Protoplasmic Action and Nervous Action

Bredig found that a stationary film formed over an inactive surface of mercury is quickly dissolved by rendering the metal cathode;^ in this process of dissolution oxygen is freed. The essential condition of the transmission thus becomes clear. When a film-covered and a bright area of the mercury surface adjoin each other, e.g., after a local rupture of the film, a local electrical circuit is formed between the two, the film-covered area being the cathode of the local circuit. The current of this circuit has the effect of dissolving the film, by cathodic reduction, for a certain distance (estimated at 1-3 milKmeters) from the boundary, oxygen being freed in the process; and by repetition of this effect at each new boundary as soon as it is formed the effect spreads rapidly over the whole surface. The Hg-HjOz pulsating catalysis thus in reality represents an intermittent electrolysis of H2O2 under the influence of the temporary local circuits formed during the alteration or removal of the surface-film.

Rhythmical chemical processes at the surfaces of metals immersed in electrolyte solutions containing compounds which interact with the metal are not infrequent;^ e.g., when the metal is undergoing solution in a strongly oxidizing acid Hke HNO3. Iron in particular often illustrates this phenomenon with great beauty and regularity; in this case the essential conditionof the rhythm is an alternation between active and passive states, due, as in the mercury catalysis, to the alternate formation and dissolution of a protective surface-film of oxidation-product. All of these inorganic rhythms are highly susceptible to variations in external conditions, and especially to electrical influences.

The rhythmical processes so frequent in living organisms (rhythms of cilia, muscle, nerve cells, vacuoles, and cell-division) show many close parallels with these inorganic "surface-reaction" rhythms. As in metals, they are associated with rhythmical variations of electrical potential and with rhythms of chemical or metaboHc alteration and surfacechange (clearly demonstrable, e.g., in cell-division), and are similarly susceptible to changes in the surrounding conditions (temperature, H-ion concentration, presence of salts and surface-active compounds, electrical polarization, etc.) . These parallels imply a similarity in the essential determining conditions in the living and the non-living systems. Since rhythmical catalysis in metals is dependent on the polyphasic character of the system — this being the condition which makes possible rapid local variations of potential, resulting from changes in the composition and structure of surface-films — the hypothesis that the organic rhythms are similarly conditioned naturally suggests itself, particularly when the film-pervaded or emulsion-like

^ For earlier observations cf. Bredig and Wienmayr, loc. cit. structure of living matter and the various facts showing the dependence of stimulation on membrane processes are taken into consideration. The general susceptibility of living matter to electrical influence suggests that in protoplasm there may be a similar dependence of the chemical reactions upon processes of electrolysis occurring at the boundaries between the protoplasmic phases. This general interpretation is also consistent with the readiness and rapidity with which chemical influence is transmitted from region to region in Hving matter; the many close resemblances between such transmissions and the transmission of the waves of electro-chemical alteration over the surface of mercury or passive iron will be considered later in detail. In these inorganic systems the chemical reactions are directly determined by the potential-differences existing between different portions of the metalhc surface; these potential-differences arise as the result of local alterations of the surface-films, and the local circuits thus arising effect the chemical change by electrolysis. Similarly in living matter the waves of chemical and physiological alteration accompanying the transmission of stimulation (i.e., excitation-waves, nerveimpulses, etc.) are always associated with waves of electromotor variation. Bernstein first showed for motor nerves (in 1866) that the physiological effect and the bioelectric variation have the same velocity of propagation;^ and all of the more recent evidence confirms the view that the electric variation is the essential component of the transmitted process.

Recently I have discussed in some detail the parallels between the transmission of chemical effects in systems consisting of metals immersed in electrolyte solutions and the transmission of physiological influence in living protoplasm.^ In all such phenomena in metals the essential condition is the presence of a thin film of electrochemically alterable material formed or deposited at the interface between the metal and the electrolyte solution. Local circuits between adjoining regions of the film-covered surface, differing in composition or physical condition in such a manner as to give rise to an E.M.F. sufficient for electrolysis, are in all cases the essential factor. By the action of these local currents the film is locally altered or removed or rendered permeable

Fig. 3. — Indicating the conditions of the local circuit at the boundary between the active and the passive areas of an iron wire in nitric acid; the direction of the current (positive stream) is indicated by the arrows, the active region (shaded) being anodal, the passive cathodal. The local intensity of the current in the passive region (and hence the reducing or activating effectiveness) decreases in the order A<B<C; beyond a certain distance from the boundary, e.g., XY , it will be insufficient to activate.

