We have found that stimuli are alterations in the external vital conditions and that the irritability of living substance consists in the capability to respond to stimuli by changes of the vital processes. It now behooves us in the interest of experimental research to investigate the relations between the nature of the alterations in the external vital conditions on the one hand, and that of the alterations of the vital process on the other; that is to say, to systematically study the effects of stimulation on the living organism. For this purpose it is above all necessary to become acquainted with the almost countless numbers of alterations which take place in the external vital conditions of an organism, and to create a systematic scheme of stimulation which differentiates and presents in comprehensive order those various elementary factors which, among the innumerable varieties of stimuli, would prove effectual. For this purpose it is necessary to select the various factors which are involved in an alteration of the external vital conditions.

The first of these factors is the quality of the stimulus. The external vital conditions are, in short, a series of chemical factors, such as foodstuffs, water and oxygen; the presence of a certain temperature; the existence of a certain light intensity; the existence of a definite static pressure; and finally the presence of an equal osmotic pressure. The stimulus according to its quality can be differentiated into chemical, thermal, photic, mechanical and osmotic varieties. To these must be added other forms of stimuli not ordinarily operative, for instance, many uncommon chemicals, and certain kinds of rays. The form of stimulation, par excellence, which has acquired the greatest importance for the experimental investigation of life, is electricity. In its manifold forms it permits, as no other, of such fine gradations of intensity and duration that it has become in the hand of the physiologist an invaluable means of research.

Alterations in those factors which act as vital conditions compose the great mass of physiological stimuli which act continuously on every living organism. The first point to be considered in every alteration is its direction. The alterations produced by stimuli may be of two different kinds, either positive or negative. The quantity of foodstuffs, water or oxygen, in the surrounding medium, can undergo an increase or diminution; as may the temperature, intensity of light, the atmospheric and osmotic pressure. The strength of the electric current, which may be applied, can also be regulated. In accordance with the definition of stimulation already referred to, we must consider these alterations, whether negative or positive, as forms of stimulation. Now the question arises: Is this point of view justifiable? Should one also consider, for example, the lessening or total removal of a vital condition as a stimulus? Should one consider the removal of water or oxygen, cooling or darkening, as a stimulus? It has, in point of fact, been occasionally attempted not to regard these negative deviations as forms of stimuli. These observers permitted themselves to be led by the dogma, that only that which produces an excitation, that is, an increase of the processes in the living substance, should be regarded as a stimulus. Such a limitation of the conception of stimuli would only result from the one-sided consideration of an all too limited circle of facts. Considered from the point of view which results from a broader range of experience, this narrow view becomes untenable.

In the first place it does not follow that only positive fluctuations of a factor, acting as a vital condition, result in excitation in the existing vital processes. The withdrawal of water produces a diametrically opposite effect. A muscle, from which water has been removed, if exposed to dry air or placed in a hypertonic salt solution, shows violent excitation, which manifests itself in great increase of irritability and development of fibrillary contractions. The breaking of a constant current which has for a long time flowed through a nerve or muscle also elicits a momentary excitation. Further, the abrupt removal of light may also bring about stimulation. To cite an example from the physiology of the single cell, I should like to call to your attention the interesting observations of Engelmann17 on the Bacterium photometricum, of which he was the discoverer. When the field containing these organisms is suddenly darkened, all the individuals contained in the drop immediately dart forward for some distance, at the same time, as is usually the case, quickly rotating around their own axis, and then after a moment of immobility, swim on quickly in another direction. An analogous responsivity has also been shown by other single cell organisms, as has been pointed out by several observers and especially by Jennings.18 In all these cases the excitation was produced by a lessening or total withdrawal of the factors which act as vital conditions; and even those who take the standpoint that only such factors are to be considered as stimuli which produce an exciting effect, are compelled to regard these alterations as stimuli, in spite of the fact that they are negative variations of external vital conditions.

