Conditioned Reflexes: An Investigation of the Physiological Activity of the Cerebral Cortex

To sum up, we may legitimately claim the study of the formation and properties of conditioned reflexes as a special department of physiology. There is no reason for thinking about all these events in any other way, and it is my belief that in these questions prejudices blunt the intellect and that generally speaking the preconceptions of the human mind stand in the way of any admission that the highest physiological activity of the hemispheres is rigidly determined. The difficulty is mainly due to the tremendous complexity of our subjective states; and, of course, these cannot yet be traced -to their primary causations.

Fie. 2—The upper tracing is a record of a conditioned salivary reflex to a tone of 637-5 d.v. The tone lasted 30 seconds—began at the first and ended at the second downward mark. The third mark shows the beginning of the unconditioned stimulus. Each mark upwards=1 drop =0-01 c.c. Each bigger mark=to each tenth drop. Reflex=68 drops. The lower tracing is a similar record, but the tone is continued for 60 seconds. Reflex =128 drops. (Experiments by Dr. Anrep.)

Fie. 3.—The s TO built for the study of conditioned reflexes, Institute of Experimental Meicme, Petrograd, The formation of conditioned reflexes by means of conditioned and direct stimuli. Agencies which can be used as conditioned stimult.—Inhibition of conditioned reflexes : external inhibition. In the previous cases a conditioned reflex was obtained by linking up the action.of a new stimulus with an unconditioned reflex. It is possible, however, to obtain a conditioned reflex less directly, by linking up yet a further stimulus with a conditioned stimulus which is already firmly established. Let us refer again to our experiment with the metronome. The sound of the beats was a conditioned stimulus so firmly and powerfully established as readily to admit of demonstration in face of the large audience present at my lecture. The effect of the metronome even under such unfavourable conditions was complete and precise. With the help of this strong conditioned stimulus it has been found possible to give still another stimulus conditioned properties like the first. For if some new and more or less neutral stimulus is applied in conjunction with the m A alone—i.e. not at the same time giving food—this new Ju also acquires the character of an alimentary conditioned lus [Drs. Zeliony, Foursikov, Frolov].

Conditioned reflexes established in this secondary conditioned reflexes, and I shall È certain precautions which must be ogey x for the successful establishment of reflexes of this aae a e essential condition is that the new stimulus should be wit n some seconds before the primary stimulus is applied. iet stimuli of a medium physio- logical strength this lapse of ti st be not less than ten seconds, while for stronger stimuli t al must be considerably increased. Any shortening of the ingadyded. minimal interval of time leads to a quite different result ing a group of extremely delicate and interesting phenomen the physiology of the hemispheres, which will be treated ifghO fifth lecture.

dog has two primary alimentary conditioned stimuli firmly estab- lished, one to the sound of a metronome and the other to the buzzing of an electric bell. The appearance of a black square in the dog’s line of vision is now used as yet a further stimulus, which is to be given the character of a secondary conditioned stimulus. The black square is held in front of the dog for ten seconds, and after an interval of fifteen seconds the metronome is sounded during 30 seconds. In the table given below the square is presented for the tenth time.

The metronome and the buzzer were continued during 30 seconds in each case. Prior to these experiments the appearance of the black square had no secretory effect at all. As seen from the above table the conditioned reflex of the second order is measured vey at this early stage of its development by 5} drops (2-5 plus owing 25 seconds. It was found impossible in the case of-@Mmentary reflexes to press the secondary conditioned stimulys (WS our service to help us in the establishment of a new conditiongd\stimulus of the third order. Conditioned reflexes of the third or ey mn however be obtained with the help of the second order Qf ténditioned reflexes in defence reactions such as that against eee of the skin by a strong electric current. But even is case we cannot proceed further than a conditioned reflex i third order.

