Irritability: A Physiological Analysis of the General Effect of Stimuli in Living Substance

by Max Verworn

Lower thick line shows duration of stimulation of 9th root; upper thick line that of 8th root.

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 Weber[21] 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 Ziehen[22] 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 Preyer[24] 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. Pfeffer[25] 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. Bowditch[26] 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. McWilliams[28] has later verified the same fact for the mammalian heart. Gotch[29] 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 Lucas[30] 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 Lucas[31] 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 Vészi[32] 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.