The Mechanism of Nervous Action: Electrical Studies of the Neurone [Reprint 2016 ed.] 9781512809794

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THE MECHANISM OF NERVOUS ACTION

THE MECHANISM OF

Nervous Action ELECTRICAL STUDIES OF THE NEURONE By E. D. M.D., D.SC.,

Adrian F.R.S.,

Foul erton Research Professor

F.R.C.P.

oj the Royal

Society

Philadelphia U N I V E R S I T Y OF PENNSYLVANIA PRESS

Copyright 1932 UNIVERSITY OF PENNSYLVANIA PRESS New Edition 1 9 5 9 Published in Great Britain, India, and Pakistan by the Oxford University Press London, Bombay, and Karachi

Printed and Bound in the United State* of America by Book Craftamen Associate* Inc., New York

THE MECHANISM OF NERVOUS ACTION

PREFACE On October 5th, 1 9 1 6 , Keith Lucas, my director of studies at Trinity, was killed in an aeroplane accident on Salisbury Plain. A biologist with the training of an engineer, he had succeeded Gotch as the foremost authority in Great Britain on the physiology of nervous conduction, and in 1914 he was planning an attack on the problems of the central nervous system. A few weeks before his death he talked to me of the great possibilities which might lie in the use of the thermionic valve for amplifying nerve action currents. His forecast was justified in a few years by the work of Forbes and Gasser: and these lectures deal with the use of the method at Cambridge for the study of the units of the nervous system. Had Keith Lucas lived, it is certain that the present stage would have been passed long ago; it is even possible that the method would have already served its turn. As it is, we are still collecting information and have scarcely begun to build up hypotheses to explain what we have found. Fortunately the main results can be seen at a glance from photographic records which need very little discussion. B y the aid of these I have tried to illustrate the chief lines of work which have been carried out by a particular technique. I have not tried to review a particular field of physiology—the list of references will be enough to show how little I have said of any other line of enquiry. But this is by no means a personal record, for much of the work described in it has been due to my colleagues, particularly to Β. H. C. Matthews, who has done so much to improve the technique, and has turned his instruments to such good account in his own work; and to Professor D. W. Bronk, with whom I have spent so many strenuous and exciting days in the laboratory and elsewhere. His kindness in vii

MECHANISM OF NERVOUS ACTION

inviting me to give the second course of Eldridge Reeves Johnson lectures is very poorly repaid in these pages, but it would take a great deal to repay the debt which I owe to him and to my friends at the University of Pennsylvania. I have to thank the Royal Society and the Physiological Society for permission to reproduce some of the figures which have appeared in their publications. E. D. A. March 26,

IQ32.

viii

CONTENTS Page PREFACE I.

THE

vii DEVELOPMENT

or

ELECTROPHYSIOLOGY

Recording Instruments Amplification of Electric Changes T h e Activity of Peripheral Nerves T h e Activity of Single Nerve Fibres T h e Nature of the Nervous Messages Gradation of Activity T h e Membrane Hypothesis II.

THE

ACTION

OF T H E

SENSE

ORGANS

Adaptation T h e Production of the Rhythmic Discharge. . . Depolarisation in the Sense Organ T h e Injury Discharge Differences in the Sensory P a t h w a y : Touch and Pressure Wever and Bray's Work on the Auditory Nerve III.

DISCHARGES

IN

MOTOR

NERVE

34 37

THE

ACTIVITY

OF N E R V E

61 64 65 73

CELLS

Respiration—The Automatic R h y t h m ix

43 44 50 53 56

FIBRES

T h e Motor Units T h e Electromyogram T h e Response of Single Units Sympathetic Discharges V.

23 27 29 30

PAIN

T h e Tactile Endings Protopathic and Epicritic Fibres Slow Impulses in the Nerves of the Frog T h e Nerve Fibres Concerned with Pain Specific Nerve Impulses IV.

2 5 8 10 14 16 19

78

MECHANISM

OF

NERVOUS

ACTION

Potential Changes in the Brain Stem Potential Changes in Insect Ganglia Periodic Discharges in Injured Nerve Fibres. . The Effect of Potential Gradients Synchronous Activity REFERENCES

81 83 86 88 89 95

INDEX

101

χ

Chapter I THE

DEVELOPMENT OF PHYSIOLOGY

ELECTRO-

N London we have just celebrated the hundredth anniversary of Faraday's discovery of electromagnetic induction, thanks to which we have every day some new comfort and some new machine to supersede the human worker. No one would blame Faraday because our social organisation cannot always keep pace with the progress of electrical engineering, but his discovery came at a time when the science of electrodynamics was well under way, and if we are really to date the present era from any one experiment a good case could be made for an observation in medical physics in the year 1786. Galvani of Bologna was investigating the effects of static and atmospheric electricity on the muscles. He had prepared the bod" of a frog and had fixed a brass hook in the vertebral canal intending to hang it up on the terrace outside his house. He placed the frog on an iron plate so that the hook touched the iron, and when it did so the body moved. " En motus in rana spontanei, varii, haud infrequentes!" and when the movements ceased they could be revived by pressing the hook more firmly against the iron. Galvani had produced an electric current and had the wit to realise that he had done so.

I

It was some time before the full meaning of this observation was understood, for the role of the frog's muscles was uncertain. Galvani had made other experiments which led him to believe that a muscle could generate electricity in the absence of metals, and it was known that a fish, the torpedo, could give a severe electric shock. For a few 1

MECHANISM OF NERVOUS ACTION years, until 1792, it seemed that Galvani's phenomena were due to a form of electricity which was peculiar to living tissues. Enthusiasts held that this 'Animal Electricity' was the true life-force, that it would explain movement and sensation and lead to the cure of all kinds of nervous disease. Then Volta pricked the physiologists' bubble by showing that when the two metals were used, the frog acted merely as indicator and a source of moisture. The electric current occurred in inanimate systems, life was not an essential ingredient, and the science of electrodynamics became a branch of physics and not of medicine or biology. But Galvani's experiments and the controversy with Volta laid the foundation of a considerable branch of medical physics, for attention was focussed on the frog's muscle as well as on the nature of the electric current. After much discussion it became clear that Galvani was right in supposing that muscles could produce electricity on their own account, and before long the two salient facts of electrophysiology had emerged, namely that a current will make a muscle contract and that a contracting muscle develops a current of its own. The two facts are true not only of the activity of muscle, but of nerve as well. Electric changes take place whenever a nerve fibre carries a message, and it is this association of electric change with nervous activity which forms the main topic we have to discuss. Owing to recent developments in technique we can now record a great deal of what takes place electrically in the nerves, and we shall have to consider how far these records can be made to reveal the working of the nervous system. Recording Instruments The history of electrophysiology has been decided by the history of electric recording instruments. Progress was very rapid at first. In spite of Voita's denial of its special character, the study of animal electricity seemed the 2

DEVELOPMENT OF ELECTROPHYSIOLOGY shortest cut to an understanding of life. I t attracted men of the stamp of du Bois R e y m o n d , Pflüger, and Helmholtz, and by 1848 du Bois R e y m o n d had published two large volumes on the subject, and the use of electric currents for stimulating-—producing the active state—had become a general method of research. I t would be hard to think of any other method which has done so much to show us how the body works, for it gives us a means of throwing a muscle or a nerve into activity at will by an agency which does no damage and can be precisely controlled. B u t the chief interest centred round the converse effect, the production of currents by active cells. Here there were great technical difficulties. T h e currents are small and as they follow every change of activity they m a y fluctuate very rapidly; the early mirror galvanometers could detect them but could not show how they changed from moment to moment; indirect evidence had to be sought and lively controversies took place. T h e next stage came when Bernstein devised an ingenious analysing instrument, the rheotome, which made it possible to follow out the true form of the potential change which occurs when a muscle contracts as the result of an electric shock. T h e events following stimulation in muscle and nerve were explored and evidence accumulated to show that the electric response was a true index of the active state and could not be dissociated from it. T h e capillary electrometer in a form especially modified for physiological work confirmed Bernstein's results. It was now possible to record the brief potential change in a stimulated nerve trunk, to measure its rate of conduction, and to compare it with that of the w a v e of activity. Then in 1903 came Einthoven's string galvanometer, an instrument far more sensitive than the capillary and yet rapid enough to follow the potential change in muscle. T h e knowledge which had seemed so academic was at once put to practical use in medicine, for 3

MECHANISM OF NERVOUS ACTION

with the string galvanometer it was possible to record the electric currents produced by the heart-beat in man. The use of the electrocardiogram for analysing the working of the heart is a good illustration of the electrical method in general. When any part of the heart muscle becomes active, a potential gradient is established between the active and inactive regions, and as the wave of activity spreads, the gradients change their position. Consequently the potential fluctuations between any two fixed points on the heart muscle are determined by the route taken by the wave of activity and by its rate of travel in different regions. T o record these changes there is no need to expose the heart. I t is conveniently placed in the thorax with the air-filled lungs on either side, so that by making electrical connection with the arm and leg of the subject we are in effect leading from the base and apex of the heart. Thus the electrocardiogram shows at a glance how the heart is behaving, although we do not directly observe the contraction of the muscle. Now in a nerve we cannot directly observe the change from rest to activity, because no visible change takes place; but when the activity is produced by electric stimulation there is the same kind of potential change as in the heart muscle and we can use this in the same way to explore the working of the fibre. If it is true then that nerve activity, however produced, is always associated with an electric change, it should be possible, given instruments rapid and sensitive enough, to analyse the normal working of the muscles and nerves as we can analyse the working of the heart. In the special field of the heart muscle the string galvanometer added an entirely new chapter to physiology, but in the more general field its increased sensitivity was not great enough to help much. It showed, however, that the electric changes in nerves and muscles were not produced only when artificial stimulation was used. When every fibre in a nerve is thrown into action by an electric shock, 4

D E V E L O P M E N T OF

ELECTROPHYSIOLOGY

t h e p o t e n t i a l c h a n g e is m u c h larger t h a n when the u n i t s a c t i n d e p e n d e n t l y ; so the earlier work, with less sensitive i n s t r u m e n t s , h a d dealt mainly with the effects of electric s t i m u l a t i o n . W i t h the s t r i n g g a l v a n o m e t e r it was possible in selected cases to record electric changes in nerve d u r i n g reflex a c t i v i t y . I t was rarely possible to say more t h a n t h a t r a p i d p o t e n t i a l changes were t a k i n g place, b u t this was e n o u g h to show w h a t m i g h t be expected with an even m o r e sensitive recording system. T h i s t a k e s us to t h e period immediately before t h e war when K e i t h L u c a s was investigating t h e nervous impulse with t h e capillary electrometer and Piper was using t h e string g a l v a n o m e t e r to record muscle action c u r r e n t s d u r i n g v o l u n t a r y c o n t r a c t i o n . B o t h i n s t r u m e n t s were still giving valuable results, b u t t h e y were results of t h e kind needed to consolidate a position already won, a n d there was n o t m u c h h o p e of f u r t h e r a d v a n c e w i t h o u t a fresh d e v e l o p m e n t on t h e i n s t r u m e n t a l side. F o r t u n a t e l y for us t h e fresh d e v e l o p m e n t has now a p p e a r e d . T h e a d v e n t of triode valve, or v a c u u m t u b e amplification has so altered t h e whole position t h a t we can c o m p a r e ourselves to a microscope worker who has been given a new objective with a resolving power a t h o u s a n d times greater t h a n a n y t h i n g he has h a d before. W e h a v e only to focus our i n s t r u m e n t on t h e field t o find s o m e t h i n g new a n d interesting. Amplification

of Electric

Changes

T h e v a c u u m t u b e amplifier is a device which will m a g n i f y small changes of potential of a n y form. T h e o u t p u t change is, within limits, a t r u e copy of t h e i n p u t , a n d as it is d e r i v e d f r o m t h e batteries or mains which feed the amplifier, t h e p o w e r available for driving t h e recording i n s t r u m e n t m a y be m a d e very large indeed. T h e result of this is t h a t t h e sensitivity of the recording i n s t r u m e n t has ceased to be an i m p o r t a n t consideration, a n d our choice can be d e t e r m i n e d entirely by t h e r a p i d i t y of the moving system. 5

MECHANISM OF NERVOUS ACTION For some experiments the ideal instrument is the inertialess cathode ray oscillograph, but the moving iron oscillograph designed by Matthews (1928) is rapid enough for most purposes, and there are various instruments of the moving coil or string type with much the same range. Another advantage which comes from the increased power at our disposal is that we are not restricted to optical recording systems. The shifting beam of light from an oscillograph can be photographed on a moving strip of film or viewed with a revolving mirror, but we can often learn something more if the amplified potential changes are made audible as well as visible, and this can be done, if the changes are rapid enough, by leading them into telephones or a loud speaker. The amount of amplification which can be obtained nowadays is far greater than we are ever likely to need in physiological work. For instance, there would be no particular difficulty in demonstrating the potential change in a frog's nerve fibre as an audible signal in the course of a radio lecture. The power available in the input circuit would be of the order of i o - M watts, and the transmitting station might radiate 50 kilowatts or more. But there is a definite limit at the other end of the scale. We can increase the magnification of a microscope as much as we like by using more and more powerful eyepieces, but the resolving power is still determined by the objective. In the same way the resolving power of an amplifier, the smallest potential change which can be detected, depends on the working of the first tube—the magnitude of the output change is immaterial. At present we can detect an input change of one or two microvolts in a circuit of high resistance like a small nerve trunk, but we cannot deal with anything less than this because fluctuations of half a microvolt or so are constantly occurring quite apart from any physiological effects. They may be due to the amplifier itself, e.g., to unsteady emission in the first tube, and if so 6

DEVELOPMENT OF ELECTROPHYSIOLOGY there is some hope of reducing them, but there must always be an irreducible minimum of disturbance due to the thermal agitation of the electrons in the input circuit, and it may be that we have already reached the limit set by this. For some purposes greater sensitivity would be an advantage, but we may have to remain content with the great sensitivity we have already. It will be seen that we have a method of detecting and recording small electrical changes which is far in advance of anything possible without amplification. We can record far smaller changes and we can record very rapid changes with far greater accuracy than before. I t would be a sad confession of failure if with these new resources we had been able to learn nothing fresh about the working of the nervous system, but in fact they have already given us direct evidence on many points and the field now open is so large t h a t it will be a long time before the method has exhausted its usefulness. The work with which I shall deal is mainly concerned with the behaviour of the units which make up the nervous system. The units, the nerve cells and the threads of protoplasm which run out from the cell body, are built up into a complex central mass, the brain and spinal cord, and a series of nerve trunks connecting the central nervous system with the periphery. The nerve trunks have a relatively simple structure, for they consist of bundles of nerve fibres, grouped together for anatomical convenience but each acting as an independent conducting unit. Now it is best to begin with the simplest case and from the point of view of electrical analysis it is much easier to decide what is going on in the nerves than in the central nervous system. All manner of potential changes can be recorded by placing electrodes in contact with the brain and cord, but it is often very hard to decide what structures are responsible for them. No doubt these difficulties will 7

M E C H A N I S M OF NERVOUS ACTION be overcome before long—some methods are already available—but meanwhile the most definite results have come from the peripheral nerves where no such difficulties arise. The Activity of Peripheral Nerves A record of the electrical activity of a sensory nerve is shown in Fig. i. The nerve is one of the small cutaneous trunks in the cat's hind foot. The animal has been

F i c . ι . Electric changes in nerve from cat's toe joint on flexing the toe slowly, rapidly and still more rapidly (Adrian and Umrath, 1929). Record made with Matthews oscillograph and amplifier. T h e potential changes are of the order of 15 microvolts. The slow rise of the base line in the lowest record is due to a movement of the nerve on the electrodes; it has no physiological significance.

decapitated under an anaesthetic and the body is kept alive by artificial respiration. The nerve has been cut through near the ankle, dissected out for an inch or so, and placed on two electrodes which lead to an amplifier and a recording system. All the terminal branches of the nerve have been cut except one very small twig which leads to a group of sense organs in the neighbourhood of the toe joint; these sense organs have not been interfered with in any way and they can be stimulated, as they would be in the intact animal, by bending the toe. The 8

DEVELOPMENT

OF

ELECTROPHYSIOLOGY

records show the potential changes which occur between the two electrodes when the toe is bent slowly or rapidly. T h e beam of light from the mirror of a M a t t h e w s oscillograph is thrown on to a moving strip of bromide paper so that any change of potential is recorded as a movement up or down of the dividing line between light and shadow. As long as the toe is at rest the line remains horizontal apart from the slight unsteadiness always present with a sensitive amplifying system; when the toe is bent a series of rapid potential changes take place in the nerve, each change consisting of a sudden deflection first above and then below the zero line. T h e deflections are all of much the same f o r m ; they v a r y in size over the same range in all three records, but they are more closely crowded when the toe is bent more rapidly. There is no doubt about the interpretation of these potential changes, for they are of the same form as the much larger changes which are produced when a motor nerve is stimulated electrically. T h e stimulus then sets up in each nerve fibre a brief impulse or w a v e of activity which travels rapidly down the fibre and produces a sudden contraction in the muscle. A t each point on the nerve the activity lasts for only a few thousandths of a second and wherever it appears it involves a potential change, the active region becoming negative to the inactive regions beyond it. T h u s if the nerve rests on two electrodes a potential change occurs as soon as the active region reaches the first (Fig. 2) and when it reaches the second the potential change is reversed. T h e diphasic potential waves shown in Fig. 1 are the exact counterpart of the diphasic w a v e which accompanies the volley of nerve impulses produced by electrical stimulation, though they are very much smaller, as they are bound to be if they are due to single nerve fibres acting independently. I t appears then that a succession of impulses is passing up the nerve fibres from the sense organs

9

M E C H A N I S M OF NERVOUS ACTION at the toe joint, and that the sensory message consists of a series of brief active periods in each fibre separated by pauses of varying length.

ι

аяш

ι

•

д

I

ι DIPHASIC POTENTIAL.

WAVE

\ Fio. a. Production of a diphasic potential wave by the passage of an impulse down a nerve fibre.

The Activity of Single Nene Fibres When a nerve is stimulated electrically the potential change in each fibre is of fixed magnitude and duration; it depends only on the state of the fibre and not on the strength of the stimulus which set it in motion. In the record in Fig. ι the potential changes are not all the same, for there are at least three different sizes. It is conceivable that the waves set up by a sense organ can vary in size although those set up by electric stimulation of the nerve cannot, but it is much more likely that the different sized waves are due to different sized nerve fibres, for the fibres running to the toe joint are not all exactly alike. T o decide this point and generally to learn what is happening in each nerve fibre the preparation must be arranged so that only one nerve fibre can come into action. There are various methods by which this can be done and they play an important, indeed an essential part, in the analysis of nerve activity. The simplest method in 10

D E V E L O P M E N T OF

ELECTROPHYSIOLOGY

theory and the most difficult in practice is to cut through nearly all the fibres in the nerve in the hope of arriving at a stage when only one active fibre remains intact. Professor Bronk and I have spent many hours in this tedious pursuit, for it is the only way of dealing with the motor nerve fibres. With the sensory fibres it is usually much better to leave the nerve alone and try to arrange matters so that only one end organ will be thrown into action by the stimulus. This cannot be done in a preparation of the sort used in Fig. i, for there the end organs are of the type known as Pacinian corpuscles and there is a bunch of eight or more between the tendon and the joint capsule. But in other situations and with other types of end organ it is often fairly easy to stimulate one at a time. For instance Matthews ( 1 9 3 1 ) has found that one of the small toe muscles in the frog contains as a rule only one end organ (a muscle spindle) which responds when the muscle is stretched; in the skin it is often possible to stimulate a single pressure organ or a single hair and so on. When one of these preparations is used the sensory message takes on a much simpler aspect. Fig. 3 is a record made by stretching the frog's toe muscle and

...

