CHAPTER VIII. Interference of Excitations

INTERFERENCE OF EXCITATIONS

Contents: Examples of effects of interference of stimuli in unicellular organisms. Interference of galvanic and thermic stimuli in Paramecia. Interference of galvanic and thermic stimuli and narcotics. Interference of galvanic and mechanical stimuli. Interference of galvanotaxis and thigmotaxis in Paramecia and hypotrii infusoria. Real or homotop interference, apparent or heterotop interference. The two effects of homotop interference of excitations: Summation and inhibition of excitations. Theory of the processes of inhibition. Hering-Gaskell theory. Inhibition as an expression of the refractory period. Individual possibilities of interference of two stimuli. Interference of an excitating and a depressing stimulus. Interference of two depressing stimuli. Interference of two excitating stimuli. Analysis of the interference of two excitations. Interference of two single stimuli. Conditions upon which the result of interference is dependent. Heterobole and isobole living systems. Intensity of the two stimuli. Interval between the stimuli. Specific irritability and rapidity of reaction of the living system. Latent period. Interference of single stimuli in a series. General scheme of the development of the effect of interference. Summation and inhibition. Apparent increase of irritability. Conditions of summation. Tonic excitations. Conditions of inhibition. Various types of inhibition. Interference of two series of stimuli. Relations in the nervous system. Peculiarities of the nerve fibers. Conversion of the nerve by relative fatigue from an isobolic into a heterobolic system.

Until now the mechanism of the single excitation has received the major portion of our attention. It was not until we reached the subject of the origin of fatigue that we became acquainted with the effects of repeated stimulation. Here we found a case of interference of individual excitations. But fatigue is simply a special instance of such interference, for the subject of interference action occupies a much greater field.

Every cell of the larger organisms, and more especially the single celled organisms, is subjected to manifold stimuli. It is indeed, quite common that two stimuli interfere with each other and manifold effects follow, depending upon the specific reaction of the cell and the quality, intensity and duration of the interfering stimuli. Sometimes the interference effect is readily understandable from a knowledge of the specific effect of the individual stimuli concerned. At other times, however, the specific reaction seems entirely different in nature than would be expected from a study of the effects of the individual stimuli.

Galvanotaxis of Paramaecium aurelia.]

When I place a drop of Paramecium culture on a slide having on two sides parallel pieces of baked clay which serve as electrodes and allow a constant current of about .2 milliampère to flow through, it will be seen that the infusoria at room temperature move toward the negative pole at a rate averaging 1–1.4 mm. per second. (Figure 39.) If I increase the temperature, the rate of movement is increased. Here the galvanic and the thermal stimuli influence each other in such a manner that the reaction to the galvanic is increased by the thermal stimulation. This summation of excitation is readily understood on the basis of the laws concerning the effect of temperature upon the velocity of chemical change established by van’t Hoff. If, however, the Paramecia are in a 1 per cent. alcoholic solution, then, as was shown by Nagai, the rapidity of movement following galvanic stimulation is decidedly reduced. The interference effect between the galvanic and chemical stimulation is, because of the depressing effect of the latter, likewise readily understood.

Nagai: “Der Einfluss verschiedener Narcotica, Gase and Salze auf die Schwimmgeschwindigkeit von Paramæcium.” Zeitschr. f. allgem. Physiologie Bd. VI, 1907.

Thigmotaxis of Paramaecium aurelia. (After Jennings.)]

