Physiological Foundations of Behavior

If this is actually the case, a knowledge of the nature of excitation and transmission is of fundamental importance for an adequate conception of the individual organism. Unfortunately our knowledge of excitation and transmission is still very incomplete. Investigation has naturally been largely concerned with the most excitable tissues, nerve and muscle and with these tissues in their most highly specialized forms in the higher animals. Even in some of the recent works on general physiology, excitation and transmission are discussed primarily from the viewpoint of nerve and muscle physiology, and little attention is given to their significance for the behavior of living protoplasm in general. Certain features of the development of our conception of excitation and transmission are of interest here and are briefly discussed«in the following paragraphs.

Earlier theories of excitation and transmission. — The complexity of the dynamic changes in living protoplasm and the difficulties involved in obtaining positive and exact knowledge of them and their relations to each other have made advance in this field slow, and this situation has favored the formulation of widely different hypotheses. With the development of physiology and the experimental method, the older metaphysical hypotheses of vital spirits and their flow through the nerves gave place to physical and chemical hypotheses, but even these differ widely.*

Galvani’s discovery that excitation and transmission in nerves could be electrically induced led him to believe that the principle of electricity and of nervous function are the same. Since Galvani’s time it has been abundantly demonstrated, on the one hand, that electric changes may bring about excitation, not merely in nerve but in other kinds of protoplasm, and on the other, that changes in electric potential are involved in excitation and transmission. The belief that the electric changes are in some way of fundamental importance in excitation and transmission and the hope of attaining a solution of the problem by investigation of these electrical phenomena and their experimental modifications has been responsible for the great development of electro-physiology during the latter part _ of the last century.2 During this period widely different hypotheses concerning the origin and rdéle of the electric changes in excitation were advanced. Originating perhaps in Du Bois Reymond’s hypothesis of the electromotor molecule, the belief in the purely physical origin of the electric phenomena was widespread and appeared in various forms. On the basis of the experiments by Matteucci the conception of the nerve, or at least the medullated nerve, as made up of two different conductors, ¢. e., the axis cylinder and the medullary sheath, between which electric polarization occurred, was developed in various publications by Hermann * and others. Boruttau

1 Only a few of the more important points can be mentioned in the text. For any adequate appreciation of the various theories and the enormous bibliography of this very interesting chapter of the history of biology, the reader must refer to the discussions, general surveys and reviews of the subject which have been published from time to time: e. g., Hermann, ’79; Biedermann, ’96, ’03; Hering, 79, 88, 99; Boruttau ’01 b; Cremer, ’09; Verworn, ’06, ’13, Chaps. V, VI; Bernstein, 12. References to the work of R. 8S. Lillie, Loeb, Tashiro, Mathews, Lapicque, Lucas, Adrian and others are given below. The discussions of excitation and transmission in the text-books of physiology are usually very largely concerned with the phenomena in nerves and muscles of the higher animals.

2 Por the theories and literature of this period see Biedermann, ’96, ’03; Bernstein, 712. (00, 01 a, b, 02) and Hoorweg (’01) went so far as to maintain that between the point of original excitation and the end organ there was no transmission of excitation in any physiological sense, but merely of electrical changes. Various other authors also held that the proc- — ess of transmission is something quite distinct from excitation, 7. e., that the excitatory change itself is not transmitted. Hermann, however, insisted that with electric polarization without excitation in a physiological sense a wave-like transmission could not occur. More recently, Bose (’02, ’06, ’07, ’13) on the basis of extensive investigation of the electrical features of response in plants and in metals, maintains that excitation is fundamentally a molecular, a physical disturbance. Macallum (’11) has suggested that the electric phenomena in nerve may originate in surface tension changes.