Τ

L ^\ L -1 LTL i ~- 1L LI LI TL kMkMi U U k b L L k L U ΙL ΙL ' k1 k k k L y ' IT 1 LI T I 1 1 1

Ι o·/ secoA/iУ .

FIG. 3 .

Impulses in a single nerve fibre from a frog's muscle spindle stimulated

by stretching

the muscle

(Tsai,

1931)·

Matthews'

toe

muscle

preparation.

The potential waves are all alike; their frequency increases with the tension and then declines slowly when the tension is constant.

recording the potential changes in the nerve. The potential changes are now of uniform size; they form a regular series with a frequency which increases to a maximum as the muscle is extended and then declines again as the stretch is maintained. The regular succession of waves is most 11

M E C H A N I S M OF NERVOUS ACTION clearly marked in the discharge of sense organs which become slowly adapted to the stimulus, for when adaptation is rapid, as in many of the organs in the skin, the discharge is too brief to show much regularity. But the potential changes are again of uniform size, and an illustration of this is given in Fig. 4, which shows the activity in a few cutaneous nerve fibres of the frog, the skin being stimulated by intermittent pressure.

FIG. 4. touch.

Impulses from sensory endings in the frog's skin stimulated by light

If these records give a true measure of the activity in the sensory nerve fibres it is clear that they transmit their messages to the central nervous system in a very simple way. The message consists merely of a series of brief impulses or waves of activity following one another more or less closely. In any one fibre the waves are all of the same form and the message can only be varied by changes in the frequency and duration of the discharge. In fact the sensory messages are scarcely more complex than a succession of dots in the Morse Code. The same kind of electrical activity is found in the motor nerve fibres. When a message passes down a motor fibre from the central nervous system to arouse a muscular contraction we find again a rhythmic succession of potential changes alike in size but varying in frequency. Fig. ς gives a record from a single motor fibre supplying the peroneus longus muscle in a spinal (decapitate) cat. The record was taken at the beginning of a flexion reflex evoked by pinching the foot; the movement developed slowly and the development goes hand in hand with the increase in frequency of the potential waves. Thus the effect produced 12

DEVELOPMENT

OF

ELECTROPHYSIOLOGY

on the motor nerve fibres by the excited nerve cell in the spinal cord is like t h a t produced on the sensory fibre by the stretched muscle spindle ( F i g . 3 ) .

It m a y be noted

that in F i g . 5 the recording instrument w a s a capillary electrometer, not an oscillograph, and as the m o v e m e n t is v e r y highly d a m p e d the true form of the potential w a v e s is not shown, although it can be worked out by a fairly simple analysis. 1*5'*«*-

FIG. 5. Impulses in a single motor nerve fibre supplying the peroneus longus in the cat (spinal). The nerve has been cut down until only one active fibre remains (Adrian and Bronk, 1929). A flexion reflex is produced by pinching the foot and the frequency of the discharge increases as the contraction develops. Record made with capillary electrometer and amplifier. The potential changes are actually diphasic though the damping of the electrometer movement is too great to show their true form. •

4?

''J-Jee.

F i c . 6. Impulses in a motor nerve supplying the tail muscles in a caterpillar (Adrian, 1930^). Record made at the end of a creeping movement showing the declining frequency of the discharge. T h e nerve has not been cut down, but the number of motor fibres is small enough to allow the individual impulses to be seen (cf. p. 7 1 ) .

T o complete the series and to show t h a t the behaviour of invertebrate nerve fibres agrees with t h a t of vertebrate, two more records are given, this time from the nerves of the caterpillar.

Fig.

6 is a discharge

f r o m one of the

motor nerves in the tail; the record w a s m a d e at the end instead of the beginning of a muscular contraction so that

13

MECHANISM OF NERVOUS ACTION the frequency of the waves declines instead of rising as in Fig. 5. Another difference is that more than one nerve fibre is in action, for there are some very small potential waves as well as the large waves of uniform size, but in spite of this the general resemblance is clear enough. Fig. 7 is also from the nervous system of the caterpillar, but in this case the electrodes are placed not on a peripheral

FJG. 7. Impulses in central nerve cord of a caterpillar. A portion of the central chain of ganglia has been isolated and one of the ganglion cells is discharging spontaneously.

nerve but on the nerve cord which joins two of the ganglia of the central nervous system. A message is passing from one ganglion to the other and it is shown b y the usual succession of diphasic waves. The Nature of the Nervous Messages According to these records nervous communication of all kinds is carried out in the same w a y by a succession of brief impulses. T h e impulses are not all exactly alike—those in the sympathetic system and in the smallest sensory fibres are conducted much more slowly than those in the large motor and sensory fibres— but the records show no evidence of any kind of activity other than that involved in the conduction of impulses. B u t can we assume that these records of potential change really tell us w h a t is happening, or all that is happening in the nerve? C a n there be nervous communication without electrical change, or if there is always an electrical change can we use it as a measure of w h a t is going on in the fibre? These are questions which must be faced before we go further, though they involve some discussion of theory. 14

DEVELOPMENT OF ELECTROPHYSIOLOGY It is of course impossible to prove that electric changes invariably occur when a nerve is in action. All we can do is to point to the large number of experiments in which they have been found, and to the close correspondence between the message, as inferred from the electric changes and as inferred from the effects it produces in the body. In every case so far investigated whenever there has been reason to suppose that a nerve is in action, the usual potential changes have been detected, provided that the conditions for recording them were favourable. This last clause offers a refuge which is seldom needed, but it is needed to explain the failure to record potential changes from non-medullated sensory fibres in the mammalia. This will be discussed further in connection with the mechanism of pain, but meanwhile it is reasonable to suppose that the failure is due not to the absence of electric effects, but to their very small intensity under the conditions of the experiment. There are many instances where the record of electrical activity has shown some unexpected feature which on investigation is found to account for some special reflex or central effect of the message. F o r instance Hoffmann (1922) found some years ago that if the patellar tendon is tapped whilst the thigh muscles are contracting, the resulting knee jerk is followed by a brief pause in the contraction. This 'silent period' has been explored by Denny-Brown (1928) and shown to be a reflex effect of the sensory discharge from the thigh muscles. Recently Matthews (1931^) has recorded the impulses coming from the muscle spindles and has found that a sudden contraction of the muscle causes a brief pause in the sensory discharge. This was unexpected but it evidently explains the silent period after the knee jerk. Another example is that of the persistent discharge of impulses in the sympathetic nerves: as the discharge is concerned in maintaining the tone of the blood vessels we supposed that the impulses 15

M E C H A N I S M OF NERVOUS ACTION would be arranged in a fairly regular and uniform sequence, but instead we found that they are often arranged in groups occurring in phase with the movements of respiration. This result, though quite unforeseen, is really quite in accord with what we should have expected if we had looked up the literature beforehand, for Fredericq showed in 1882 that the blood pressure may rise and fall with the frequency of respiration, although mechanical effects on the blood vessels have been excluded by opening the chest. Unexpected agreements of this kind are the most satisfactory vindication of the electric record as a true index of the message in the nerve fibres, and so far there has been no clear instance of lack of agreement. In fact the correspondence has occurred so often that according to all the rules we are justified in assuming that it is universal. Gradation of Activity There remains the second question, whether we can assume that the potential changes are a true measure of the impulses in the nerve fibre, whether the impulses can v a r y in size without there being any corresponding variation in the electric response. There is certainly no evidence to suggest that the impulses are graded in size, for the fact that sensory messages may produce a small or a large effect according to the intensity of the stimulus is naturally explained by the varying number of fibres in action and by the varying frequency of the discharge in each fibre. B u t the point is so important that it is worth trying for the moment to take up the role of a hostile critic with a rooted belief in the complexity of nature. Such a critic might argue like this: " I f I look out on to a main road at night I see a succession of bright lights travelling rapidly. T h e y are all of much the same intensity, but would you ask me to believe that they are all due to motor cars of the same make? This is what you expect me to believe of the nerve fibre when you argue from the potential wave to the 16

DEVELOPMENT OF ELECTROPHYSIOLOGY impulse. Surely each impulse in a message may have a distinct individuality, and instead of being like a succession of dots in the Morse Code the message may be like a succession of numbers, or words, or sentences. And I am not at all sure that the message is necessarily made up of distinct impulses. To account for your potential changes let us suppose that when any part of the nerve fibre becomes active there is an immediate breakdown of a polarised surface membrane, giving a potential gradient of fixed intensity, that the breakdown is immediately repaired, but that if the underlying activity persists the surface breaks down again giving another potential wave, and so on. On this view the potential change may be merely incidental: the essential activity which the nerve fibre transmits may be perfectly continuous, rising and falling with the excitation of the sense organs or nerve cells and capable of much more rapid and delicate fluctuations in intensity than are revealed by the electric record. You have something which you can measure and no doubt it is very closely related to the activity of the nerve fibre. But changes in lactic acid content seemed to be just as closely related to the contraction of muscle, and we have had to give up the belief that they tell the whole story. The potential changes may show that a message is passing, but I see no reason to believe that the whole content of the message is revealed by them." In answering this we have to be careful to define what is meant by the impulse or the wave of activity in a nerve. It must be taken to mean not the whole sequence of changes which take place at each point in a nerve fibre after a stimulus, but only the change which propagates itself down the fibre and leads to the activity of other structures such as muscles or glands. The passage of a single impulse down a fibre may give rise to chemical and thermal changes which are still in evidence five minutes later, five minutes after the impulse has done all that it can in the way of 17

M E C H A N I S M OF NERVOUS ACTION activating other regions. These chemical and thermal changes are no doubt of graded intensity, since each new impulse must add its own after-effects, and in this sense the activity of a nerve fibre may be graded and persistent. But the 'propagated disturbance,' the activity which arouses other parts of the fibre, is a momentary affair and its intensity cannot be altered except by changing the local condition of the fibre. It is true that the evidence must be taken from experiments on motor nerves stimulated electrically, but there is abundant proof that the impulses set up in this way are identical with those arising from sense organs or nerve cells. The impulse produced by a single electric shock is certainly incapable of any kind of gradation which might play a part in the working of the nervous system, for one set up by a strong stimulus can do no more than one set up by a weak. It travels no faster and no further (if there are obstacles to its progress) and causes no greater effects on the structures which are activated by it. Its brevity is shown most clearly, I think, by an old experiment of Boycott's (1899). If two stimuli are sent into a frog's nerve at an interval of less than about .003 sec. the muscle gives a twitch no greater than if only one stimulus is used. When the interval is lengthened progressively the twitch suddenly increases. Evidently the second stimulus has now become able either to prolong or intensify the first propagated disturbance or else to set up a fresh disturbance of its own. Now if the nerve is cooled somewhere between the stimulated region and the muscle, the twitch reverts to its original height. This is easily explained if there are two brief impulses but not if there is one long one. On the former view the failure of a very early second stimulus is due to its falling at a time when the nerve fibre is still disorganised by the passage of the first disturbance, and this refractory state will be lengthened in the region where the nerve is cooled. On the other hand if the second 18

DEVELOPMENT OF ELECTROPHYSIOLOGY stimulus, when successful, produces not a second disturbance but a prolongation of the first there is no reason why it should cease to be effective when the nerve is cooled. The Membrane Hypothesis There are many other arguments of the same kind depending on the phenomena of the refractory state, but when all is said and done the best argument comes from the whole body of evidence in favour of what is known as the membrane hypothesis of nervous conduction. According to this hypothesis the resting nerve fibre is enclosed by a polarised membrane, and this breaks down locally under the action of the stimulus, establishing a potential difference between the active and inactive regions. The potential gradient (or the concentration gradients which produce it) causes a differential movement of anions and cations at the boundary of the depolarised region, and this leads to a spread of the depolarisation and at the same time to a restoration of the surface already depolarised (Fig. 8). The restored surface is at first refractory and therefore unable to break down again, and thus the area

REFRACTORY DIRECTION

ACTIVE

OF TRAVEL

RESTING >

FIG. 8. Spread of active (depolarised) area according to the membrane hypothesis. The local currents cause a repair of the active region and a breakdown of the resting surface beyond.

19

MECHANISM OF NERVOUS ACTION of breakdown shifts down the nerve fibre; the potential change in each section acts as the stimulus to the next section and the surface is automatically restored to the polarised state after a brief period of activity. It follows that the potential change is an essential link in the transmission of the impulse: if it is found not to vary with the stimulus there can be no possible variation in the impulse: the duration of the period of surface breakdown must coincide with that of the potential change, and the surface breakdown is, in fact, the impulse, the disturbance which propagates itself down the nerve fibre. If we accept the membrane hypothesis in its general outlines we need not hesitate to take the potential changes as a faithful record of the way in which the nerve fibre performs its function. There is no one experiment which excludes all other explanations of nervous conduction but there are very many phenomena of nerve and muscle activity which can be most simply explained on this basis and none which contradict it. It has been supported most strikingly by R. S. Lillie's iron wire model—a non-living system in which surface changes are rapidly transmitted by the agency of the local currents set up at the margins of the active region—and by the recent work of Α. V. Hill (1932) which shows that only an extremely small amount of heat is evolved during the passage of an impulse in comparison with the amount evolved afterwards in restoring the free energy of the fibre. Lillie's work shows that a transmission of this kind is a physical possibility, that it would be likely to happen in a structure such as a nerve fibre and that the character of the transmission would agree with that found in nerve. Hill's shows that the main event in the conduction of an impulse is most probably a physical change like the movement of ions postulated on the membrane hypothesis. The hypothesis is in no sense a complete picture of nerve activity but it is the only satisfactory picture of the mechanism of conduction. 20

DEVELOPMENT OF ELECTROPHYSIOLOGY We come back then to our records of nervous messages with a reasonable assurance t h a t they do tell us what the message is like. It is a succession of brief waves of surface breakdown, each allowing a momentary leakage of ions from the nerve fibre. The waves can be set up so t h a t they follow one another in rapid or in slow succession, and this is the only form of gradation of which the message is capable. Essentially the same kind of activity is found in all sorts of nerve fibres from all sorts of animals and there is no evidence to suggest that any other kind of nervous transmission is possible. In fact we may conclude that the electrical method can tell us how the nerve fibre carries out its function as the conducting unit of the nervous system, and that it does so by reactions of a fairly simple type.

21

Chapter I I THE

ACTION OF

THE

SENSE

ORGANS

Ε sensory discharge is something which can be .neasured. It gives us our most direct information about the working of the sense organs, for there is no adequate measure of sensation, and reflex effects, though measurable, are too far removed from the sensory apparatus. A record of nerve impulses cannot tell us what effect the message will have when it enters the central nervous system, but it shows how the sense organ responds to the stimulus. Unfortunately we cannot always identify the sense organ which gives rise to a particular series of impulses, for over most of the skin the different types are so closely spaced that it is impossible to say which of them are in action. I t is for this reason that much of our information relates to sense organs which have not been identified histologically, to pressure receptors, temperature receptors, etc., and not to Meissner's corpuscles or Golgi Mazzoni bodies. But there are some receptors whose action can be identified, e.g., the muscle spindles, the Pacinian corpuscles, the hair endings, and certain types of ending in the viscera, and no doubt the list could be extended without much difficulty. The sense organs listed above are all stimulated mechanically, and with all of them the effective change seems to be a stretching of the terminal part of the sensory nerve fibre. As with most sense organs, the ending of the fibre has various accessory structures in close contact with it. These may be intimately concerned with the process of excitation, but their most obvious effect is to produce a given deformation of the ending in response to a given stimulus. 22

ACTION OF T H E S E N S E ORGANS With the hair organ a lateral movement of the tip of the hair will distort the ring of endings round its base; with the Pacinian corpuscle pressure in any direction will elongate the central core and stretch the endings in it; the muscle spindles will be stretched by a pull on the tendon, and so on. T h e form of the accessory structures will determine the direction in which the force must be applied, and their rigidity will decide the amount of force needed for a given extension of the endings. They will act like a system of levers, springs, and shock absorbers, and it is possible that this is their only function. I f so the different kinds of corpuscles, etc., may serve merely to fix the range of stimuli to which each ending will respond and so to provide sense organs differing greatly in their excitability to mechanical forces. B u t the sense organs do not differ merely in excitability. There are, of course, the receptors for thermal and chemical stimuli which are not activated mechanically, but if we confine ourselves to the receptors which are activated by deformation we find great differences in the time course of the discharge. With some of them the discharge only takes place during the actual movement, with others it persists as long as the deformation remains, though at a gradually declining frequency. Adaptation T h e rapid failure in the exciting effect of a constant stimulus is a well-known phenomenon in nerve physiology. A constant current applied to a nerve gives as a rule only one impulse, and a current which increases gradually from zero may never excite at all. T h e excitation only occurs whilst the conditions are actually changing, and the rate of change must exceed a certain value. T h e persistent stimulus does not give a persistent discharge because the fibre becomes rapidly adapted to the new conditions. 23

MECHANISM OF NERVOUS ACTION Adaptation is perhaps a dangerous term to use, for it seems to imply a positive reaction on the part of the nerve fibre. There may be such a reaction, but for all we know the rapid failure of the stimulus may be due to simple physical changes such as diffusion or polarisation. The change may not even take place in the nerve fibre at all, for Bishop (1928) has suggested that polarisation in the nerve sheath may be largely responsible. At any rate we find the same rapid or slow decline in the effect of a stimulus to a sense organ. Here we are justified by long usage in speaking of adaptation, and it is unlikely that there is any great difference in the process as it occurs in the sense organ and in the nerve fibre. The variations in adaptation rate can be seen most clearly by recording the discharges of the sensory fibres in a mixed nerve, or better in one of the dorsal nerve roots. When one of these is placed on the electrodes it is found that impulses are constantly passing up from sense organs in the periphery. They come mainly from deep-seated sense organs which adapt very slowly and signal the posture of the limb. The slightest interference with the limb produces a sudden but transient increase in the discharge. As long as the movement continues, impulses pass up in the nerve fibres from hairs and tactile endings, but most of this extra discharge ceases when the movement is over, for the endings adapt rapidly and are no longer excited although the hairs remain in the bent position. The steady discharge from the postural organs also increases during the movement and may be left with an altered frequency corresponding to the altered distribution of muscle tension and pressure. Almost any preparation containing a good many sense organs will react in this way, with a persistent discharge in some nerve fibres during an abnormal posture, and a brief discharge, confined to the period of actual movement, in others. In the skin the rapidly adapting endings are 24

ACTION OF T H E S E N S E ORGANS in the majority, in mammalian muscles both are present in varying proportions, and in frog's muscle nearly all the endings adapt slowly. But the distinction is one of degree only. It is worth making when we are discussing the function of the different organs, but it does not mean that there is any fundamental difference between the mechanism of the muscle spindle and of the hair ending. They are merely at opposite ends of the scale, and in fact some muscle spindles adapt fairly rapidly and some hair endings fairly slowly. It should be pointed out that, as adaptation always takes place to some extent, there is no sense organ in which the frequency of the discharge can be said to depend entirely on the intensity of the stimulus. We can say if we like that with all sense organs the frequency is determined by the intensity of the excitation, though this is merely defining what we mean by intensity of excitation. But the stimulus, the mechanical change inflicted on the sense organ, is always discounted more or less rapidly by the adaptation which it produces, and the time factor is quite as important as the intensity factor, even with the organs which adapt very slowly. The slowly adapting or postural end organs which have been investigated up to the present are those responding to muscle stretch in the frog and mammal, the Pacinian corpuscles and various unidentified organs responding to pressure, the sensory endings of the vagus in the lung root and those of the cardiac depressor nerve and the nerve to the sinus caroticus. With all of them the frequency of the discharge depends on the rate of increase, the final intensity and the duration of the mechanical change which acts as the stimulus, and to obtain the maximum frequency the stimulus must not only reach a great intensity but must reach it very quickly. For instance Matthews (19310) finds that to make the frog's muscle spindle discharge at the highest possible rate the muscle must be suddenly pulled out by a spring, and 25