Greater difficulty meets us, however, in the following instance. The forward movements of the Paramecia follow in consequence of the fact that the individual cilia of the body lash more powerfully backward than forward. If now the Paramecia, while moving forward, meet with a resisting body, they withdraw sideways while executing a sudden strong forward ciliary stroke. The strong mechanical stimulation brings about retraction of the organism. Entirely different are the results when the impact is weak. If Paramecia while slowly swimming touch a resisting object with the anterior portion of the body, withdrawal does not occur. The infusoria remain under proper conditions in contact with the resistance, and the rhythmic activity of the cilia directly against resistance, as well as those on the other side toward the posterior portion of the body, are more or less inhibited. (Figure 40.) The degree of inhibition brought about by this weak mechanical stimulation may vary considerably. At times the cilia of the whole body suddenly cease their movement. (Figure 41, A.) At other times, this cessation is limited to the cilia in the anterior portion of the body (Figure 41, B), while the movements of those on the posterior portion of the body are of less amplitude or are irregular and weak. In all cases the infusorium remains quiescent in the water in contact with the resistance, and it is not uncommon to find numerous individuals in apposition with particles of ground, slimy detritus, plant fibers and so forth. (Figure 41, C.) In short, the rhythmic activity of the cilia of the Paramecia receiving their normal impulses of excitation from the ectoplasm of the cell body interfere with strong mechanical stimuli in such a manner that a negative thigmotaxis develops; following weak mechanical stimuli a positive thigmotaxis results. Here is an instance of the relation between the intensity of the stimulus and the manner in which its effects interfere with an already existing excitation.

A B C

Fig. 41.

Thigmotaxis of Paramaecium aurelia.]

However, the strength of the inhibitory effect of a weak contact stimulus upon another excitation is best appreciated when positive thigmotaxis is interfered with by the effect of a thermal or galvanic stimulus. Jennings and especially Pütter have, at my request, more thoroughly investigated my original observations and have given us a complete analysis of these interesting interference effects. If the freely swimming Paramecia are subjected to a constantly increasing temperature, the movements of these infusoria become more and more active. At 30° C., the rapidity is very violent and at about 37° C. they reach their maximal. If now the same experiment is repeated with Paramecia which have in consequence of thigmotaxis fixed themselves to particles of slime, the temperature may be increased to 30° C. without an observable effect. The infusoria remain throughout in contact with the resistance. Only when the temperature is 37° C. do they release their contact and move violently through the water. If a drop containing Paramecia is placed on a slide, between parallel pieces of fired clay which serve as electrodes, it will be seen that some freely swim about, whereas others remain thigmotactically in contact with particles of slime. When a constant current of about .2 of a milliampère is passed through, it is observed that the freely swimming individuals hasten towards the cathode. Those attached to objects, on the contrary, do not respond in this manner to the electrical current. (Figure 42.) The intensity of the current can be greatly increased without bringing about detachment of the individuals from their position of fixation. The typical influence of the strong current upon the movement of the cilia of the thigmotactically fixed individuals can be clearly seen. Nevertheless, the inhibition, brought about by the contact stimulus, predominates over that of the excitating effect of the current, so that a freeing of the organisms from their position does not occur. Not until the current becomes very strong is the excitation thereby produced sufficient to bring about a separation of the infusoria, whereupon they immediately swim toward the cathode. In this interference between the contact stimulus, on the one hand, and the thermal or galvanic on the other, the inhibitory effect of the former may overpower the strong excitation of the latter.

Herbert S. Jennings: “Studies on reactions to stimuli in unicellular organisms. I. Reactions to chemical, osmotic and mechanical stimuli in the ciliate infusoria.” Journal of Physiology, Vol. XXI, 189 F.

Pütter: “Studien über Thigmotaxis bei Protisten.” Arch. f. Anat. and Physiologie, physiol. Abt. Suppl. 1900.

Interference of galvanotaxis and thigmotaxis in Paramaecium aurelia. The individuals which are thigmotactically attached to slime particles remain at rest while the freely swimming individuals move toward the cathodic pole. ]

Fig. 43.

Hypotrichous infusoria. A--Stylonychia. B--Urostyla.]

