Chapter VIII: Interference of Excitations (2)

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.

Fig. 55.

Interference of two series of stimuli. A--Effect of the one series alone. Development of tonus by summation. The dots below the curve indicate the points of time at which the stimuli of the second series will operate. B--Effect resulting from the interference of both series. By the addition of the second series the frequency has been doubled. The result consists in an inhibition. ]

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 _Sherrington_[191] 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 _Sherrington_[192] and his coworkers on the dog, and _Fröhlich_,[193] _Vészi_,[194] _Tiedemann_[195] and _Satake_[196] on the frog.

[191] _Sherrington_: “Ueber das Zusammenwirken der Rückenmarksreflexe
and das Princip der gemeinsamen Strecke.” Ergebnisse der Physiologie.
Jahr. IV, 1905.

[192] _Sherrington_: “The integrative action of the nervous system.”
New York 1906.

[193] _Fr. W. Fröhlich_: “Der Mechanismus der nervösen
Hemmungsvorgänge.” Med. Natur. Arch. Bd. I, 1907. The same: “Beiträge
zur Analyse der Reflexfunction des Rückenmarks, etc.” Zeitschr.
f. allgem. Physiologie Bd. IX, 1909. The same: “Das Princip der
scheinbaren Erregbarkeitssteigerung.” _Ibid._

[194] _Julius Vészi_: “Der einfachste Reflexbogen im Rückenmark.”
Zeitschr. für allgem. Physiol. Bd. IX, 1910.

[195] _Tiedemann_: “Untersuchungen über das absolute Refractärstadium
und die Hemmungsvorgänge im Rückenmark des Strychninfrosches.”
Zeitschr. f. allgem. Physiologie Bd. X, 1910.

[196] _Satake_: The researches are not yet published.

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.

Summation of two excitations in the rabbit. The one proceeds from the paw, the other from the motor sphere of the cerebral cortex. _S_--Time in seconds. _Pf_--Stimulation of the paw. _H_--Stimulation of the motor sphere. _M_--Contractions of the abductor pollicis. (After _Exner_.) ]

_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.

Fig. 57.

Summation of two excitations in the spinal cord produced by stimulation of the ninth and tenth posterior root. Lower line indicates faradic stimulation of the tenth, upper line of the ninth root. ]

Fig. 58.]

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 Bonn[198] 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.

[197] _Sherrington_: “Experimental note on two movements of the
eye.” Journ. of Physiology XVII, 1895. The same: “On the reciprocal
Innervation of antagonistic muscles.” Proceed. of the Royal Soc.,
1897.

[198] _Max Verworn_: “Die einfachsten Reflexwege im Rückenmark.”
Zentralblatt f. Physiologie Bd. XXIII. _Tiedemann_: “Untersuchungen
über das absolute Refractärstadium und die Hemmungsvorgänge im
Rückenmark des Strychninfrosches.” Zeitschr. f. allgem. Physiologie
Bd. X, 1910. _Julius Vészi_: “Der einfachste Reflexbogen im
Rückenmark.” Zeitschr. f. allgem. Physiologie Bd. XI, 1910. _Oinuma_:
“Ueber die asphyktische Lähmung des Rückenmarks strychninisierter
Frösche.” Zeitschr. f. allgem. Physiol. Bd. XII, 1911. _Satake_: Not
yet published.

Scheme of the simplest unilateral reflex arc of the spinal cord.]

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.

[199] _Gotch_: “The submaximal electrical response of nerve to a
single stimulus.” Journ. of Physiology, Vol. XXVIII, 1902.

[200] _Thörner_: “Weitere Untersuchungen über die Ermüdung des
markhaltigen Nerven: Die Ermüdung in Luft,” etc. Zeitschr. f. allgem.
Physiologie Bd. X, 1910.

[201] _Vészi_: “Zur Frage des Alles oder Nichtsgetzes beim
Strychninfrosche.” Zeitschr. f. allgem. Physiologie Bd. XII, 1911.

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.