MECHANISM OF NERVOUS ACTION Bronk and Stella (1932) find that the rate of rise of the arterial pressure is a very important factor in the discharge of the sense organs in the aorta and sinus caroticus. Records of the sensory discharge from the vagal endings in the lung are given in Fig. 9. In the lowest record the lung is inflated suddenly and the inflation is maintained. T h e

С Fic. 9. Sensory impulses in the vagus from a single end organ in the lung. Nerve cut down to show single fibre discharge. A. Decerebrate cat breathing normally; the record shows the discharge during a single movement of inspiration, maximum frequency 16/sec. B. Another animal, hyperpnoea due to breathing into a closed space, maximum frequency 72/sec. C. Same preparation as B. Discharge produced by sudden, forcible inflation of the lungs. The frequency rises to 150/sec. and has fallen to 1 1 5 after the first second.

frequency of the discharge falls appreciably in the first second, though the impulses are too closely crowded for this to show well in the reproduction. B u t provided we specify the whole evolution of the stimulus we can often predict the response with very great accuracy indeed. With a mammalian preparation it is naturally difficult to keep all the conditions constant over long periods, but with a frog's muscle spindle M a t t h e w s could repeat a series of stimuli knowing that the response to them would v a r y by less than 5 % in an experiment lasting several hours—and the response is a complex affair 26

A C T I O N OF T H E

SENSE

ORGANS

rising and falling in the w a y shown in F i g . 3. T h i s machinelike regularity of behaviour m a y be taken as a proof that the working of the nervous s y s t e m ought not to be beyond mechanical description. B u t those who dislike mechanism might well retort that the sense organs would be of little use to the body if they could not be trusted to give the s a m e message for the same stimulus. T h e receptor and effector a p p a r a t u s must respond with rigid precision if the central nervous system is to be in full control, and it is only in the central nervous system that our models m a y be of questionable value. The Production of the Rhythmic Discharge When we come to the actual mechanism concerned in the discharge of impulses we are on less certain ground. T h e main evidence is that concerning the frequency and regularity of the discharge. When a frog's muscle spindle is stretched the discharge is regular, in the sense t h a t the intervals between successive impulses lie on a smooth c u r v e , as long as the frequency is above about 20 a second. Below this there is much greater variation, though the intervals are never shorter than one-twentieth of a second. W i t h m a m m a l i a n sense organs the regularity persists at much lower frequencies: the pressure receptors often discharge regularly at 1 0 a second and the muscle spindles are still regular at 5 a second. T h e r e is a simple explanation of this behaviour, but u n f o r t u n a t e l y it does not t a k e us v e r y far. A nerve fibre itself can only be excited intermittently, for each impulse sets up a r e f r a c t o r y state which passes a w a y gradually. B u t if the end of the fibre were altered in such a w a y that it could exert a continued stimulating effect on the rest of the fibre it could not fail to produce a regular discharge. T h e discharge would be regular because a f t e r each impulse the normal fibre recovers along a smooth curve. An impulse must be set up each time the excitability returns 27

MECHANISM OF NERVOUS ACTION to the level at which the stimulus is effective, and if the stimulus and the rate of recovery do not change the impulses will be evenly spaced. The regularity would cease when the frequency falls below a limiting value; the excitability does not go on rising indefinitely after each impulse, and a necessary condition for the automatic firing is that it should occur before recovery is complete. An irregular response must have some other explanation, but it is clear that any condition which can act as a persistent stimulus to a nerve fibre would give a regular series of impulses over a certain range of frequency. The mere regularity of the discharge can only tell us that a persistent stimulus is acting on a structure which must respond intermittently, but in the sensory discharge the particular range of frequency tells us a little more. It shows that the structure in question is not the unaltered nerve fibre, but is some transitional region between the nerve fibre proper and the part of the ending which is sensitive to the stimulus. A region of this kind is necessary to account for the wide range over which the discharge may vary without losing its regular character, for with a mammalian nerve fibre the recovery is so rapid that a persistent stimulus could not produce a regular discharge at a frequency much lower than 150-100 a second. When they were first examined it seemed that the whole range of frequencies in the sensory discharge was lower than it would be in a stimulated nerve fibre, but later work has shown that there is no clear difference at the upper end of the scale. With intense stimulation the frequency from a sense organ can be made to rise to a value very little below the maximum frequency for nerve (Matthews, 1931л, Adrian, Cattell and Hoagland, 1931). Thus the structure in which the discharge arises must have an absolute refractory period scarcely longer than that of the nerve fibre, but the later stages of recovery must be slower. It is by no means certain that rapid and slow 28

ACTION OF THE SENSE ORGANS discharges arise from the same point: there may be a gradual transition from nerve fibre to nerve ending with a gradual slowing of time relations, and an intense stimulus may take effect at a point where recovery is rapid. But in any case the intermittent activity, the succession of impulses, must begin at some point in the nervous apparatus of the sense organ and the recovery rate is a matter of detail. Our chief concern is with the persistent stimulus which sets up the discharge. We must look for some kind of change in the sense organ which would have this activating tendency and would be brought about by such diverse causes as mechanical deformation, temperature change, and change in chemical environment. Depolarisation in the Sense Organ One simple possibility is that the change in the sense organ is a surface depolarisation like that occurring in the active nerve fibre, but persistent instead of momentary. This is suggested by the recent work of R . S. Lillie on the iron wire model of nervous conduction. Lillie's model is an iron wire coated with a thin protective film, probably an oxide, by immersion in strong nitric acid. If the film is destroyed locally, a w a v e of surface disintegration travels down the wire under the influence of the potential gradient between the active and inactive surfaces. As in nerve, the surface film is re-formed in the wake of the wave and the activity at each point lasts only a short time. T h e analogy with the nervous impulse is very close indeed, and the analogy m a y be extended to the sense organ. If the conditions are arranged so that one end of the wire is kept permanently in the active state, this exerts a persistent stimulating effect on the rest of the wire and a succession of waves travel down it (Lillie, 1929). T h e stimulating effect is due simply to the difference of potential between the exposed or active iron at the end of the wire and the 29

MECHANISM OF NERVOUS ACTION passive film beyond it, in fact t h e active region sets u p a train of waves for the same reason t h a t causes t h e spread of the individual wave from one point to another. T h e frequency of t h e waves depends on the rate of recovery of the wire and on the size of the permanently active area; it can be varied therefore by increasing or reducing this area. In the same way persistent activity, or, in terms of the m e m b r a n e hypothesis, persistent depolarisation in a sensory nerve ending might account for the r h y t h m i c impulse discharge. A partial or complete breakdown of a polarised surface is an event which would be likely to follow mechanical deformation; and if the extent of the breakdown depends on the a m o u n t of deformation it would determine the frequency of the rhythmic discharge as in the iron wire model. T e m p e r a t u r e change or chemical change might have the same destructive effect on the surface of the endings which respond to these stimuli, and again the area involved or the degree of depolarisation would depend on the intensity of the stimulus. The Injury

Discharge

Whether or not depolarisation explains the discharge from sense organs, there is no doubt t h a t i n j u r y , which involves p e r m a n e n t depolarisation, can set up a rhythmic discharge in a nerve fibre. These injury discharges are abnormal effects, but the injured and the active states are so closely allied t h a t it is worth spending a little time over them. Both give the same potential change, for both involve a breakdown of the polarised surface membrane, though in the intact fibre the breakdown is promptly repaired. Now we suppose t h a t an impulse travels down a fibre because the depolarisation of one section causes a depolarisation of the next. I t follows t h a t an injury should s t a r t an impulse down the fibre, and if nothing occurs to diminish its effect we should expect it to produce fresh impulses whenever the fibre is ready to conduct them. 30

A C T I O N OF T H E S E N S E

ORGANS

In many nerve fibres this repeated activity is not found. A permanently depolarised area is formed whenever a nerve is cut through, but the response may v a r y from a single impulse to m a n y thousands: in fact the rate of adaptation to the stimulus may v a r y as much in a nerve fibre as it does in a sense organ. In the nerve of a frog it is unusual to find much persistent activity due to nerve section, and mammalian motor fibres give only a brief discharge when they are cut through. B u t mammalian sensory fibres are often much more active (Adrian, 1930a). A medium-sized nerve trunk removed from the body and kept in a warm, moist atmosphere is seldom free from impulses. T h e y are due to the smaller nerve fibres and arise from one or other of the cut ends. T h e discharge m a y subside after a few minutes but it is often renewed by slight changes in the condition of the nerve, e.g., by irrigation, readjustment on the electrodes, or a draught of cool or warm air. Another factor which affects the injury discharge is the presence or absence of a thick sheath round the nerve. If the sheath is stripped a w a y the discharge ceases, and if there is a v e r y thin sheath (as in the smallest nerves) there is usually v e r y little activity. W h y the sheath should make so much difference is not very clear, but the effect is not confined to the sensory fibres, for the motor discharge is also longer when a nerve is cut in a region where the sheath is well developed. T h e simplest type of injury discharge is of high frequency; it begins when the nerve is cut through and it can always be produced in an intact nerve by placing on it a crystal of calcium chloride or of any salt which will give a high osmotic pressure. As this treatment gives a progressive injury it allows us to study the beginning of the discharge as well as its later phase. T h e sequence of events is then as follows: at first an occasional impulse appears, then the rate quickens, but the discharge in each fibre is still irregular until it suddenly becomes regular at a frequency in the 31

MECHANISM OF NERVOUS ACTION neighbourhood of 150/sec. (at 35 0 C.). The frequency rises to 500-800/sec. and the loud speaker record changes from a low note to a high-pitched wail with more and more fibres taking up the cry as they feel the effects of the injury. Eventually the frequency in each fibre declines again and there is the same abrupt change from the regular to the irregular discharge below 150 impulses a second. An example of the high frequency discharge in a single nerve fibre is given in Fig. 10. In this case the discharge was brought to an end by cooling the preparation slightly and the records show the onset of the irregular phase.

FIG. 10. High frequency injury discharge. Dorsal cutaneous nerve of cat, removed from the body and set up in a moist chamber. Continuous discharge (300/sec.) changing to an irregular discharge of low frequency. The change was produced by lowering the temperature about 5 0 C .

Discharges of this type show what happens when a persistent stimulus acts on a nerve fibre rather than on the transitional region which we have postulated in the sense organ. The stimulus in this case is the injury and pre32

ACTION OF T H E S E N S E ORGANS sumably the depolarisation which occurs at the injured region, and the discharge resembles that from a sense organ, though it occurs over a higher range of frequencies. The frequency range is explained by the fact that a mammalian nerve fibre at body temperature takes about 1/150 sec. to recover its full excitability after an impulse. Consequently the regular discharge cannot occur at a lower frequency than 150/sec. and it must vary between this and the upper limit set by the refractory period of the nerve fibre. T o account for the irregular discharge is as difficult here as it is with the sense organs; we must suppose that there are irregular fluctuations in the threshold of the nerve or in the strength of the stimulus, though this merely amounts to the statement that something is irregular— and this we knew already. T o revert now to the sense organs; we have a reasonable working hypothesis in the notion that the stimulus causes a persistent depolarisation, or surface leakage, of variable extent and that this sets up the intermittent waves of depolarisation which spread down the nerve fibre. But there is another possibility, though it can only be stated in vague terms. It rests on the fact that an electric stimulus appears to act on a nerve fibre by setting up some preliminary change which is not itself a depolarisation. Bishop (1927) has shown this by recording the potential changes in the region under the stimulating electrodes: an inadequate stimulus, though it increases the excitability of the fibre, causes no potential change and therefore no depolarisation, and a slowly increasing current causes no depolarisation until the moment when the impulse is fired off. This means that the excitability of the fibre, or, to be more concrete, the instability of the surface membrane, can be made to increase up to the point when the surface breaks down, although until it does so there has been no change in permeability. Thus the essential change in the sense organ may be not a depolarisation but a development 33

MECHANISM OF NERVOUS ACTION of the condition which leads up to it. There would then be no persistent depolarisation in any part of the ending or fibre but merely the brief waves set up in the region where the surface has become unstable. To decide the point we should have to record the potential difference between the sense organ and its nerve fibre and this, though simple in theory, would be very difficult to carry out experimentally. So for the present we must leave this part of the picture in obscurity. It is very much better to do so, for we have so little real knowledge of the physics and chemistry of the cell surface that any picture must be a crude likeness with half the features left out. Differences in the Sensory Pathway: Touch and Pressure Variations in excitability and in adaptation rate are the chief differences which we can observe in the reactions of the sense organs which respond to mechanical stimulation. We shall see later that there are differences in the rate of conduction of the impulses as well—the differences which have been worked out by Gasser and Erlanger. But apart from the peripheral apparatus we find that there are also great variations in the time course of the central events. These are revealed, I think, by the quality of sensation which we experience when different receptors are stimulated. Arguments which jump from the material plane to the mental may land us in all kinds of error, but this is the argument for what it is worth. Firm pressure on the surface of a limb will stimulate some of the slowly adapting endings, and these will give a regular succession of impulses at a frequency depending on the pressure. An example of such discharge is given in Fig. I i . It was made from one of the sensory nerve roots in the cat and shows the effect of pressure on the side of the foot. A t the beginning, with very light pressure, the frequency of the impulses averages only 9 a second. This may be below the threshold of sensation, but sooner or 34

A C T I O N OF T H E

SENSE

ORGANS

later the frequency will become a d e q u a t e . Y e t pressure applied to our own sense organs gives a sensation w h i c h is perfectly continuous: it rises and falls along a c u r v e which seems to run closely parallel to the c u r v e of rising and falling impulse frequency and it never becomes i n t e r m i t t e n t . A s a rule, no d o u b t , a good m a n y sense organs m a y be in action and the composite discharge in several nerve fibres would not h a v e any definite r h y t h m , but a restricted stimulus m u s t occasionally t a k e effect on a single pressure organ and there is no reason to think t h a t the sensation would then be intermittent. It follows t h a t somewhere on the p a t h w a y between the sensory nerve fibre and the

FIG. II.

R e c o r d from one of the lumbar sensory rootlets in the c a t .

caused by pressure applied gradually to the side o f the foot. shows the beginning o f the discharge.

Discharge

T h e upper record

In the lower it has reached a f r e q u e n c y of

about ιοο/sec. and another nerve ending has begun to discharge at a lower frequency (20/sec.).

T i m e marker gives intervals of o . l j sec.

mind the intermittent message from the pressure organ must be s m o o t h e d o u t into a s t e a d y a c t i v i t y . F o r this to t a k e place each impulse m u s t p r o d u c e an excitation which rises and declines so slowly t h a t successive impulses can sum their effects. T h i s is not quite the same thing as slow a d a p t a t i o n , but it implies a sluggish reaction in some part of the central mechanism. Sherrington has given m a n y examples of ' i n e r t i a and m o m e n t u m ' in reflex arcs and the same conception m a y be applied here. N o w if we turn to the receptors for light t o u c h we find an entirely different s t a t e of affairs. T o produce a regular succession of impulses at all c o m p a r a b l e w i t h those in F i g . 11 we h a v e to use an intermittent stimulus r e p e a t e d at regular 35

MECHANISM OF NERVOUS ACTION intervals, a vibrating strip of metal bending the hairs rhythmically or a succession of puffs of air (Cattell and Hoagland, 1931). The message in the sensory fibre is then indistinguishable from that set up by the pressure receptor, but the sensation would be discontinuous instead of continuous. At a low frequency we feel each stimulus as a distinct event, and the frequency must be raised to several hundred a second before the discontinuity is completely lost. Here then we have a receptor which adapts very rapidly and a pathway which has very little of the smoothing effect which is found for pressure. As before, the argument ignores the fact that most stimuli will affect a number of receptors: the composite discharge to a rhythmic stimulus will be in phase in all the nerve fibres whereas that to a continued pressure will be out of phase. But again there is nothing to suggest that the distinctive character of the sensation would be lost if only one sense organ were in action. This question of the central summation of impulses will come up later in connection with pain; it is introduced here because it shows that a rapidly adapting sense organ may go hand in hand with a rapid decline in central activity after each impulse, but it has to be admitted that the association is not universal. Neurologists used to consider the periosteum as specially sensitive to vibration, but von Frey (1915) has shown that vibration is appreciated by means of the tactile organs and by no others. He finds for instance that the nerve fibres running to the skin can give a discontinuous sensation when they are stimulated electrically at frequencies up to 100/sec., but in all other sensory fibres what we may call the critical flicker frequency is very much lower. Y e t there are certainly organs (or endings, for they may be nothing more) in the deep fascia which adapt rapidly: they may give no distinct sensation, but clearly their existence makes it unwise at the moment 36

ACTION OF T H E S E N S E ORGANS to lay much stress on the relation between adaptation rate in the sense organ and inertia in the sensory pathway. IVever and Bray's Work on the Auditory Nerve From another point of view the reaction of the tactile organs is of great interest at present, for it has some bearing on the nervous mechanism of the ear. As we have seen, the tactile pathway reacts so rapidly that the series of impulses produced by a vibrating stimulus is not summed into a steady sensation; thus we appreciate a change in the frequency cf the impulses not as a change in intensity but as a change in the rate of vibration, and appreciation of intensity must depend in the main on the number of fibres excited by each vibration. T h e nervous mechanism of the inner ear has often been likened to a collection of specially sensitive tactile receptors, and we might therefore expect to find that the receptors of the cochlea would show the same very rapid adaptation, that appreciation of tone would depend on the frequency of the impulses and appreciation of intensity on the number of fibres in action. The auditory nerve is a short thick trunk very difficult to insulate electrically from the surrounding tissues, and so, apparently, very poor material for electric investigation. B u t two years ago Wever and B r a y (1930) had the courage to connect it with an amplifier and telephones and they were rewarded by a surprising result. Any sound reaching the ear was reproduced in the telephones: speech could be understood and the speaker identified by his voice and notes of high as well as low pitch were rendered without distortion. Clearly something was acting as an efficient microphone, translating the sound oscillations in the cochlea into electrical oscillations in the circuit leading to the amplifier. Wever and B r a y carried out a number of controls which satisfied them that the effect was due to impulses in the auditory nerve fibres giving a composite potential wave which copied the sound wave striking the 37

M E C H A N I S M OF NERVOUS ACTION ear. I have to confess that I thought they were mistaken (Adrian, 1 9 3 1 0 ) , and as it turns out I was mistaken myself (Adrian, Bronk and Phillips, 1 9 3 1 ) . The fact is that very large potential changes are generated within the cochlea and these confuse the issue. They can be detected by an electrode resting on the bony wall of the inner ear on the membrane of the foramen rotundum, or, with sufficient amplification, from almost any part of the brain whether it is alive or dead; consequently they can be detected in the auditory nerve after it has been killed or put out of action by an anaesthetic. But in spite of the ubiquitous appearance of the Wever and Bray effect I think there is no doubt that they are right in considering that some of the potential change is actually generated in the auditory nerve fibres by the impulses passing up them. The potential changes in the cochlea may be non-nervous or they may be due to the nerve endings and nerve cells and this may account for their great intensity. But Davis and Saul have given what appears to be a conclusive proof of active participation by the intracranial fibres and the auditory tracts in the brain stem. They find that if the brain substance is explored with a needle electrode, bared only at the tip, the potential changes become much more intense when the auditory tract is reached, but this localised response disappears when the animal is deeply anaesthetised. It appears from their work that the response in the auditory tracts can go no higher than 1000 a second, whereas that in the cochlea may reach 6000, but the tract response copies the frequency of the sound below 1000 a second and speech can be recognized as such though the words are unintelligible. We have therefore to account for the production by nerve impulse potentials of composite waves which may have a very high frequency and a very complex form which copies the form of the sound wave. So far no one has recorded the impulses in single fibres of the nerve, and 38

