The Integrative Action of the Nervous System

It is necessary to be clear as to what we understand by the expression " reflex " action. In plants and animals occur a number of actions the initia- tion of which is traceable to events in their environment. fThe event in the environment is some change which acts on the organ- ism as an exciting stimulus, \The energy which is imparted to the organism by the stimulus is often far less in quantity than the energy which the organism itself sets free in the movement or other effect which it exhibits in consequence of the applica- tion of the stimulus. This excess of energy must be referred to energy potential in the organism itself. The change in the environment evidently acts as a releasing force upon the living machinery of the organism. The source of energy set free is traced to chemical compounds in the organism. These are of high potential value, and in immediate or mediate consequence of the stimulus decompose partly, and so liberate external from internal energy. It is perfectly conceivable, and in many undif- ferentiated organisms, especially in unicellular, e. g. amoeba, is

actually the case, that one and the same living structure not only undergoes this physico-chemical change at the point at which an external agent is applied, but is subject to spread of that change from particle to particle along it, so that there then ensue in it changes of form, movement 1- In such a case the initial reaction or reception of the stimulus, the spatial transmis- sion or conduction of the reaction, and the motor or other eftd- effect, are all processes that occur in one and the same living structure.] But in many organisms these separable parts of the reaction are exhibited by separate and specific structures. Sup- pose an animal turn its head in response to a sudden light Large fields of its body take part in the reaction, but also large fields of it do not. Some of its musculature contracts, particu- larly certain pieces of its skeletal musculature. The external stimulus is, so to say, led to them by certain nerves in the altered form of a nervous impulse. If the neck nerves are severed the end-effect is cut out of part of the field ; and the nerves themselves cannot exhibit movement on application of the stimulus. The optic nerve itself is unable to enter into a heightened phase of its own specific activity on the application of light Initiation of nervous activity by light is the exclusive (in this instance) function of cells in the retina, retinal receptors. In such cases there exist three separable structures for the three gTQcesses — initiation, conduction, and end-effect.

These reactions, in which there follows on an initiating reac- tion an end-effect reached through the mediation of a conductor, itself incapable either of the end-effect or, under natural condi- tions, of the inception of the reaction, are " reflexes." The con- ductors are nerve./ Usually the spaces and times bridged across by the conductors are quite large, and easily capable of measure- ment Now there occur cases, especially within the unicellular organism and the unicellular organ, where the spaces and times bridged are minute. In them spread of response may involve " conduction " (Poteriodendron, Vorticella) in some degree specific. Yet to cases where neither histologically nor physi- ologically a specific conductor can be detected, it seems better not to apply the term '* reflex." It seems better to reserve that

expression for reactions employing specifically recognizable nerve-processes and morphologically differentiated nerve-cells ; the more so because the process of conduction in nerve is probably a specialized one, in which the qualities of speed and freedom from inertia of reaction have been attained to a degree not reached elsewhere since not elsewhere demanded. The conception of a reflex therefore embraces that of at least three separable structures, — an effector organ, e. g.y gland cells or muscle cells; a conducting nervous path or conductor leading to that organ ; and an initiating organ or receptor whence the reaction starts. The conductor consists, in the reactions which we have to study, of at least two nerve-cells, — one con- nected with the receptor, the other with the effector. For our purpose ftRe receptor is best included as a part of the nervous system, and so it is convenient to speak of the whole chain of structures — receptor, conductor, and effector — as a reflex-arc/^ All that part of the chain which leads up to but does not include the effector and the nerve-cell attached to this latter, is conven- iently distinguished as the afferent-arc, ^^^^^^^^

The reflex-arc is the unit mechanism of the nervous system when that system is regarded in its integrative function. The unit reaction in nervous integration is the refleXy because every reflex is an integrative reaction and no nervous action short of a reflex is a complete act of integration. The nervous synthesis of an individual from what without it were a mere aggregation of commensal organs resolves itself into co-ordination by reflex action. But though the unit reaction in the integration is a reflex, not every reflex is a unit reaction, since some reflexes are compounded of simpler reflexes. Co-ordination, therefore, is in part the compounding of reflexes. In this co-ordination ) there are therefore obviously two grades. --J