Still more complex and striking is finally the following case of interference between thigmotaxis and galvanotaxis. The hypotrichous infusoria as Stylonychia, Urostyla, Oxytricha, etc., have a marked functional and morphological differentiation of their cilia. They possess a bow-like row of perioral cilia, which sweep in the food; a number of cilia on the ventral surface used for locomotion by which they move about upon objects in the water; a row of border cilia on each side, which, during swimming, contribute the propelling force. The perioral cilia also form the elements which bring about a screw-like movement on the axis. They further possess several cilia, which permit a rebounding of the organism, and finally certain forms have anal cilia, which probably serve as breaks and to steer the organism. (Figure 43.) Their usual mode of locomotion is that of creeping, moving by means of the cilia on the ventral surface. These movements depend upon the positive thigmotaxis of the cilia of locomotion. At the same time there is inhibition of the cilia on the sides. When the infusoria are excitated by a new stimulus, the cilia used for rebounding become active, the body frees itself from its position of attachment and begins to swim, wherein the cilia on the sides, as well as the perioral cilia, act in the manner mentioned above. I have made the striking observation that the hypotrichous infusoria respond differently to the galvanic current, depending on whether they are swimming or in a fixed position. If one places a drop of water with numerous Urostyla on a slide between parallel pieces of fired clay which serve as electrodes, it will be seen, upon the closing of a current, that all of the individuals which are freely swimming and turning in a screw-like manner around their axis, steer immediately toward the cathode, exactly as in the case of the Paramecia. On the other hand, those which are fixed to the bottom of the slide as a result of thigmotaxis, upon closing of the current, make a short turn and assume a position wherein the long axis is at right angles to the direction of the current, and the perioral rim is directed toward the cathode. In this position they move through the field. (Figure 44.) When the current is broken the individuals draw backwards, distribute themselves and creep and swim in all directions in the water. If during the course of the passage of the current, an individual which has been swimming begins to creep, the axis immediately assumes the position above described in the case of the organisms which are in contact with the bottom and vice versa. The thigmotaxis, therefore, influences galvanotactically swimming organisms in a most characteristic manner. As a consequence of the interference of thigmotaxis and galvanotaxis, the organisms move in a direction transversely to the direction of the current. This most striking reaction has been cleared up by Pütter, the explanation being based upon an accurate investigation of the mechanism of ciliary activity. The galvanotactic swimming toward the cathode is explained by the same principle as that applicable to all galvanotaxis. As a result of the excitation produced by the anode, the cell body must assume a position wherein the border cilia, which are of greatest importance in swimming, are equally stimulated on both sides of that part of the body directed toward the anode. It is only in this position that forward swimming is possible, for as a result of unsymmetrical excitation of the border cilia a turning must at once occur, which automatically brings about a resumption of the position of the long axis. The perioral cilia bring about the screw-like movement around the axis during swimming. It follows that the freely swimming individuals must necessarily move towards the cathode. In the case of the thigmotactically moving individuals the activity of the border cilia is inhibited. The perioral and the locomotion cilia bring about the assumption of the position of the axis, above described. The perioral cilia during movement bring about a turning of the body on the vertical axis toward the side opposite that of the orifice and it follows that the body can occupy only that axial position wherein the perioral cilia are least excitated. This is, however, only the case when the long axis of the body is transverse to the direction of the current, and the perioral cilia are directed toward the cathode, for stimulation arises from the anode. The reason why the infusoria do not turn toward the anode from this transverse position of the axis is to be found in the fact that the anterior locomotion cilia are stimulated to a greater extent by the turning toward the anode, and bring about a movement in the contrary direction. The transverse position of the axis is thus the result of an antagonistic action between the perioral and the anterior locomotion cilia. It therefore follows that the characteristic position, which is necessarily assumed by the thigmotactically creeping individuals, is brought about by an interference action between tactile and galvanic stimulation.

Pütter: l. c.

Max Verworn: “Allgemeine Physiologie.” V Aufl. Jena 1909.

Urostyla grandis. Interference of galvanotaxis and thigmotaxis. The freely swimming individuals move towards the cathode (left side). The creeping individuals move in transverse direction. ]

These, then, are a few examples of the interference action of various stimuli on the single cell. They show us in part fairly simple, and in part very complex states. It now behooves us to obtain a general understanding of interference action, to learn the fundamental laws in connection with these complex actions, to shell out, as it were, the general factors involved in the special conditions. In this connection the examples already referred to furnish all of the data necessary for our first orientation. In the simple instance in which the effect of galvanic stimulation was augmented by increase of temperature and again in the case where there was a diminution of excitation resulting from the alcohol, the interference of the two stimuli is consequent upon the fact that the location of attack is the same. The constant current acts upon a portion of the infusorium, which also responds to elevation of temperature. We have a real, or, as I may term it, “homotopic interference,” for it is an interference in which the general point of attack is the same for both stimuli.