ACTION OF T H E SENSE

ORGANS

u n t i l we can find some w a y of n e u t r a l i s i n g t h e large cochlear effect it is unlikely t h a t a n y o n e will. N o one h a s r e c o r d e d t h e form of the p o t e n t i a l c h a n g e w h e n t h e fibres are s t i m u l a t e d electrically, t h o u g h t h e r e s h o u l d be no ins u p e r a b l e difficulty in d o i n g so. B u t t h i s research belongs t o t h a t large class which we a r e all v e r y glad t o leave t o s o m e o n e else, for t h e c h a n c e s are t h a t t h e i m p u l s e s would n o t differ a p p r e c i a b l y f r o m t h o s e in t h e t a c t i l e fibres, a n d we should all say Ί told you so.' T h e y m i g h t p e r h a p s leave a s h o r t e r r e f r a c t o r y period t h a n t a c t i l e i m p u l s e s : s o m e of t h e fibres in the a u d i t o r y n e r v e are v e r y large (18 μ d i a m . ) a n d large d i a m e t e r goes h a n d in h a n d w i t h s h o r t t i m e relations, b u t it is difficult to believe t h a t t h e y would be able to r e s p o n d a t r a t e s as high as six or even o n e t h o u s a n d a second for long periods. T h u s the high f r e q u e n c i e s f o u n d in t h e c o m p o s i t e p o t e n t i a l w a v e s are m o s t p r o b a b l y d u e to m a n y fibres, each r e s p o n d i n g a t a s u b m u l t i p l e of t h e s t i m u l u s f r e q u e n c y a n d a r r a n g e d so t h a t each w a v e of the s t i m u l u s finds some fibres r e a d y to r e s p o n d to it. W e v e r a n d B r a y h a v e w o r k e d o u t t h e c o n s e q u e n c e s of this a n d of o t h e r possible a r r a n g e m e n t s which m i g h t a c c o u n t for t h e c o m p o s i t e w a v e f o r m , a n d t h e r e is o n e piece of e v i d e n c e w h i c h m a k e s it a l m o s t c e r t a i n t h a t if the effect is d u e to n e r v e fibres t h e i n d i v i d u a l fibres m u s t be able to p r o d u c e a c o m p o s i t e high f r e q u e n c y w i t h o u t themselves responding at this frequency. T h e evidence is t h a t t h e t e m p e r a t u r e of t h e whole of t h e n e r v o u s m e c h a n i s m m a y be lowered t h r o u g h m a n y d e g r e e s w i t h o u t a l t e r i n g t h e p i t c h of t h e s o u n d s which c a n be r e p r o d u c e d . I n t h e c a t , c o v e r i n g t h e p e t r o u s bone a n d t h e a u d i t o r y n e r v e with c r u s h e d ice m a k e s little or no d i f f e r e n c e to the e f f e c t : in t h e g u i n e a pig, t h e b o n y cochlea p r o j e c t s i n t o the t y m p a n i c bulla, a n d B r o n k , Phillips, a n d I f o u n d t h a t p a c k i n g t h e bulla w i t h ice p r o d u c e d a g r a d u a l fall in i n t e n s i t y a n d u l t i m a t e l y a c o m p l e t e d i s a p p e a r a n c e of t h e p o t e n t i a l c h a n g e s — b u t t h e q u a l i t y of r e p r o d u c t i o n 39

M E C H A N I S M OF NERVOUS ACTION for high as well as low notes is scarcely altered as long as anything can be heard. These observations were made without any exact method of estimating the sounds produced by the electric changes, and as the ear takes a good deal on trust there may have been some weakening of high frequencies relative to low. But there is no doubt that high frequencies were still reproduced and that the obvious effect of the cooling was to lower the intensity throughout the whole scale. N o w the cooling must increase the refractory period of the nerve fibres to three or four times its normal length, and the maximum impulse frequency in each fibre will be correspondingly reduced. I t is unlikely that at normal temperature any of the nerve fibres can respond several thousand times a second, and the chances that they can do so after cooling are vanishingly small. B u t if the frequency in each fibre need not be more than a fraction of the composite frequency, the increase in refractory period will not necessarily affect the latter. It will reduce the intensity, however, because it will have the same effect as reducing the number of fibres in action. Suppose that the frequency of the sound wave is iooo/sec. and that a composite potential wave of the same frequency is built up by 200 fibres each responding at 500/sec. The total number of impulses contributing to the potential change in one second will then be 100,000. If each fibre when cooled responds at 250/sec. (i.e., to every fourth instead of to every second stimulus), the total number of impulses in a second will be reduced to 50,000, and the composite potential waves will be correspondingly smaller. T h u s cooling should have the same effect as reducing the intensity of the stimulus or destroying some of the fibres in the auditory nerve—and this is what we find. If the explanation is correct it follows that there must always be a good many nerve fibres in action, whether the sound is a pure tone or a noise. It is, I think, an open question whether there will be much left of the resonance 40

ACTION OF THE S E N S E ORGANS hypothesis of the cochlea when Wever and Bray have finished their investigations; the structure of the cochlea is the main argument for the resonance hypothesis, but it is clear that we might expect to obtain something like the Wever and Bray effect in any preparation of tactile receptors thrown into rapid vibration. The difficulty is to produce high frequency vibrations of amplitude large enough to stimulate, but with frequencies up to three or four hundred a second we can certainly obtain composite potential waves in a cutaneous nerve trunk which look and sound like sinusoidal oscillations. In fact the more receptors there are the more difficult does it become to distinguish individual nerve impulses, and the more nearly does the composite response follow the contour of the stimulus. The conclusion seems to be that with the auditory as with the tactile nerve fibres we judge the intensity of the stimulus by the number of impulses making up each volley, and that we judge the pitch of a note by the frequency of the volleys without regard to the frequency in each nerve fibre. As von Hornbostel points out, this raises some interesting questions with regard to the auditory centres in the brain; it is unlikely that any of the neurones can respond at a much higher frequency than the peripheral nerve fibres, yet clearly there must be something which distinguishes one composite high frequency from another. But it will be time to discuss these knotty problems of central activity when we are more certain of the peripheral events.

41

Chapter III PAIN

P

I E R E is one problem of the sensory mechanism which has a medical as well as a physiological interest. W e h a v e come to realise n o w a d a y s that, although pain m a y be a valuable danger signal, it m a y be better to h a v e no signal at all than to have one that makes life a burden. W e h a v e also lost some of our respect for the nervous s y s t e m and surgeons h a v e begun to operate on it for the relief of pain with less fear of doing irreparable d a m a g e to tbe b o d y . T h e s e surgical experiments are bound to lead to a m u c h clearer understanding of the nervous mechanism of p a i n : they h a v e the enormous a d v a n t a g e of dealing w i t h h u m a n subjects w h o can say w h a t they feel, but their progress will be the more rapid if they can be controlled b y w o r k on more o b j e c t i v e lines, and one such line is the s t u d y of the sensory impulses. I h a v e another reason for dealing with the pain mechanism in spite of the absence, as y e t , of a n y t h i n g like a complete picture. Some years ago, when the technique of recording single impulses was still in its i n f a n c y , I a t t e m p t e d to record pain messages and drew various conclusions from the records (Adrian, 1926). Some of the conclusions may be right, but they do not follow from the evidence, for I m a d e the beginner's mistake of assuming that the m e t h o d w a s perfect. I t is still not perfect enough to detect all t h a t is happening in m a m m a l i a n nerves, b u t in the nerves of the frog it shows a great deal that was not o b v i o u s in the early records. T h e earlier conclusions need rather drastic revision and they emerge w i t h a much better a g r e e m e n t with other lines of w o r k , in particular with the 42

PAIN work done in America by Ranson and by Gasser and Erlanger. The main problem is that of the specific effects of different sensory fibres. If the skin is compressed we feel first touch, then pressure, and finally pain. There is no doubt that the frequency of the discharge in each nerve fibre will increase as the stimulus becomes more intense. Is the change in the quality of sensation due to this increase in frequency, or is each kind of sensation due to a specific nervous apparatus? Is pain due to a very high frequency of discharge, or is it due to nerve fibres which can give rise to no other sensation? On the whole current teaching favours specific nerve fibres. For the special sense organs Johannes Müller answered the query by his doctrine of 'Specific Nervous Energy.' For the sense organs of the skin it has been answered by von F r e y , who holds that the skin surface can be mapped into small spots, each with a particular quality of sensation attached to it. However it is stimulated a touch spot will give a feeling of touch and a cold spot that of cold. The pain spots are so widely distributed that it is difficult to map them so accurately, but von F r e y considers that they produce no other sensation than that of pain. On the other hand, Goldscheider (1926) considers that pain may be caused by intense stimulation of the receptors for mechanical change. The Tactile Endings Although we can record the activity of the sensory nerve fibres, this does not help us much in deciding their effects on the central nervous system for in a reflex preparation it is seldom possible to ensure that an intense stimulus will affect only one kind of end organ. B u t the study of the sensory discharge does allow us to rule out one and only one kind of sense organ as having no connection with pain. It is the organ responding to light touch. T h e 43

MECHANISM OF NERVOUS ACTION main features of its response have been discussed already: the point is that although the receptors for light touch become very rapidly adapted they can be forced to give a prolonged high frequency discharge by the use of a rapidly fluctuating stimulus. Cattell and Hoagland ( 1 9 3 1 ) used an interrupted air j e t for stimulating the frog's skin and found it possible to produce frequencies as high as 250-300 a second· The discharge can be maintained at this rate for about sec. and at a slightly lower rate for longer periods. Now there is a limit to the number of impulses which the nerve fibre can conduct in a second, and for the frog 250-300 a second is close to this limit, so close that in Cattell and Hoagland's records the impulses are reduced in size by the overcrowding. There is no way in which the message could be further intensified; yet it is clearly not painful, for an intact frog pays no more attention to the air blast than it does to a touch. The same result is found in mammals by stimulating the hairs by a vibrating rod. Here again very high frequencies can be maintained for long periods, but there is no evidence of pain. Thus the nerve fibre which conveys the message aroused by the light touch cannot be responsible for the pain aroused by severe pressure. T o this extent there must be a distinction between touch endings and pain endings. The distinction might depend merely on the excitability of the end organs. For instance Sherrington has pointed out that the free nerve endings are likely to be concerned with pain because they should be accessible to any form of stimulus and have no accessory structures to give them an increased sensitivity. But there is some reason to suppose that there might be a distinction in the nerve fibres as well. Protopathic and Epicritic Fibres This was first suggested by the work of Head, Rivers and Sherren (1905) on nerve regeneration. They considered that the sensory fibres could be divided into two distinct sets,

44

PAIN 'protopathic' fibres which regenerate early and are concerned with pain and extremes of temperature, and 'epicritic' fibres concerned with moderate temperatures and with light touch. On their view the fibres of the two systems are differently distributed, the protopathic fibres of a nerve trunk covering a wider area than the epicritic, and the activity of the protopathic fibres is supposed to be restrained in some way by the epicritic. The idea of a sharp distinction between the two systems has not always found favor with neurologists, but evidence has accumulated to show that the smaller nerve fibres are more likely to be concerned with pain than the large. Some years ago Ranson ( 1 9 1 1 ) was able to demonstrate the existence of non-medullated fibres in sensory nerves and to show that they give reflex effects which are associated with pain. Recently he has traced these fibres in greater detail and found that they are present in large numbers in most cutaneous nerves (Ranson, 1931). The important work carried out by Gasser and Erlanger (1927) at St. Louis tends in the same direction. They find that the sensory nerve fibres can be grouped according to their size and rate of conduction, and that the slowest and smallest fibres need the strongest stimulus to excite them and cause the most pronounced reflex effects. Their measurements of conduction rate have recently divided the sensory fibres into two distinct groups, group A conducting at 80-30 metres/sec. in the mammal and group С conducting at 1.3-0.7 metres (Erlanger and Gasser, 1930). There is an intermediate group В in a mixed nerve (conducting at 1 4 - 1 0 metres) but the function of the fibres in this group is uncertain, for they pass into the sympathetic chain and have not yet been detected in the sensory roots of the cord. They will come up again at a later stage in the argument, but for the present we need consider only the two groups A and C. 45

MECHANISM OF NERVOUS ACTION Now it is clear, I think, that the distinction between groups A and С does not correspond to that between epicritic and protopathic or painless and painful fibres, though it may well correspond to that between medullated and non-medullated. It is fairly certain that in mammals some of the messages which arouse pain travel in fibres which conduct rapidly. If pain is a danger signal it is difficult to suppose that it would be sent by the slowest possible route, yet in man if the impulses travelled entirely in fibres of the С group it would take them one second to go from the foot to the spinal cord. Measurements of reflex reaction times to painful stimulation all give much faster rates. For instance Dennig (1929) found a rate of 40 metres/sec. for the sensory fibres in the splanchnic which produce reflex contractions of the abdominal muscles, and Eccles and Sherrington one of 30 metres/sec. for the sensory fibres concerned in the flexion reflex of the leg. It is conceivable that the message which produces the protective reaction is not the message which produces the sensation of pain, and that this may depend on slower nerve fibres. But Pieron (1929) has measured the reaction time for pain in man with stimuli on the foot, hand, and forehead, and although his figures give a lower rate for sensory conduction (4-20 metres/sec.) the rate is still far above that for the С fibres. This does not show that the С fibres are not concerned with pain, but merely that other fibres can give rise to it as well. Gasser and Erlanger have suggested the smaller fibres of the A group: these have conduction rates in the region of 30 metres/sec. and it is interesting to find that the impulse discharges which may result from nerve injury are mostly set up in fibres of this type. There is also another line of evidence pointing to the smaller medullated fibres as one source of pain. It rests on the earlier studies of Head, Rivers, and Sherren, which led them to believe that the skin area supplied by a given nerve with proto46

PAIN pathic fibres is usually much larger than that supplied with epicritic. If this is so a stimulus at the margin of the area should give impulses in the protopathic fibres alone and we should be able to compare them with the impulses in the epicritic fibres. Although the distinction between the epicritic and protopathic systems has not been generally accepted, ii seems to be agreed that the area supplied with pain endings by a particular nerve is usually larger than that supplied with tactile endings. T o abolish pain in a given area it is necessary to carry out much more extensive nerve sections than are needed to abolish touch. For instance, section of both median and ulnar nerves abolishes pain over the whole palmar surface of the hand, but section of either nerve alone gives only a small analgesic area: evidently there is great overlapping in the distribution of the pain fibres from the two nerves, but there is no overlap for light touch, for when either nerve is cut this is lost over the corresponding half of the hand. Now in mammalian nerves there is certainly a considerable difference in the size of the impulses produced by stimulating the margin and the centre of the receptive field. When a small branch of the cat's ulnar nerve is examined, a light touch on the ulnar side of the pad gives impulses of large potential conducted at 50 metres a second or more, and there are smaller impulses as well if the stimulus is enough to deform the skin surface (Fig. 1 1 A\ Adrian, 1931c). On the median side of the pad, deformation of the skin gives the small impulses without the large (Fig. 12 B ) , and there is a sharp line of demarcation between the two parts of the receptive area (Fig. 13). The same result is found with the dorsal cutaneous nerves of the guinea pig, for each supplies a central zone giving large and small impulses and a peripheral zone giving only the small (Fig. 12 С and D). 47

MECHANISM

OF N E R V O U S

ACTION

υ

FIG. 12. A and B, discharges in a branch of the ulnar nerve (cat). A, large action potentials due to touching the ulnar side of the paw. B , small action potentials due to touching median side. С and D, discharges in a dorsal cutaneous nerve of the guinea pig. C, large and small impulses due to touching the centre of the receptive field on the skin of the back. D, small potentials from the margin of the receptive field. Time marker gives intervals of 0.15 sec.

Flo. 13. Receptive fields on the cat's paw giving large and small action potentials. Stimulation of the dotted region gives large potentials (Fig. 12 A), stimulation of the median side gives only the small potentials (Fig. 12 B).

T h e small impulses are certainly conducted less rapidly than the large—some of them seem to be travelling as slowly as 1 5 - 2 0 metres/sec., though it is difficult to measure 48

PAIN their rate very accurately. E v i d e n t l y they travel in nerve fibres of small diameter which have a wider distribution than the large fibres, and as f a r as the ulnar is concerned the distribution of epicritic and protopathic sensitivity in man agrees with that of the large and small fibres in the cat. T h e latter can scarcely be classed as pure pain fibres, however, for they are brought into action by stimuli which would not be painful to a normal animal. I t is more likely that they supply receptors of the type suggested by Goldscheider, giving sensations of contact or of pain according to the intensity of the stimulus. A n d clearly they are not the only pain mechanism in the skin. T h e y become rapidly adapted to mechanical stimulation: the discharge produced by cutting or crushing the skin, though great enough at the moment of injury, ceases almost entirely when the damage has been done, and there is nothing to correspond to the persistent dull pain which would follow. Unless the skin of the cat or guinea pig is much less sensitive than our own we must conclude that the brief discharge during the injury does not represent all that takes place in the nerve—that it is followed by a more lengthy message which for some reason does not appear in the record of potential waves. A t this point we m a y recall Ranson's non-medullated sensory fibres and the v e r y slow С group of Erlanger and Gasser. T h e y are most likely to be concerned with pain, and the impulses in them would be likely to give very small potential changes at the recording electrodes. If they give potentials which are less than 2 - 3 microvolts, i.e., less than 1/20 of the potential in the tactile fibres, they could scarcely be detected in the usual cutaneous nerve preparations, for they would be below the limit of usual amplification. T h u s the failure to record an adequate pain discharge after injury m a y be due to the very small potentials developed in the slow pain fibres.

49

MECHANISM OF NERVOUS ACTION It should be possible ultimately to devise a way of detecting the slow impulses in mammalian nerves. Until this has been done we can go no further with the mammal. But in the frog slow impulses can be detected and here they supply just what is lacking in the mammalian records. Slow Impulses in the Nerves of the Frog T h e slow impulses appear whenever the skin is stimulated in a way which would be likely to damage it or to cause pain. This may be seen from the records given in Figs. 14 and 1 5 . T h e y were made from the dorsal cutaneous nerves in the frog (R. temporaria), the skin being stimulated by gradually increasing pressure (Fig. 14) or by light touch

FIG. 14. Record from cutaneous nerve of frog, the skin being stimulated by gradually increasing pressure (signalled by white line). Large, rapid potential waves appear at first, but later small, slow waves begin and eventually the discharge consists almost entirely of these.

and dilute acetic acid (Fig. 15). Light contact produces the usual large potential waves and nothing else. T h e impulses travel so rapidly that the potential wave appears as a very narrow vertical line. With acid or increasing pressure the slow impulses appear as well: they are much smaller and their slow rate of travel can be seen from the SO

PAIN greater duration of each response. T h e y are not all of the standard diphasic form, but this is probably due to the great branching of the fibres which takes place in the dorsal cutaneous nerves. T h e slow impulses continue to appear for some time after the injury has been inflicted. If the injury is severe, e.g., if the skin is crushed or scraped with a knife, they may persist for several hours at a low frequency. T h e y are produced by heat and by the application of weak acid as well as by various forms of mechanical injury. In fact they are produced by stimulation which would be painful I- i I I !

