summation and inhibition resulting from the effect of a series of stimuli. At the same time the first part of the curve to the fall of irritation to the level of the sub-threshold equilibrium can be shortened to a minimum by strong stimulation or greater frequency of the same, and we have then the type of inhibition with primary excitation. As example of this I wish to again recall the strychninized frog which was used in the fundamental experiments for understanding of the theory of inhibition. If we stimulate a sensory nerve of a strychninized frog, in which the refractory period is already lengthened, with rhythmic single induction shocks of slow frequency, the muscle arranged to make a graphic record will show reflex contraction following each stimulus. If, on the other hand, we apply a series of stimuli, consisting of single stimuli rapidly repeated, contraction is produced only by the first, or the first few stimuli (Figures 45 and 46, pages 202, 203). For the succeeding stimuli the centers remain inhibited, because each succeeding stimulus occurs in the refractory period of the former. The origin of this inhibition shows us with particular clearness how excitation produced by each single stimulus depending upon the frequency of the same, falls rapidly or slowly beneath the threshold of perceptible response. In this case, the state of equilibrium is reached which is maintained by the following stimuli. That a single stimulus is not entirely without effect upon this state of equilibrium follows from the fact that during the continuation of the stimulus a recovery to the point of observable response does not occur, whereas such is the case immediately upon the discontinuation of the stimulus. In inhibition, then, the dissimilatory excitation produced by a single stimulus falls to a low level as a result of the reduction of irritability and remains at this level continuously. Inhibition as well as tonus is based upon the development of a state of equilibrium between excitation and recovery, or disintegration and restitution of the living substance under the continuous effect of a rhythmic series of stimuli. They differentiate themselves essentially by the height of this equilibrium, which is dependent upon the intensity of the stimulus.

We have to the present considered only the simplest conditions existing as a result of the effect of a single series of stimuli and also of the interference of its individual members. These elementary conditions are at the basis of an understanding of complicated interference effects which arise when two series of stimuli interact. In that these processes can be readily explained by the elementary processes previously described, I will, therefore, dwell but briefly on this subject. From the standpoint already taken it may be readily presumed what will happen when two series of stimuli act upon the same system.

When there is interference of two series of stimuli, there are two resultant possibilities. In one type the stimuli of the one are active simultaneously with that of the other. In this instance both stimuli would act as a single stimulus of greater intensity, and we have essentially the same condition as exists when a single series is operative. Nevertheless, such cases are practically hardly realized in the physiological happenings of the organism. More often a state exists wherein the single stimuli of one series occur in the intervals of the stimuli of the other. In these cases there is an increase in the frequency of the stimuli applied in a given length of time. We have here, then, in principle the same conditions as when a series of greater frequency is operative. (Figure 55.) The effect of such alteration in the frequency consists in an increase of the velocity of the development of summation or inhibition, as the general scheme (Figure 55) has shown us. Depending upon the special combination of the factors involved in interference, we may have a summation of the exciting effect of each series of stimuli or an inhibition of one series by the exciting effects of the other series. If the frequency of both series is essentially different, we may have here the conditions for periodically increasing and decreasing excitations. Nevertheless these conditions have not been systematically analyzed and experimentally studied.

The greatest number of instances of the interference of two series of stimuli have been given to us by investigation of the physiology of the nervous system. In the functionation of the nervous system the fact that two series of stimuli from different tracks affect the same ganglia plays a very important rôle. It is this to which Sherrington191 has alluded as “the principle of the common path.” Where two nervous excitations involve the same paths, there arises an interference of the effect of the two series of stimuli, for the impulses in the nervous system, as already stated, possess a rhythmic character. This principle has a broad application in the phenomena of association in the cerebral cortex. The simpler and, therefore, the most easily understood cases are, however, in the spinal cord. The motor neurons of the anterior horns of the spinal cord are the junction of a great number of tracks, for example, the sensory neurons of the spinal cord at different levels, the neurons of the cerebellum, the pyramidal tracks from the motor areas of the cerebral cortex, etc. On the contrary, for example, the sensory neurons of the spinal cord are strictly “private paths” in the sense of Sherrington, for excitation can enter by this means only from the special paths of the spinal ganglia and, therefore, from the periphery. The motor neurons of the anterior horns offer, therefore, excellent opportunities for the experimental investigation of the interference of two series of excitations which enter by different paths. The spinal cord consequently has become a much-used object of investigation for this purpose. In fact, we can observe and produce all types of interference in the spinal cord. These conditions have been quite thoroughly investigated by Sherrington192 and his coworkers on the dog, and Fröhlich,193 Vészi,194 Tiedemann195 and Satake196 on the frog.