I shall describe t 673) ts of an experiment of Dr. Foursikov illustrating a conditia reflex of the third order : The unconditioned stimulus to a def eaction in a dog was given by the application of an electric stitlus to the skin over the front paw. A mechanical stimulation’ ghe skin over the hind paw to which the dog was formerly è indifferent had been converted by the usual procedure into WN itioned stimulus of the first order, while for the establish-

ment of the second order of reflex a sound of bubbling water had been employed. By combining with the sound of bubbling water a tone, previously indifferent, of 760 double vibrations per second, a con- ditioned stimulus of the third order was now established. In these conditioned, reflexes, passing from the first io the third order, the latent period progressively increases. In the same order we pass from the strongest to the weakest conditioned defence reflex. All these conditioned reflexes were maintained by Dr. Foursikov by means of appropriate reinforcement for over a year, but here again many attempts to combine a still further stimulus with the con- ditioned stimulus of the third order were quite unsuccessful.

So far we have discussed two distinct modes of formation ‘of a conditioned reflex, one in which it is based directly upon an uncon- ditioned reflex and the other in which it is based upon another conditioned reflex which has already been firmly established. There is, however, yet another method of establishing conditioned reflexes. We were led a considerable time ago to perform experiments of the following type: A dog was given a small dose of apomorphine subcutaneously and after one or two minutes a note of a definite pitch was sounded during a considerable time. While the note was still sounding the drug began to take effect upon the dog : the animal grew restless, began to moisten its lips with its tongue, secreted saliva and showed some disposition to vomit. After hes menter had reinforced the tone with apomorphine se imes it was found that the sound of the note alone suffic Q Ta all the active symptoms of the drug, only in a less dd@eé [experiments

of Dr. Podkopaey]. Unifortanately, Dr. Po v was. prevented from pursuing his experiments and extendj m by modifications in technique. However, quite recently, lov, of the Tashkent Bacteriological Laboratory, has madeome interesting observations bearing on this matter, in the cour certain serological investi- gations, when he had occasion O to inject morphine into dogs hypodermically. It is nown that the first effect of a hypodermic injection of Jis to produce nausea with profuse secretion of saliva, folloy y vomiting, and then profound sleep. Dr. Krylov, ee) rved when the injections were repeated regularly that afte 6 days the preliminaries of injection were in themselves es to produce all these symptoms—nausea, secretion of s mo) , vomiting and sleep. Under these circumstances the symp S re now the effect, not of the morphine acting through

the blood stream directly on the vomiting centre, but of all the external stimuli which previously had preceded the injection of morphine. The connection between the morphine itself and the various signals may in this instance be very remote, and in the most striking cases all the symptoms could be produced by the dogs simply seeing the experimenter. Where such a stimulus was in- sufficient it was necessary to open the box containing the syringe, to crop the fur over a small area of skin and wipe with alcohol, and perhaps even to inject some harmless fluid before the symptoms could be obtained. The greater the number of previous injections of morphine the less preparation had to be performed in order to evoke a reaction simulating that produced by the drug. Dr. Krylov was able to demonstrate these facts quite easily in my laboratory. In a series of experiments specially adapted to the purpose he showed that the phenomena described are absolutely identical with con- ditioned reflexes. The experiments readily lend themselves for lecture demonstration.

Demonstration.—The dog has repeatedly been injected with morphine on previous occasions, and is now held quietly on the table by an attendant who has never had anything to do with injecting the morphine. When the experimenter approaches, the dog gets restless and moistens its lips, and as soon as the experimenter touches the animal, severe nausea and profuse secretion of sąliva begin. This experiment provides a clue to the well- eNet that dogs will eat meat the first time it is offered them, emoval of their parathyroids, or after an Eck fistula and t Of the portal vein, but on all subsequent occasions refuse it. idently in these cases the appearance and smell of meat pro Of themselves a reaction identical with that produced BAGA ect pathological action in the absence of the ving konge e portal circulation, by those