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 (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.

M. Schiff: “Lehrbuch der Physiologie des Menschen.” Bd. I, Lahr 1858.

Among other investigations, which since this time have been made to explain the mechanism of inhibition, those of Gaskell, Hering and Meltzer 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. 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.) 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 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, 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.

Gaskell: “On the innervation of the heart with especial reference to the heart of the tortoise.” Journ. of Physiology, Vol. IV, 1884.

Ewald Hering: “Zur Theorie der Vorgänge in der lebendigen Substanz.” Lotos IX. Prag 1888.

Meltzer: “Inhibition.” New York Medical Journal, 1899.

Max Verworn: “Erregung und Lähmung. Vortrag gehalten in der allgemeinen Sitz. der Gesellsch.” Deutsch. Naturf. u. Aerzte zu Frankfurt a. M. 1896. Verh. d. Ges. Deutsch. Nat. u. Aerzte 1896.

Max Verworn: “Zur Kenntniss der physiologischen Wirkungen des Strychnins.” Arch. f. Anat. u. Physiol. physiolog. Abth. 1900. The same: “Ermüdung, Erschöpfung and Erbolung.” Ibidem Suppl. 1900.

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

Fr. W. Fröhlich: “Die Analyse der an der Krebsschere auftretenden Hemmungen.” Zeitschr. f. allgem. Physiologie Bd. VII, 1907. The same: “Der Mechanismus der nervösen Hemmungsvorgänge.” Medizin. naturwiss. Arch. Bd. I, 1907. The same: “Beiträge zur Analyse der Reflexfunction des Rückenmarks mit besonderer Berücksichtigung von Tonus, Bahnung und Hemmung.” Zeitschr. f. allgem. Physiologie Bd. IX, 1909. The same: “Experimentelle Studien am Nervensystem der Mollusken 12. Summation und scheinbane Bahnung, Tonus, Hemmung und Rhythmus am Nervensystem von Aplysia limacina.” Zeitschr. f. allgem. Physiol. Bd. XI, 1910.

Lower line indicates stimuli.]

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. ]

Before going back to the cases of inhibition and explaining them by this general principle, it is necessary that we penetrate more deeply into the details of the characteristic course of the refractory period. By this means we will find the conditions which universally determine the interference in the effects of stimulation.

First of all, it is self-evident that the occurrence of interference of stimulation in a living system can only take place when the succeeding stimulus is applied before the effects of the previous one have completely disappeared. Within the interval, however, which is involved from the moment of the beginning of a stimulus until its effect disappears through the self-regulation of metabolism, there is the possibility of various interference results from stimulation.

If we take into consideration the various instances which can arise, perhaps we may best start with that type wherein the first stimulation produces depression, whereas the second has an exciting effect on disintegration. In this type the response to the second stimulus is weaker than when the second stimulus alone is applied. As a concrete example of this type, we may refer to the interference of an induction shock in a nerve during the relative want of oxygen. We arrange a nerve of a nerve muscle preparation of a frog in a glass chamber, as already described, and determine the threshold of stimulation of the stretch within the chamber by the weakest induction shocks which produce response. The oxygen is then removed and the effect on the threshold determined. As shown by Baeyer it is found that with increasing asphyxia the threshold of stimulation for induction shocks becomes continually higher. The irritability is likewise decreased. This occurs, as the investigations of Lodholz show, at first slowly, then more and more rapidly. The curve of the decrease of irritability has a logarithmic form. During the continuation of the depressing stimulus, i.e., the want of oxygen, the exciting stimulus has less and less effect. If oxygen is again brought in contact with the nerve, irritability immediately returns to its original height. The cessation of the depressing stimulus has, therefore, the effect that the exciting stimulus again brings about its original response.