The simple reflex. There is the co-ordination which a reflex action introduces when it makes an effector organ responsive to excitement of a receptor, all other parts of the organism being supposed indifferent to and indifferent for that reaction. In this grade of co-ordination the reflex is taken apart, as if separable from all other reflex actions. This is the simple reflex. A simple reflex is probably a purely abstract conception, because all parts of the nervous system are connected together and no part of it is probably ever capable of reaction without affecting and being affected by various other parts, and it is a system certainly never absolutely at rest. But the simple reflex is a convenient, if not a probable, fiction. Reflexes are of various degrees of complexity, and it is helpful in analyzing complex reflexes to separate from them reflex components which we may consider apart and therefore treat as though they were simple reflexes.

In the simple reflex there is exhibited the first grade of co- ordination. But it is obvious that if the integration of the animal mechanism is due to co-ordination by reflex action, reflex actions must themselves be co-ordinated one with another ; for co-ordination by reflex action there must be co-ordination of reflex actions. This latter is the second grade of co-ordination. The outcome of the normal reflex action of the organism is an orderly coadjustment and sequence of reactions. This is very patently expressed by the skeletal musculature. The co-ordina- tion involves orderly coadjustment of a number of simple reflexes occurring simultaneously^ i. e, a reflex pattern, figure, or " com- plication," if one may warp a psychological term for this use ; orderly succession involves due supercession of one reflex by another, or of one group of reflexes by another group, /. e, orderly change from one reflex pattern or figure to another. For this succession to occur in an orderly manner no com- ponent of the previous reflex may remain which would be out of harmony with the new reflex that sets in. When the change from one reflex to another occurs it is therefore usually a far- reaching change spread over a wide range of nervous arcs.

This compounding of reflexes with orderliness of coadjust- ment and of sequence constitutes co-ordination, and want of it inco-ordination. We may therefore in regard to co-ordination distinguish co-ordination of reflexes simultaneously proceeding, and co-ordination of reflexes successively proceeding. The main secret of nervous co-ordination lies evidently in the compounding of reflexes. Co-ordination in the simple reflex. It is best to clear the way toward the more complex problems of co-ordination by considering as an earlier step that which was termed above, the first grade of co-ordination, or that of the simple reflex. From the point of view of its office as integrator of the animal mechanism, the whole function of the nervous system can be summed up in the one word, conduction* In the simple reflex the evidence of co-ordination is that the outcome of the reflex as expressed by the activity induced in the effector organ is a response appropriate to the stimulus imparted to the receptor. This due propriety of end-effect is largely traceable to the action of the conductor mediating between receptor and affector. Knowledge of the features of this " conduction " is therefore a prime object of study in this connection.

But we have first to remember that in dealing with reflexes even experimentally we very usually deal with them as reactions for which the reflex-arc as a whole and without any separation into constituent parts is laid under contribution. (The reflex- arc thus taken includes the receptor. It is assuredly as truly a functional part of the arc as any other. J But, for analysis of the arc's conduction, it is obvious that by including the receptor we are including a structure which, as its name implies, adaptation has specialized for excitation of a kind different from that obtaining for all the rest of the arc. It is therefore advanta- geous, as we have to include the receptor in the reflex-arc, to consider what characters its inclusion probably grafts upon the functioning of the arc.