But further, the restriction of the term stimulation to those alterations which increase the course of the changes in the living substance involves the observer in still greater contradictions. It can easily be shown that one and the same factor in one and the same form of living substance has now an exciting, now a depressing effect on the vital processes. This fact can be readily demonstrated19 by means of the infusoria Colpidium colpoda, which can be grown without difficulty in a hay infusion. A number of individuals in a drop of fluid may be placed in a warm stage and observed under the microscope; one then sees that at room temperature they swim about by moving their ciliary processes at a definite rate. Now if the temperature is raised to about 35° C., the ciliary movement becomes enormously increased. The infusoria swim madly through the field of vision. They are in a state of violent excitement. The increase has, therefore, acted as a strong, exciting stimulus. But if one allows the temperature to further increase only a few degrees the ciliary movements are suddenly greatly retarded. The infusoria now swim sluggishly through the field of vision and finally remain stationary. In this case the increase in the temperature has had a depressing effect. If the infusoria are not quickly removed, the depression is followed by death. Should the increase in temperature be regarded in the first instance as a stimulus, and not as such in the second, in which the temperature rises only a few degrees higher? Here the change in the vital conditions concerned is in both instances positive. In all cases of overstimulation we are confronted by the same question. Nevertheless it is not at all necessary to refer to such strong or even life-endangering stimuli for the observation of these conditions. In this connection I would like to cite an even more striking instance and which is of special interest for the understanding of the phenomena in nerve centers. If the posterior spinal roots of a Rana temporara are severed, and the eighth root stimulated with a faradic current, whilst the musculus Gastrocnemius of the same side is connected with a writing lever, one obtains, as Vészi20 has found, at the moment of the beginning of stimulation a contraction of the muscle. The faradic stimulus has, therefore, produced an excitation reflexly. If instead of the eighth the ninth posterior root is stimulated, the result obtained is also an excitation of the muscle. In this case, however, the excitation in the form of a tetanic contraction lasts for some time, provided that the stimulation is not at once stopped. If now during tetanic stimulation of the ninth root the eighth is at the same time stimulated, with a strength of current equal to that which previously brought about contraction of the muscle, instead of an increase and a strengthening of contraction there is, on the contrary, an inhibition which continues throughout the time during the stimulation of the eighth root. If the stimulation of the eighth root is discontinued, the tetanic response of the ninth root reappears. If, on the other hand, the faradic stimulation of the ninth root is interrupted and the eighth root now again stimulated, one obtains once more, as in the beginning, with each stimulation a contraction of the muscle. This fact is illustrated by the accompanying tracings. (Figure 2.) In this investigation undertaken in the Göttingen laboratory it was further shown that a faradic current of the same strength and the same frequency had at one time an augmenting, at another an inhibitory effect, and these effects could be produced alternately at will. Should the faradic current at one time be called a stimulus, at another not? It is here clearly shown to what absurd consequences it leads if the conception of stimulation is limited solely to the cases in which an external factor has an exciting effect; and yet an immense number of instances of a like nature could be cited to show the untenability of this view.

It follows from this, that it is altogether impracticable to define the stimulus itself in relation to the nature of the effects which the stimulus has upon the substances in the living system. One can only appreciate the nature of stimulation in relation to the vital conditions and without considering the nature of the action of the stimuli on the living substance. It is true that every stimulus is followed by an alteration in living processes, but this is to be expected when one clearly understands the nature of vital conditions. A stimulus is in all cases an alteration in vital conditions and, in that each of the vital conditions is necessary for the continuance of life, it follows of necessity that every alteration in the vital conditions, so intimately connected with the living processes, will also be followed by an alteration in the processes occurring in the living system. In short, response is produced. Nevertheless, a definite alteration of an external vital condition, depending upon the state of other vital conditions, that is, according to the state of living substance at the moment, can produce quite opposite effects. Although it may appear expedient to include in the conception of stimulation in given instances, distinctions between stimuli according to the nature of their effects upon the living substance, in all cases the conception must under all circumstances be so formulated that it comprises all alterations in the external vital conditions, either positive or negative, that is to say, an increase or decrease, an augmentation or diminution in those factors, acting as vital conditions.