over a certain area (usually cathodal, e.g., XY , Fig. 3), adjoining the boundary between the two regions, and the similar circuit which is then formed at the boundary between the newly altered area and the unaltered area beyond repeats the effect; hence the alteration automatically spreads over the whole surface. A wave of such transmission is necessarily associated with a wave of electromotor variation. A brief account of the phenomena of activation and transmission in passive iron will indicate more clearly

the general nature of such processes.' Passivity is readily induced in an iron wire by immersion in strong nitric acid (sp. gr. 1.42); the metal then remains unaltered or chemically inactive when transferred to weak acid (sp. gr. 1.2), unless it is artificially "activated." Activation may be induced by various means, chemical, mechanical, and electrical. The following simple and readily performed experiments will bring out clearly the chief resemblances between the processes of activation and transmission in the metallic systems and in Kving protoplasm.

When the passive iron wire is immersed in a dish of nitric acid of about 60 volumes per cent concentration (i.e., of commercial HNO3 of sp. gr. 1.42), no change occurs, and the surface of the metal remains bright and unaltered. If, however, it is then touched with a piece of ordinary ''active" iron, or with a base metal Uke zinc, a local reaction, accompanied by effervescence and a darkening of the bright metaUic surface, is at once initiated and sweeps rapidly over the whole wire from end to end. In acid of the foregoing concentration, the local reaction ceases in one or two seconds (at 20°), and the metal reverts automatically to the passive state. Immediately after this repassivation it is resistant to activation and transmits the reaction imperfectly; on standing, transmissi\dty gradually returns and within a minute is usually again complete; the metal can then be activated as before and the same phenomenon is repeated. The passive wire may be activated mechani-

^ For a general review of the phenomena of passivity in metals cf. Bennett and Burnham, Journal oj Physical Cheviistry, XXI (1917), cally by jarring or bending or by scraping with a piece of glass; summation effects are a conspicuous future of this form of activation; a single scrape or blow, or a succession of these at infrequent intervals, being usually ineffective, while several scrapes in rapid succession cause typical activation. Chemical activation may be shown by the appucation of a reducing agent Uke sugar. The same kind of effect is produced in the wire, whatever the method of activation, the local change simply initiating a propagated effect whose nature and extent depend on the special conditions existing in the metal-electrolyte system. There is here an evident analogy with explosions or other kinds of ^'trigger effects.'' Hence the system, when in a fully transmissive state, behaves in the " all-or-none " manner.

In reality electrical activation is illustrated in all these cases, even when the local alteration initiating the reaction is mechanical or chemical; i.e., the electrical factor is the essential one in the transmission of the effect. The special conditions of electrical activation are, however, best shown by a somewhat different kind of experimental arrangement. Two passive wires, placed parallel one or two centimeters apart, are immersed in a vessel containing dilute HNO3 and are connected by wires and an open key to a battery (e.g., of about 2 volts E.M.F.). When the key is closed, the cathodal wire (that connected with the negative pole or zinc of the battery) is at once activated, while the anodal wire remains unchanged. This experiment shows that activation is a polar effect and dependent on cathodal reduction. Activation also requires a certain minimal E.M.F. in the battery, usually exceeding one volt, and a certain minimal

duration of flow of the current. Electrical summationeffects similar to those of mechanical activation can also be demonstrated under appropriate conditions.^ Another influence of the current is especially interesting from its resemblance to the physiological phenomenon of electro tonus; this consists in a modification of the susceptibiHty of the wire to mechanical or other activation. During the flow of the current the automatic return of passivity in the active (cathodal) wire is delayed, or with sufficient strength of current prevented, and the anodal wire becomes more resistant to mechanical or other activation. If with two passive wires in a circuit, as above, a constant current too weak to cause activation under these conditions (e.g., the current from one Edison cell) be passed, the cathodal wire, although remaining passive, is rendered temporarily more susceptible than before to activation by other means, e.g., mechanical treatment, while the anodal wire becomes less susceptible.^