But even during the period when these purely physical conceptions of excitation and transmission were very generally current, various physiologists called attention to the probable significance of “physiological factors,” 7. e., factors characteristic of living protoplasm and including the chemical reactions of metabolism. Hermann in some of his earlier papers (’67 a, b) maintained that excitation of a nerve results from a sudden acceleration of metabolic processes. Later, however, he abandoned this purely chemical view as incomplete, but insisted on the importance of a “physiological z.”’ Hering (’79, ’88) also maintained that the electric phenomena of nerve and muscle result from changes in chemical function. Biedermann (’96), a pupil of Hering, adopted essentially this viewpoint and called it the Hermann-Hering theory. Waller (97, ’03) maintained that metabolism was concerned in the electric phenomena of excitation and tramsmission. Bernstein (99) and Hérmann (99) developed the idea that irritable substance consists of chains of molecules surrounded by nutritive fluid. These molecular chains may - take up certain atoms or atomic groups from the nutritive fluid and these are given off or broken down in functional metabolism and in excitation. According to Hérmann, transmission is a transmission of chemical reactions and is not necessarily associated with electric changes.

Later theories of excitation and transmission. — With the rapid development of physical chemistry toward the end of the nineteenth century, the application of its conceptions to the phenomena of excitation and transmission began. The theory of electrolytic dissociation with its definition of the ion as an atom or atomic group bearing pos- 1 Fer a more extended account of these views see Hyman and Bellamy, ’22. ‘itive or negative electrical charges, offered new possibilities of accounting for the electric phenomena characteristic of excitation and transmission. The rapid increase of knowledge concerning the properties of colloids in general and especially of semipermeable membranes has likewise afforded general ideas which have played an important part in the more recent development of our conceptions of these and _ many other physiological processes. Applications to the problem of excitation and transmission of some of these principles and conceptions of physical chemistry were soon made by Bernstein, Nernst, Loeb, _ Lapicque, Boruttau and many others. Loeb, for example, showed in a series of papers the important part played by ions in excitation and inhibition.! Nernst (’08) advanced a theory of electrical stimulation in terms of polarization effects in relation to a semipermeable membrane. Lapicque presented much experimental evidence in favor of the view that excitation is a process of polarization and also called particular attention to the chronological factor in excitation. He showed that an electric current of a certain intensity must act for a certain length of time to excite and on this basis he established a chronological coefficient which he called chronaxie. This coefficient differs in different nerves and muscles and with different conditions and this difference, heterochronism, is of great physiological importance, And finally, he maintained that all these features of excitation can be interpreted in terms of electrical polarization of semipermeable membranes.2. This conception of excitation, like various others of this period,’ is essentially electrolytic in character, but some physiologists maintained that the chemical reactions of metabolism play an essential part in the complex of changes which constitute excitation.

Among the theories which belong to this group, that of Verworn (713) asserts that excitation is fundamentally an acceleration in the rate of breakdown or protoplasmic molecules so labile that the excitatory process may be regarded as more or less explosive in character. Verworn also points out that the necessity of oxygen for the maintenance of irritability in aérobic organisms indicates that oxidation is a fundamental factor in the reaction. As regards transmission, he holds that the experimental evidence supports the view now generally

1 See Loeb, 06, Chap. V and numerous special papers of earlier and later date. accepted, though opposed by some of the earlier authorities, that the excitation itself, not merely some electric or other change, is transmitted. Nevertheless, electric changes resulting from the decomposition of the labile molecules at one point are regarded by Verworn as the factors primarily concerned in inducing the decomposition at another point. If the colloid membranes of protoplasm are permeable to positive, and not to negative ions, the chemical decomposition at the point of primary excitation brings about changes in electric potential with flow of current, and this initiates the decomposition at another point. R.S. Lillie’s theory considered below is somewhat similar to this as regards réle of the electric current.

It is well known that excitation in organisms generally and in many organs is associated with increased respiratory exchange, and Tashiro has recently shown that excitation in the nerve fiber is accompanied by increase in CO: production ! and various other authors have found that metabolism occurs in nerve and is increased during excitation.2 Mathews (15, pp. 584-593) also regards metabolism as a fundamental factor in nervous excitation. Lillie’s theory of excitation and transmission. — In the course of the last twelve years R. S. Lillie? has developed a general theory of excitation in terms of current physico-chemical conceptions and based on extensive experimental evidence. Because this theory represents the most recent generalization in this field of physiology, because it is not merely a speculative modification of earlier theories, but is based on various lines of experimental investigation, because it is concerned to some degree, not only with the highly specialized processes of nervous excitation and conduction, but with excitation and transmission in general, and finally, because it will serve very well as a point of departure for discussion of the relations