A second type of interference is produced when both stimuli bring about depression. As an example, we may select the interference of cold and deficiency of oxygen. If we assume, for instance, that each of these stimuli of itself brings about only a partial reduction of living processes and not a complete suppression, then it would be possible to think of a summation of both depressions. Nevertheless, the conditions for the summation of depression have never been carefully analyzed. Quantitative investigations upon the interference of depressing stimuli are entirely lacking. One should not, however, in physiology presuppose what may happen under certain given conditions without first making the necessary experiments. The strength of scientific investigation depends upon the fact that every deduction, no matter how small, must be substantiated by experience before further progress can be made. So, likewise, we must await the results of thorough experimentation upon the interference of depressing stimuli before we can establish a law. The conditions are not as simple as they appear on first observation, for the point of attack of the various kinds of the depressing stimuli upon the chain of metabolic processes may be very different. In such a case it is not at once possible to understand the results of the interference.

There is a third type in which two dissimilatory excitations interfere with each other. Fortunately there is a great amount of experimental data at our command so that today we have a clear understanding of the essential points of the conditions necessary for the development of summation of excitation on the one hand, and inhibition on the other. If we take an instance of a momentary dissimilatory excitation operating upon an aërobic system in metabolic equilibrium, it is necessary to recall the two effects thereby produced. The stimulus brings about an oxydative decomposition of the living substance. Likewise there is a reduction of irritability. Both of these alterations are the foundation of interference. Both processes have a specific time of occurrence. The disintegration, determined by energy production, reaches a maximum suddenly, then diminishes, at first rapidly, then more and more slowly until the zero point is reached. In an analogous manner the irritability abruptly reaches a minimum, then increases rapidly, then more slowly, until it again reaches its previous value. When we represent these processes by a curve, they assume the following form. (Figure 47.) In this diagram the abscissa is the time, the ordinate value zero is the level of the metabolism of rest and the specific irritability. The points above the abscissa represent disintegration, that is, energy production, those under the abscissa, the reduction of irritability. A consideration of the latent period may be omitted. At the end of the curve the effect of stimulation may be assumed to have disappeared and the state of metabolic equilibrium reestablished. If we base our further observations upon this curve of excitation, we can study in them the factors upon which responsivity is dependent when a second exciting stimulus is operative during the course of the first.

It is from the beginning apparent that the response to the second stimulus is determined by the intensity of the second stimulus in relation to the degree of irritability which exists at the moment when this is effective. This relation is dependent first upon the absolute intensity of the second stimulus. In the following diagram the intensity of the existing threshold value is fixed for convenience as ordinates beneath the abscissa. If, for example, at the time point x, a stimulus of weak intensity R{1} acts, this stimulus being under the existing threshold, produces no perceptible effect. (Figure 48.) If now instead of a weak stimulus, one of stronger intensity acts at the time point x, this stimulus will produce an appreciable response. (Figure 49.) If the second stimulus is of the same strength as the first, this second stimulus will bring about relatively less disintegration, because the system is then in a state in which irritability is still reduced. But this lessened disintegration in that it summates the excitation still existing as the result of the first stimulus can produce an absolute increase of the height above that of the abscissa. Here then we see the possibility of an increase of response resulting from summation. Accordingly the increase of disintegration must occur simultaneously with a diminution of irritability and this must fall below the level of the reduction of irritability produced by the first stimulus. This augmentation of the response through summation above the level of that produced by the first stimulus acting upon an unexcitated system is, however, connected with another condition. The above example refers to systems in which weak stimuli bring about weak response and strong stimuli strong response, that is, the response is capable of increase. In systems in which the “all or none law” is applicable, such an alteration in the absolute height of excitation, as results in summation, is not possible. In order to characterize these two types of living systems by a short expression rather than by a long sentence, we will call the first a “heterobolic system,” the latter in which the “all or none law” is operative an “isobolic system.” The former term expresses various degrees of discharge depending upon the intensity of the stimulus, the latter term refers to the constancy of discharge following stimuli of various intensities. Isobolic systems are in contradistinction to the heterobolic systems not capable of summation. The response to the second stimulus of equal intensity cannot be greater than that of the first, it may be equal to the first (Figure 50) or be less in extent, but it can never be greater than that resulting when a single stimulus is applied. These facts have been known for a long time in the case of the heart muscle. A word is necessary, however, concerning the effect of stimuli beneath the threshold in heterobolic systems. We must here distinguish between the “ideal” threshold, beneath which the influence of a stimulus is nil, and the threshold of perceptible effect_, beneath which a stimulus apparently has no effect; nevertheless a weak effect does occur, as is shown by succeeding reactions. This effect is manifested by a sub-threshold disintegration and a corresponding slight reduction of irritability. (Figure 51.) The presence of such a sub-threshold effect is recognized by various facts as, for example, the summation of the sub-threshold stimuli to production of a perceptible result. Thus stimulation of a sensory spinal cord root with a single sub-threshold induction shock will not produce any evidence of a reflex excitation, whereas, when induction shocks of the same strength and of sufficient frequency are applied, a strong reflex contraction results. The fact that sub-threshold stimuli can bring about sub-threshold effects is also important in consideration of the result of interference. The relation between the intensity of the second stimulus and the degree of irritability of the system, the intensity of the stimulus being absolutely constant, depends, secondly, upon the momentary amount of irritability which exists just at the time when the second stimulus produces its effects. It is, therefore, clear that the response produced by interference must also alter with the momentary degree of irritability in a manner analogous with variations of the intensity of the second stimulus. One must, therefore, know the factors which control the momentary degree of excitation.