II,

A

F i c . 15. Discharges in dorsal cutaneous nerves of frog. Λ , large rapid impulses due to touching skin. B , slow impulses produced by 3.% acetic acid on skin.

and they continue after an injury as we should expect the pain to continue. In the records in Figs. 1 4 and 15 the impulses fall quite clearly into two groups, fast and slow, but the rate of conduction of the slow impulses varies greatly. T h i s m a y be seen from the record in Fig. 16, which contains slow impulses of three distinct sizes and velocities, as well as one fast impulse. As the size varies with the rate of conduction there may be yet slower impulses which are too small to detect, and it is highly probable that there are, for much slower potential waves can be recorded in the sensory roots which have no connective tissue to short-circuit the electric changes. Of the impulses which can be detected in the 51

MECHANISM OF NERVOUS ACTION cutaneous nerves a few travel as slowly as 0.5 metres/sec., most of them range between 1 and 3 metres, and some go as rapidly as 5 metres. This is well above the rate of conduction of Gasser and Erlanger's С group (0.6-0.3 nietres/sec. in the frog) and in fairly close agreement with their В group ( 1 - 4 metres/sec.), but it is not yet possible to attempt an exact equation with Gasser and Erlanger's results for the data have been obtained by such different methods. We have then a large group of nerve fibres conducting at rates ranging from 5 metres/sec. downwards, giving small action potentials and excited by injury to the skin. They are clearly sensory, for impulses of the same size relative to

FIG. 16. Impulses due to pressure of the skin (frog), showing the variation in the size and form of the waves. The very small oscillations of the base line are due to the amplifier and not to changes in the nerve.

the tactile impulses can be detected in the sensory roots, though their conduction rate has not yet been measured. They do not correspond to the small ' protopathic' impulses which can be found in mammalian nerves, for they are a good deal slower than these (making due allowance for temperature differences) and their receptors are much less excitable and become adapted much less rapidly. They are in fact much more like true pain endings. Incidentally it may be said that the frog has nothing quite corresponding to the mammalian arrangement with smaller fibres supplying the outer zone of the receptive field. Instead of this there is great overlapping in the tactile fields of different nerves (Fig. 17) and the field giving rapid impulses corresponds more or less with that giving slow ones. It is true that the impulses coming from the ex52

PAIN treme edge of the field are often smaller than those from the central area, but the-largest impulses seem to come from a few scattered points which are particularly sensitive, and there is no sharp cleavage between the central and the marginal zone.

I-'IG. 1 7 .

Areas

supplied with

tactile endings

by

different cutaneous

t r u n k s in the frog, s h o w i n g the g r e a t o v e r l a p in p e r i p h e r a l d i s t r i b u t i o n Cattell, and H o a g l a n d ,

nerve

(Adrian,

J931).

The Nerve Fibres Concerned with Pain If we can argue from the frog to the m a m m a l and back again, the nerve fibres which can give pain seem to belong to no one distinct group. T h e evidence from reflex times in the mammal shows that some of them conduct r a p i d l y , nerve impulse records in the frog show them conducting slowly but at widely v a r y i n g rates, and the evidence of Ranson and of Gasser and Erlanger makes it clear that some conduct v e r y slowly in the mammal also. Arguing from the frog we should expect to find the slow impulses in the mammal covering a wide range of speed extending well into Gasser and Erlanger's group B . A t the moment this В 53

MECHANISM OF NERVOUS ACTION group is a puzzle, for neither in the frog nor in the m a m m a l do they find a n y sign of a В wave in the sensory or motor roots of the l u m b a r region. It is difficult to believe that the В fibres are not sensory, for the efferent sympathetic fibres conduct at the slower rate of the С group and we must suppose either t h a t there is a change in velocity between the sensory root and the peripheral nerve, or t h a t the В fibres enter the cord by way of the sympathetic system and the thoracic instead of the lumbar roots. But even if we leave the В group out of consideration there is no escape from the conclusion t h a t both medullated and non-medullated fibres are responsible for pain. We may guess that the more rapid fibres do not give pain unless the frequency of the impulses in them is very high and the discharge prolonged, but this is no more than a guess. On the whole then it is unlikely that pain is always due to specific pain fibres. It may be nearer the mark to say t h a t the sensation produced by nerve fibres of a given type becomes a closer and closer approach to pure pain in proportion to the slowness of conduction of the fibre and the lack of sensitivity in the end organ. T h e most sensitive tactile endings and their rapid nerve fibres cannot cause pain: the slow non-medullated fibres with their endings which respond only to noxious stimuli can cause little else, but for all we know the smaller medullated fibres may give both contact or pain according to the magnitude of the discharge. T h e r e is obviously a great deal more to do before a satisfactory account of the pain mechanism can be given, and other methods m a y give much more fruitful results. Clinical and histological research, the study of reflexes and of the effects of electric stimulation, have all contributed so much already t h a t records of the impulse discharges m a y not do more than demonstrate what is already known -—and until we can be sure of recording the slowest impulses they will not even do t h a t . But they demonstrate one 54

PAIN point which is worth consideration, though it has been mentioned elsewhere. The feeling of pain can rise to such an intensity that it dominates the whole field of consciousness, yet it seems to depend on the smaller and slower nerve fibres. The fibres from the tactile receptors are large and conduct rapidly, yet the sensation of touch never rises to great intensity, in fact it can scarcely be said to vary in intensity at all. Both touch and pain are evoked by messages which are made up of brief impulses which cannot vary in size; thus the intensity of the effect must depend on a summation of the changes caused by each impulse. Is it not likely then that the different character of the sensations of touch and pain may depend, partly at least, on a difference in the amount of summation which can occur in the two pathways? The argument has been dealt with already in connection with touch and pressure. In the pathways from the most sensitive touch receptors there can be little opportunity for temporal summation, for each volley of impulses is felt as a separate event. There cannot be much spatial summation, for if two points are touched simultaneously we feel two touches and not one of greater intensity. Thus the nature of the pathway, the lack of inertia and of convergence, will prevent the development of intense central activity. Convergence and inertia—a persistence of the effects left by each impulse—will favour the building up of intense activity, but in the region where the activity is summed there can be no very rapid changes in intensity and no means of distinguishing the origin of the impulses from different points. This does not rule out all possibility of localising the stimulus and of feeling sudden changes, for we need not suppose that the mind is tied down, so to speak, to a particular region of the central nervous system. But it is true nevertheless that poor localisation and a slow rise and decline are characteristic features of pain, though there are a good many pains which change rapidly and are 55

MECHANISM OF NERVOUS ACTION well localised. We might expect therefore t h a t the sensation which can rise to the greatest intensity would have some of the qualities of pain, and we might have guessed t h a t it would depend on a nervous mechanism of relatively slow time relations. Specific Nerve

Impulses

This chapter would not be complete without some reference to a very difficult problem—that of the specific reactions of the nerve fibres from different kinds of receptors. All of them conduct impulses which are fundamentally alike, but we have seen t h a t there are q u a n t i t a t i v e differences which are quite large enough to appear in a record of the potential changes. T h e physiologist can form some idea of the nature of the stimulus by finding out what kind of impulses appear in the nerve. Can the central nervous system do the same? T h e question needs stating with greater precision. T h e effect of a sensory message in a particular nerve fibre is bound to depend to some extent on the situation of the fibre: clearly tactile messages from the foot or the hand have different effects because they enter the cord by different routes. W h a t we have to decide is whether these anatomical differences are the sole basis for the difference in the reactions of the animal or whether the character of the impulses is another factor. D o slow impulses produce pain reactions because, in virtue of their slowness, they can excite particular neurone systems, or because the fibres which transmit them are distributed in a particular way? T h e question cannot be answered in the present state of our knowledge, but it is worth while discussing the possibilities. If the time relations of the impulses are a determining factor we must assume t h a t slow and fast impulses retain their character (relatively at least) in the terminal dendrites as well as in the axons. If they do, it is quite conceivable that a neurone in touch with dendrites from 56

PAIN slow and fast fibres would react to the one and not to the other because of the difference in the impulses. But the difficulty is t h a t slow and fast impulses can only keep their distinctive character when they are travelling in the neurones belonging to the slow or fast system; if it could be shown t h a t both kinds could appear in the same conducting units in the cord discrimination would have to depend on the form of the impulses, for there would be nothing else to show their origin. But as it is their origin might be shown by all manner of differences between the slow and fast neurones—different kinds of dendrite, different capacities for summation in synaptic areas, different distribution, etc. There is no need to regard the cord on the old telephone exchange simile, as a bundle of anatomical pathways: even if we think of the afferent impulses as discharged into a common pool, there is still the strong probability that the impulses due to touch and pain will preserve their differences only as long as they are carried by fibres of different type. But in saying as much we have admitted that the effect of the message may depend on the type of fibre in which it travels, and this after all is the main point. It would be better to restate the question in another form—Are the reactions of the nerve fibres from different kinds of receptor sufficiently characteristic to make it likely that they would produce distinctive effects on the central nervous system? Until Gasser and Erlanger made their well-known analysis of conduction rates in mixed nerve trunks there was no evidence of any difference in reaction. We know now, as the result of their work, that the sensory fibres can be ranged in decreasing order of size, velocity of conduction, and excitability to electric stimuli, and that pain reactions are mainly, if not entirely, due to the smaller fibres. The evidence as to the size of fibre concerned in anything but pain reactions is indirect. The sensory fibres from the skin are on the whole smaller than those from muscles and 57

MECHANISM OF NERVOUS ACTION they conduct less rapidly, but the fibres from the skin are not sharply grouped into several sizes—there are several peaks on the curve showing the number of fibres of each diameter, but that is all that can be said. It must be remembered, too, that many nerve fibres, both motor and sensory, branch on their way to the periphery, and the branches are of smaller diameter than the parent fibre. I t is therefore unlikely that there is any sharp division of fibre size corresponding to muscle sense, touch, and temperature. But if we record the impulses set up by different kinds of stimulus we do find quite distinct differences in potential and conduction rates. Matthews has shown that impulses from muscle spindles travel faster than those due to touch or pressure on the skin. Again, if the frog's skin is heated by passing a current through a platinum wire held close to it, the sensory discharge is made up of impulses with a potential and conduction velocity midway between that of the fibres responding to touch and to injury. The tactile impulses travel at 1 8 - 1 5 metres/sec. at 16 0 C. in Rana Temporaria, the heat impulses at 9-6 metres/sec. and those due to injury at 5-0.5 metres and probably at even slower rates. Heating the skin ultimately produces the slow impulses as well, and if the heat is intense enough to cause visible damage, impulses of every variety may appear at the height of the discharge; but the characteristic impulses of medium rate are produced by less violent heating and they are not found with any kind of mechanical stimulus. Records showing tactile, heat, and injury discharges are given in Fig. 18, and it will be seen that the differences are quite unmistakable. We have no evidence as yet about the nature of the temperature fibres in the mammal, but in the frog it is clear that they might produce a distinctive effect on the central nervous system in virtue of their reaction time. Y e t in spite of this it is exceedingly unlikely that the quality of 58

PAIN sensation depends entirely on the time relations of the impulse. With some fibres the frequency of the discharge is just as likely to be the determining factor. Moreover, the fibres in the optic and auditory nerves vary in size and many of them have the same diameter as the fibres in a nerve from the skin. Their conduction velocity has not been measured, but the whole range of conduction velocities is so well covered by the cutaneous fibres that no reasonable gaps are left for the fibres giving visual and auditory

FIG. Ι 8. Impulses from different kinds of sense organ in the frog's skin, showing variation in size and rate of conduction (indicated by the degree of separation of the two phases of the wave). T o p record—impulses due to light touch. Middle—heat. Bottom—severe pressure. All the records are from the same preparation.

sensation. T h e distinctive character of their effects must depend in a large measure on their anatomical distribution. This at the moment is as far as we can go. T h e idea of specific fibre reactions is attractive, because it would fit in with modern views of the central nervous system which discount the importance of precise connections. Lapicque has shown how impulses which develop at a particular rate might excite neurones of particular Chronaxie, and how changes in Chronaxie might alter the whole pattern of response to a given message. We have seen that the 59

MECHANISM OF NERVOUS ACTION impulses from a particular kind of skin receptor have on the whole a characteristic rate of development. But there is no need to go further and to assert that this factor is the only one which determines the quality of sensation; fibre connections do exist and some of our judgments must certainly depend on them, and we cannot rule out the possibility that with certain fibres a change in the discharge frequency may alter the quality as well as the intensity of sensation.

60

Chapter IV DISCHARGES

IN MOTOR

NERVE

FIBRES

H E chief function of the central nervous system is to send messages to the muscles which will make the body move effectively as a whole, and for this to take place the contraction of each muscle must be capable of delicate adjustment. By recording the electrical changes in the motor nerve fibres and the muscles we can see how this adjustment is brought about and how the motor nerve cells behave under varying excitation. Much of the evidence has come from other methods, and the whole subject of muscular adjustment has been discussed most clearly by Sir Charles Sherrington (1931) in a recent Hughlings Jackson lecture; for this reason we need only consider certain aspects of the motor discharge which fit in with the general picture of nerve activity. Its study will not throw much light on the problems of the central mechanism, but will at least tell us how its activity is translated into movement. The translation depends, as with the sensory messages, on a fusion of the effects of repeated impulses, and, like sensation, the contraction is graded by changes in the frequency of the impulses in each nerve fibre and in the number of fibres which are brought into play. The Motor Units A single motor nerve fibre supplies a number of muscle fibres varying from twenty to a hundred or more, and all these muscle fibres act as a single unit. Each can be made to contract independently by direct stimulation, but as the nerve impulses cannot be graded, the contraction produced by an impulse must involve all the muscle fibres which 61

MECHANISM OF NERVOUS ACTION make up the 'motor unit.' But although the motor units are incapable of fractional activity, there are quite enough of them in a muscle of medium size to allow a fairly delicate gradation of the contraction. For instance Eccles and Sherrington (1930) find that there are about 430 motor nerve fibres to the gastrocnemius of the cat and 250 to the soleus. Thus the contraction of the gastrocnemius might be varied by 430 steps merely by varying the number of motor nerve fibres in action. There is no doubt that reflex and voluntary contractions are graded mainly in this way by changes in the number of units. This can be demonstrated very easily by recording the electric changes in the muscle with a needle electrode system, for it is then possible to detect the activity of more and more motor units as the contraction increases in force. Gradation by change in number is the only form possible when the contraction is a single twitch —due to a single volley of motor impulses—and in all very rapid movements it must be by far the most important factor. But in a sustained contraction there is obviously another possibility, namely, gradation by change in the frequency of the motor impulses. Before we deal with the evidence which shows that this kind of gradation does occur we ought to consider how it can occur. A muscle fibre, like a nerve fibre, is said to follow the all-or-none principle: how then can it give contractions of graded strength? Questions of this kind are bound to arise whenever we deal in vaguely defined Laws or Principles, and the ' all-or-none principle' has been responsible for a great deal of confusion, because it has a simple title which seems to make further definition unnecessary. It would be wiser, I believe, to say not that muscle and nerve obey the principle but, that in both of them there is an 'all-or-nothing relation between the stimulus and the propagated disturbance,' for this expresses the facts in a form which is all the better for being less 62

DISCHARGES IN MOTOR

FIBRES

attractively phrased. T h e facts are that a stimulus to a sense organ, a nerve, or a muscle fibre produces local effects which vary with its strength, but the explosive waves which travel away from the affected region cannot be changed in intensity by making the stimulus stronger or weaker. They are not invariable, for they depend at each point on the state of the fibre at that point; and the relation holds only for the individual waves, for clearly the total activity of a nerve fibre per second may range from nothing to several hundred impulses. In a muscle fibre the propagated disturbance itself seems to differ only in time relations from the impulse in a nerve fibre; it gives the same kind of potential change, refractory state, and so on. B u t it has the further effect of setting off the contractile mechanism of the fibre and this may or may not be of the explosive type. When its activity is aroused by the passage of a single disturbance the tension cannot be graded according to the strength of the stimulus, since the propagated disturbance is not graded; but if several disturbances pass over the fibre in rapid succession the tension will rise higher and higher, each disturbance causing a fresh accession of contractile activity which is added to that existing previously. All this is merely an elaborate way of stating the fact that successive contractions may be fused into a tetanus which gives a tension much higher than that developed in a single twitch. For the present we need not consider whether the summation of contractions depends on the mechanical properties of the muscle (viscosity, etc.) or on a summation of the physical and chemical changes which cause the contraction. All that matters is that in a sustained contraction, produced by stimulating the nerve repeatedly, the average tension will vary with the frequency of the stimuli as well as with the number of units in action. T h e variation with frequency comes to an end when the impulses follow so closely that the contraction is perfectly 63

MECHANISM OF NERVOUS ACTION smooth; it seems only to occur during the stage of 'incomplete tetanus' when the tension fluctuates with the rhythm of the stimulus. Thus if all the motor units are acting synchronously the muscle will not give a steady contraction until the frequency of stimulation is above the range in which grading can occur; but if the different units work independently the tension developed in the whole muscle may be steady enough, although each unit gives a jerky response. This is the state of affairs in reflex or voluntary contraction, though until the last few years the evidence seemed to point in another direction. The Electromyogram The evidence came from records of the electric changes in contracting muscle. The first attempts to study their rate in voluntary contraction were made by Wedensky (1883) with the telephone as indicator. He found that as a rule the electric changes gave a rushing noise of no definite pitch, but by leading from the biceps with needles thrust into the muscle he was able to make out a frequency of 36-40/sec. during a powerful contraction. This work was published 48 years ago, but until the last few years very little could be added to Wedensky's conclusions. They were confirmed by Piper ( 1 9 1 2 ) , who recorded the electromyogram with the string galvanometer and found large waves at a frequency of about 50/sec. in a strong contraction, and small, irregular waves of no definite frequency in a weak contraction. Other investigators doubted the regularity of Piper's large waves and were more impressed by the irregularity of the small. The only thing which seemed quite clear was that the frequency showed no sign of increasing with the contraction. T h e tantalising feature about the electromyogram was the Piper (or Wedensky) rhythm—the appearance, at least in certain muscles, of a fairly regular succession of large waves when the contraction was strong (Fig. 19). The

64

D I S C H A R G E S I N MOTOR

FIBRES

obvious explanation was to suppose that the motor nerve impulses occurred with the same r h y t h m , i.e., about 50/sec., but if so, why did the rhythm disappear when the contraction was weaker? One school held that the frequency of the motor impulses must be so high that any rhythm appearing in the muscle would be determined by the refractory period of the muscle fibres and not by the

FIG. 19. contraction.

S t r i n g g a l v a n o m e t e r records of e l e c t r o m y o g r a m P a d electrodes o v e r biceps ( E . D . Α . ) .

during

voluntary

T h e u p p e r record is m a d e

during a w e a k contraction and shows r a p i d , irregular w a v e s of small a m p l i t u d e ; the lower, f r o m a p o w e r f u l contraction, s h o w s large w a v e s with a regular r h y t h m of 3 5 - 4 0 / s e c .

moderately

T i m e m a r k e r g i v e s i n t e r v a l s of 1/40 sec.

frequency in the nerve. T h e other supposed that a definite rhythm in the muscle implied the same rhythm in the nerve, and that in general there would be a close correspondence between the electric changes in the muscle and those in the nerve. T h e latter view was nearer the mark, but neither of them made any attempt to decide what happened in each unit in a weak contraction with an irregular response.