1 Tashiro, ’17 and earlier papers. Bayliss and Lucas have criticised Tashiro’s conclusions, in part on the ground that Hill (12) has been unable to discover any appreciable heat production associated with the nervous impulse. They suggest that the carbon dioxide may be dissolved in the tissues and that its increase on electric stimulation may be due to the rise in temperature. The demonstration by Riggs (19) that chemical, as well as electrical stimulation is accompanied by increase in CO» appears to answer this objection. Moore (19), using a colorimetric method, was unable to confirm certain of Tashiro’s results, but Tashiro and Hendricks (’21) maintain that the colorimetric method is unsuitable because the nerve produces a volatile base, presumably ammonia, as well as COz. More recently Sheaff (’22) has determined the oxygen consumption of resting and stimulated nerve, the latter being two to four times the former.

* Thunberg, Skand. Arch. Physiol., XLII, 1923 and papers there cited. between excitation-transmission phenomena and physiological gradients, its chief points must be stated somewhat fully. Various experimental data, as well as theoretical considerations, indicate that protoplasmic limiting surfaces, the plasma membranes, are the seat of electrical polarization, and the belief in the existence of such polarization is widespread among physiologists. Moreover, the so-called membrane theory of stimulation (Nernst, ’08) has been very generally accepted. According to commonly accepted views the membrane in the unexcited condition acts as if it were permeable or reversible to certain or all positive ions and impermeable or less permeable to certain negative ions, which are present in higher concentration in the cell than outside. Consequently the unexcited

Fic. 144.—Diagram illustrating transmission wihout decrement. Explanation in text. membrane is electropositive externally, electronegative internally. Proceeding on the basis of these conclusions, Lillie’s experimental investigations have provided many new data in support of the view that excitation involves an increase in permeability to the negative ions and that consequently a more or less complete depolarization of the membrane is associated with excitation. Since the increase in permeability permits the negative ions to pass out, some or all of the positive charges on the outside of the membrane will be neutralized and the region of excitation will show externally an increased electronegativity (negative variation), which must be accompanied by an increased electropositivity internally.t These changes in electric potential determine electric currents between excited and unexcited regions, and Lillie agrees with certain of the earlier investigators in regarding the electric currents initiated by the excitation at one point as the means by which transmission of the excitation to adjoining regions is accomplished. The action of these currents is briefly as follows: since the excited region A (Fig. 144) is electro-

1 According to recent work by Heilbrunn (’23), protoplasm, at least the protoplasm of certain animal eggs, bears a positive electric charge internally and a negative charge externally. If this is true for protoplasm in general, it appears that the electrical changes which have been found to be associated with excitation must involve an increase in the potential difference across the membrane. negative externally and electropositive internally to an unexcited region 5, the positive current must flow from A to B through the tissues and in the opposite direction through the external medium. Such a current must increase the external electronegativity and the internal electropositivity of all other parts within the range of effec- - tiveness, AB, determined by strength of current and resistance. At the same time it must decrease the external negativity and the internal positivity at A. In other words, the electric currents produced by excitation at A bring about excitation at other points within a certain range, AB, and at the same time tend to reverse the state of excitation at A and to bring about repolarization of the membrane there. As points between A and B become excited they likewise become the source of electric currents, and if the excitation at these points is of the same degree or intensity as that at A these currents at B will excite points within the range BC and thus transmission to an indefinite distance without decrement may occur. Because of the existence of a refractory period following excitation, the excitation of B and of C cannot reéxcite A and by the time A has recovered from the refractory period the wave of transmitted excitation is so far distant that A is beyond the range of the currents arising from it.

