Comparative Electro-Physiology: A Physico-Physiological Study

contraction, that is’to’say, in stagé B,we shall find that the rate of transformation becomes very rapid. The second test, by which we may judge of the progress of molecular transformation in the experimental specimen, consists, as we have seen, in the nature of its reply to stimulus. Thus, in the sub-tonic condition, with its tendency to elongation, the responses are abnormal. positive. From this they pass gradually, with the progress of molecular.

transformation, into the normal negative, the intermediate responses being either diphasic or zero. As the process is very rapid after passing the point of transition, the succeeding responses near this point show a staircase increase. Or if we do not wish to record the intermediate series, but merely to observe the terminal transformation into negative, or enhanced negative, due to the ascent of the molecular curve above the transitional point, we may apply a rapid series of stimuli, or tetanisation. We may here, according to circumstances, and the point started from, obtain either (1) abnormal positive transformed to normal . negative responses; or (2) diphasic, passing into normal negative; or (3) feeble, becoming enhanced, negative response. The idea has been put forward, as already said, that tetanisation enhances the responsiveness of the nerve, by some supposed evolution of carbonic acid. That this, however, is erronéous, has been shown by numerous experi- ments already related, and by the fact that even in inorganic substances, under given circumstances, tetanisation enhances response. Nor is it invariably true, in any case, that its effect is always to enhance response. Under certain conditions, it may actually cause depression. The decisive ‘element in the question of its effect lies in that part of the characteristic curve at which it is applied. If this be immediately after the point of transition its result will be an enhancement. Should tetanisation, however,.be applied above the maximum or highest point in the curve, its effect will be the diminution of response by fatigue. ;

molecular transformation shows itself in two different ways— by a progressive physical change of the substance itself as exhibited’ by the characteristic curve, and also by a pro- gressive variation in the character of the responses—I shall here give a pair of records of the mechanical response of frog’s nerve. In fig. 382 the continuous molecular trans- formation caused by impinging stimulus is shown by the growing contraction, or responsive mechanical negativity of the nerve, as seen in the shifting of the base-line upwards. It is also in- teresting to notice here the continuous trans- formation of the in- dividual responses from the abnormal positive through diphasic to the normal negative. There is also the noticeable additional fact that after the point of transition

is passed the response Fic. 383. Mechanical Response of Frog’s undergoes a marked Nerve, showing Conversion of Abnormal . ; Positive into Normal Negative Response staircase increase. In after Tetanisation fig. 383 is given another Note also the shifting of the base-line up- : : wards, and that the individual period of record, obtained with positive is shorter than that of negative frog’s nerve, where, after responses. an intervening period of tetanisation, the abnormal positive response is converted into normal negative with staircase increase. The shifting of the base-line upwards is also very noticeable here. Effects pre- cisely similar are observed in the mechanical response of vegetal nerve.

If we now turn to a different ae of observation—-say that by the electro-motive variation—the records will. be found to bear a remarkable resemblance, in every. particular, continuous transition, from abnormal positive to normal negative, :as before, through intermediate diphasic, with: a shifting: of ‘the base-line upwards, exhibiting an increasing negativity. “The gradual transformation of the character of the response may be seen when a long series of successive responses to successive stimuli is taken (cf fig. 277). Or the abnormal positive may be-séen’ transformed: into normal negative, after an intervening period .of tetanisation. (cf fig. 276). Or when the point of molecular transition is passed, ‘the effect of intervening tetanisation is to enhance the ampli- tude of response (cf fig.275). It will thus be seen that the characteristic response in the sub-tonic condition A is abnormal positive ; and that, when the substance ‘is transformed by stimulation, to a point above the transitional B, the response is con- verted into normal negative, and lastly, since the rate of transforma- tion is very rapid above the point B, that successive responses in that region exhibit a. staircase increase, or moderate negative becomes the | enhanced negative, after an_inter- Fic. 384. Photographic Re- yening period of tetanisation.. The

and also by the shifting of the base- line upwards, in exhibition of the characteristic curve. These changes, which have now been described in the case of nerve, will be found to apply in all other instances of melecular transformation equally, Results in every way parallel are obtained with inorganic substances. In fig. 384 is seen the abnormal electro-motive response, represented as ‘down,’ converted into normal ‘up’ after an intervening period of tetanisation. In the

next figure (fig. 385) is shown how this abnormal response in platinum, in consequence of successive ‘stimulation, is Fic. 385. Gradual Transformation from Abnormal to Normal Response in Platinum The transition will be seen to have commenced at the third and ended at the seventh, counting from the left. eradually transformed-into a growing normal, through the intermediate diphasic. In fig. 386 is seen how the normal Fic, 386. Normal Electro-motive Response in Tin, enhanced after Tetanisation