Besides the quality there is another highly important factor to be considered in the study of every alteration in the living process, namely, its amount. The chemical concentration of the medium, temperature, amount of light, the static and osmotic pressure may undergo more or less variation. The electric stimulus can rise from zero to great intensity and from great intensity can fall to zero. The extent of the alteration determines the intensity of the stimulus. In relation to the intensity, a differentiation of stimulation has been introduced, which is not dependent upon the absolute intensity of the stimulus, that is, upon the extent of the alterations in the external vital conditions, but the intensity of the response that can be observed. One refers frequently to threshold stimulation, to stimulation beneath the threshold, to submaximal, maximal and supermaximal stimulation. Such a classification is in many ways very valuable. It is not only of practical value for the establishment of definite intensities of stimulation, but also for the study of the state of irritability in the living organisms.

The threshold of stimulation furnishes roughly a standard for the degree of irritability of a living system. The threshold value of a stimulus is then that degree of intensity which is just sufficient to bring about a perceptible response. The threshold of stimulation is low, that is, the irritability is great, when the intensity of the threshold stimulus is small; the threshold is high, that is, the irritability of a system is small, if the intensity of the threshold stimulus is great. All intensities of stimuli beneath the threshold are sub-threshold stimuli. Here a point must not be overlooked, which in older physiology did not generally meet with sufficient attention. From the fact that the sub-threshold stimuli produce no apparent effects, the wrong deduction must not be made, that they have no effect whatsoever. The conception of the threshold of stimulation originated in the field of muscle physiology and that of the special senses. Here the indicator of the response is, on the one hand, contraction of the muscles, and on the other, conscious sensation. There was a great temptation to consider the stimulus altogether ineffectual, if it produced no conscious sensation or no contraction of the muscle. Today with our finer and more sensitive indicators for the study of the alterations in the living substance, we know in reality that sub-threshold stimuli, which produce no apparent effect in the living substance, can have an effect in reality.

I will call your attention later to the fact that these sub-threshold stimuli play a very important rôle under certain conditions in the activities of the central nervous system. It only depends upon the sensitivity of our special senses, or the indicators used for this purpose, as to whether the alterations can be observed or not. The conception of the threshold of stimulation, therefore, has meaning only when used in relation to a certain indicator. The threshold of the same living system may be different for different indicators. When we use the term threshold we must necessarily know the indicator employed in its determination. The threshold stimulus produces only barely perceptible effects. The amount of response in most living substances increases with the intensity to a certain limit. If this limit is reached, that is, if the response is maximal, the stimulus of the weakest strength necessary to produce this result is termed the maximal stimulus, whereas all intensities lying between the threshold and the maximal stimulus are termed submaximal stimuli. If the intensity of the stimulus is increased above that of the maximal, the response, as in the case of the muscle, does not increase, and therefore one could say that all intensities above the maximal could also be called maximal stimuli.

In realty, however, the response to stimuli of different intensities is never equal, even though it may appear so, when measured by an indicator, as for instance, the height of the maximal muscle contractions. This is clearly shown, for example, when the electrical stimulus is increased far beyond that intensity which is necessary to produce maximal effect. Injury is thereby produced, which is manifested, for instance, in the muscle contraction by the nature of its course and also by its height. One is, therefore, justified in a certain sense in calling the intensities of the stimulus, which are above the value which barely produces maximal contraction, “supermaximal stimuli,” notwithstanding this is logically far from being a happy expression. The term “maximal stimulus,” then, is limited to the intensity of the stimulus which just produces a maximal effect. I wish to point out this distinction between maximal and supermaximal stimulus, as there is often a lack of clearness in the use of these terms.

In that the nomenclature of intensity of stimulation is based upon the intensity of response, the question arises as to the relation between the intensity of stimulus and the amount of response. It is well known that this question has met in one special field of physiology with a very detailed and comprehensive treatment. I allude to the teaching concerning sensation. Ernst Heinrich Weber21 first called attention to the relation between increase in sensation and that of the stimulus in the case of the sense of touch. His observations, which have been formulated into “Weber’s law,” have been the object of animated discussion. A presentation of this law is the following: “The amount of pressure necessary to produce a perceptible increase of sensation always bears the same ratio to the amount of the stimulus already applied.”

