SOCIETY, PHYSIOLOGICAL PROCEEDINGS. January 11th, (3) stale or modified.

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1 PROCEEDINGS OF THE PHYSIOLOGICAL January 11th, CHARING CROSS HOSPITAL. SOCIETY, The effect of C02 upon nerve and the production of CO2 by nerve. By A. D. WALLER. PRELIMINARY. Considered with reference to the current of action, isolated nerve may be recognised as existing in three states or stages, which may be roughly characterised as (1) fresh, (2) transitional, (3) stale or modified. During the first stage, the galvanometric response to excitation consists in a large negative deflection succeeded by little or no positive after-deflection. During the second stage, the response consists in a small negative deflection succeeded by a large positive after-deflection. During the third stage, the response consists in a positive deflection succeeded by a positive or by a negative after-deflection. This division into three stages is of course more or less arbitrary, the transitions fromn first to second and from second to third being not sudden but gradual; during, the first and second stag,es the negative effect progressively dimirnishes and the positive after-effect progressively increases; late in the second stage the negative effect is vanishing, early in the third stage the positive effect is appearing, and there is thus an intermediate period in which excitation gives no visible effect followed by a positive after-effect; this period has been assig,ned to the second stage. With regard to the third stage I have been led to distinguish two kinds of response according as the positive deflection has been followed by a positive or by a negative after-deflection. a

2 ii PROCEEDINGS OF THE PHYSIOLOGICA L The characterising features of the three stages respectively are: of the 1st stage, a predominant negative effect. S. of the 2nd stage, a predominant positive after-effect. N. of the 3rd stage, a predominant positive effect. N. The negative effect is du Bois-Reymond's "negative Schwankung," the positive after-effect is presumably Hering's " positive Nachschwankung," the positive effect (as far as I know) has not hitherto been described. In accordance with the plan of recording previously described and demonstrated (Proc. Phys. Soc. Nov. 1895), i.e. current of injury upward or northward, negative variation downward or southward, these statements are contained in the following " Formula of Deflections." Isolated nerve During excitation After excitation 1st stage S n 2nd stage s or 0 N 3rd stage N N or s The successive stages have presented themselves most clearly and quickly in summer and autumn; in winter they have been less apparent, nerves having then often remained for more than 24 hours in the second stage s.n., occasionally (e.g. in January and with strong excitation) exhibiting a deflection that might have been expected to be more common, viz. a negative effect followed by a negative after-effect. The principal object of the present communication is to exhibit individually and comparatively: A. The effect of CO2 upon nerve in these three states. B. The effect of prolonged tetanisation upon nerve in these three states. Stated seriatim the facts, apart from all hypothesis, are as follows: 1. The effect of a small quantity of C02 upon nerve in the first stage is an augmentation of the normal deflection. 2. The effect of prolonged tetan-isation (5 minutes) upon nerve in the first stage is an augmentation of the normal deflection. 3. The effect of a small quantity of CO2 upon nerve in the second stage is an augmentation of s. and a diminution of N.

3 SOCIETY, JANUARY 11, iii An original deflection sn is replaced by a deflection Sn. Otherwise stated the relation S or - or quotient N or + after-deflection is increased. 4. The effect of prolonged tetanisation upon nerve in the second stage is an augmentation of the above defined quotient N 5. The effect of CO2 in small quantity upon nerve in the second stage, giving a response ON, is to substitute for it the response S.N. 6. The effect of prolonged tetanus upon nerve in the second stage, giving the response ON, is to substitute for it the response S.N. Nerve in the third stage reacts in two apparently different ways to C02 and to tetanus, which for convenience may be designated as " clear " or " disguised." Strict parallelism of statement concerning the effects of CO2 and of tetanus inight here be misleading; the experimental results frequently diverge in the two cases, in so far that CO2 most frequently gives a " clear " result when tetanus only gives a " disguised " result. The experimental data are accordingly more properly expressed in the following contingent statements: 7. With nerve in the third stage, giving the deflection N and the after-deflection S or N, the effect of prolonged tetanus (5 minutes) is either a or b (a) substitution of the response S.N., viz. reversal of the deflection N during excitation, being what has been designated above as the "clear" result. In such case the regular effect of CO2 is to produce a similar reversal. The reversal is in both cases temporary. or (b) simple diminution of the original N deflection during excitation, being what has been designated above as the " disguised " result. In such case the effect of CO2 has been either to produce a similar diminution of N, or an actual substitution of S, generally the latter. With regard to statements 7a and 7b relating to the two effects of tetanus, it is to be remarked that they are not contradictory, but complementary. In both cases we have a diminution of N-in (a) amounting to stibstitution of S, in (b) not reaching even to abolition of N Ẇith regard to the corresponding statements under 7a and 7b relating to the effects of CO as compared with those of tetanus, that under 7a needs no comment, and the divergence expressed under 7b is perhaps not surprising, inasmuch as in stale nerve CO. from without