All this brings us to thg Mportant question of the intimate mechanism by which ne rvous connections are established in the hemispheres. It js to suggest an explanation on the basis of the actual facts a YX are known at present. Any unconditioned, or any firmly e ed. conditioned, stimulus undoubtedly evokes a state of nervolSctivity in some definite part of the brain. Using the general Scepted terminology, let us refer to such areas of the brain as Ove not however thereby implying any idea of ana-

tomig alization, During the period of excitation of such centres all other external stimuli which happen to affect the animal are conducted to these centres, and the paths by which they are con- ducted through the hemispheres become thereby specially marked out. This is the only possible interpretation of the facts, and upon this interpretation was planned the series of experiments with apomorphine which have just been described as corroborating so thoroughly the experiments of Dr. Krylov with morphine. Arguing that excitations set up in the cells of the cortex were constantly transmitted to the salivary centre when this was reflexly excited to activity by external agencies, we had to expect a precisely similar phenomenon to take place when the centre was stimulated directly (i.e. automatically) by changes in the internal environment due- to alterations in the composition of the blood. Excitations set up in the cortex would now also be transmitted to the salivary and to the vomiting centres. This assumption was fully justified in the sequel.

The facts dealt with so far reveal another important feature of this mechanism, namely, that such external stimuli as have been from the very birth of the animal transmitted to a definite centre, can, notwithstanding, be diverted and made to follow another route, becoming linked up by the nervous connection to another centre, provided always that this second centre is ‘ paysiologicaliy, more powerful than the first. This linking up of impulses in different areas of the ve rain, by the formation of new nervous connections, is the first Lipset hanism we have encountered in our study of the physiolg the hemi- spheres. The question as to the site where this ervous connec- tion occurs has not yet been clearly answered 9) within the cortex exclusively, or does it take place see and the sub- cortical areas ? Both possibilities are Cuvable. In the latter case it must be assumed that when ae its, one in the cortex, the other in a subcortical area, are si eously excited by different stimuli, a path is established ca transmission of the excitation

direct from the former point t latter. If on the other hand the WY thin the cortex, it is necessary to eptor organs (including internal recep- tors) of the organis represented in the cortex, in which case impulses originatipg different organs during their activity would be transmi to the corresponding cortical point, which would then enter Be sina with a point excited by the external stimulus, that stimuli which lead to activity of an organ gain direct representation in the cortex independently of the simultaneous excitation of a subcortical area. Of the two last mentioned alter- natives I have reason to believe that the latter represents what probably takes place in the intact brain when the hemispheres are in a state of alertness. In any case it appears that the cells predomi- nantly excited at a given time become foci attracting to themselves the nervous impulses aroused by new stimuli—impulses which on repetition tend to follow the same path and so to establish con- ditioned reflexes. |

We must now take some account of the agencies which can be transformed into conditioned stimuli. This is not so easy a problem as appears at first sight. Of course to give a general answer is very simple ; any agent in nature which acts on any adequate receptor apparatus of an organism can be made into a conditioned stimulus for that organism. This general statement, however, needs both amplification and restriction. We can, in the first place, divide up natural agencies into their ultimate component parts as regards their properties as physiological stimuli. Even a very small single component of such agency may acquire in itself the properties of a conditioned stimulus. Such, for example, may be a very small variation in loudness of a tone, or a small and barely distinguishable variation in luminosity, and so on. In this way alone the number of potentially effective stimuli in nature is extended almost in- definitely, although it is also obvious that a limit j o the fineness of gradation of such stimuli by the degree of itivity and per- fection of the peripheral receptor organs oi QF breanism On the other hand, the animal may be affected RG sum total of numerous elementary stimuli acting together a ole. For example, i distinguishing facial appearance we R account TE iea con form, dimensions, shades, colo e behave very much in the same way when making out maa in a more or less familiar neighbourhood. Such exangjes*of compound stimuli can be multi- plied indefinitely, and w e consider the unlimited possibilities of grouping the very umber of single elementary stimuli, we shall arrive at a ver midable figure. Yet in this case also a limit is undoubtedly ¢ ed by the intrinsic structure of the cerebral hemispheres the ves. But I wish at present only to give some

idea of the RDidle number of conditioned stimuli, leaving a more detailed A Qon of this important matter to a subsequent lecture. stimuli, namely those derived from the appearance of any natural agency. But the disappearance also of such an agency may become the stimulus to a conditioned reflex. Let us take the following example as an illustration. A metronome is sounding continuously in the experimental laboratory when the dog is brought in. The sound of the metronome is now cut out, and immediately an uncon- ditioned stimulus, say food or a rejectable substance, is introduced. After several repetitions of this procedure it is found that the dis- appearance of the sound has become the stimulus to a new conditioned reflex [Dr. Zeliony and Dr. Makovsky].