If in accordance with Ziehen22 we designate the relative increase in pressure to that already applied, which is necessary to produce a perceptible increase in sensation, as the threshold of relative differentiation, we can formulate the law in the simplest way thus: The relative threshold of differentiation is constant. Fechner,23 who indeed attempted to apply this law, applicable to the sense of pressure, to all the other special senses, has given us a mathematical formula, based on the assumption that the just perceptible increase of sensation has the same value at all levels. By this assumption he was able to establish for the first time a relation between the intensity of sensation and that of stimulus, for it follows that “the sensation increases in intensity in arithmetical progression, whereas the intensity of the stimulus increases in geometrical progression.” From this Fechner has worked out a psychophysical formula, which today is generally termed the Fechner law. This is the law: The intensity of sensation varies with the logarithm of the intensity of the stimulus.

Soon the Weber as well as the Fechner law had been extended over the whole field of sensation and stimulation. In this connection Preyer24 has formulated his “myophysical law,” which states that there is the same relation between strength of stimulus and the intensity of response of the muscle as is laid down by the Fechner law for stimulation and sensation. Pfeffer25 has found that Weber’s law applied also to the relations of the chemotaxis of bacteria, to the intensity of the chemical stimulus, and likewise the attempt has been made to show that all living substances respond in the manner laid down by the Weber-Fechner law. Unfortunately the innumerable investigations in this field have shown more and more clearly that it is not possible to formulate a general mathematical law, which strictly fixes the relations of the intensity of the stimulus and the intensity of response. Even in the field of the physiology of the special senses many voices have opposed the general application of the Weber and the Fechner law. Lotze, G. Meissner, Dohrn, Hering, Biedermann and Löwitt, Funke and numerous other investigators have already demonstrated for some decades, partly by means of critical inquiry, partly by experimentation, that these laws are not strictly valid. Above all these experiments have shown that logarithmic relations are not tenable and likewise are not applicable to very strong stimuli. The assumption made by Fechner, that is, the acceptance that all barely perceptible increases of sensation have an equal value, has been set aside as incorrect, and with this his mathematical formulation within those boundaries of intensity of the stimulus, in which the Weber law has proven itself valid, must also be abandoned. That which we can say today with certainty concerning the relation between the intensity of stimulus and the amount of response is as follows: A law generally applicable to the relation between the strength of the stimulus and the amount of response cannot be mathematically formulated. For a great number of living systems the rule which holds for the intensity of stimulation within certain boundaries is the following: With increase of the intensity of stimulation the response at first increases rapidly and later more and more slowly.

This rule of course only applies within the boundaries of the intensity between the threshold of stimulation and maximal stimulus. The interval, however, between these intensities varies considerably in different living substances. In this connection there are several forms of living substance which call for our special attention. In these the surprising condition seems to exist, that the interval between the threshold and the maximal stimulus is zero; that is, every stimulus which acts at all always produces a maximal response. Bowditch26 first observed this behavior in the frog’s heart and this has also been confirmed by Kronecker.27 The induction current produces, as Bowditch says, either a contraction or nothing. If the former, it is the strongest contraction which can be produced by an induction shock at the given time. Here for the first time a constancy of response was discovered which has been termed the all or none law. McWilliams28 has later verified the same fact for the mammalian heart. Gotch29 has also arrived at the same conclusion in connection with the nerve. He states that “the comparison of submaximal with maximal responses shows that although there is an obvious difference in the amount of E. M. F., there is little or no difference between such time relations as the moment of commencement, the moment of culmination of E. M. F. and the rate at which E. M. F. disappears.” Further: “the rate of propagation of the excitatory wave is the same whether this is maximal or submaximal.” He likewise assumes that the “all or none law” is applicable to the constituent fibers, and that the variations in the strength of response with weak and strong stimulation are brought about in the first instance by stimulation of a few, in the latter by a greater number of fibers in the nerve trunk. The same conclusion has been reached by Keith Lucas30 for the single cross-striated fiber of the skeletal muscle, founded on the fact that by direct stimulation of a bundle of curarized muscle fibers, the contraction only increases inconstantly and not regularly with the increasing intensity of the stimulus. This is only comprehensible if one takes into consideration that, with the increasing intensity of the stimulus, a greater and greater number of fibers are stimulated. Keith Lucas31 came to the same conclusion in the case of the muscle stimulated indirectly through the nerve. He, therefore, sees, because of the nature of the response of the single muscle cell, no difference between heart muscle and skeletal muscle. The “all or none law” applies to the individual muscle cells of both kinds. The difference between the heart and skeletal muscle, according to him, lies in the fact that in the heart the individual muscle cells in their totality stand together as conductors of excitation, whereas in the skeletal muscle the individual muscle fibers are separated, as far as conduction of excitation is concerned, by the sarcolemma. Finally, the recent investigations of Vészi32 with strychnine poisoned ganglia cells of the posterior horns of the spinal cord, have made it appear probable that “the all or none law” can be applied likewise to the individual ganglion cell. He draws this conclusion not only from the fact that all reflex contractions of a muscle of a strychninized frog are maximal, whether they are produced by weak or strong stimuli, but also especially because of the loss in the strychninized spinal cord of the capacity of the summation of irritability. The normal spinal cord does not reflexly respond at all to weak single stimuli, but responds to equally weak faradic stimulation very readily. Therefore, the threshold lies very high for the individual induction shock and very low for faradic shocks. But these differences are equalized in the strychninized frog. This seems intelligible, when we assume that the strychninized cell responds to every stimulus, to which it responds at all, to the maximal extent which is permitted at that moment by its stored up energy, otherwise the excitation would necessarily be summated by faradic stimulation.