The Response of Single Units Looking back on the arguments which were used I feel that, in spite of our denials, we were all thinking too much of the whole muscle and too little of the units. There must have been some strong preoccupation to cloud the issue, for the explanation is very simple indeed. With a weak contraction the impulses come at a v e r y low frequency; each motor unit gives an incomplete tetanus or 65

MECHANISM OF NERVOUS ACTION even a series of distinct twitches, but the units work asynchronously, and this is responsible (a) for the smoothness of the contraction and (b) for the rapid, irregular character of the electric response. As the contraction increases, the frequency rises and the different motor nerve cells come to work more and more in unison. They can do so without prejudice to the smoothness of the contraction, for there will be a nearer approach to a complete tetanus in each unit. Eventually, when the frequency reaches the neighbourhood of 50/sec. each unit is giving its maximum tension, and the synchronisation is enough to allow a definite rhythm to appear in the electromyogram. Higher frequencies of discharge would not cause any further increase in tension and (in an unfatigued muscle) lower frequencies would not be compatible with a smooth contraction if the units were synchronised. Thus the rhythm only appears in a strong contraction and its frequency shows very little variation. The first clear indication of this appeared in a paper by Wachholder in 1923. He used needle electrodes driven into the muscle instead of the usual pads on the skin and he found that in very weak contractions there was a succession of small, brief waves all alike in form and repeated in a regular series like the impulses in a sensory nerve. The frequency might be as low as 5/sec. in a muscle which was not completely relaxed. During a contraction of gradual onset the frequency rose, but very soon another effect appeared as well, a confused medley of large, irregular waves, the usual electromyogram in fact. The small regular waves were swamped, to appear again with a declining frequency as the contraction was relaxed. The two phenomena looked so different that Wachholder considered the suggestion that they were caused by two distinct mechanisms in the muscle. It was soon clear, however, that the irregular waves were merely due to fresh motor units acting out of phase with one another. The

66

DISCHARGES IN MOTOR

FIBRES

small regular waves come from the unit which is nearest to the electrodes and among the first to take part in the contraction. Such units would be scattered throughout the muscle, but those at some distance from the needles would have an inappreciable effect on the record—for Wachholder was using a string galvanometer without amplification—but as more and more units came into play their composite effect would swamp the initial rhythm. T h e evidence has come from two distinct lines of work— from a further analysis of the electric changes and from measurements of the rate of relaxation of a contraction which is suddenly inhibited. T h e latter method was due to Denny-Brown (1929), who used it for an exceedingly ingenious piece of analysis. When a nerve is stimulated rhythmically, the rate at which the muscle relaxes when the stimulus is over depends on the amount of summation that has occurred and so on the frequency of stimulation. B y producing a sudden inhibition of the crossed extension reflex and measuring the rate of relaxation, Denny-Brown showed that the motor units could not have been activated at rates much higher than 50/sec. and that many of them must have been working at much lower rhythms. Evidently the notion of a very rapid firing of motor impulses was quite untenable. At about the same time Bronk and I (Adrian and Bronk, 1928) recorded the impulses in single motor nerve fibres, first of the phrenic and then of nerves to various limb muscles (1929), and found rhythmic discharges varying in frequency with the force of the contraction and covering a range from 10 to 80 or 90/sec. (Fig. 20). Since these motor nerve fibres were chosen at random, and since all of them gave the same kind of discharge, it is most unlikely that there are other nerve fibres which give a much higher frequency. Indeed we found that records almost indistinguishable from Wachholder's could be obtained by leading from several motor nerve fibres, for to begin with a single series of impulses 67

MECHANISM would

appear

with

an

OF

NERVOUS

increasing

ACTION

frequency,

and

the

r h y t h m would then be s w a m p e d by large irregular w a v e s due to the composite effect in the other fibres ( F i g . 20 D ) .

FIG. 20. Discharges in motor nerve fibres. Capillary electrometer records. Nerves cut down to show activity of individual fibres. A and В from upper root of phrenic nerve (rabbit). A , normal breathing—impulse frequency 28/sec. B , forcible inspiration due to clamping air inlet—frequency 50/sec. (Adrian and Bronk, 1928). C, nerve to vastus lateralis (decerebrate cat), showing persistent discharge at 25/sec. D, ditto, beginning of crossed extension reflex, showing single fibre in action at first and the entry of more fibres as the contraction develops (Adrian and Bronk, 1929). Time marker gives intervals of 0 . 1 2 5 sec.

B y using a v e r y small needle electrode s y s t e m with the two poles close together these r h y t h m s can be recorded from the muscle as well as the nerve and t h e y can be studied in v o l u n t a r y contractions in man.

W i t h the best

will in the world it is impossible to send a regular succession of impulses into one's triceps at a frequency lower than 5 - 1 0 / s e c . , but above this the regularity is v e r y good; the

68

D I S C H A R G E S I N MOTOR

FIBRES

upper limit seems to be in the neighbourhood of 45-50/sec., but usually so m a n y units are in action in a strong contraction that their rhythms cannot be distinguished. In an increasing contraction some of the units begin at relatively high frequencies (15-20/sec.) but many begin at 10/sec. or less although their neighbours are already working at a much higher rate. A good example of the change in frequency is shown in Fig. 2 1 . These records were made with a needle electrode system from the internal intercostal muscle in a cat

FIG. α ι . intercostal

D i s c h a r g e during inspiration in a single motor unit of the internal muscle (interchondral portion) in a cat under luminal.

w a v e s are due to the heart.

The

large

I n the lower records the a c t i v i t y of the intercostals

is g r a d u a l l y suppressed b y administration of chloroform; the frequency of the impulses falls from 27 to 6/sec. and the total number from 20 to 2 at each inspira-

anaesthetised with Luminal. T h e electrodes were in the interchondral part of the muscle which contracts during

69

MECHANISM OF NERVOUS ACTION inspiration and helps to elevate the ribs. The large waves are due to the heart (the electrocardiogram is always an unwelcome intrusion in records from the chest wall) and have nothing to do with the intercostal muscle: our concern is with the small waves which are the action currents in a single motor unit. Each strip records the discharge during one inspiration, and in the successive strips the movement of the ribs is progressively weakened by giving chloroform. The discharge becomes shorter and shorter, its maximal frequency falls from 27/sec. in A to 14/sec. in В and eventually only two impulses appear with i/6th sec. between them. Under the action of the chloroform the sphere of influence of the respiratory centre becomes more and more contracted; the motor nerve cell which supplies the unit under consideration is at first well within the range of the periodic excitation, but in the lowest record it is barely affected by it. The diaphragm is still active, but the intercostal muscles may be likened to those motor units in a limb muscle which are only brought into play in a powerful contraction. As the movement becomes weaker these units take a smaller part in it; they come in only at the height of the discharge, for a short time and at a low frequency, and eventually they drop out altogether. It is interesting to compare the motor discharge to the intercostals with the sensory discharge in the vagus from the lung (Fig. 9): there is really very little difference between the reaction of the motor nerve cells and of the sensory nerve endings. As regards the grading of contraction there is not much more to be said unless we go into details over the frequency range in different muscles and different kinds of muscle fibre. Some kinds contract and relax much more rapidly than others; for instance, Cooper and Eccles (1930) find that 90 impulses a second are needed to produce a smooth maximal contraction in the quadriceps femoris and only 35/sec. in the soleus (cat). Thus a motor unit in the 70

DISCHARGES

I N MOTOR

FIBRES

soleus would develop its full tension when the motor nerve cell sends out 3 5 impulses a second. T h e evidence at present suggests that the motor impulses to the soleus are not discharged at a higher frequency than this in a normal contraction, whilst the discharge to the quadriceps may be as high as 90/sec. I t would certainly make for economy in nerve impulses if the rate of discharge never rose higher than is needed for a maximal contraction, but at the moment we do not know what sort of factors would govern the maximum discharge frequency. T h e motor neurones can be driven at higher rates by electrical stimulation of afferent nerves, and there is no evidence of wide variations in refractory period, etc., as between one group and another. In vertebrate muscles there are so many motor units that changes in the number in action will provide a much more extensive grading than can be produced by a change in frequency. B u t this is not a universal rule for all muscles. In Crustacea and insects Mangold (1905) has shown that an entire muscle is usually supplied by not more than three or four motor nerve fibres. In some insects this is not surprising, for the entire muscle m a y be no larger than the 100 or more muscle fibres which make up the motor unit in a vertebrate; but even in the claw muscles of the crayfish (Astacus) there are only 3 - 5 motor fibres (Hoffmann, 1 9 1 4 ) , although the muscle is as large as any in the frog. T h e result of this restricted nerve supply must be that the contractions are mainly graded by frequency change. Records made from insects confirm these points, for they show not more than two or three distinct series of impulses in an entire nerve trunk or muscle, and the frequency varies as it does in the vertebrate motor discharge (Fig. 6, Fig. 22). Since there are so few units at work it is remarkable that the movements begin and end smoothly without assuming the character of an incomplete tetanus, but Richet's (1882) well-known figure 71

M E C H A N I S M OF N E R V O U S

ACTION

of the contraction in the c r a b ' s claw shows that muscles of this kind are capable of much more summation than we find in the vertebrates.

FIG. 11. Above. Record from the abdominal muscles of the water beetle (Dytiscus Marginalis) showing movement of breathing. Owing to the small number of motor nerve fibres the discharge in the entire musculature resembles that of two or three motor units in a vertebrate. Below. Record from the muscles of a caterpillar during the middle and end of a creeping movement. T h e individual waves are clearly distinguished. They are monophasic, and owing to the position of the muscles relative to the electrodes some give an upward and some a downward deflection.

T h i s is not the whole s t o r y ; some of the reactions of arthropod muscles are exceedingly puzzling, and so f a r no one has investigated the a c t i v i t y of the inhibitory nerve fibres which are supposed to s u p p l y them, but a comparison of records from vertebrates and insects makes it clear that their motor nerve cells discharge messages which rise and fall in frequency in the s a m e w a y . Synchronous

Activity

I f we leave the muscles and turn to the motor nerve cells, the chief point of interest is the tendency to synchronous a c t i v i t y when the cells are discharging at a high f r e q u e n c y , the tendency that is responsible for the appearance of a definite r h y t h m in the e l e c t r o m y o g r a m . We shall meet with synchronous discharges later on when we deal with the electrical changes in nerve cells. The essential condition seems to be t h a t a large number of cells should be in action close together at a b o u t the s a m e level 72

DISCHARGES

IN MOTOR

FIBRES

of excitation, and in the motor nerve cells this condition will only be realised when the contraction is powerful and most of the cells are discharging at the maximum rate. Another condition seems to be that the motor cells should not be very directly influenced by afferent impulses. Synchronous action occurs in powerful voluntary contractions in man and in the discharge of the phrenic nerve during inspiration (Gasser and Newcomer, 1 9 2 1 , Gasser, 1928, Adrian and B r o n k , 1929), but there is not much sign of it in the limb reflexes of spinal or decerebrate animals, unless evoked by an afferent discharge which is itself in synchronous volleys. Presumably in these reflexes connection between the afferent and the motor neurones is so close that the rhythm of each motor cell is influenced by the rhythm of particular afferents, and the cells are not free to discharge in phase with one another. B u t it is difficult to be sure of this, for we have no reliable criterion of the degree of synchronisation and can only detect it when it involves the m a j o r i t y of the units in action. There is the further difficulty that in voluntary contractions the rhythm may sometimes be set by afferent discharges from the muscle. H o f f m a n n ( 1 9 1 9 ) and Preisendorfer ( 1 9 1 9 ) have shown how important this influence may be, for the motor discharge takes up a r h y t h m imposed on the muscle by mechanical vibration. In some cases the rhythm of the electromyogram may be determined in this w a y , the effect being due to vibration of the muscle giving synchronous afferent discharges and not to a synchronisation established in the motor centres. B u t there is no doubt that the latter can occur, for the effect of afferent discharges can be ruled out in a case such as that of the phrenic where the nerve is cut before it reaches the muscle.

Sympathetic Discharges I t will be obvious that the efferent messages to skeletal muscles are often scarcely distinguishable from the afferent 73

M E C H A N I S M OF NERVOUS ACTION messages from sense organs, for the impulses which produce a sustained contraction are as regular as those in a sensory fibre from a stretched muscle spindle. The frequency is on the whole lower but it varies in the same way with the intensity of excitation. But there is another kind of efferent discharge which looks at first as though it must depend on a much less orderly mechanism. The sympathetic nerves maintain the tonic contraction of the blood vessels, and it would be reasonable to guess that they do so by discharges as regular as those in the motor nerves to the limbs, but in no record of sympathetic impulses is there any such regularity. Examples of the persistent discharge in various sympathetic nerves are given in Fig. 23 (Adrian, Bronk,

.с FIG. 23. discharge).

Potential

waves

in sympathetic

nerves

(persistent

vaso-motor

A. Rabbit, nerve from coeliac ganglion. B. Rabbit, left cervical sympathetic. C. Cat, left hypogastric. Time marker gives intervals of 0.25 sec.

and Phillips, 1932). They are presumably vaso-motor, or mainly so, for the discharge increases during asphyxia and is reduced by raising the blood pressure peripherally by adrenalin. The records are made from entire nerve trunks containing many fibres, but the waves are not very closely 74

D I S C H A R G E S IN MOTOR

FIBRES

crowded and many of them are much larger than we should expect from single non-medullated fibres. T h e reason is probably simple enough. T h e waves are due to postganglionic fibres, and these would tend to work in groups like the muscle fibres of a single motor unit, for a large collection of post-ganglionic fibres is supplied by a single preganglionic nerve fibre. Ranson and Billingsley (1918) give a ratio of 32 to 1 for the cervical sympathetic, and a synchronous volley in 32 fibres would give a large potential wave. Occasionally the waves are definitely complex, but in many of them the different fibres work in such close unison that the waves are simple diphasic changes, all of the same form and duration. Their duration is much longer than that of the wave in a medullated nerve fibre (cf. Fig. 24) and they are conducted very slowly at a rate (0.8 metres/sec. in the cat) which agrees with measure-

•0/ Sac.

JJJ-JLJ FIG. 24. Form of individual waves in sympathetic nerves compared with that in somatic nerves. A and В from the hypogastric nerve in the cat. Temp. 32° C . , 9 mm. between electrodes. The wave in В has a double crest and is probably due to several fibre groups not perfectly synchronised. C, sensory impulses due to touching frog's skin. Temp. 160 C., 11 mm. between electrodes.

75

MECHANISM OF NERVOUS ACTION ments of the conduction velocity made by electrical stimulation. It is often possible to pick out repeated waves of the same size, but such waves do not occur at regular intervals. It is true that their frequency is often below the limits of regular discharge in sense organs or motor nerve cells: we should expect, however, to find a lower limit in neurones which react so slowly. But another reason for the lack of regularity becomes obvious when the nerve discharge is compared with the respiration of the animal, or in some cases with the heart-beat, for there is often a waxing and waning of the discharge in time with these events (cf. Figs. 25 and 26). The respiratory grouping (as in Fig. 25) is due, or can be due, to a direct effect of the respiratory centre on the vaso-motor centres, for it persists in animals in which all respiratory movement has been abolished by nerve section or curare. The cardiac grouping has only been found with the aortic and sinus caroticus nerves intact and it probably depends on the afferent volleys which pass to the brain stem from these nerves at each heart-beat. In some animals the sympathetic discharge shows no kind of grouping until the vagi are divided, but even so it is clear that the sympathetic neurones can never remain steadily excited for any length of time, since they are exposed to a fluctuating influence from the respiratory centre and from the nerves from the large blood vessels. The latter can be thrown out of action, but the respiratory centre is so closely bound up with the vaso-motor centre that it must always provide a background of waxing and waning excitation. There is some evidence to show that the tone of the blood vessels fluctuates with the sympathetic discharge, but the muscle reacts so slowly that most of the fluctuation in the discharge would be smoothed out when it is translated into movement.

76

D I S C H A R G E S IN MOTOR

FIBRES

в

FIG. 25. Grouping of sympathetic discharge in phase with respiration. В and C, rabbit, vagi cut, nerve from coeliac ganglion. B , normal breathing. C, dyspnoea from breathing into a closed space. D, rabbit, left cervical sympathetic. Respiration signalled by white line.

FIG. 26. Cardiac grouping of the sympathetic discharge. A , cat, hypogastric nerve. B , rabbit, nerve from coeliac ganglion. In В there is evidence of respiratory as well as cardiac grouping. Time marker gives intervals of 0.25 sec.

In this case then the smoothing is peripheral. T h e activity of the sympathetic neurones is constantly changing and there is no opportunity for a steady rhythmic discharge since there is no opportunity for a steady excitation.

77

Chapter V T H E ACTIVITY OF NERVE

CELLS

W

E have dealt so far with the messages which enter and leave the central nervous system, and though they raise a good many problems which are still unsolved their main outlines are fairly clear. When we try to go further and to decide what happens within the central nervous system electrical methods are of less value. They can tell us something about rapid changes in activity but very little about the slower events, the changes involved in the differentiation of a reflex arc or in the formation of a habit. They show something of the mechanism but little of the way in which it is built up and controlled. Eventually they may do more on these lines, but there are so many other methods which hold out as good, or better, hopes of advance that it would be a waste of time to discuss all the possibilities of electric recording from the central nervous system. Instead I shall deal with a few disconnected facts which have given some indication of what may happen in groups of nerve cells. Respiration—the Automatic Rhythm One of the activities of the central nervous system which is particularly easy to study is that concerned with respiration. The movements are fairly simple and they are repeated rhythmically at convenient intervals: they continue in the anaesthetised animal, their force and rate can be controlled by changing the air supply, and no external stimulation is needed to evoke them. The efferent messages have been described already and we have seen how the impulses increase and decrease in frequency with each period of contraction. A group of nerve cells in the brain 78

ACTIVITY OF N E R V E

CELLS

stem enters periodically into the active s t a t e : as shown by the motor discharge the activity rises and falls, to zero in some neurones and to a low level in others, and the cycle is constantly repeated. T h e r e are two possible explanations of a periodic activity of this sort. One t h a t it is s p o n t a n e o u s — t h a t the cells of the respiratory centre tend to beat like the h e a r t : the other t h a t it is reflex—that each m o v e m e n t produces a sensory discharge which determines the next m o v e m e n t and so on. In a sense both explanations are correct. T h e r e is no d o u b t at all t h a t sensory discharges are responsible for the normal r h y t h m of breathing. T h e lung root contains a n u m b e r of afferent endings from the vagus which discharge periodically when the tissues are stretched a n d have the effect of cutting short the m o v e m e n t of inspiration. T h e frequency of respiration is governed by these and can be altered by periodical inflation of the lungs. T h e normal m o v e m e n t s are reflexly controlled as are all t h e movements of the body, but respiration is not a reflex if by reflex we mean a reaction which would not take place at all without the afferent discharges. This raises the awkward question of w h a t we mean by a reflex, and nowadays this is hard to answer. Physiologists, since they are partly engaged in teaching the principles of their science, are inclined to emphasize whatever principles are in fashion at the m o m e n t ; then finding they have gone too far in one direction they go a long distance in the other. Some years ago the idea of reflex action so d o m i n a t e d neurology t h a t we could t h i n k of nothing else. As usual those who specialised in the field were not to blame. Sherrington, for instance, was a m o n g the first to point out t h a t the reflex arc is a convenient a b s t r a c t i o n ; t h a t the functional unit of the central nervous system is the whole system and not a diagram of two or three neurones and synapses. B u t now the p e n d u l u m seems likely to swing the other way. Coghill's studies of Ambly79

M E C H A N I S M OF NERVOUS

ACTION

stoma (1929) h a v e shown the central nervous system behaving at first as a whole and then its parts developing a greater and greater power of separate a c t i v i t y ; Lashley (1929) has raised the whole question of specific p a t h w a y s in the grey matter, and for one reason and another the notion of the reflex arc (like the all-or-none principle) is losing some of its popular appeal—a loss which no one will regret. Y e t it is still true that the reflex arc is one of the most valuable conceptions we have in analysing the working of the central nervous system: all that has happened is a wider recognition of its true significance. A s regards respiration the position seems to be comparable to that of r h y t h m i c walking or running movements. These can take place in the absence of sensory discharges from the limbs ( G r a h a m B r o w n , 1 9 1 4 ) , though in the intact animal there is no doubt that the sensory discharges help to control the r h y t h m . In the same way the respiratory centre continues to discharge periodically after the sensory messages have been cut off, although normally they are in control. T h e most conclusive evidence is that of Winterstein ( 1 9 1 1 ) . T h e possibility of afferent control can be reduced to a minimum by cutting the vagi and then abolishing the respiratory movements with curare. Sensory impulses will still be able to reach the cord and brain stem, but in the absence of all movement there will be no periodic waxing and waning of the sensory discharge to determine the motor rhythm. T h e motor discharge can be recorded in the phrenic nerve, and as F i g . 27 shows, it is still a series of outbursts with the slow r h y t h m of breathing as it occurs in the vagotomised animal. In the rabbit and cat (anaesthetised or decerebrate) the only sensory nerve which seems to have much effect on the r h y t h m is the vagus, for when the vagi are divided passive inflation and deflation of the chest does not alter the r h y t h m of the phrenic discharge. I t is possible that 80

ACTIVITY OF NERVE CELLS after a time the impulses from receptors in the chest wall might take over the function of the vagal impulses, but it is clear that the slow breathing which occurs after v a g o t o m y

F i c . 27.