Not only can the cessation of a stimulus be made the signal to a conditioned reflex, but also a diminution in its strength, if this dimi- nution is sufficiently rapid. The effect of rate of change of some property of a stimulating agent is well brought out in the following experiment by Dr. Zeliony. The sudden stoppage of a powerful pneumatic tuning fork D--2 had been made into the signal for a conditioned alimentary reflex, which was measured by 32 drops of salivary secretion during the test interval; but a gradual damping down of this tone over a period of 12 minutes, though ending in complete extinction, did not yield a single drop of saliva. So we see that not only can the appearance of some external agency act as a conditional stimulus, but its disappearance also, or the rapid weaken- ing of its strength. Thus the number of potential stimuli to a con- ditioned reflex is once more greatly increased.

The next group of conditioned stimuli can be S d as a variation, or further development, of the type of sti action which has just been discussed. The sti s this time is not the actual disappearance of an external a ut the trace left by the action of this agent on the centr ous system after the agent itself has been removed. The p e of development of such reflexes is as follows. Any coMyenient external stimulus is applied to the animal and continued Q? to 1 minute. After another definite interval of 1-3 minute yod or a rejectable substance is

introduced, into the mouth. und that after several repetitions of this routine the stim% not itself evoke any reaction ; neither will its disap O: but the appropriate reaction will occur after a defini erval, the after-effect of the excitation caused by the stiprylus being the operative factor. We have to of réflex from the type described previously, ditioned stimulus coincided for part of its duration with the conditioned stimulus. The type described in this paragraph is termed a trace conditioned reflex.

I shall describe here an experiment by Dr. Grossman with trace conditioned reflexes : A tactile stimulation of the skin was employed as a stimulus for the trace reflex to injection of acid. The tactile stimulus was applied during one minute and acid was introduced into the mouth after a further period of one minute. The conditioned stimulus was always reinforced by introduction of acid at the end of the pause. Trace reflexes may be of different character, depending on the length of pause between the termination of the conditioned stimulus and the appearance of the unconditioned stimulus. When the pause is short, being a matter of only a few seconds, they»iQe trace left by the conditioned stimulus is still fresh, and the r is what we may term a short-trace reflex. On the other h if a considerable interval, one minute or more, is allowed pse between the ter- mination of the conditioned and the bed g of the unconditioned stimulus we have a long-trace refle3 all these cases on account of t rey tial peculiarities exhibited by long-trace reflexes.

We come now to the EO) of those agents which can be transformed into a condi i@ed stimulus, and this one is peculiar in that it originates ap tly quite regularly and spontaneously. Its operation depen the fact that every stimulus must leave a trace on the ner stem for a greater or less time—a fact which has long been ķecĝgnized in physiology under the name of after effect. The feyther agency I wish to introduce to you is no less real, but the on apprehension of its nature is apt to present some difficulty

First of all I shall describe an experiment of a general nature. One dog was given food at regular intervals of time ; another had acid introduced into the mouth at the same intervals. After this had gone on for a little time it was found that food or acid was no longer necessary to produce the alimentary or mild defence reflex, but that these reflexes appeared spontaneously at the regular intervals of time. This may be illustrated by the following detailed experiment of Dr. Feokritova: A- dog is placed in the stand and. given food regularly every thirtieth minute. In the control experi- ments any-one feeding after the first few is omitted, and it is found that despite the omission a secretion of saliva with a corresponding alimentary motor reaction is produced at about the thirtieth minute. Sometimes this reaction occurs exactly at the thirtieth minute, but it may be one or two minutes late. In the interval there is not the least sign of any alimentary reaction, especially if the routine has been repeated a good number of times. When we come to seek an interpretation of these results, it seems pretty evident that the duration of time has acquired the properties of a conditioned stimulus.