Such are the instances to which one has up to the present applied the “all or none law.” The question if, as a matter of fact, such a condition has ever been realized in any living substance has until now found no final answer. Most authors, who accept the validity of the “all or none law” for certain living substances, do so with a certain reserve and speak only of the possibility or probability of such behavior. The subject has, however, as will be shown later, a great and even vital interest in another direction. For this reason I should prefer to postpone the treatment of the same to a later occasion. Here I wish simply to say, that if the “all or none law” is valid in a strict sense for certain structures, then there exists no general constancy of the relations of the intensity of the stimulation and the amount of response, applicable to all living organisms.

We will now return from this digression concerning the relations between the intensity of the stimulus and the response, to the further characterization of the properties of the stimulus. Besides the quality, the direction and the intensity of every alteration in vital conditions, an equally important factor is the duration of the alteration. The time relations, under which a deviation of the external vital conditions takes place, present immense and manifold variations in nature. In many cases the change is very complicated, as for instance, the alteration of the static pressure or the temperature under the influence of air or water currents, the osmotic pressure or chemical factors in diffusion currents, and the light intensity produced by the movement of clouds. These very irregular alterations have practically little interest for us. Here we are concerned rather with the differentiation of the time alterations of the processes of the simplest fundamental types, which are of importance in studying the course of the reaction. For it is of such simple elements that the complicated and irregular alterations of the above-mentioned kinds are composed.

The simplest form of an individual change in the external vital conditions would be a regular and constant alteration of intensity which can be graphically represented as a straight line, wherein the intensities are the ordinates and the time the abscissa. (Figure 3, A.) A regularly rising pressure would, for instance, represent a stimulus in its simplest form. But such forms of stimuli are only very rare in nature and are also experimentally very difficult to produce. It is, for example, not easy to give the electrical stimulus, so much used for experimental purposes, this form. Fleichl and v. Kries have only accomplished this by means of complicated apparatus. The usual form of the individual stimulus is not a straight line, but a logarithmic curve. (Figure 3, B.) The alteration hardly ever progresses with equal rapidity from its beginning until it reaches its highest point, but as a rule, with decreasing rapidity. This is the usual course of alterations of concentration, also of chemical and osmotic stimuli, of changes of temperature and of electric stimulation.

The rapidity of alterations in vital conditions has quite an important influence on the development of the response to stimulation. It is well known that if a constant current, which reaches its highest intensity rapidly, is permitted to act upon a muscle, the effect differs from that following the application of a current of the same intensity but in which this is reached very slowly. In the first case there is a sudden strong twitch, in the second none at all. In spite of this there can be no doubt whatever of the current in the last case being effective. That the muscle is also excited when the current is slowly increased is shown by the contracture, which grows more and more plainly perceptible with the increasing intensity of the current and in higher intensities by the so-called Porret’s phenomenon, which consists in a curious wave-like movement of the muscle-substance. In reference to the rapidity of the alterations in the factors which act as stimuli, the behavior varies greatly. Many stimuli because of their nature never have a steep ascent or descent of intensity, as, for instance, alterations in the concentrations of soluble substances, that is, chemical or osmotic stimuli; likewise temperature variations may be mentioned. They always act relatively slowly. On the contrary there are forms of stimuli which have now a rapid, now a slow, ascent or descent of their intensity, such as the photic and mechanical stimuli. Finally, there are other stimuli that nearly always show a very abrupt change of intensity, such as the electrical form.