response is enhanced, after an intervening cet, in a specimen of tin wire. We pass next to the third mode of record, that, namely, by the Conductivity or Resistivity Variation. A selenium Fic. 387. Photographic Record of Abnormal Response of Selenium Cell converted into Normal after Tetanisation cell I find to be sometimes in a certain molecular condition in which it will respond to high frequency equi-alternating FIG, 388, Photographic Record showing Moderate Normal Response of Selenium enhanced after Tetanisation

electrical shocks, of the order of a million times per second, by an increase of resistance. ‘Tetanisation is found to induce a transformation, attended by a diminution, or negative variation, of resistance. After. this, the responses are found to be converted into normal: that is to say, they now take place by the diminution of resistance. Fig. 387. gives a photographic record of these effects. Selenium cells, again, under normal conditions, respond to light by a diminution of resistance. After tetanisation, or continued application of light, the normal responses, under certain circumstances, undergo an enhancement. The transformation induced by tetanisation, it is interesting to note, also shows itself by the shifting of the base upwards (fig. 388).

I have found similar effects, again, to be exhibited by various metallic powders, under the stimulus of electric radiation. The record given in fig. 389 exhibits the given by tungsten. After a short period of tetanisation the base-line is. seen to be shifted upwards, the molecular condition being transformed, in a negative direction, and response in this particular transformed condition is seen to be diphasic—positive followed by negative. A further period of tetanisation carries this transformation still further in the negative direction, and the individual responses now seen are augmented normal negative. I give also a second pair of records in which the normal response of moderate amplitude in aluminium is enhanced, after an ee rsning period of tetanisation (fig. 390). gf

We have seen, lastly, that molecular response may be recorded by means of the magnetic variation. «And it is interesting to see, by employing this mode of record, that under certain conditions tetanisation will enhance erence response (fig. 391). - 7 In order to make a striking demoristration of Hie fact that the various phenomena described are not the result of some specific property of living tissues, with their hypo- thetical assimilation and dissimilation, but are determined by molecular conditions common to matter both living and inorganic; I shall now give in vertical. columns; several series of records of responses, obtained, under parallel conditions,

from living tissues, animal and: vegetal, and from inorganic bodies. As the methods also, by which these records were Fic, 389. Photographic Record ot Abnormal Response of Tungsten to Electric Radiation, converted after Tetanisation into Diphasic and Normal obtained, were so different as those of the mechanical, the electro-motive, the resistivity and the magnetic variations, it Fic. 390. Moderate Normal Response of Aluminium, enhanced after Tetanisation

follows that their similarities under parallel circumstances can only be due to certain fundamental molecular reactions, which are common to all alike. Further, since some of th arrangements offered no. possibility of chemical reaction, it follows that similar responses, in other cases like- wise, are determined, not» by some antecedent chemical, but by molecular action, though chemical action may take place as a consequence of. their responsive molecular derangement., _In the first of the series of records in vertical columns (fig. 392) we have: (a) a mechanical record of abnormal response by expansion,

FIG. 391. Photographic Record of Enhancement of Magnetic Response after Tetanisation passing into normal response by con- traction, after intervening tetanisation, in frog’s nerve. In (0) we observe a similar transformation, as seen in the electro-motive response of frog’s nerve. The abnormal response by galvano- metric positivity is here converted by tetanisation into the normal megazzve. Turning next to inorganic substances, and taking the method _ of Resistivity Variation, we find in (c) the abnormal postive response of tungsten converted by tetanisation into normal negazzve, Finally (d) where the specimen is tin wire, and the record made by electro-

Records showing Trans- formation of Abnormal into Normal Response after Tetanisation in Living and Inorganic alike in the A phase Mechanical response of frog’s nerve to electric stimulation ; 4, Electro- motive response of frog’s nerve to thermal stimu- lation; c, Response by resistivity variation in tungsten to electric radia- tion; .d@, Electro-motive response of tin wire to mechanical stimulation. motive variation, the abnormal response is seen to be converted into normal after tetanisation. It will be noticed, in all these cases, that the antecedent molecular transformation, on which the conversion from abnormal to normal . response depends, is also shown independently, by the shifting of the base-line of the record in the direction of the normal response—that is to say, upwards,

In the next series, again, in fig. 393, is shown the effect. of tetanisation in enhancing feeble normal response. This moderate normal response, it will be remembered, is characteristic of the molecular condition, just above the point of transition from abnormal to normal. In (a) is seen the enhancement of mechanical response in nerve of fern. In (6) we have the enhanced electro- motive response of frog’s nerve. In (c) a similar enhancement of electro-motive response is shown in plant nerve. In (@) we see the enhancement of response after tetanisation in aluminium powder by the method of resistivity variation, the stimulus employed being Hertzian radiation. In (e) the method of record is also by resistivity variation, in a selenium cell, under the stimulus of light. And finally, in (7) are given the responses of platinum wire, under the

a, Mechanical response of frog’s nerve; 6, Electro-motive response of frog’s nerve; c, Electro-motive’ response of plant-nerve; @, Response by resistivity variation in aluminium powder; ¢, Response of selenium ; f, Electro-motive response of tin. method of electro-motive variation, before and after mechanical tetanisation. The antecedent molecular transformation to which this enhancement is due may also be gauged, in all these cases, by the shifting of the base-line upwards.