All of the foregoing phenomena have their parallels in the behavior of Hving irritable tissues under the influence of the electric current; the corresponding physiological phenomena are summation, polar stimulation, chronaxie, enhancement of irritabihty near cathode, and its decrease near anode (''electro tonus"). Phenomena of a similar kind are seen in the mercuryperoxide system; here also the inactive mercury may be activated by making it the cathode in a circuit, or

^ E.g., by using the brief contact of a copper wire as an activating agent. The local current thus produced may be too brief for activation by a single contact, while several contacts in close succession will produce the effect. " For a somewhat fuller description cf. Jour. Gen. Physiol.^ Ill the rhythm of an automatic pulsation may be altered. During the flow of the current the catalytic effect at the cathode is heightened, while at the anode it is decreased or the rhythm may be abolished/ The parallelism betwxen these effects and those produced by the constant current on the action of rhythmical tissues like the heart is evident.

A more detailed account of the phenomena in filmcovered metallic systems of this kind is not possible within the limits of space, but attention should be called to another interesting feature of the electrical initiation of these reactions. A pecuHarity of the electrical activation of passive iron is that it is not readily produced by currents which rise slowly from a minimal strength to a strength sufficient to activate with sudden closure.^ In other words, the rate of change of the activating current is an essential factor in the effect produced. This is a well-known and highly characteristic feature in the response of living tissues to electrical activation. Each tissue has its characteristic time-factor of electrical excitation or so-called "chronaxie," and this is closely related to the rate of change required of a stimulating current (cf. p. 288). The time-relations of the activating current in the metalHc system resemble those in Hving tissues in the further respect that in the case of alternating currents the relation between the intensity required for activation and the rate of alternation follows the same law, as shown by Bredig and Kerb for the mercury H2O2 system;^ that is, there is an inverse relation be-

tween the intensity required to activate and the root of the number of alterations (i/i/n = const.). This relation has been shown by Nernst^ and others to be generally characteristic of electrical excitation in living tissues; it indicates that a current of a given intensity must flow for a certain minimal time in one direction through the irritable system in order to cause activation. I.e., the change in the electrical polarization of the surface concerned in activation must last for more than a certain critical time, presumably the time necessary to produce a certain critical degree of chemical change. The physical conditions of response to electrical influence thus appear to be of the same kind in the living system and in the inorganic model.

Responsiveness to stimulation is a universal characteristic of living matter. Typically the reaction to a stimulus involves a performance of work (i.e., transformation of energy) which has no definable proportion to the work done by the stimulating agent upon the living system. The stimulus usually acts locally, yet the whole living system — cell, tissue, or even entire organism — may be thrown into activity. Transmission of physiological influence from the immediate site of stimulation to other regions of the living system is thus a constant feature of stimulation. Hence the subject of the essential conditions determining this transmission is one of fundamental biological interest; evidently the living system can react as a whole, i.e., in a unified or correlated manner, only in so far as the physiological processes in any single region occur in correlation with those in other regions. This transmissive property of protoplasm is the primary integrative factor in organisms; its highest development has been attained in the nervous system of higher animals.^

In general, local variations in protoplasmic activity, implying variations in the rate or character of the underlying chemical or metabolic processes, influence other processes occurring at a distance from the active ^ Cf. my review of the subject of protoplasmic transmission in Physiological Reviews, II (1922), i. region. The physical constitution of the living substance is evidently of such a nature as to permit rapid transmission of chemical influence to a distance; in other words, some form of '^ chemical distance-action" is a constant feature of protoplasmic action. It is natural to connect this feature with the essential or fundamental features of the physical structure of protoplasm. We have already seen that this structure is polyphasic and film-pervaded, or emulsion-like. It is therefore highly interesting to note that the inorganic transmissive processes just considered, which bear such a striking resemblance to the transmissive processes of protoplasm, are in fact determined by chemical and structural alterations in thin surface-films, and that these alterations occur under the influence of local electric circuits. In such a system as passive iron in nitric acid the chemically reactive material whose alteration determines the transmission is spread out in a thin layer or film at an interface (metal-electrolyte) which is the seat of a potential difference. The surface of contact of this material with the adjacent layer of electrolyte solution is a large one, relatively to the total mass of reacting substance. This arrangement makes for a rapidly acting and sensitive type of reaction-system, since the removal or alteration of a very small quantity of material may, by altering electromotor conditions at the surface, form the condition for a spread of chemical effect, electrically conditioned, which may be very extensive and rapid.^ Transmission depends on the instantaneous