Rhythmic

discharge

respiratory m o v e m e n t by curare.

in p h r e n i c

nerve

persisting after

abolition

of

D e c e r e b r a t e c a t , u p p e r r o o t o f l e f t p h r e n i c on

e l e c t r o d e s , v a g i c u t , all m o v e m e n t p a r a l y s e d b y c u r a r e .

T h e r e c o r d is t a k e n d u r i n g

a r t i f i c i a l v e n t i l a t i o n o f the l u n g s ( s i g n a l l e d b y f a i n t w h i t e l i n e ) , b u t t h e d i s c h a r g e c o n t i n u e s w i t h o u t it a n d the r h y t h m is n o t i n f l u e n c e d b y the m o v e m e n t s o f the chest wall.

T i m e m a r k e r g i v e s i n t e r v a l s o f 0.25 sec.

is due to an automatic beat of the respiratory centre. T h e r e is, of course, nothing very new in this conclusion, for it was put forward over forty years ago by H e n r v Head (1889).

Potential

Changes in the Brain

Stem

W e can get some clue to the nature of this automatic a c t i v i t y by recording the potential changes which take place in the region of the active nerve cells. In a mammal, however, the brain stem cannot be electrically insulated from the rest of the body and any potential changes appearing in it must be treated with caution, since they m a y be due to activity elsewhere, e.g., in the heart or the skeletal muscles. T o avoid all difficulties of this kind B u y t e n d i j k and I (1931) decided to work on the isolated brain stem removed from the body with as little damage as possible. W e chose the brain stem of the goldfish: that of a warm-blooded animal would be unlikely to survive the loss of blood supply, and that of a frog would be unlikely to show periodic respiratory a c t i v i t y , but in goldfish the r h y t h m i c gill movements can be trusted to appear whenever there is a poor oxygen supply, and goldfish are easy to get and live well in the simplest aquarium. 81

MECHANISM OF NERVOUS ACTION The isolated brain stem shows fairly clear evidence of respiratory activity. The primitive fore-brain is destroyed and the brain stem is then removed from the animal and connected by electrodes to the usual amplifier and recording apparatus. At first there may be very little to record, but sooner or later in about half the preparations a regular succession of slow potential waves appears. T h e y are caused by the vagal lobes (immediately behind the cerebellum) becoming negative to the rest of the brain stem, and they recur with a frequency ranging from 20 to 60 a minute (Fig. 28). In the normal animal the gill movements 1

nsr

fasp/'raf/on F i c . 28. Rhythmic potential changes in the isolated brain stem of the goldfish compared with record of gill movements in an intact fish.

have much the same frequency range; there are occasional double gill movements and occasional double potential waves in the isolated brain stem, and in fact the potential waves are a close copy of the respiratory activity. Since impulses cannot pass down nerve fibres without causing potential changes, the existence of a wave might mean no more than the existence of a discharge of impulses in the nerve tracts of the brain stem. But the form of the waves does not suggest that they are built up out of impulse potentials in nerve fibres. T h e y rise and subside slowly and are often quite free from the very rapid irregularities which would be present in a wave formed by the summation of impulse potentials. T h e y suggest instead a slow change of potential taking place in the nerve cells or 82

A C T I V I T Y OF N E R V E

CELLS

dendrites, the duration of the change in each cell being of the same order as the duration of the recorded wave. B u t impulses must occur if nerve cells are active and it is often possible to make out more rapid potential fluctuations which are superimposed on the slow waves. T h e only way of deciding how these different effects are produced is to proceed as with motor and sensory nerves and restrict the activity to v e r y few units. This is one of the chief difficulties in work on the central nervous system; it m a y perhaps be overcome by the use of a very small electrode arrangement like that used for muscle, but for the moment it is easier to avoid it by working with a nervous system which has very few neurones. T h e nerve cells of an insect are not much smaller than those of a vertebrate. T h e number of cells in the central nervous system is therefore very much less and the chances of confusing a slow change with a summation effect will be less in proportion. Potential Changes in Insect Ganglia T h e most remarkable feature about the nervous system of insects is the persistent activity which occurs in excised portions of the central ganglion chain. Impulses are constantly passing up and down the central nerve cord: they arise from the ganglia and not from the cut ends of nerve fibres; they may be due to the abnormal conditions to which an excised preparation is exposed, but they continue for as long as 24 hours after excision. Most of this activity is too confused for analysis, sudden outbursts at high frequency are interspersed with slow regular discharges (5-15/sec.) and these cease and are renewed for no obvious reason. B u t in the water beetle, Dytiscus marginalis, the activity often takes on the characteristic rhythm of respiration (Adrian, 1931^). Periodic discharges occur in the nerves from the abdominal and thoracic ganglia at 5 to 20 a minute (the frequency range of the normal respiratory movements), and in each discharge the 83

M E C H A N I S M OF NERVOUS ACTION impulses are grouped as they are in the respiratory muscles (Fig. 29).

F i c . 29.

Λ , irregular discharge in abdominal nerve from isolated

chain in the water beetle ( D y t i s c u s ) .

ganglion

B , later, rhythmic discharge with

the

frequency of respiration.

Now if an active ganglion is included between the electrodes we find that the impulse discharge is superimposed on a slow potential change like that in the brain stem of the goldfish. T h e ganglion becomes negative to the nerve fibres and the onset of the negativity seems to precede the discharge (Fig. 30). T h e slow changes cannot

FIG. 30.

Slow potential w a v e s in abdominal ganglia of D y t i s c u s corresponding

to each outburst o f impulses in the nerve.

Isolated preparation o f ganglion chain

with one electrode on ganglion and the other on abdominal nerve.

84

ACTIVITY OF NERVE CELLS always be d e t e c t e d , a n d even t h o u g h we are dealing with a ganglion the size of a pin's h e a d , t h e r e are several h u n d r e d n e r v e cells which m a y be t a k i n g p a r t in t h e a c t i v i t y . T h u s there is still some u n c e r t a i n t y a b o u t t h e origin of the slow w a v e s a n d we c a n n o t be q u i t e sure t h a t t h e y are n o t built u p o u t of r e p e a t e d brief changes. B u t it is p r o b a b l e t h a t t h e y are n o t and if this can be a s s u m e d it looks as t h o u g h the discharge of impulses in t h e axon is heralded by a slow depolarisation of t h e cell b o d y or d e n d r i t e s , a surface b r e a k d o w n which develops a n d subsides gradually a n d gives a discharge of increasing a n d decreasing frequency. W e h a v e discussed the same idea in c o n n e c t i o n with the sense organs. B o t h with t h e m a n d w i t h t h e n e r v e cells the depolarisation m u s t be a m u c h less explosive affair t h a n in the nerve fibre a n d it m u s t be c a p a b l e of g r a d a t i o n . T h e r e m a y be some a n t e c e d e n t c h a n g e which precedes the depolarisation, Cor between t h e w a v e s there are long i n t e r v a l s where no obvious p o t e n t i a l c h a n g e occurs. Y e t on the whole it is reasonable to conclude t h a t the active s t a t e in a g r o u p of nerve cells implies a s u r f a c e c h a n g e like t h a t in the nerve fibre, b u t one which can persist for long periods a n d can v a r y in i n t e n s i t y . W h e r e this change t a k e s place it is impossible to say. T h e direction of the p o t e n t i a l g r a d i e n t shows t h a t t h e a c t i v e cell a n d its d e n d r i t e s become negative to t h e axon w h e n the l a t t e r is at rest, i.e., in t h e intervals between impulses. If such a c h a n g e can occur in the d e n d r i t e s of a n e r v e cell it m i g h t also occur in the t e r m i n a l d e n d r i t e s of a sensory neurone, in fact it m a y be t h a t the brief explosive i m p u l s e is the reaction of the specialised axon a n d t h a t in t h e j u n c t i o n a l regions of t h e c e n t r a l nervous s y s t e m t h e c h a n g e s which occur are o f t e n slow a n d partial d e p o l a r i s a t i o n s which can v a r y c o n t i n u o u s l y , instead of t h e s u d d e n a n d complete reactions of the nerve fibre. 85

M E C H A N I S M OF NERVOUS ACTION But in any case we have these slow potential waves in the regions which produce the respiratory discharge, and slow waves of the same kind appear from time to time in other parts of the central nervous system. The depolarisation hypothesis does not explain why the respiratory discharge is periodic, but it is worth remarking that a nerve fibre itself seems to contain all the machinery necessary for giving periodic groups of impulses. Periodic Discharges in Injured Nerve Fibres The injury discharges in excised sensory nerves have been mentioned already as an argument in favour of depolarisation in sense organs. Some are irregular and some are regular and of high frequency, but there is another type which appears later and consists of a repeated discharge of a group of anything from 2 to 20 impulses. The grouped discharge usually arises from connective tissue and small blood vessels adhering to the nerve sheaths. It develops gradually and seems to be increased by repeated irrigation with saline and reduced or stopped altogether by placing the preparation in serum, as though it were due to the loss of some normal constituent of the fibre or ending. It may be that the actual cutting of the nerve fibres has little to do with it and that the discharge arises from nerve endings in an abnormal medium. At any rate the discharge is periodic and the arrangement of the impulses in the group shows that each is due to an excitation which rises suddenly and then declines slowly to the subthreshold value (Figs. 3 1 , 32). In such a case we have a structure (injured nerve fibre or abnormal nerve ending) with a fairly slow periodic activity; this is connected with a nerve fibre which reacts more rapidly and gives a sequence of impulses for each beat of the slower region. The discharge of the respiratory neurones differs from the grouped injury discharge in that the nerve impulses come at a much lower frequency which may rise and decline 86

A C T I V I T Y OF N E R V E

CELLS

symmetrically. In spite of this it is difficult to avoid the conclusion that the same kind of mechanism must be at work in the two cases.

FIG. 3 1 . Grouped injury discharge. Isolated dorsal cutaneous nerves of the cat, set up in moist chamber. Time marker (black lines) gives intervals of 0 . 1 5 sec

Time FIG. 32. Production of grouped frequency in each group.

injury

discharge

with

declining

impulse

We can only guess at the cause of a periodic outburst of this kind. There are m a n y physico-chemical systems which react periodically—Lillie's iron wire in nitric acid is the most familiar to physiologists. A n d for those who wish to look at it from a more strictly physical point of view van der Pohl (1929) has analysed the properties of a particular type of oscillation which he calls a ' R e l a x a t i o n oscillation.' This occurs when the system is so arranged that it becomes periodically unstable and then rapidly changes until the oscillation is brought to an end by the building up of some inhibiting factor. A s examples of this 87

MECHANISM OF NERVOUS ACTION kind of oscillation he quotes the waving of a flag in the wind, the squeaking of a slate pencil, the beat of the heart, and the periodic recurrence of epidemics and economic crises. So the respiratory neurones are in important if not very cheerful company. One interesting property of the relaxation oscillation is that it is easily synchronised with external periodic phenomena acting upon the system, and this is certainly true in the case of the respiratory centre and the periodic discharges of the vagus. The Effect of Potential Gradients The rhythmic potential waves in the brain stem are so large that there must be a considerable movement of ions in and near the active region. It is worth enquiring, therefore, whether the cells in neighbouring regions may not be directly influenced by the potential gradients. For instance, when the vaso-motor centre discharges in phase with the respiratory centre, does it do so because of a direct nervous connection between the two, or because it is caught up in the electrical eddies from the respiratory centre? T h e dendrites have none of the elaborate sheathing arrangement which surrounds the axon, and apart from this they spread so widely and elaborately that any potential gradient in their neighbourhood is almost bound to produce some kind of effect on them. Clearly the whole of the interactions which take place in the central nervous system are not to be explained on these lines, for the connection is bound to be more direct when there is actual contact of dendrites with a nerve cell or with other dendrites. There is also a point of fundamental importance which has not yet been dealt with, namely, that an area of activity in the central nervous system, whether spontaneous or due to incoming messages, usually produces a dual effect: it promotes the activity of certain regions and reduces or inhibits that of others. For instance, with each 88

ACTIVITY OF N E R V E

CELLS

respiratory discharge there is probably an inhibition of vagal as well as an increase in sympathetic activity. This, however, is not a very serious objection to the idea that electric fields may influence the distribution of activity in the grey matter. At present the humoral hypothesis— of separate excitatory and inhibitory substances liberated at specific nerve endings—has the evidence of vagal and sympathetic action on the heart in its support. But it is worth recalling that electric phenomena were explained for many years on a two-fluid basis and that the effects at anode and cathode are of opposite sign. It is at least conceivable that a potential gradient tending to make the dendrites positive to the axon would inhibit, and one in the reverse direction would excite. Another possibility is that the dendrites belonging to one neurone may have different degrees of stability so that some may become active whilst others remain inactive. This would give rise to a potential gradient between the active and inactive dendrites, and its direction might affect the activity of neighbouring cells. These ideas are so speculative that nothing would be gained by elaborating them, but at least we can point to phenomena of another kind which support the idea of electrical communication between units which are not directly connected. Synchronous

Activity

R. S. Lillie has pointed out that the beat of cilia or of spermatozoa may sometimes come into phase, although the only possibility of interaction is by way of electric currents. Another example may be taken from that overworked source—the injury discharge of mammalian sensory fibres. In a medium-sized nerve trunk when there is an intense activity arising from the cut ends of the fibres the record is usually a rapid irregular series of brief potential changes, just what would be expected from a nerve in which a number of fibres are discharging independently 89

MECHANISM OF NERVOUS ACTION and at different rates. But sometimes a slight readjustment of the nerve on the electrodes, a drop of Ringer's fluid or a draught of cool or dry air produces a dramatic change in the picture. The fibres begin suddenly to work in unison and the discharge becomes a large regular oscillation at a high frequency (Fig. 33). The unison is not complete, for the oscillations approach a sinusoidal

FIG. 33. Synchronisation of high-frequency injury discharge in a number of nerve fibres. Isolated nerves in moist chamber, capillary electrometer records. A and B, long thoracic nerve (cat)—the discharge became synchronised when the nerve was exposed to cool air by opening the door of the chamber. C, popliteal nerve (cat).

curve and there may be beats in the curve; but the very large potential change shows that most of the active fibres are close enough in phase to sum their potentials. It is scarcely possible that a synchronisation of this kind could be brought about except by the electric fields set up by the impulses. A slight change in the surroundings of the nerve would alter the potential distribution near the cut end, but would be unlikely to affect the diffusion of metabolites or any other manifestation of activity which could lead to synchronisation. Moreover, the conditions would be favourable to an electrical interaction, for at the

90

A C T I V I T Y OF N E R V E

CELLS

cut ends of the fibres the polarised surface is destroyed and their interiors will be in free electric communication. These synchronised injury discharges must be taken as an example of interaction due to the brief impulse potentials in nerve fibres; they are of course no proof that electrical interaction can occur in the central nervous system. But one cannot avoid comparing them with the synchronised discharges which come from groups of nerve cells. These have been mentioned in connection with voluntary contraction where the motor discharge becomes more or less synchronous in the different motor units when the activity is at its height. T h e frequency of the volleys is much lower than in the injury discharge—50/sec. as against 200500. B u t the record from the motor nerve or the muscle has the same appearance of a regular oscillation. Oscillations of the same kind can be detected in the isolated brain stem of the goldfish. Fig. 34, for instance, gives two

Mail

F i c . 34. Spontaneous discharge in isolated brain stem of goldfish. The activity occurs in the mid-brain and consists of rapid oscillations superimposed on a slow potential change.

complex potential waves which occurred spontaneously in the mid-brain; in both of these the sinusoidal oscillations are imposed on a slow potential change which recalls the respiratory effect. Another example of a synchronous discharge is to be found in the retina and the optic nerve 91

MECHANISM OF NERVOUS

ACTION

(Adrian and M a t t h e w s , R . , 1928). Fig. 35 is a capillary electrometer record of the potential in the optic nerve of the eel when the retina is exposed to a uniform bright light. Here the w a v e s are slower still (8-10/sec.), but it is inter-

F i c . 35.

Synchronous discharges in the optic nerve o f the conger eel on

exposure of the retina to uniform bright illumination. records.

Capillary

electrometer

T i m e marker (black lines) gives intervals of 0.125 sec.

esting to find that the synchronisation seems to follow the same rule as in the motor discharge, for it does not appear unless the majority of the neurones are strongly excited. Incidentally the retina is in some respects an ideal preparation for the study o f the interactions between nerve cells, for the dendrite area is spread out into a thin plate and the excitation can be confined to particular regions or spread over the whole area b y altering the illumination of the rods and cones. In this case also the oscillations can be detected in the dendritic or nerve cell region as well as in the nerve trunk coming from it. There are slow potential changes too, but their origin may be complex, for we h a v e to reckon with the receptor elements as well as with the nerve cells and dendrites: for this reason it would 92

ACTIVITY OF N E R V E

CELLS

be unsafe to compare them with the slow changes in the brain stem. Because all these records look alike it does not follow that the synchronisation is due to the s a m e factors in all of them. In groups of nerve cells there will be frequent opportunities for direct conduction of impulses from one neurone to another and no need, therefore, for the interaction to depend on potential changes, except in so far as these are involved in the conduction of impulses. B u t if neurones are never continuous with one another but only in contact, it does not seem unreasonable to suppose that they may influence one another even though a layer of fluid intervenes between them, and that the influence merely becomes less and less as the separation is increased. I fear it will need a great deal more work to s u b s t a n t i a t e any views of this kind, though perhaps it may not need much to upset them. You will see that they are based on a series of casual observations made with very little coherent plan. In all branches of natural science there are two methods of approach, that of the strategist who can devise a series of crucial experiments which will reveal the truth by a sort of Hegelian dialectic, and that of the empiricist who merely looks about to see what he can find. T h e development of electrical technique has given a new way of looking about, and so much is going on in the nervous system that it is hard to resist the temptation to record anything that turns up. This method has had the merit of showing many unexpected resemblances in the activity of different parts of the nervous a p p a r a t u s , but it gives us facts rather than theories, and the facts may not always mean very much. All conclusions about the central nervous s y s t e m must be tentative, and the conclusion of this work is little more than a restatement of the cellular hypothesis. T h e nervous system is built up out of specialised cells whose reactions do not differ fundamentally from one another or from the 93

MECHANISM OF NERVOUS ACTION reactions of the other kinds of excitable cell. They have a fairly simple mechanism when we treat them as individuals: their behaviour in the mass may be quite another story, but this is for future work to decide.