4 iv PROCEEDINGS OF THE PHYSIOLOGICAL might be expected to effect more completely a change that tetanisation has only effected less completely. And in point of fact we may sometimes successively demonstrate upon a nerve in this state a diminution of N by tetanus, a diminution of N by little CO2, and a temporary substitution of S for N by more CO2. We cannot from the character of the deflection of the third stage foretell with certainty what will be the character of the response, i.e. whether the N deflection will be reversed or only diminished. We may however with certainty (as far as my experience has gone) make this forecast, as soon as we have witnessed the final deflection occurring at cessation of the prolonged tetanus. This terminal deflection c may be N or S. If it is N the next and subsequent deflections will be S diminishing, if it is S the next and subsequent deflections will be n. increasing. 8. With nerve in the three stages above described the deflections at outset of, during, and at the end of a prolonged tetanus are as follows: a During w 1st S S. ward N 2nd s S. ward N 3rd N S. ward N or S Whenever the terminal deflection co is N, the effect of tetanus comes out "clear"; whenever w is S, the effect of tetanus comes out " disguised." And it is probable (but not yet sufficiently certified by experiment) that the direction of C depends upon the duration of tetanus in relation with the state of nerve. On review of any considerable number of records it will be noticed that with nerve in the first and second stages, tetanus (and C02) give rise to an augmented dimiiinishing deflection, and that with nerve in the third stage tetanus (and CO2) may give either an augmented diminishing or a diminished augmenting deflection; the diminution by tetanus in this stage simuilates a fatigue effect, but is evidently of the same nature as the undisguised augmentation of S in the first and second stages. Staircase effects. Under favourable conditions, and more especially during the second and third stages, a similar effect (augmnentation of S, diminution of N) may be witnessed in progressive development in the

5 SOCIETY, JANUARY 11, course of the series of brief tetani of 7-5 sees. duration at minute intervals used to excite the nerve. The alteration taking place in the deflections from isolated nerve is very similar to the well-known staircase phenomenon occurring in contractile tissue (medusa, heart, skeletal muscle) and, considered in connection with the evidence already offered, is probably a CO2 phenomenon. (Whether or no the phenomenon is of CO2 production in muscular as well as in nervous tissue is for the present left an open question.) The essential points concerning the staircase deflections in isolated nerve may be briefly expressed as follows: 9. The negative deflections of nerve inl the first and second stages progressively increase at each brief tetanus (7 5 seconds), with a diminishing incremnent. (This increase is apparently more pronounced in the secon(l stage than in the first.) 10. The positive deflections of nerve in the third stage progressively dimlinish at each brief tetanus, with a diminishing decrement. The diminution may in certain instances be such that the positive deflection falls to zero, and passes into a gradually increasing negative deflection. CONCLUSION. Subject to the explanatory comments in connection with particular statements, these may be still furthier summarised in the following table, thus bringing into clearer relief that the proposition common to all is that in all states of nerve the effect of CO2 and the effect of prolonged tetanisation consist essentially in an augtmentation of the negative (S) effects of excitation. I Stage Type Defl. after CO2 Defl. after Tet. a Tet. W ~~~~~~~~~~~~During I S auigm. S augm. S S S N I IsN or on S S s or o S N III NN or Ns S or n S or n N S N or S Apart from their interest in se the results are presented in establishment of the conclusion that tetanised nerve evolves C02, and in this connection the experiments belonging to statements 1 and 2 and 7 (augmentation of a inegrative deflection by C02 and by tetanus, and reversal of deflection by CO2 and by tetanus) may be indicated as being the most directly cogent. v

6 vi PROCEEDINGS OF THE PHYS. SOC., JAN. 11, Note. The oscillation period of the galvanometer magnet is in most experiments 15 secs.; in some of the earlier observations, e.g. in 741, it was 8'5 secs. The decrement in the first case is approximately = 3, and in the second case = 2. The duration of excitation in all experiments was 7'5 secs. at intervals of 60 secs., with a strength of 10 units of a Berne coil (secondary 37 cm. distant from primary, interruptions per second). With the magnet at the period of 15 secs. and an excitation time of 7-5 secs., the value of a purely iinstrumental swing-back should be '58 the original swing, and departures from such a value should be indicative of a positive or negative after-effect. With the magnet at the period 8'5 secs., and decrement = 2, it should be '7. With the period 12 secs. and the decrement = 2'1 it should be *69. But taking into account the duration of a tetanic state (= 7 5 secs.) we may not directly correct for the instrumental swingback, which must be measured under the conditions of experiment with e.g. a pressure of 0'001 volt. lasting via the interrupter 7'5 secs. This gave for the swing-back at the periods 15, 8'5, 12 the values '5, '3, '66 of the swing. These are the numbers taken into reckoning in the estimation of physiological after-effect contributive to the after-deflection, and in alterations of the N quotient. Inferences are however based on none but very coarse differences, e.g. a swing-back equal to or greater than the original swing or the suppression of a swing-back. Such changes are obviously not concealed by instrumental oscillations. Finer changes which may have occurred have not been considered inasmuch as their measurement under the conditions of observation would have been attended by too great uncertainty; for instance, in fig. 741 no attempt is made to say whether or no there is positive after-deflection in the back-swing, and all that is inferred is that during the first stage the relation - is not grossly altered by tetanus. It is obvious that no uncertainty is presented by such coarse effects as reversal of deflection, suppression of swing-back &c. There can e.g. be no doubt that in 710, 762 a positive after-deflection is present, and that in both cases the quotient N is greater after CO, and after tetanus. There may e.g. be doubt of the presence of a negative afterdeflection in 982, 984; there can be no doubt of the presence of a positive after-deflection in 858, 859; and there can be no doubt that the afterdeflection is more positive in 858, 859 than in 982, 984. The substitution of S for N by 0O0 and by tetanus in 858, 859 is obviously not open to question. The most doubtful case is that of a S after-deflection following a N deflection as in 758. N.B. not here reproduced. These references apply to records demonstrated at the meeting and