Marshall Hall ^3 * drew attention to the greater ease with which reflexes can be elicited from receptive surfaces than from afferent nerve-trunks themselves ; and this has often been con- firmed (Eckhard, Biedermann). Steinach ^^ has measured the lowering of the threshold value of stimulation when in the frog a reflex is elicited by a mechanical stimulus applied to skin instead of to cutaneous afferent nerve. The lowering is con- siderable. There are numerous instances in which particular reflexes can be elicited from the receptive surface by particular

* The reference numbers in the text refer to the bibliographical list at the end of the volume. stimuli only. Goltz*^ endeavoured in vain to evoke the reflex croak of the female frog by applying to the skin electrical stim- uli. Mechanical stimuli of non-nocuous kind were the only stim- uli that proved efifective. From the afferent nerve itself by direct stimulation the reflex could but rarely be elicited at all. Later Goltz's pupil Gergens ^^ succeeded in provoking the reflex by ap- plying to the skin a mild discharge from an influence machine.

A remarkable reflex ^^ is obtainable from the planta of the hind foot in the " spinal " dog. The movement provoked is a brief strong extension at knee, hip, and ankle. This is the " extensor-thrust." It seems obtainable only by a particular kind of mechanical stimulation. I have never succeeded in eliciting it by any form of electrical stimulation, nor by any stimulation applied directly to an afferent nerve-trunk. Again, a very characteristic reflex in the cat is the pinna- reflex.^ If the tip of the pinna be squeezed, or tickled, or in some cases even touched, the pinna itself is crumpled so that its free end is turned backward, as in Darwin's ^ picture of a cat prepared to attack. The afferent nerve of this reflex appears to be in part at least not the cranial fifth nerve, but the foremost cervical. The reflex emerges very early from the shock of de- cerebration and is submerged very late in chloroform narcosis. This reflex, easily elicitable as it is by various mechanical stimuli to the skin, I have never succeeded in provoking by any form of electrical stimulation.

The same sort of difference, though less marked in degree, is exhibited by the scratch-reflex.^'. ^^, 251, 252, 300 j^is reflex is one in which various forms of innocuous mechanical stimula- tion (rubbing, tickling, tapping) applied to the skin of the back behind the shoulder evoke a rhythmic flexion (scratching movement) of the hind limb, the foot being brought toward the seat of stimulation. This reflex in the spinal dog, although usually elicitable, varies much under various circumstances in its degree of elicitability. When easily elicitable it can be evoked by various forms of electrical stimulation as well as by mechan- ical ; but when not easily elicitable electrical stimuli altogether fail, while rubbing and other suitable mechanical stimuli still evoke it, though not so readily or vigorously as usual.

A question germane to this is the oft-debated sensitivity of various internal organs. Direct stimulation of various afferent nerves of the visceral system is itself well known to yield reflexes on blood-pressure, etc. But in regard to the sensitivity Figure i. — Rise of arterial pressure produced, in the cat under CHCl and curare, after double vagotomy, by the rapid injection of 2.5 c.c. of saline solution in the common bile-duct, i. g., by distension of the duct. Time marked below in seconds Ccf. Bibliogr. No. 194).

of the organs themselves we have, on the one hand, the passage of bilestones, renal calculi, etc., accompanied by intense sensa- tions, and on the other hand the insensitivity of these ducts and various allied visceral parts as noted by Haller^ and observed by surgeons working under circumstances favorable for examin- ing the question. The stimulation which excites pain in these internal organs is usually of mechanical kind, e.g. calculus, and the surgeon's knife and needle provide mechanical stimuli, and Haller and his co-workers in their research employed multiform stimuli, many of them mechanical in quality. But though mechanical, the latter are remote in quality from the former; the former are distensile. The action of a calculus can be imi- tated by injecting fluid of itself innocuous. Marked reflex effects can then be excited ^^ from the very organs (Fig. i), the cutting and wounding of which remains without effect. For H^lkr's and the surgical experience to be harmonized with the medical evidence from calculi, etc., all that is necessary is that the mechanical stimulation be adequate^ and to be adequate it must be of a certain kind. Thus we see that when the mechan- ical stimulation employed resembles that occurring in the natural accidents that concern medicine, the experimental results fall into line with those observed at the bedside.