Effect of sub-threshold stimuli. o--Level of the ideal threshold. s--Level of the threshold of perceptible effect.]

The first factor to be considered is the moment of time in which the second stimulus is applied, that is, the interval between the first and the second stimulus. If, for example, a weak second stimulus follows very quickly after the first, the stimulus will bring about no response, as the system at the time of its application is in a relative refractory period. (Figure 48.) The stimulus is, therefore, under the threshold. If, however, a stimulus of the same strength is applied somewhat later, when the irritability has already increased to a somewhat greater extent, then at this moment the stimulus is above that of the threshold and a response is obtained which, on account of the state of irritability existing, is summated. (Figure 52.) But further, it is not a question of the absolute interval between the stimuli, but rather to the relative interval to the specific rapidity of the reaction of the living substance under consideration. There are living substances, as we have seen, in which the refractory period is unusually short, as, for instance, the nerve. There are other substances wherein this period lasts a considerable time after stimulation, that is, before the irritability returns to the original level, as, for example, the smooth muscle. Indeed, depending upon the specific properties of a system, a short or a long interval is required before a stimulus of a given intensity is again operative. Finally, in one and the same living system the duration of the refractory period can be very different, depending upon the momentary state of the system. Above all we know that the refractory period is considerably prolonged in fatigue and likewise after the influence of other agents, as narcotics, lowering of the temperature, etc. In such states a second stimulus remains inoperative when it follows at a definite interval from the first, whereas under normal conditions the same stimulus applied at the same interval would be operative.

Finally, there is another factor to be considered, namely, that the latent period of the second stimulus is more and more prolonged as the second stimulus approaches more closely to the absolute refractory period of the first. In the above schemes the latent period was not taken into consideration because practically for all the intervals of stimulation considered at that time it could be assumed to be the same. When, however, a decrease of the intervals between the individual stimuli takes place, the prolongation of the latent period can then not be overlooked, as it leads to a retardation of response. (Figures 29, 30.) This fact was shown in the classic investigations of Marey upon the refractory period of the heart, and more recently has been the subject of study by Samojloff, Keith Lucas and Gotch in the muscle and nerve. These, then, are the essential factors which bring about interference, and although there are special details which deserve more close analysis, nevertheless, we are in a position to attribute to them the origins of summation and inhibitory processes, which occur in all living systems, especially the nervous system.

Marey: “Des excitations artificielles du cœur.” Trav. du lab. de M. Marey II, 1875. The same: “Des mouvements que produit le cœur lorsqu’il est soumis à des excitations artificielles.” Compt. rend. de l’acad. des sciences T. LXXXVII, 1876.

Samojloff: “Actionsströme bei summierten Muskelzuckungen.” Arch. f. Physiologie Suppl. 1908. The same: “Über die Actionsstromkurve des quergestreiften Muskels bei zwei rasch aufeinanderfolgenden Reizen.” Zentralblatt f. Physiol. 1910.