94

REFERENCES A d r i a n , Ε . D . 1926. T h e impulses p r o d u c e d b y sensory n e r v e - e n d i n g s . P a r t 4. I m p u l s e s f r o m p a i n r e c e p t o r s . J . P h y s i o l . , 62, p . 3 3 . A d r i a n , E . D . 1930л. T h e effects of i n j u r y on m a m m a l i a n n e r v e fibres. P r o c . R o y . Soc. В., 106, p . 596. A d r i a n , E . D . 1930^. T h e a c t i v i t y of t h e n e r v o u s s y s t e m in the c a t e r p i l l a r . J . Physiol., 70, 34 P . A d r i a n , E . D . 1 9 3 1 л . T h e m i c r o p h o n i c action of t h e cochlea; an i n t e r p r e t a t i o n of W e v e r a n d B r a y ' s e x p e r i m e n t s . J. P h y s i o l . , 7 1 , 28P. Adrian, E. D. 1931^· P o t e n t i a l changes in t h e isolated n e r v o u s s y s t e m of D y t i s c u s M a r g i n a l i s . J . Physiol., 72, p . 1 3 2 . A d r i a n , E . D . 1931^"· T h e messages in sensory nerve fibres a n d t h e i r i n t e r p r e t a t i o n . P r o c . R o y . Soc. В., 109, p . x. A d r i a n , E . D . a n d B r o n k , D . W . 1928. T h e discharge of i m p u l s e s in m o t o r nerve fibres. P a r t 1. I m p u l s e s in single fibres of t h e p h r e n i c nerve. J . Physiol., 66, p. 8 1 . A d r i a n , E . D . a n d B r o n k , D . W . 1929. T h e discharge of impulses in m o t o r nerve fibres. P a r t 2. T h e f r e q u e n c y of d i s c h a r g e in reflex a n d v o l u n t a r y c o n t r a c t i o n . J . P h y s i o l . , 67, p . 1 1 9 . A d r i a n , E . D . , B r o n k , D . W . , a n d Phillips, G . 1 9 3 1 . The n e r v o u s origin of t h e W e v e r a n d B r a y effect. J . Physiol., 73, 2 ΡA d r i a n , E . D . , B r o n k , D . W . , a n d Phillips, G. charges in m a m m a l i a n s y m p a t h e t i c nerves.

1932. DisJ. Physiol.,

74, P· " 5 · Adrian, E. D . and Buytendijk, F. J. J. 1931. Potential c h a n g e s in t h e isolated b r a i n s t e m of t h e goldfish. J . P h y s i o l . , 7 1 , p . 121. A d r i a n , E . D . , C a t t e l l , M c K . , a n d H o a g l a n d , H . 1931. Sensory d i s c h a r g e s in single c u t a n e o u s n e r v e fibres. J . Physiol., 72, p . 377·

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OF N E R V O U S

ACTION

Adrian, E . D . and Matthews, R . 1928. The action of light on the eye. Part I I I . T h e interaction of retinal neurones. J . Physiol., 65, p. 273. Adrian, E . D . and Umrath, K . 1929. The impulse discharge from the Pacinian corpuscle. J . Physiol., 68, p. 139. Billingsley, P. R . and Ranson, S. W. 1918. On the number of nerve cells in the ganglion cervicale superius and the nerve fibres in the cephalic end of the truncus s y m p a t h e t i c a in the cat, and on the numerical relations of preganglionic and postganglionic neurones. J . Comp. Neurol., 29, p. 359. Bishop, G . H . 1927. T h e form of the record of the action potential of vertebrate nerve at the stimulated region. Amer. J . Physiol., 82, p. 462. Bishop, G . H . 1928. T h e effect of nerve reactance on the threshold of nerve during galvanic current flow. Amer. J . Physiol., 85, p. 417. Boycott, A . E . 1899. Note on the muscular response to two stimuli of the sciatic nerve. J . Physiol., 24, p. 144. Bronk, D . W. and Stella, G . 1932· Afferent impulses in the carotid sinus nerve. I. The relation of the discharge from single end organs to arterial blood pressure. J . Cell, and Comp. Physiol., 1 , p. 1 1 3 . Denny-Brown, D . 1928. On inhibition as a reflex accompaniment of the tendon jerk and of other forms of active muscular response. Proc. R o y . Soc. В., 103, p. 3 2 1 . Denny-Brown, D. 1929. On the nature of postural reflexes. Proc. R o y . Soc. В . , 104, p. 252. Graham Brown, T . 1 9 1 4 · On the nature of the fundamental activity of the nervous centres. J . Physiol., 48, p. 18. Cattell, M c K . and Hoagland, H. 1 9 3 1 . Response of tactile receptors to intermittent stimulation. J . Physiol., 72, p.

392· Ccghill, G . E . 1929· Anatomy and the problem of behaviour. Cambridge. Cooper, S. and Eccles, J . C. 1930. The isometric response of mammalian muscles. J . Physiol., 69, p. 377. Dennig, H. 1929· Die Leitungsgeschwindigkeit Sympathetischer nerven und afferenter Eingeweidenerven. Ztsch. f. Biol., 88, p. 395.

REFERENCES Eccles, J . C. and Sherrington, C. S. 1930. Number and contraction values of individual motor units examined in some muscles of the limb. Proc. R o y . Soc. В., ю б , p. 326. Erlanger, J . and Gasser, Η. S. 1930. The action potential in fibres of slow conduction in spinal roots and somatic nerves. Amer. J . Physiol., 92, p. 43. Fredericq, L . 1882. Arch. Biol., 3 , p. 55. von F r e y , Μ . 1 9 1 5 . Physiologische Versuche über das Vibrationsgefühl. Ztsch. f. Biol., 65, p. 4 1 7 . von Frey, M . 1927· Eine Bemerkung über den sogennanten Vibrationsinn. Ztsch. f. Biol., 85, p. 539. Gasser, H. S. 1928. The analysis of individual waves in the phrenic electroneurogram. Amer. J . Physiol., 80, p. 522. Gasser, Η. S. and Erlanger, J . 1927. The role played by the sizes of the constituent fibres of a nerve trunk in determining the form of its action potential wave. Amer. J . Physiol., 80, p. 522. Gasser, Η. S. and Newcomer, H. S. 1 9 2 1 . Physiological action currents in the phrenic nerve. An application of the thermionic vacuum tube to nerve physiology. Amer. J . Physiol., 57, p. I. Goldscheider, A. 1926. Bethe's Handb. norm, pathol. Physiol., I i , p. 193. Head, H. 1889. On the regulation of respiration. J . Physiol., 10, p. I. Head, H., Rivers, W. H. R . , and Sherren, J . 1905. A new conception of the elements of sensation. Brain, 28, p. 99. Hoffmann, P. 1914. Über die doppelte Innervation der Krebsmuskeln. Zugleich ein Beitrag zur Kenntnis nervöse Hemmung. Ztsch. f. Biol., 63, p. 4 1 1 . Hoffmann, P. 1919. Über die relative Unermüdbarkeit der Sehnenreflexe. Ztsch. f. Biol., 69, p. 5 1 7 . Hoffmann, P. 1922. Untersuch, ü. die Eigenreflexe. Berlin. Lashley, K . S. 1929. Brain mechanisms and intelligence. Chicago. Lillie, R . S. 1923. Protoplasmic action and nervous action. Chicago. Lillie, R . S. 1929. Resemblances between the electromotor variations of rhythmically reacting living and non-living systems. J . Gen. Physiol., 1 3 , p. 1. 97

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ACTION

Mangold, E . 1905. Untersuchungen über die Endigung der Nerven in den quergestreiften Muskeln den Arthropoden. Ztsch. allgm. Physiol., 5, p. 1 3 5 . Matthews, В . Η . С. 1928. A new electrical recording system. J . Physiol., 65, p. 225. Matthews, В . H . С. 1931л. The response of a single end organ. J . Physiol., 7 1 , p. 64. Matthews, В . H. C. 1931^. The response of a muscle spindle during active contraction of a muscle. J . Physiol., 72, p · I53" Pieron, H. 1929. L a dissociation des douleurs cutanees et la diflferenciation des conducteurs algique. L'Annee Psychol., 30, p. I. Piper, H. 1 9 1 1 . Über die Rhythmik der Innervationsimpulse bei willkürlicher Muskelcontraktion und über verscheidene arten der künstlichen Tetanisierung menschlicher Muskeln. Ztsch. f. Biol., S3, p. 140. Piper, H . 1 9 1 2 . Elektrophysiologie menschlicher Muskeln. Berlin. Preisendorfer, F . 1919. Versuche über die Anpassung der willkürlichen Innervation an die Bewegung. Ztsch. f. Biol., 70, p. 505. Ranson, S. W. 1 9 1 1 . Non-medullated nerve fibres in the spinal nerves. Amer. J . Anat., 12, p. 67. Ranson, S. W. and Billingsley, P. R . 1918. The superior cervical ganglion and the cervical portion of the sympathetic trunk. J . Comp. Neurol., 29, p. 3 1 3 . Ranson, S. W. and Davenport, Η. K . 1 9 3 1 . Sensory unmyelinated fibres in the spinal nerves. Amer. J . Anat., 48, p. 3 3 1 . Richet, Ch. 1882. Physiologie des muscles et des nerfs. Paris. Sherrington, C. S. 1 9 3 1 . Quantitative management of contraction in lowest level coordination. Brain, 54, p. 1. Tsai, Chiao. 1 9 3 1 . Action of narcotics on the conduction of nerve impulses from a single end-organ. J . Physiol., 73, p. 382. Van der Pohl, В. and Van der Mark, J . 1929. The heart beat considered as a relaxation-oscillation, and an electrical model of the heart. Arch, neerl. de Physiol., 14, p. 418.

98

REFERENCES Wachholder, К . 1923. Untersuchungen über die Innervation und Koordination der Bewegung mit Hilfe der Aktionströme. Pflüger's Arch., 199, p. 595. Wedensky, N . 1883. Arch. f. Physiol., 1883, p. 316. Wedensky, Ν . 1884. Recherches telephoniques sur les phenomenes electriques dans les appareils musculaires et nerveux. St. Petersburg. Winterstein, H. 1 9 1 1 . Die automatische Tätigkeit der Atemzentren. Pflüger's Arch., 138, p. 159.

99

INDEX A waves, 45-46

COCHILL, G . E . ,

A d a p t a t i o n , differences in rate o f , for

Conduction,

79

nature

of

nervous,

, nature o f , 2 3 - 2 4

Contraction frequency, 64-69

, of nerve fibres, 23 et seq., 3 1

COOPER, S., 70

, of sense organs, 1 2 , 24 et seq.

Crustacean nerve, 7 1 - 7 2

A D R I A N , F.

17,

19-20

various receptors, 2 4 - 2 6

D . , 8, 1 3 , 2 8 , 3 1 , 3 8 , 3 9 , 4 2 ,

4 7 . 65, 67, 68, 7 3 , 74, 8 1 , 83, 92

DAVIS, H . ,

38

A l l or none principle, 18, 62

DENNIC, H.,

Amplifiers, 5-6

D e p o l a r i s a t i o n , as result of i n j u r y , 3 0 - 3 1

46

A n i m a l Electricity, 1 - 2

, of nerve cells, 8 5 - 8 6

A o r t a , sensory impulses from, 2 5 - 2 6 , 76

, of nerve fibres. 24, 2 9 - 3 4

A u d i t o r y nerve, effect of

D i p h a s i c potential w a v e s , 9

, impulses in, 3 7 - 4 1 , 59 Automaticity

of

respiratory

DU B o i s REYMOND, E . , З

center, ECCLES, J . C . , 46, 62,

81-&4

В waves, 45-46, 52-54 BERNSTEIN,

, of sense organs, 2 9 - 3 0 , 3 3 - 3 4

temperature

on, 3 9 - 4 0

3

BLLLINCSLEY, P. R.,

75

BISHOP, G . H . , 24, 3 3 BOYCOTT, A . E .

Electrocardiogram, 4 E l e c t r o m y o g r a m , 4, 6 4 - 6 6 , 7 3 E p i c r i t i c fibres, 4 4 - 4 7 F.RLANGER, J . , 34, 43, 45, 46, 49, 52,

18

B R A Y , C . W . , 37 et seq. BRONK, D . W . , v, I I , 1 3 , 26, 38, 39. 67,

68, 7 3 , 74 DENNY-BROWN, D., 1 5 , 67 G R A H A M B R O W N , Т . , 8O BUYTENDIJK, F. J. J.,

70

EINTHOVEN, 3

81

С w a v e s , 4 5 - 4 6 , 49. 5 2 _ 5 4 C a p i l l a r y electrometer, 3 CATTELL, M C K . , 28, 3 6 , 44

FARADAY, Μ . ,

I

Flicker frequency, 36, 4 1 FORBES, Α., Ν FREDERICQ, L.,

16

F r e q u e n c y of impulses, in motor n e r v e s , 6 7 - 6 8 , 7 0 - 7 1 , 91 , in sensory nerves, 2 5 , 2

7 _ 2 8 , 3 2 , 4 0 - 4 1 , 44 ·, to d i f f e r e n t

C e n t r a l nervous s y s t e m , 78 et seq. , convergence in, 55

53,

57

muscles,

70-71

, potential changes in,

VON F R E Y , Μ . , 3 6 , 4 3

, summation in, 3 5 , 55

GALVANI, L . , Ι et seq.

78, 8 2 , 9 1 Chemical stimulation, 51 Chronaxie, 59 Cochlea, effect of temperature on, 3 9 , potential changes in, 3 7 - 4 0

G A S S E R , Η . S . , Ν, 3 4 « 4 3 > 4 5 . 4 6 , 4 9 .

52.

53. 57. 73

Goldfish, potential changes in brain o f , 81-83

INDEX GOLDSCHEIDER, Α., 43, 49 GOTCH, F . , • Gradation of activity, in motor nerves, 6 j et seq. , in muscle, 61-63,66-69, 70 , in nerve cells, 85 , in nerve fibres, 1 6 - 1 9 , in sensory nerves, 04 et seq. Grey matter, specific pathways in, 79-80 Hair receptors, 1 4 - 2 5 HEAD, H., 44, 46, 81 Heat production in nerve, 20 HELMHOLTZ, H., 3 HILL, Α. V., 20 HOAOLAND, Η., 28, 36, 44 HOFFMANN, P., 15, 7 1 , 73 VON HORNBOSTEL, Ε . M . , 41 Humoral hypothesis, 89

Muscle spindles, 1 1 , 23, 25-26, 58, 74 NEWCOMER, H. S., 73 Optic nerve impulses, 92 Oscillographs, 6, 9 Pacinian corpuscles, 8, 1 1 , 22-23, 2 5 Pain, 42 et seq. , relation of tactile endings to, 4 3 44. 47 PFLÜCER, 3 PHILLIPS, G., 38, 39, 74 Phrenic nerve impulses, 67, 80-81 PI£RON, H., 46 PIPER, H., 5, 64 Polarisation, of nerve, 24, 29-34 , of nerve cells, 85-86 , of sense organs, 29-30, 3 3 - 3 4 PREISENDORFER, F., 73 Pressure receptors, 22, 24-25, 34-36 Protopathic fibres, 44-47

Injury discharge, 30-34, 86-90 , depolarisation as cause of, 30 et seq. , grouped impulses in, 86-87 , synchronisation of, 89-90 Insects, ganglia, 83 , motor nerves, 1 3 - 1 4 , 7 1 - 7 2 , water beetle, 72, 83-84 Intercostal muscle action currents, 69-70 Invertebrate nerves, 1 3 - 1 4 , 71^72 Iron wire model, 20, 29-30, 87

RANSON, S. W., 43, 45, 49, 53, 75 Receptive field, of cat's paw, 48

LAPICQUE, L . , 59 LASH LEY, K . S., 80 LILLIE, R . S., 20, 29, 87, 89 LUCAS, KEITH, V, 5 Lung, sensory impulses from, 25-26, 70, 79-81

76 Retinal potentials, 92 Rheotome, 3 RICHET, CH., 71 RIVERS, W. H. R . , 44, 46 Rhythmicity of discharge, cause of,

MANGOLD, E . , 71 MATTHEWS, Β. H. C., v, 6, 9, 1 1 , 15, 25, 26, 28, 58, 92 Meissner's corpuscles, 22 Membrane hypothesis, 19-20 MÜLLER, JOHANNES, 43

, of frog, 52-53 Reflex action, basis for, 79-80 Refractory period, 1 8 - 1 9 , 27-28, 39, 65 Resonance theory of audition, 41 Respiratory centre, rhythm of: , in insects, 83-84 , nature of, 78-82, 87-88 , relation to afferent impulses, 79-80 , relation to sympathetic discharge,

27-34 , following injury, 30 SAUL, L. U., 38 Sensation, relation of adaptation

to,

34-37 , relation of stimulus to, 34-36, 41

INDEX SHERREN, J., 46

, relation to p a i n , 4 3 - 4 4 , 4 7

SHERRINGTON, С . S . , 3 5 , 4 4 , 46, 6 1 , 62,

, rhythmic stimulation of, 35-36 T e m p e r a t u r e receptors, 5 8 - 5 9

79

T o n e o f blood vessels, 15, 7 4 , 7 6

Silent period, 15

T s AI, С . , 1 1

Sinus caroticus, impulses from, 25-16 Specific n e r v o u s e n e r g y , 43

U M R A T H , 1С., 8

S p e c i f i c i t y o f sensory fibres, 43, 5 4 - 5 6 , 59 STELLA, G . , 26

V a g u s impulses, 2 5 - 2 6 , 70, 7 9 - 8 1

String galvanometer, 3

V A N DER P O H L , В . , 8 7

S y m p a t h e t i c i m p u l s e s , 15, 7 3 - 7 7

V a s o m o t o r discharge, 7 4 , 7 6 , 88

- — — , relation to c a r d i a c r h y t h m , 7 6

V e l o c i t y o f nerve c o n d u c t i o n , 4 5 - 4 8 , 52,

, relation to respiratory r h y t h m , 7 6 ,

58. 7 5

88

V i b r a t i o n , sense o f , 36

, synchronisation of, 7 5 - 7 7 Synchronisation,

in

sympathetic

VOLTA, Α . , 2

dis-

Voluntary

charge, 75-77 , in v o l u n t a r y c o n t r a c t i o n s , 7 2 - 7 3 , of injury discharge, 87-92

WACHHOLDER, К . , 66, 67

, o f m o t o r units, 7 2 - 7 3 Tactile

receptors,

43-44. 4 7 . 5 4 - 5 9

24, 3 5 - 3 7 ,

contractions,

68,73

WEDENSKY, Ν . , 64

39,

41,

WEVER, E . G . , 37 et seq. WINTERSTEIN, Η . , 8ο

103

frequency

in,