The most important factor to be considered in producing the response to variations of intensity, is not the absolute rapidity, but rather the relative rapidity; that is, the rapidity in relation to the characteristic rapidity of reaction of the particular living substance concerned. The rapidity of the reaction to stimuli is very different in various forms of living substance. On the one hand, we have forms reacting very quickly, as the nerve and the striated muscle; on the other, those which respond very slowly, such as a great number of unicellular organisms. Between these are a great number of living substances which, as far as the rapidity of the reaction is concerned, occupy intermediate positions of every varying degree. It is clear that the adequate stimuli for slowly reacting substances must be those having also a slow change of intensity; for quickly reacting, those having a rapid change of intensity.33 If a nerve muscle preparation is simulated with the single induction shock, the “break” as well as the “make” shock has effect. But even here a difference is noticeable. The “make” shock has a weaker effect than the “break” shock. This difference is due to the difference of abruptness in its course, which when the current is made is less than that of opening, for, when the current is made, the ascent of the primary current is retarded by the extra current flowing in the opposite direction, whereas, when broken, with the fall of the intensity of the primary current, the extra current in the primary coil flows in the same direction. In consequence of this there is a perceptible difference in the rapidity of the alteration of the “make” and “break” shocks. (Figure 4.)

Now slowly reacting forms of living substance, such as certain foraminifera, in which the extended pseudopods are stimulated with single induction shocks, the break as well as the make shocks are wholly without effect, as both take place far too quickly for the slow responsivity of these organisms. I have made such observations on various forms of foraminifera of the Red Sea, on Orbitolites, Amphistegina and others. The movement of granules in the pseudopods is not influenced by the induction shocks in the least. It also continues without interruption when the pseudopods are extended. Even with the strongest induction shocks at my disposal I could not induce them to contract; the faradic current, also, the intensity of which I found quite unbearable, remained utterly without effect.34 These two extreme cases, the nerve and the foraminifera, show plainly that the effect of a stimulus is not produced by the absolute rapidity of the increase of intensity, but is solely influenced by the relative rapidity of the same.

A further point for consideration in the duration of an alteration in a vital condition in producing a stimulant action is the length of time the stimulus remains after reaching its highest point. In the forms of stimuli occurring in nature the duration of the alteration after reaching its highest level can vary considerably. The stimulus may remain indefinitely at a certain level, when this is once reached. (Figure 5, A.) The alteration likewise persists. This would be the case, for instance, with the changes of concentration in the transfer of an organism from fresh into sea water. The alteration can also, however, immediately after attaining its highest level, return, so that the original state is at once reestablished. (Figure 5, B and C.) Here it is a case of a quick deviation in the external vital conditions. A sudden jar would be a case in point. Between these two extremes we have all variations in the duration of all natural and experimental forms of single stimuli.