^ It may be pointed out here that the importance of extremely small quantities of certain special substances, e.g., vitamines in animals, is probably a correlative of the control of chemical reactions in protoplasm passage of an electric current through the circuit constituted by the two chemically or structurally different portions of this thin interfacial film, together with the electrically conducting phases (in this case metal and nitric acid) between which it is interposed. In living protoplasm, with its film-partitioned constitution, it seems probable that the structural arrangement or disposition of the chemically reactive material which determines the response to stimulation is of a similar kind; i.e., that this material is disposed in the form of a thin film between two electrically conducting phases, a type of arrangement allowing transmissions to occur under conditions of essentially the same physical kind as in the foregoing inorganic type of system.

It has already been pointed out that stimulation processes cannot be considered separately from the processes of transmission or conduction. In general the effects of local alteration in protoplasm tend to spread; i.e., to produce chemical and physiological effects in other regions than those immediately acted upon by the stimulating agent. In some cases this spread is limited in extent; but in others, especially nerve, there appears to be no limit to the distance through which the change of activity may be transmitted. Hence the total effect of any stimulation has no fixed relation, quantitative or qualitative, to the direct physical effect produced by the stimulus at its point of application. In many

by film-structure. When material is in a film, small quantities may determine large chemical effects, because under these conditions what is important is not so much the quantity of material as the area which it covers. Surface relations rather than mass or volume relations then become the controlling factor. irritable systems with highly developed transmissive properties, e.g., the nerve fibers and muscle cells of higher organisms, the character and intensity of the response are quite independent of those of the stimulus, provided the latter attains the threshold value. A full response, involving the whole irritable element, results from either a ''weak" or a "strong" stimulus; this is the ''all or none" type of behavior, which is found also in many physical systems in unstable equilibrium, and also in explosive systems or others in which chemical change is rapidly transmitted; e.g., the passive iron system. In all such cases there is a "release" of stored energy, and the work performed by the releasing agent has no definite relation to the energy transformed in the resulting process.'

The phenomena of stimulation in living organisms are so various that one hesitates to regard them all as determined by conditions of the same physico-chemical kind. Nevertheless, it is a striking fact that whatever the special peculiarities of the organic activity or response in different living systems may be, the conditions of initiation and control are remarkably uniform. The universal susceptibility to the electric current, to mechanical disturbance, and to certain kinds of chemical influence, especially the influence of inorganic salts and the lipoid-solvent or surface-active group of organic compounds, indicates that the fundamental structural and chemical conditions underlying the response to stimulation are the same in all forms of protoplasm. It is

* The typical case is one of "trigger action," which is a characteristic feature of all modes of organic response (cf. the interesting discussion of Lotka: "Natural Selection as a Physical Principle," Proceedings of the National Academy of Science, VIII [1922], 151). especially to be noted that the two of the most general features of stimulation-processes, viz., the susceptibility to the electric current, and the reversible modification or suppression of irritability by the surface-active groups of compounds (anaesthesia or narcosis), indicate definitely a dependence of protoplasmic activity on the polyphasic structure of the system. The inference from such facts is that the chemical reactions of protoplasm are controlled by the peculiar conditions resident at the protoplasmic interfaces or phase-boundaries; and the resemblance between the conditions of activity of irritable protoplasmic systems and of the inorganic models just described confirms this inference.

Some of the more general features of the phenomena of stimulation in living organisms have already been discussed briefly. Since continued life depends on a regulated interchange of material and energy with the environment, it is to be assumed that all fundamental vital activities are capable of varying in correlation with, or "in response to," environmental change; the character and rate of the interaction of the living system with its environment are thus controlled. Normally the responses of any organism to stimulation are of such a kind as to favor its continued or stable existence in this environment. A certain difficulty in defining the conception of stimulation arises here, since many cases exist where physiological activities, which in themselves are injurious or destructive to the living system as a whole, may be induced by environmental change;^ such

^ The oxidation rate of sea-urchin eggs may be increased by pure NaCl solution to a degree which apparently is directly destructive. The case of fatigue carried to an injurious extreme is analogous. instances would scarcely be classed as responses to stimulation. In fact many opportunities for verbal mystification arise in attempting to ''define" the concept ^'stimulation." In order to limit the following discussion, we shall regard as a "stimulus" any influence acting from without upon the living system which changes the rate or the character of the normal vital activities; the resulting change of physiological activity is the "response." Even with this simplified conception, the range of phenomena is still too great to be readily included under any strictly drawn definition; but such a definition need not be insisted upon, provided the general nature of the relations between organism and environment is clearly understood. Variation of vital activity, within the physiological range, occurring as a constant correlative or sequence of environmental change of some kind, is the essential phenomenon whose conditions we are considering.