This brief sketch will perhaps suffice to indicate the lines along which Lillie’s interpretation of excitation and transmission proceeds. He has also made various Suggestions concerning details of the process, but only certain of those need concern us here. In one of his earlier papers he says regarding permeability that the evidence indicates “that the change in permeability associated with stimulation is not a direct effect due to merely physical changes in the protoplasmic surface layer, but is the consequence of a chemical reaction which alters the character of the surface film and temporarily deprives it of its normal semipermeable and electromotor properties, and that this chemical process may in a highly irritable tissue like nerve be initiated by any slight local decrease in polarization, provided the change is sufficiently rapid” (R. 8, Lillie, 714, p. 443).

In various other later papers ' he maintains that the chemical reaction involved in the increase in permeability is a metabolic reaction probably oxidative in nature. Whether this chemical reaction or some colloidal change or a change of some other sort is the primary effect of the depolarization Lillie does not attempt to say, but since the whole series is indissociable and mutually related, it makes little difference which factor we regard as primary and which as secondary.

It is not impossible that, at least in some organisms or tissues, the primary change may differ with different forms of energy as exciting factors. This conception of excitation and transmission resembles that of Verworn and some others in insisting that a chemical reaction is a fundamental factor somewhere in the process. It is evident that according to such a theory the velocity of transmission of excitation is not the velocity of electric transmission, but a variable dependent upon the velocity of the chemical reactions and any other changes concerned in giving rise to the electric currents.

As we have scen, changes in permeability and in electric polarization of membranes are, according to Lillie, essential factors in excitation and transmission. If this is the case, it follows of course that excitation and transmission are phenomena of plasma membranes or of limiting surfaces in protoplasm. Such semipermeable membranes or limiting surfaces are commonly believed to constitute the external boundaries of all cells and protoplasms, but it may be pointed out that limiting surfaces or membranes must also exist between the colloid phases in the interior of protoplasm and the possibility exists that excitation-transmission phenomena, differing perhaps in certain respects from those occurring at the external limiting surfaces, may take place in the limiting surfaces of the continuous phase of the protoplasm. The assumption made by some that excitation and transmission are phenomena of external cellular or protoplasmic surfaces only, seems therefore unnecessary.

Lillie has devised inorganic models of excitation and transmission, consisting of iron wire, the excitation being the activation of the surface of the wire which has previously been passivated. The activation supposedly consists in the decomposition of a surface film previously formed by the action of strong nitric acid (R. 8S. Lillie, 18, 19). Excitation in such models may be brought about electrically or by other means, even mechanically, and the excitatory change is transmitted by means of the electric currents associated with the chemical change at any point. The velocity and range of transmission differ according to experimental conditions and can be controlled and modified. ‘These models also show the refractory period following excitation and a gradual recovery of transmissivity (R. 8. Lillie, ’20).

The advance of our knowledge of the phenomena of excitation and transmission in general makes it more and more probable that they are very complex processes, involving, as Lillie maintains, both chemical reaction, probably the fundamental metabolic reactions, and physical changes. Various facts, such as the difference in rate of transmission in different protoplasms or in the same protoplasm under different conditions, e. g., at different temperatures, the relation between oxygen and excitability and between respiration and excitation, etc., indicate clearly that the electrical changes are closely associated with and dependent upon other changes, probably usually, if not always, chemical. And finally, the evidence points more and more definitely to the electric currents and their effects as the factors determining the progress or transmission of excitation from point to point. Lillie’s theory takes all these and various other points into consideration and may therefore serve as a general foundation for the following discussion, but it may be pointed out that the interpretation of the physiological gradients and their significance for the organism in terms of excitation and transmission is not dependent on this particular theory of excitation nor upon any other, but is based primarily on experimental evidence from many different lines.

Excitation and metabolism. — As already noted above, many of the earlier physiologists believed that metabolism is not concerned in nervous conduction, while others maintained that it is an essential factor. Certainly the natural conclusion from Tashiro’s demonstration of increase in CO, production during stimulation in nerve is the one which he draws, viz., that oxidative metabolism is concerned in the process, but certain critics have questioned the correctness of his conclusions on various grounds, some of which are certainly not adequate (see pp. 178, 190). For example, Hill’s failure to find appreciable heat production in nervous excitation has been regarded by some as conflicting with Tashiro’s conclusions, since oxidation, if it occurs, ought to liberate heat. According to current views, however, oxidation. is an essential factor in the production of light by living organisms, but no appreciable heat production has been observed in bioluminescence. Light production is unquestionably one form of excitatory change and if oxidation without heat production may occur in it, it seems possible that it may also occur in other forms of excitation.