Now we arrive at the question: Has a prolonged stimulation really a prolonged effect? This question might seem superfluous, as from a conditional standpoint it is self-evident that every alteration in any one of the conditions of a system is followed by an alteration in the system. But this very question played an important rôle in older physiology and led to prolonged discussions for the reason that a special case was taken into consideration in this connection, which at that time was not clearly understood. Du Bois-Reymond,35 as a result of his investigations on the nerve muscle preparation of the frog, formulated a law of nerve excitation, according to which it is not the absolute value of the intensity of the constant current which produces an excitation of the nerve and contraction of its muscle, but an alteration of the intensity from one moment to another. The more rapidly these changes are produced, the greater is the excitation. His arguments were based upon the fact that a contraction can only take place on the “making” or “breaking,” or by rapidly strengthening or weakening the constant current; it is possible to subject a nerve muscle preparation to a current of considerable strength without a muscle contraction resulting, provided it is slowly increased. One might be disposed to conclude from this that the constant current, when showing no fluctuations, has no stimulating effect whatsoever. Should this observation be carried even further and the attempt made to extend it into a general law of excitation by assuming that the effects of stimulation are only produced by variations in the intensity, not by its continued duration, one would commit the error of judging the occurrence of a stimulus only by the unsatisfactory criterion of an abrupt muscle contraction. Today we know with positiveness that a continued effect also exists during the uninterrupted flowing of a constant current in nerve or muscle, though much weaker, however, than in the case of the excitations produced by sudden fluctuations of the intensity. This is shown in the nerve by an altered excitability, which continues at the poles during the whole duration of the current. In the region of the anode the excitability is diminished, in that of the cathode it is increased. An excitation can also be demonstrated which extends from the cathode through the nerve, which can easily be detected by sufficiently delicate methods. Among other effects of prolonged stimulation is that of cathodal contracture, which remains localized in the region of the cathode and which excitation persists as long as the current continues. This permanent excitation can be particularly well observed in the single cells of the rhizopods. If a constant current is allowed to flow through an Actinosphærium,36 the straight, smooth, ray-shaped pseudopods of the cell body at the moment of “making,” show evidence of contraction by being drawn in, particularly those directed towards the anodic and in less degree also those towards the cathodic pole. This excitation, greatest at the time of “making” of the current, though diminishing rapidly in intensity during its continuance, remains, however, to a less degree, and leads to a progressive disintegration of the protoplasm on the side towards the anode, which lasts until the current is again broken. (Figure  6.) Thus even though there can be no doubt, on the one hand, that the effect of stimulation, which appears at the moment of the entrance, is to produce alterations, which develop very rapidly, and that by a continuation of this state there is a more or less rapid fall to a low level; on the other hand, it is just as certain that the alterations in the living system persist throughout the duration of the changed external conditions, or to put it more concisely: the effect of the stimulus never wholly disappears unless the changes in the external vital conditions return to their original state.

But more, an effect of the stimulus cannot indeed take place without a certain duration of stimulation, which is related in its turn to the rapidity of reaction of particular living system. This can be much more readily observed in more slowly reacting substances. Fick37 first proved this fact on the muscle of the Anodonta. I have also been able to demonstrate the same fact in the slowly reacting sea rhizopods38 by the use of the constant current. When Orbitolites is stimulated with a constant current lasting approximately the tenth of a second, no response is seen in its extended pseudopods, which are directed towards the poles. The same is the case if the induction current is employed. Only when the constant current of the uniform strength lasts approximately .05 seconds, a barely perceptible response occurs, manifested by the sudden stoppage of the centrifugal flowing of granules in the anodic pseudopods, which, however, after the lapse of one to three seconds continues again unaltered. Should the duration of the constant current be still further prolonged, typical symptoms of contraction are seen being manifested by a heaping up of the protoplasm in the pseudopods in the form of spindles and balls, whilst the protoplasm flows in a centripetal direction towards the central cell body. (Figure 7.)

Two effects can be realized by the alteration in the living system as the result of prolonged stimulation. Either a new state of equilibrium is established by the prolonged action, or sooner or later death develops. In considering both results, however, we will ignore for the present the fact that every living system in the absence of such prolonged stimulation is always in a state of change, i.e., development. Only with this restriction can an equilibrium of the living system be spoken of.

It is sometimes the case that under the influence of a stimulus a new equilibrium is developed, which may remain as long as the stimulus persists. This most frequently occurs as a result of weak stimuli. That which is usually termed “individual adaptation” belongs in this category. Likewise some of the natural and artificial immunizations may also be included. The continued stimulation in such cases of adaptation as we learned before in the example of Amœba limax and radiosa or Branchipus stagnalis and Artemia salina becomes a vital condition for the living substance in its new state.

The other result, namely, that of death ensuing sooner or later, is most frequently produced by stronger stimulation. Through the effect of the prolonged stimulation, the change in the living system is so great that all harmonious interaction of the various processes of life become after a time impossible. The disturbance of this equilibrium after a longer or shorter time becomes so great that life ceases. By far the greater number of all diseases furnish examples of this kind. Disease is nothing else but reaction to stimulation. Should a constant stimulus persist and if the development of a new equilibrium of this system is not established, the result is premature death.