Therefore we may infer provisionally — for the facts justify only a guarded judgment — that the part played by the re- ceptor in the reflex-arc is in the main what from other evidence it is inferred to be in the case of the receptors as sense-ox^dSis ; namely, a mechanism more or less attuned to respond specially to a certain one or ones of the agencies that act as stimuli to the body. We may suppose this special attuning acts as does specialization in so many cases, namely by rendering more apt for a certain kind of stimulus and at the same time less apt for stimuli of other kinds. The main function of the receptor is therefore ^^ to lower the threshold of excitability of the arc for one kind of stimulus y and to heighten it for all others. This is quite comparable with the low threshold for touch-sensation under mechanical stimulation applied to a hair (v. Frey) ^"^ contrasted with the high threshold under electrical stimulation of the skin

(v. Frey). Adaptation has evolved a mechanism for which one kind of stimulus is the appropriate, that is, the adequate stim- ulus', other stimuli than the adequate not being what the adaptation fitted the mechanism for, are at a disadvantage. Electrical stimuli are in most cases far the most convenient to use for experimental work, because of their easy control, espe- cially in regard to intensity and time. But electrical stimuli not being of common occurrence in nature, there has been no chance for adaptation to evolve in the organism receptors appropriate for such stimuli. Therefore we may say that electricity never constitutes the adequate stimulus for any receptor, since it is always an artificial form of stimulus, and every adequate stimulus must obviously be a natural form of stimulation. It is therefore rather a matter for surprise that electrical stimuli applied to receptor organs are as efficient excitors of reflexes as they in fact prove to be. It is particularly in regard to a class of reflexes whose receptive cells seem attuned specially to react to nocuous agents, agents that threaten to do local damage, that electrical stimuli are found to be excellently effective. But the conditions of adaptation to stimuli appear here peculiar ; and there will be better opportunity of considering them later.

We infer, therefore, that the main contribution made to the mechanism of the reflex-arc by that part of it which constitutes the receptor is selective excitability. It thus contributes to co-ordination, for it renders its arc prone to reply to certain stimuli, while other arcs not having that kind of receptor do not reply, and it renders its arc unlikely to reply to certain other stimuli to which other arcs are likely to respond. It will thus, while providing increase of responsiveness on the part of the organism to the environment, tend to prevent confusion of re- actions (inco-ordination) by Hmiting to particular stimuli a particular reaction.

On the whole, we may regard the receptor as being con- cerned with the mode of excitation rather than with the features of conduction of the reflex-arc, and may now return to that conduction, which itself has important co-ordinative characters. Nervous conduction has been studied chiefly in nerve-trunks. Conduction in reflexes is of course for its spatially greater part conduction along nerve-trunks, yet reflex conduction in toto difl"ers widely from nerve-trunk conduction.

Salient among the characteristic differences between con- duction in nerve-trunks and in reflex-arcs respectively are the following : Conduction in reflex-arcs exhibits (i) slower speed as meas- ured by the latent period between application of stimulus and appearance of end-effect, this difference being greater for weak stimuli than for strong; (2) less close correspondence between the moment of cessation of stimulus and the moment of cessation of end-effect, i.e.y there is a marked " after-discharge; " (3) less close correspondence between rhythm of stimulus and rhythm of end-effect; (4) less close correspondence between the grading of intensity of the stimulus and the grading of intensity of the end- effect; (5) considerable resistance to passage of a single nerve- impulse, but a resistance easily forced by a succession of impulses (temporal summation) ; (6) irreversibility of direction instead of reversibility as in nerve-trunks ; (7) fatigability in contrast with the comparative unfatigability of nerve-trunks ; (8) much greater variability of the threshold value of stimulus than in nerve- trunks ; (9) refractory period, " bahnung," inhibition, and shock, in degrees unknown for nerve-trunks; (10) much greater de- pendence on blood-circulation, oxygen (Verworn, Winterstein, v. Baeyer, etc.); (11) much greater susceptibility to various drugs — anaesthetics.