We have up to this time dealt with the first part only of the characteristic curve, up to a point slightly above that of transition. The responding substance, however, in con- sequence of the after-effect of stimulation, now passes into FIG. 394. Photographic Record showing Responses corresponding with different parts of characteristic curve in frog’s nerve a, Abnormal subtonic ; 4, Staircase ; c, Uniform ; d@, Fatigue decline ; : ¢, Fatigue reversal,

various different phases of molecular condition, These may be short-lived, or more or less persistent. We shall next study all the responsive modifications dué to these induced molecular conditions, from the subtonic A to the post-maximum E conditions,-in order, Selecting as our specimen for this purpose the nerve of frog, the different phases through which this is capable of passing. may, for convenience, be divided into five classes (fig: 394). . In the first of thesé—the abnormal A phase—the nerve is sub-tonic. It is here undergoing a relaxation, and its characteristic

response to -individual stimulus. is abnormal: positive. In consequence- of stimulation, however; we have seen this relaxation to be arrested, and to pass into growing con- traction. ‘The characteristic’ of response at this transitional stage is to be diphasic, passing gradually into the normal negative. On reaching this, the B phase, the responses, as we have seen, commence with feeble normal, and undergo a molecular transformation, in this and succeeding phases, from the curve of the mechanical response of nerve under tetanisation (cf fig. 313).. We there saw that in the B, or transitional, phase, the rate of contraction was very rapid ; we also found the individual responses at this stage to show a staircase effect. The rate of contraction next became slower, and the curve was afterwards more or less horizontal. Beyond this, fatigue-relaxation set in.

We have now to observe the responsive variations characteristic of these different phases. For this purpose, a high magnification of three hundred times has to be em- ployed. Records so obtained are given in fig. 394. The method of procedure is as follows: We first take two or three test-responses to individual stimuli of definite intensity, at the A phase. This test-stimulus is subsequently main- tained at the same intensity. When the record of the A stage has thus been taken, continuous stimulation is applied for a time, till we arrive at the B stage, when the record of responses to individual stimuli is taken once more. The contraction due to the previous tetanising stimulus employed for the conversion of phase, is now so great that the record- ing spot of light is carried out of the field. At the com- mencement of each phasic record, therefore, the spot has to be brought back to the plate by suitable adjustment of. the reflecting mirror. Thus the first record of each series really shows the effect of the termination of tetanisation, the sub- sequent records showing response to individual stimuli. We may, however, obtain some idea of the characteristic changes occurring in the nerve as a whole, by joining the tops of the

response records, Fromm the inclination of the line thus pro- duced it is possible to. see whether the nerve at each ‘different phase was contracting, had assumed a stable length, or was relaxing. -In the B phase, as here shown, for instance, it will be seen that the nerve, when undergoing an. increasing con- traction, shows a staircase enhancement of response; at C we observe this change to arrive at a climax,: with con- sequent stability of condition and uniformity of response.

_ _ The characteristic curve, after this, undergoes a reversal : that is to say, responsive contraction is now diminished, and eventually gives place to relaxation ; and it is curious to find that all the responsive phenomena observed during the ascent are now repeated, but in the reverse order, That is to say, during the ascent of the curve we obtained the se- quence of abnormal positive, diphasic, and increasing normal responses. And during the reversed process we obtain diminishing normal, diphasic, and the culminating abnormal positive response. The cycle of molecular phases, with their attendant variations, is thus complete.

An inspection of D shows the change in the condition of the nerve from the contracted to the relaxing state. The onset of fatigue is also seen in the diminishing amplitude of the responses, This process is seen accentuated, to the actual reversal of response, in the last phase E, I shall later give a special record exhibiting the diphasic responses inter- mediate between D and E, | The response of nerve has hitherto been supposed, as already mentioned, to be specifically different from that of ordinary tissues. One characteristic particularly’ insisted upon was its indefatigability, or incapacity for fatigue, the nerve in this respect differing essentially from the muscle. On taking a general review, however, of nerve and muscle- response, we find that there is no essential difference between the two. During the first phase of contraction, both alike show staircase increase. This is followed, in both, by a series of uniform responses. And in the stage of fatigue, in both, the process of contracture gives place to one of

relaxation. Theé’only difference lies in the fact that fatigue — makes its appearance in the one case earlier than in the other. When dealing with the subject of the enhancement of response by tetanisation, I stated that here it was not tetanisation, as such, which formed the determining factor in bringing about the increase of response; this was rather due to a phasic molecular transformation, induced by tetanisation. If the substance happen to be in the transitional B phase, then and then only will tetanisation enhance its response. If, however, it should happen to be in the optimum C phase, then the same tetanisation will have the effect of carrying it into D and E, the phases of fatigue. The response here,