A summation of two excitations was observed already by Exner. This investigator connected the abductor pollicis of the rabbit with an apparatus for making graphic records. He then stimulated first the paw and then the motor areas of the cerebral cortex with faradic shocks, the intensity of which was just sufficient to bring about perceptible effect. If both stimuli were simultaneously operative, an increase in the response was observed. Even when the stimuli were sub-threshold in type, as a result of summation there was a perceptible muscle contraction. (Figure 56.) Exner had at that time referred to this increase of the response as “Bahnung” (reinforcement). However, the word “Bahnung” has more than one meaning, for processes of various types are involved in this term. Thus writers have differentiated real and apparent “Bahnungen.” On account of this lack of clearness in the meaning of the term “Bahnung,” I wish to discard its use as it is not at all essential. We will speak simply of a summation of excitation, for here it is simply a question of summation of two excitations of the motor cells of the spinal cord.

Fröhlich has shown that summation of two excitations upon a motor cell of the anterior horn coming by way of different paths is more readily obtained when the stimuli are somewhat strong, or when the duration of the excitation processes in the ganglion cells are somewhat prolonged by fatigue.

On the other hand, the conditions for the production of inhibition are favored when the intensity of the series of stimuli is weak. Here it is a question of the development of a relative refractory period for the weak stimuli by increase in their frequency. A relative fatigue of the motor ganglion cells for weak stimuli rapidly occurs, and there develops a state of equilibrium beneath that of the threshold of perceptible effect throughout the continuation of stimulation. Vészi succeeded in isolating these types of summation and inhibition in the spinal cord. His method consisted in cutting the posterior roots of the spinal cord of the frog and stimulating faradically the central ends, and at the same time graphically recording the response of the gastrocnemius muscle. Upon faradic stimulation of the ninth posterior root, one obtains tetanic reflex contraction of this muscle. When the tenth posterior root is then stimulated, tetanus is also produced but of somewhat shorter duration. If, while obtaining tetanus reflexly by stimulation of the ninth root, a faradic current of short duration and not too weak is applied to the tenth root, then a summation of excitation occurs, an increase in the reflex contraction. (Figure 57, A and B.) When, on the other hand, the tenth root is stimulated with weak shocks, one can obtain an increase of the tetanus of short duration followed by inhibition. Here, as the result of interference, we have an instance of inhibition with primary tetanus. (Figure 58.) When the tenth root is stimulated with very weak shocks, inhibition of the tetanus produced simultaneously from the ninth root occurs without primary summation. (Figure 59.) The fact that two series of stimuli, both of which produce dissimilative excitation, bring about an inhibition by their combined action, is sufficient to show the untenability of the Gaskell-Hering hypothesis, that inhibitory processes result from assimilatory excitation. It would be impossible to understand how two dissimilatory exciting stimuli, by their simultaneous action, could bring about assimilatory excitation. When the eighth or the seventh root is stimulated with stronger faradic shocks during the time when tetanus is produced reflexly by faradic stimulation of the ninth, an inhibition is practically always obtained. Indeed, faradic currents that are so weak as to be far below the threshold of perceptible response bring about when applied to the seventh or eighth root a decided inhibition of the tetanus, brought about by simultaneous stimulation of the ninth root. The inhibitory effect of weak sub-threshold excitations are here particularly apparent. This inhibition resulting from excitation far below that of the threshold of perceptible response is a common occurrence in the functional activities of the central nervous system. In various parts of the nervous system, the excitation in its conduction is weakened when passing through intervening ganglion stations so that it has undergone a strong decrement before reaching the responding structure, where an inhibitory effect may be manifested. In this connection it is of interest that the reciprocal “antagonistic reflexes” discovered by Sherrington,197 who recognized their importance in the functional processes of the nervous system, can be explained, as Fröhlich showed, upon this principle of inhibition resulting from weakened excitation. On the basis of numerous investigations in the Göttingen laboratory as well as that of Bonn198 we have come to look upon the reflex arc in the spinal cord as consisting of the following elements: a neurone in the spinal ganglion, a neurone in the posterior horn and a motor neurone in the anterior horn. This is the most direct route between the point of stimulation and that of the responding organ of a unilateral reflex. (Figure 60.) It is known that the excitation becomes weaker in passing from the entrance of the excitation into the spinal cord to the motor elements of a lower level on the same side or to those on the opposite side. In order to obtain a response a stronger stimulus is necessary. Here the weakening of the excitation as well as the prolongation of the reaction time is brought about by the introduction of intercalated neurones. The reflex arc contains more stations. (Figure 61.) If we accept the most plausible assumption that the central connection of antagonistic muscles possesses like relations, then the effects discovered by Sherrington are self-explanatory. In this case stimulation of the sensory path, which brings about a strong reflex excitation of the motor neurons of the anterior horns controlling a muscle, at the same time stimulates the antagonistic muscle with sub-threshold stimuli. The result of this as shown by the experiments of Vészi is not a motor response of the antagonists, but an inhibition if the motor neurons of the antagonists are at the time in a state of excitation. It is, therefore, understandable that reflex excitation of a muscle under normal conditions of irritability has an inhibitory effect on its antagonist.

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. Gotch199 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 Thörner200 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. Vészi201 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.