These differences between conduction in reflex-arcs and nerve- trunks respectively appear referable to that part of the arc which lies in gray matter. The constituents of gray matter over and above those which exist also in nerve-trunks are the nerve-cell bodies (perikarya),^'^ the fine nerve-cell branches (dendritic and axonic nerve-fibres), and neuroglia. Neuroglia exists in white matter as well as in gray, and there is no good ground for attributing the above characteristics of con- duction in reflex-arcs to that part of the arcs which consists of white matter. It is improbable, therefore, on that ground that the features of the conduction are due to neuroglia. Indeed there

no good evidence that neuroglia is concerned directly in lervous conduction at all. As to perikarya (nerve-cell bodies) the experiment of Bethe^"* on the motor perikarya of the ganglion of the second antenna of Carcinus, and the experiments of Steinach^^ on the perikarya of the spinal-root ganglion, also the observation by Langley ^^^ that nicotin has little effect when applied to the spinal-root ganglion, though breaking conduction in sympathetic ganglia, all indicate more or less directly that it is not to the perikarya that the characteristic features of reflex- arc conduction are referable. Similarly, the experiments of Exner,'^ and of Moore and Reynolds,*^^ detecting no delay in transmission through the spinal-root ganglion, — though observa- tions by Wundt *' and by Gad and Joseph ^^ had a different result, — withdraw from the perikaryon the responsibility for another feature characteristic of reflex-arc conduction. Again, histolog- ical observations by Cajal, van Gehuchten, and others, indicate that in various cases the line of conduction may run not through the perikaryon at all, but direct from dendrite stem to axone.

As to the nerve-cell branches (dendrites, axones, and axone- collaterals) which are so prominent as histological characters of gray matter, they are in many cases perfectly continuous with nerve-fibres outside whose conductive features are known by study of nerve-trunks, and they also are themselves nerve-fibres, though smaller in calibre than those outside. It seems therefore scarcely justifiable to suppose that conduction along nerve-fibres assumes in the gray matter characters so widely different from those it possesses elsewhere as to account for the dissimilarity between reflex-arc conduction and nerve-trunk conduction respectively.

In this difficulty there rises forcibly to mind that not the least fruitful of the facts which the cell-theory rests upon and brings to- gether is the existence at the confines of the cells composing the organism of " surfaces of separation " between the adjacent cells. In certain syncytial cases such surfaces are not apparent, but with most of the cells in the organism their existence is undisputed, and they play an important r6le in a great number of physio- logical processes. Now in addition to the structural elements

of gray matter specified above, there is one other which certainly in many cases exists. The gray matter is the field of nexus between neurone and neurone. Except in sympathetic ganglia, the place of nexus between neurone and neurone lies nowhere else than in gray matter. We know of no reflex-arc composed of one single neurone only. In other words, every reflex-arc must contain a nexus between one neurone and another. The reflex-arc must, therefore, on the cell-theory, be expected to include not only intracellular conduction, but intercellular con- duction. But on the current view of the structure of the nerve- fibres of nerve-trunks the conduction observed in nerve-trunks is entirely and only intraceWulsLr conduction. Perhaps, therefore, the difference between reflex-arc conduction and nerve-trunk conduction is related to an additional element in the former, namely, ^"«/^n:ellular conduction. If there exists any surface or separation at the nexus between neurone and neurone, much of what is characteristic of the conduction exhibited by the reflex- arc might be more easily explicable. At the nexus between cells if there be not actual confluence, there must be a surface of separation. At the nexus between efferent neurone and the muscle-cell, electrical organ, etc., which it innervates, it is generally admitted that there is not actual confluence of the two cells together, but that a surface separates them ; and a surface of separation is physically a membrane. As regards a number of the features enumerated above as distinguishing reflex-arc conduction from nerve-trunk conduction, there is evi- dence that similar features^ though not usually in such marked extent y characterize conduction from efferent nerve-fibre to efferent orgatty e. g.y in nerve-muscle preparation, in nerve-electric-organ preparation, etc.