In view of all the facts it appears improbable that any sort of excitation or transmission is possible in any sort of living protoplasm without at least, some metabolic change at some stage of the process between its initiation and the attainment of the “resting” condition. A point to which I wish particularly to call attention, however, is that the processes of excitation and transmission are not necessarily exactly the same in character in all protoplasms and perhaps not even in the same protoplasm under different conditions. Whatever the — nature of the processes in certain highly specialized tissues, it is a wellestablished fact that increase in rate of respiration is a characteristic feature of the more generalized and more primitive forms of excitation in living protoplasm. In short, it appears to be true, essentially as Verworn (713, Chap. V) maintains, that excitation in general is primarily an acceleration in the rate of living, or in certain fundamental dynamic factors of life, and we may agree with Verworn on this point, even though we differ from him as regards what constitutes living.

Living in different protoplasms and even in different organs and tissues and in different stages of development of a single organism does not remain the same complex of changes. Factors in the complex which are closely associated in primitive protoplasm may be more or less independent in some highly specialized tissues and vice versa. In primitive protoplasm, for example, changes in permeability appear to be closely associated with changes in metabolic conditions, but in highly specialized membranes with definite physical structure, changes in permeability, at least to certain substances, probably occur with little, perhaps with no metabolic change. It is conceivable that in some forms of excitation physical changes in permeability, surface tension, etc., may be the primary factors and the metabolic changes may be merely incidents or results. In other forms the reverse may be the case. Moreover, excitations of different degree or intensities may differ in character: a weak excitation may bring about only the decomposition of certain molecules and certain physical changes, while a strong excitation may bring about also the breakdown of other molecules with formation of other products and the determination of other physical changes. Excitation and transmission undoubtedly differ in character, not only with differences in the protoplasms in which they occur, but also with differences in the environmental conditions. Nevertheless, in a broad sense, excitation, particularly in its more primitive forms, appears to be fundamentally an acceleration in rate of living.

Excitation in different protoplasms and in a particular protoplasm under different conditions differs also as regards the rate at which the acceleration occurs. In general the more primitive excitation processes are the slower, the more highly specialized the more rapid, nervous excitation being the most rapid of all. In fact, an important feature of the specialization of excitation consists in decrease in the latent period, 7. e., the time between the impact of the external factor and the excitation itself. The velocity with which the excitation rises to its maximum after initiation also increases in general with specialization. Evolution of the excitatory mechanisms and processes along these lines has been of fundamental importance in the evolution of structure and function in general. Without such evolution of excitation and its mechanisms, structural and functional evolution along other lines, particularly as regards animals, would have been very narrowly limited.

To sum up, the conception of excitation to which the facts point us is not that of a process swt generis superimposed on life by the impact of energy from without, but rather that of excitation as life itself accelerated by these impacts. Rhythmicity, automaticity, self-excitation. — It is evident that in general excitation occurs as a response to action of a factor external to the protoplasm concerned, but the question whether any kind of protoplasm is capable of self-excitation requires some attention. At first glance many cases of rhythmic contraction of muscles suggest an “internal stimulus” or self-excitation. Such contractions have been observed in smooth, cardiac and skeletal muscle under various conditions in which nervous or other rhythmic excitation from without is excluded. For example, rhythmic contraction of smooth muscle fibers has been observed in tissue cultures by M. R. and W. H. Lewis (17) and of skeletal muscle fibers by M. R. Lewis (15). Wintrebert (20) states that rhythmic contractions of the myotomes occur in certain fish embryos before nervous connections are established. These contractions pass both anteriorly and posteriorly from a myotome acting as pacemaker, but this function of pacemaker moves from myotome to myotome in the posterior direction as development advances. It is a familiar fact that heart muscle, completely isolated from nerve centers may contract rhythmically under a continuous stimulus such as a constant current. Biedermann, Loeb and others have observed rhythmic contraction of isolated skeletal muscle in certain salt solutions.! There is also considerable evidence indicating the presence of a rapid rhythm in at least some nervous stimuli. Various other organs, from cilia and flagella through different de-