In multicellular organisms, "internal" and "external" (proprioceptive and exteroceptive) stimuli are often distinguished,^ since in many cases the environment which furnishes the normal stimuli for an irritable cell or cell-system may be not the external world but some other part of the same organism. Responses of special organs or organ-systems to stimuli originating elsewhere within the same organism form, in fact, a regular part of many normal physiological cycles in higher animals; thus the pancreas is stimulated by secretin in the blood stream, and the respiratory center by increased H-ion concentration of the blood; the central nervous system is continually adjusting its

* Cf. Sherrington, Integrative Action of the Nervous System. activity to changes in bodily conditions, and so on. Evidently the effects of external stimuli upon the sense organs cannot be regarded as forming a significantly different class from these phenomena, so that from the standpoint of general physiology the foregoing distinction is a purely formal one and has little objective importance. Various terms are applied to special processes which may be included under the general conception of stimulation, as just defined. The term ''activation" is used with reference to the initiation of development in a resting egg cell by a spermatozoon or a parthenogenetic agent; acceleration, or simple increase in the rate of an already existing process, is a frequent form of response (e.g., secretion, the heart-beat, or other regular muscular movement, growth, etc.); retardation or inhibition is perhaps equally frequent. In cases of automatism, like that of the heart, the rhythm may be regarded as determined by periodic stimuli furnished by processes within the cell. Since all of these phenomena may occur, or undergo modification, in response to changes of environmental condition, all are to be considered under the general conception of stimulation.

The most general features of the stimulation-process are best studied in those irritable tissues or cells which give a prompt and definite response to electrical or mechanical stimulation, such as the nerves and muscles of higher animals; and the majority of investigations, on stimulation, especially those of a quantitativ^e kind, have been carried out with these tissues, usually after isolation. The results gained have, however, a general applicability to other irritable living systems.

It is well known that different living systems may vary widely in their sensitivity to the same stimuli, and also that irritability is often specialized with reference to particular physical agents. Sensory elements wdth special sensitivity to light, contact, slight changes of temperature, or chemical substances, are found in all higher animals. These differences are referred to special features of chemical and structural organization. Chemical sensitivity in particular is often minutely specialized; and such instances as the special sensitivity exhibited by the sensitized smooth muscle of guinea-pigs in anaphylaxis indicate clearly that many forms of specific chemical irritability are dependent on the presence of specific chemical compounds (apparently in this case proteins) in the irritable cell, probably in the protoplasmic surface layer. Similarly, photo-sensitive elements like the retinal rods and cones contain compounds of definite photochemical properties (visual purple and related substances) upon which the special responsiveness undoubtedly depends.^ We must recognize, therefore, in addition to the general susceptibility to mechanical or electrical stimuli possessed by all forms of protoplasm, a variety of specific or selective forms of irritability depending on special features of structure or organization. Selective irritability is shown especially by the sensory nerve-termini or receptors of higher animals; these are classified, according to the agents to

* Thus Hecht and Williams have recently shown that the curve of absorption of visual purple is almost identical with tlie curve of visual sensitivity for different wave-lengths {Jour. Gen. Physiol., IV [1922], i). which they are specially responsive, as chemo-receptors, thermo-receptors, photo-receptors, etc. Such special sensitivity may be described as consisting in a lowering of the threshold of stimulation for a particular agent, and need not affect the general sensitivity to mechanical and electrical stimulation. Some specific irritability is superposed upon the general or nonspecific irritability. Thus a nerve or muscle may be stimulated by mechanical, thermal, chemical, osmotic, and electrical stimuli; similarly, a highly specialized receptor such as a retinal element may be stimulated by these agents as well as by light of a definite wavelength. In all cases, however, the response following stimulation has a specific character which is dependent on the special structure or organization of the irritable system or on its relations with other systems. In the field of sensory stimulation this generalization is known as the ''law of specific energies."