Here change in character of conduction is not due to perikarya (nerve-cell bodies), for such are not present. The change may well be referable to the surface of separation admittedly existent between efferent neurone and effector cell. If the conductive element of the neurone be fluid, and if at the nexus between neurone and neurone there does not exist actual confluence of the conductive part of one cell with the conductive part of the other, ^.^. if there is not actual continuity

of physical phase between them, there must be a surface of separation. Even should a membrane visible to the microscope not appear, the mere fact of non-confluence of the one with the other implies the existence of a surface of separation. Such a surface might restrain diffusion, bank up osmotic pressure, restrict the movement of ions, accumulate electric changes, support a double electric layer, alter in shape and surface- tension with changes in difference of potential, alter in difference of potential with changes in surface-tension or in shape, or inter- vene as a membrane between dilute solutions of electrolytes of different concentration or colloidal suspensions with different sign of charge. It would be a mechanism where nervous con- duction, especially if predominantly physical in nature, might have grafted upon it characters just such as those differentiating reflex-arc conduction from nerve-trunk conduction. For in- f stance, change from reversibility of direction of conduction to irreversibility might be referable to the membrane possessing irreciprocal permeability. It would be natural to find in the arc, each time it passed through gray matter, the additive intro- duction of features of reaction such as characterize a neurone- threshold (Goldscheider).^^'^ The conception of the nervous impulse as a physical process (du Bois Reymond) rather than a chemical, gains rather than loses plausibility from physical chemistry. The injury-current of nerve seems comparable in mode of production (J. S.

Macdonald) ^^ with the current of a " concentration cell," a mode of energy akin to the expansion of a gas and physical, rather than chemical, * volume-energy.* Against the Hkelihood of nervous conduction being pre-emi- nently a chemical rather than a physical process must be reck- oned, as Macdonald well urges, its speed of propagation, its brevity of time-relations, its freedom from perceptible tempera- ture change, its facile excitation by mechanical means, its facilitation by cold, etc. If it is a physical process the inter- calation of a transverse surface of separation or membrane into the conductor must modify the conduction, and it would do so with results just such as we find differentiating reflex-arc con- duction from nerve-trunk conduction.

As to the existence or the non-existence of a surface of separation or membrane between neurone and neurone, that is a structural question on which histology might be competent to give valuable information. In certain cases, especially in In- vertebrata, observation (Apathy, Bethe, etc.) indicates that many nerve-cells are actually continuous one with another. It is note- worthy that in several of these cases the irreversibility of direc- tion of conduction which is characteristic of spinal reflex-arcs is not demonstrable ; thus the nerve-net in some cases, e.g. Medusa, exhibits reversible conduction (Romanes, Nagel, Bethe, and others). But in the neurone-chains of the gray-centred system of vertebrates histology on the whole furnishes evidence that a surface of separation does exist between neurone and neurone. And the evidence of Wallerian secondary degeneration is clear in showing that that process observes strictly a boundary between neurone and neurone and does not transgress it. It seems therefore Hkely that the nexus between neurone and neu- rone in the reflex-arc, at least in the spinal arc of the vertebrate, involves a surface of separation between neurone and neurone ; and this as a transverse membrane across the conductor must be an important element in intercellular conduction. The characters distinguishing reflex-arc conduction from nerve- trunk conduction may therefore be largely due to intercellular barriers, delicate transverse membranes, in the former.

In view, therefore, of the probable importance physiologically of this mode of nexus between neurone and neurone it is con- venient to have a term for it. The term introduced has been synapse}'^ The differences between nerve-trunk conduction and reflex- arc conduction are so great as to require for their exhibition no very minute determination of the characters of either ; but we may with advantage follow these differences somewhat further. In doing so we may take the reflexes of the hind limb of the spinal dog as a field of exemplification.