grees of motor specialization, show either rhythmic response to constant stimuli or rhythmic behavior in the apparent absence of external stimuli. The usual interpretation of rhythmic response to constant stimuli is based on the existence of a refractory period. For a certain length of time after a response the organ is not excitable; then excitability gradually returns until the point is reached at which the constant stimulus initiates a new response, and so on. For those cases in which a constant stimulus of any kind is known to be present this interpretation appears to be satisfactory, but the question whether a stimulus of any kind, rhythmic or constant, is present in all cases of rhythmic activity remains. It has been maintained by certain authors that some such activities result from alternate accumulation and spontaneous breakdown of excitable material, 7. ¢., that a real self-excitation occurs. This view, however, does not appear at present to have any adequate physico-chemical basis.

It may still appear difficult, however, to account for such cases as the rhythmic contractions of muscle fibers in tissue cultures or even of certain myotomes in embryos in the absence of nerves. But even in these cases there is the possibility of stimulation by mechanical tension. The Lewises state that the muscle fibers in their cultures appear to be under more or less tension and the cytoplasm is elastic. Moreover, stretching them often serves to initiate rhythmic contraction. In the case of the myotomes the tensions associated with growth may start the rhythm in a particular myotome at a certain stage. In a recent paper E. J. Carey (’21 b) has laid great stress on the importance of mechanical tension in determining, not only the development and differentation of muscle, but rhythmic response. He maintains that the stimulus to the heart beat is primarily the tension caused by the blood and that the continuation of the beat in the differentiated heart in the absence of blood results from the reciprocal tension of different muscle layers or regions. Carey does not discuss those cases in which heart beat begins in the absence of circulation, but if it is true that tension is the essential factor, the tensions associated with growth and development may be effective on the heart in the absence of blood, or fluid accumulating in the cavity of the heart may exert tension in the absence of circulation.

In the cases of muscles contracting rhythmically in salt solutions mechanical tension is not necessary and the stimulus must be chemical or electrolytic. Concerning the origin of rhythm in nervous discharge we know practically nothing beyond the fact that it is not directly dependent upon a rhythmic stimulation, but may occur even with a single stimulus. Given the original stimulation, the rhythm of the nervous impulse must result from conditions within the cell, but, so far as we know, impulses do not originate without a stimulus of some sort from without.!_ What appears to be spontaneity may be in some cases merely failure to recognize the exciting factor and the relation between this factor and the response may be so indirect that recognition is difficult.2 As the facts stand at present there is no reason for assuming the occurrence of self-excitation. Spontaneity in the strict sense is far from being a demonstrated fact. One cell region, cell or cell group may of course excite another, but the original source of excitation and of the initiating energy is apparently always outside the region, cell or cell group excited. Transmission in all its forms from the primitive protoplasmic transmission to the highly specialized nervous conduction is such excitation of one region by energy transfer from without.

These conclusions of course raise the question whether, or to what extent life itself is fundamentally excitation, that is, whether it would not in the absence of the energy relations to the external world undergo gradual retardation and finally attain a static equilibrium. Doubtless so long as material exchange between a protoplasm and its environment occurred, certain chemical reactions would go on, but it is by no means certain that such reactions alone would constitute anything that we could recognize as life. Certainly without excitation nothing in the way of reaction or response to an environment could occur and to most biologists it is this capacity for response that distinguishes the living from the non-living,

The decrement in intensity, energy or in short effectiveness of excitation which is characteristic of many forms of transmission has been repeatedly discussed in earlier publications (Child, ’15 b, Chaps. II, V, VI, ’21, Chaps. IV, XII). This decrement apparently 1Some discussion of the rhythms of nervous discharge and their probable réle in the analysis and correlation of neuromotor activities in higher animals will be found in Herrick’s work (24, Chap. IX).