Keith Lucas: “On the refractory period of muscle and nerve.” Journ. of Physiology, XXXIX, 1909–10. The same: “On the recovery of muscle and nerve after the passage of a propagated disturbance.” Ibid. XXXXI, 1910–11.

Gotch: “The delay of the electrical response of nerve to a second stimulus.” Journ. of Physiology, XXXX, 1910.

For the analysis of summation and the inhibitory processes which occur in the physiologically active organisms or which are experimentally produced, a very important point should be observed, that is, the fact that the stimuli which bring about these phenomena are practically always a series of single stimuli. The nerve impulses, for example, consist of a shorter or a longer series of single discharges which follow each other in rapid rhythmic sequence. Here, then, we have the conditions necessary for the production of interference effects when these single stimuli follow each other with sufficient frequency and also when there is the combined action of two series.

Curve showing the general development of the effect produced by interference of the stimuli of the same series in an heterobolic system. The effect is first summation and then inhibition. R indicates the intensity of the stimuli, S the level of the threshold of perceptible effect. ]

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, Boruttau, Boruttau and Fröhlich, Thörner 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. Fröhlich 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. Reinecke 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.

Waller: “Observations on isolated nerve.” Croonian Lecture, Philosophical transactions. 1897.

Boruttau: “Die Actionsströme und die Theorie der Nervenleitung.” Pflügers Arch. Bd. 84, 1901.

Boruttau und Fröhlich: “Electropathologische Untersuchungen. Ueber die Aenderung der Erregungswelle durch Schädigung des Nerven.” Pflügers Arch. Bd. 105, 1904.

Thörner: “Die Ermüdung des markhaltigen Nerven.” Zeitschr. f. allgem. Physiologie Bd. VIII, 1908, und Bd. N, 1910.

Fr. W. Fröhlich: “Ueber die scheinbare Steigerung der Leistungsfähigkeit des quergestreiften Muskels im Beginn der Ermüdung (Muskeltreppe), der Kohlensäurewirkung und Wirkung anderer Narkotica (Aether, Alkohol).” Zeitschr. f. allgem. Physiologie Bd. V, 1905. The same: “Das Princip der scheinbaren Erregbarkeitssteigerung.” Zeitschr. f. allgem. Physiologie Bd. IX, 1909.

Fr. Reinecke: “Ueber die Entartungsreaction und eine Reihe mit ihr verwandter Reactionen.” Zeitschr. f. allgem. Physiologie Bd. VIII, 1908.

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. 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.

Max Verworn: “Psychophysiologische Protistenstudien. Experimentelle Untersuchungen.” Jena 1889.

The same: “Die physiologische Bedeutung des Zellkerns.” Pflügers Arch. Bd. 51, 1892.

Development of tonus by interference of sub-threshold stimuli. S--Level of the threshold of perceptible effect.]

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 Thörner 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. Fröhlich 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, 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.

Thörner: “Weitere Untersuchungen über die Ermüdung des markhaltigen Nerven. Die Ermüdung in Luft.” Zeitschr. f. allgem. Physiologie Bd. X, 1910.

Fr. W. Fröhlich: “Ueber die scheinbare Steigerung,” etc. Zeitschr. f. allgem. Physiol. Bd. V, 1905.

Keith Lucas: “On the gradation of activity in a skeletal muscle fiber.” Journ. of Physiology, Vol. XXXIII, 1905–06. The same: “The all or none law of contraction of the skeletal muscle-fiber.” Journ. of Physiology, Vol. XXXIII, 1909.

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 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 and his coworkers on the dog, and Fröhlich, Vészi, Tiedemann and Satake on the frog.

Sherrington: “Ueber das Zusammenwirken der Rückenmarksreflexe and das Princip der gemeinsamen Strecke.” Ergebnisse der Physiologie. Jahr. IV, 1905.

Sherrington: “The integrative action of the nervous system.” New York 1906.

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.

Julius Vészi: “Der einfachste Reflexbogen im Rückenmark.” Zeitschr. für allgem. Physiol. Bd. IX, 1910.

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

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, 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 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.

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.

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 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 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 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.

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

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

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.