In most cases, as, for instance, the nerve impulses which move toward an organ, or better still the electrical stimuli as used for experimental purposes, it is not a question of a permanent but of a temporary alteration in the external vital conditions. The stimulus starts, then ceases after a longer or shorter period. In this way there is added to the deviation at the start also the alteration at its termination. The latter takes place with different degrees of rapidity, in a manner analogous to that of the initial alteration, and can bring about response. With this the curve of the duration of the course of the stimulus becomes somewhat more complicated and in consequence a like effect is observed in the response. The “making,” duration and “breaking” of the constant current furnishes the example of this type. The “making” of the current being a quick alteration calls forth a strong and sudden excitation (in the muscle contraction); the continuation of the current maintains weak excitation of equal intensity (in the muscle a continued contraction) and the “breaking,” being a sudden alteration, is followed again by a stronger excitation (in the muscle a contraction). The duration of the change can, however, be so short that its intensity does not remain at two periods of time at the same height, but instead the ascent of the intensity is immediately followed by its descent to zero. Induction shocks of short duration, the duration of which have been observed more in detail especially by Grützner,39 offer typical examples. Here a single effect of the stimulus results from the rise and fall of the intensity curve. Hence the induction shocks as momentary stimuli are universally used for experimental purposes.

In contrast to the single stimuli, which find their ideal in induction shocks, another form of stimulation should receive our attention, namely, the series of stimuli which produce a rhythmical alteration of vital conditions. These show among their complex combination of simultaneous and successive actions of their single stimuli relatively the simplest and most easily understood regularity in their effects. They are of particular interest, because they develop in the normal physiological happenings of the animal body in the form of rhythmical intermittent impulses of the nervous system.

Here again it is self-evident that with regard to the course of response, we must first consider the character of the single stimulus of the series, and this must be done from all those standpoints already here discussed. However, a new factor is met with here, that is, the frequency of the single stimuli of the series, or that which has the same meaning, the duration of the intervals between them. This is a feature upon which the result of stimulation depends in a very high degree. But here, too, however, it is not a case of the absolute frequency of the single stimulus, but simply of the relative frequency in regard to the rapidity of reaction of the particular living system. I should like to remark here that it is of greatest importance whether the interval between the two single stimuli of the series is sufficiently long or not to allow the living system time to completely recover from the effect of the preceding stimulus. In the cases, for instance, where we have recovery, we have the same rhythm of stimulation as that of response. When recovery does not occur, interferences of the response are developed, which are of great physiological importance, with the analysis of which we shall later on find occasion to occupy ourselves in detail. The physiological example for these stimuli is the rhythmical discharge of impulses of the nerve centers; the physical method, which is most widely used for experiments, is the faradic current.

It is apparent that the question of frequency must again be combined with all those factors previously discussed in connection with the single stimulus. In consequence another complication arises and with this another point must be taken into consideration, namely, the fact that the duration of the single stimulus in a series undergoes alteration by increasing frequency beyond a certain limit. Beyond this limit the duration of the single stimulus must become less and less. As the result of the fact that stimulation is, as we have seen, dependent on the duration of stimulus, it is evident that, depending upon the rapidity of response of the living system, sooner or later the rhythmical stimulation must become ineffectual. Nevertheless, this effect of shortening the duration of the single stimulus can be compensated by a corresponding increase of its intensity. In this connection Nernst40 showed a very simple relation for induction currents of higher frequency of interruption, which furnishes a law according to which such a compensation takes place. In conjunction with Barratt he found, namely, that the intensity must increase proportionately to the square root of the number of single stimuli if the threshold value of the stimulus is to be maintained, that is, I : √m = const., in which I is the intensity of the current and m the frequency of interruptions. The limits of the validity of this law cannot at present be conclusively established.

This exhausts the small number of elementary factors concerned in the course of the stimulation, and which are of importance in considering its effect. The combination of the different varieties of these single factors, that is, the nature, the direction, the intensity, the rapidity, the duration and number of alterations in the external vital conditions of the organism produce the enormous variety of effects of stimulation which we observe in the living world.