The experiment just described may be performed with the following modification. The animal can be given food regularly every thirtieth minute, but with the addition, say, of the sound of a metronome a few seconds before the food. The animal is thus stimulated at regular intervals of thirty minutes by a pation of two stimuli, one of which is the time factor and the the beats of the metronome. In this manner a conditioned reff@xSs established to a compound stimulus consisting of the soun the condition of the hemispheres at the thirtieth minute, w th are reinforced by food. Further, if the sound is now not at the thirtieth minute after the preceding feeding, & , at the fifth or eighth

minute, it entirely fails to produc y alimentary conditioned reflex. If it is applied slightly later it\pfoduces some effect ; applied at the twentieth minute the e Qis greater ; at the twenty-fifth minute greater still. At the D minute the reaction is of course complete. If the sound i r combined with food except when applied at the full int n time it ceases to have any effect even at the twenty-ninth nXgyte and will only produce a reaction at the

thirtieth minute— then a full reaction. An illustration is given from experimen Dr. Feokritova: A dog is given food every half-hour, we ing being preceded by the sound of a metronome, which is continued for thirty seconds; the effect of the metronome is tested at the twenty-ninth minute. Of course in the establishment of a conditioned reflex of this type any length of time interval can be employed. No experiments, however, were made with longer intervals than half an hour.

What is the physiological meaning of these time intervals in their role as conditioned stimuli? Only a tentative approach can be made to a definite answer to such a question at present: Time is measured from a general point of view by registering different cyclic phenomena in nature, such for instance as the rising and setting of the sun or the vibration of the pendulum of a clock. But many cyclic phenomena take place inside the animal’s body. In the course of 24 hours the brain receives a very considerable number of stimuli, becomes fatigued, and again restored t gh sleep. The alimentary canal is periodically filled or em ? and, in fact, changes in practically all the component tj and parts of the organism are capable of influencing th@€\cerebral hemispheres. This continuous cycle of direct and Dect influences upon the nervous activity constitutes the phygi cal basis for the estimation of duration of time. We may co the following simple case of physiological registration of srt intervals of time by the hemi- spheres. It is well known thd) 3 fresh stimulus—we will take for example an olfactory sting@jus—produces a very definite nervous excitation. This, how. gradually and progressively weakens. The physiological s Q e nervous elements, under the influence

of the continued ulation, without doubt undergoes a series of simultaneous akd giccessive changes. The same is true for the reverse condition : When a stimulus is withdrawn the change is perceived for es) very acutely, but quite soon its influence diminishes condition of the nerve cells is, doubtless, undergoing the reverse series of changes. From this point of view we can give an inter- pretation of the establishment of conditioned. reflexes to an inter- ruption of a stimulus, and to a trace of a stimulus, as well as, apparently, to a duration of time. In the experiment described the administration of food was accompanied and followed by a definite activity in a large number of organs, which all underwent a series of definite cyclic changes. All these changes were reflected in the cerebral hemispheres where they fell on appropriate receptive fields, and a definite phase of these changes acquired the properties of the conditioned stimulus.

To conclude this part of our discussion I shall suggest the following modification and amplification of our definition of agencies which can become conditioned, viz. that innumerable individual fluctuations in the external and internal environment of the organism may, each and all of them, singly or collectively, being reflected in definite changes in the cells of the cerebral cortex, acquire the properties of a conditioned stimulus. We shall now follow out another important group of phenomena. Hitherto we have been dealing with reflexes of a positive character —j.e. reflexes which ultimately gave rise to positive reactions, both motor and secretory, all of them associated with various processes of excitation in the nervous system. There is, however, another manifestation of nervous activity which is in no way garior in physiological and vital importance to that positive ZW féstation which has just been considered. I refer to ner inhibition. When we come to investigate the highly compl nctions of the cerebral hemispheres, we naturally expect to across inhibitory phenomena, for these are very constantly gaddvpry intimately mixed