Fic. 395. Photographic Record of Response of Tungsten showing Enhancement of Response after moderate Tetanisation, and Reversal of Response, due to Fatigue under stronger Tetanisation instead of being enhanced, will be decreased or reversed. This is seen in the following record (fig. 395) obtained with tungsten when moderate tetanisation enhances response, whereas strong tetanisation, by bringing on fatigue, reverses the normal response. | How universal are these phenomena will be seen from the accompanying series of records, obtained. not only with various living tissues, but also with inorganic substances under parallel conditions, the normal responses being in all these cases reversed by tetanisation, in consequence of the transformation from the C to the E phase. In fig. 396 (a) is seen the normal contractile response of a frog’s nerve reversed to the positive or expansional, after tetanisation.

In (6) is seen the reversal of the normal electro-motive response in the digesting leaf of Drosera, after tetanisation, the stimulus here also being electrical. reversal after tetanisation in the elec- tro-motive response of the pulvinus of Mimosa. And in (d) is given a similar reversal after tetanisation, in the response of tungsten powder, the variation, under the stimulus. of Hertzian radiation. These, and other results already given, have _been obtained by the employment. of different forms of stimulation. We may, therefore, regard these charac- teristic transformations as: brought about by all forms of stimulus alike.

We thus see that one identical stimulus may give rise to opposite effects, according to the molecular condition of the responding tissue. This molecular transformation, more- over, may be brought about by the previous action of the stimulus itself. These considerations will, I think, be found to elucidate the very obscure question of the effect of drugs, with special reference’ to the opposite actions of large and small doses. a manner. not unlike that-of other stimulating agents, a moderate dose of a given reagent might be expected to induce effects similar to that of the action of moderate stimulation.

G. 396. Series showing reversal of Normal Re- sponse by fatigue due to strong Tetanisation in- ducing the E phase Mechanical response of frog’s nerve; 4, Electro- motive response of Dvo- sera; ¢, electro-motive response of pulvinus of Mimosa; ad, Response by resistivity variation of tungsten powder. Hence_its effect in inducing molecular transformation will generally be to en- hance excitability, as from B to ©. Too long-continued action, ‘however, carrying the substance acted upon ‘to the phase of D or E, will cause depression, Or it is conceivable that the same depression might be more rapidly induced by more intense stimulation—that is to say, by a larger dose. Now that this is what actually takes place has already been shown in several experiments which have been described, We saw, for example (fig. 95) that the continued action of the moderately stimulating agent, sodium. car- bonate, at first induced an exaltation of response, followed later by depression. In the case of vegetal nerve, again (ff. fig. 297), we found that the same agent, in smaller doses, caused at first an enhancement of conductivity, followed later by slow depression. A stronger dose of the same reagent, however, was found to cause rapid depression (fig. 298). Even in the case of poisons, so-called, the same facts make their appearance. Here an agent which’ proves toxic in large, appears as a stimulant when given in minute, doses, Thus in studying the effect of various chemical agents on growth-response, I found that while a one per cent. solution of copper sulphate was toxic, the same reagent proved stimulatory, if given in a solution of ‘2 per cent. _ A more detailed account of these experiments will be found in my work on ‘Plant Response,’ from which I quote the following summing up: | ‘A survey of the effects of drugs, both stimulating and poisonous, reveals the striking -fact that the difference between them is [often] a question of quantity. Sugar, for instance, which is stimulating. when given in solutions of, say, I to 5 per cent., becomes depressing: when the solution is very strong. Copper sulphate, again, which is regarded as a poison, is only so at I per cent. and upwards, a solution of ‘2 per cent.

being actually a stimulant, The difference between sugar and copper sulphate is here seen to lie in the fact that in the latter case the range of safety is very narrow. Another fact which must be borne in mind in this connection is that a substance like sugar is used by the plant for general metabolic processes, and thus removed from the sphere of action. Thus, continuous absorption of sugar could not for a long time bring about sufficient accumulation to cause depression. With copper sulphate, however, the case is different. Here, the constant absorption of the sub-tonic stimulatory dose. would cause accumulation in the system, and thus ultimately bring about the death of the plant’? . =