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

On the whole the experiments upon conditioned reflexes brought forward in the last three lectures confirm the observations of old and recent authors upon the same problem, though we have also been able to add some new facts and to formulate some new problems. But what our experiments do most emphatically refute is the doctrine of special “association ” centres, or, more generally, of the existence in the hemispheres of some special area on which the higher functions of the nervous system depend—a doctrine which has already been strenuously opposed by H. Munk.

The general characteristics of the present investigation and its special difficulties —Discovery of certain errors necessitating the modification of some earlier interpretations. A SCIENTIFIC investigation of biological phenomena can be conducted along several different lines each of which would treat the problem from a different point of view. For instance, one may have in view the purely physico-chemical aspect, analysing the elements of life by the methods of physics and chemistry. Again, keeping in view the fact of evolution of living matter one can try to elucidate the functions of complex biological structures by studying the functions of individual cells and of elementary organisms. Finally, one can make an attempt to elucidate the activities of complex structures in their fullest range directly, seeking for rigid laws governing this activity, or, in other words, trying to define all those conditions which determine the form this activity takes at every instant and in all its variations. The line of inquiry which has been adopted in the present investigation obviously belongs to the third poj view. In this research we were not concerned with the ulti excitation and inhibition as such. We took them as properties, the two most important manifestati the living nervous elements. Nor was it o to interpret the activity of the hemispheres in terms of el ry functions of the nervous system, as has been done, forgextwfple, in the physiology of the nerve fibres. We intentionallpglsted also the contro- versial problem of the actual localizgtith of these two fundamental processes, and did not attempt ign them to either of the two elements of the nervous IN amely, the nerve cell and the

synaptic junction or fibril connection between two individual nerve cells. The mid ie of the more general conception of the two processes of inhibitħex and excitation as the basic functions of the nervous cellu ructures was sufficient for the purposes of our research, the @idy of conditioned reflexes being of the nature of a general investigation of the functions of the cellular structures of the cortex as exhibited in various reactions of the organism to a multitude of separate stimuli which originate from within or from without the organism—stimuli for the reception of which there is such an unbounded number of separate cortical cells and which after extirpation of the cortex lose their significance for the organism. It is highly probable that excitation and inhibition, the two functions of the nerve cell which are so intimately interwoven and which so constantly supersede each other, may, fundamentally, represent only different phases of one and the same physico-chemical process. The primary aim of our research was the accurate deter- mination and tabulation of different phases of the cortical activity— the absence or presence of an inhibitory or excitatory phase, the exact conditions under which the intensity of the excitatory or inhibitory process varied, and the mutual interrelation between these processes. It is obvious that in its intrinsic nature our work is closely allied to the work of Sherrington and his co-workers upon the spinal cord, and it is impossible not to notice in how many points the different aspects of the nervous activity of the cortex correspond with those described in the physiology of the spinal cord; a fact which seems strong evidence of a similarity of the fundamental laws governing the nervous activity in the two cases.

Research upon the activity of the cortex along these lines must unavoidably present exceptional difficulties. extraordinary reactivity of the cortex, on the one hand, and th be@unded volume of stimuli continually pouring into it, on the hand, are respon- sible for the two fundamental peculiarities e cortical activity— namely, first, that it is determined in y minutest detail, and second, that it is in a state of perpe ay , changing so rapidly that it becomes practically impossible bServe any aspect of it in an . entirely pure and uncontaminat® form and to appraise and control all the determining condition he minutest changes in the en- vironment or inside the pnism itseli—changes which may be imperceptible to us een spected—have a profound effect upon the cortical activiti is obvious that these special peculiarities

of the research a any instances the cause of fallacies, especially since it is so t ing to adhere to different fancied analogies and plausible geyeralizations—a tendency which cannot be too much guarded t in the present state of the research. The mind, so interrelations, and this is why our interpretations were often too limited and led to errors which have had to be constantly corrected. Indeed I have no doubt that the presentation of the subject-matter attempted in these lectures will in the future still be corrected in many details. Errors in interpretation, and errors sometimes in the methods of observation, are naturally to be expected in a study of such astounding complexity. These special peculiarities of our subject is the reason why I thought it advisable to delay a systematic presentation of our prolonged researches until now : new problems are perpetually arising, and at the same time an equally large number of questions are still left unsettled. We often feel compelled to, turn our attention from problems which directly confront us to some un- expected new phenomena which introduce fresh problems or which necessitate a revision of old points of view. This general aspect of the investigation into the cortical activity I want particularly to emphasize in the present lecture, taking for my examples some fresh observations which have not been discussed in the preceding lectures.

The surprising minuteness of detail in which the cortical activity is determined by external and internal agencies, and the extraordinary precision and delicacy of the responsiveness of the cortex to even the minutest changes in these agencies, are clearly illustrated by the two following observations, which are both taken from the later © period of our work. The dog used in the first of these experiments has been referred to in the preceding lectures. It passed thro By e experi- ence of the great flood in Petrograd, and sternage erred for an investigation of a functional disturbance of QO oustic analyser (p. 316). In the course of a month in whi e animal behaved again normally a differentiation of pitch O eloped. During the isolated action of the conditioned stimufgs (TO seconds) the secretory

effect was as much as 5 drops; the Qijierence between the effects of strong and weak stimuli was definite, and the food given in reinforcement was always t with avidity. In the stand the animal stood quietly. KGio introduced an apparently very small modification in the iment, the isolated action of the con- ditioned stimulus being pyòlonged a further 5 seconds. As a result of this the entire Ne ioned activity was immediately disturbed. of the PEO N

Salivary Time Conditioned stimulus| Secretion in Remarks during 10 seconds | drops during 10 seconds Experiment of 24th June, 1926 (experiment after prolongation of the isolated action of the conditioned stimulus). Time Conditioned stimulus | Secretion in Remarks during 15 seconds | drops during 15 seconds 10.28 a.m. Tone, 250 d.v. 7 Alimentary reaction ; takes the food During the interval the animal is very excited 10.34 _,, Lamp 2 Weak alimentary re- action ; takes the food During the interval the

10.54 ,, Lamp l4 entary reaction ; takes the food at once TE A O are Buzzer Turns away; does not The first application of the tioned stimulus in the experiment of 24th June produced a er secretory effect than usual, for the obvious reason that the Gi action of the conditioned stimulus had been TEDAS ther 5 seconds. The alimentary motor reaction in respons¢y AS stimulus was lively, the food being con- sumed at once ;(ev a te promised a normal experiment, and there were so far indications of any special deviation from normal. However, dy during the interval between the first and second stimuli imal showed an unusual state of excitation. This was

followed later on by an obvious paradoxical phase : a strong stimulus (buzzer) failed to elicit the secretory reaction while the motor reflex considerably diminished. The animal on the first application of the buzzer (10.49 a.m:) accepted the food after some delay, and on the second application (11.1 a.m.) did not touch the food at all. A weak stimulus (lamp) nevertheless continued to evoke a secretion (although | a diminished one) and to evoke a motor alimentary response. We returned to the usual length of isolated action of the conditioned stimulus (10 seconds) on the following day. The disturbance, | however, became still more pronounced, the secretory effect being absent throughout the experiment, while the animal turned to the food only after weak stimuli and would not touch it after strong ones. On the third day all reflexes returned to normal, except that the tone which had been the first stimulus employed on the day (24th June) when the isolated action of the stimuli was prolonged, still gave a diminished secretory effect (only a half of its usual secretion during 10 seconds). A further experiment with a temporary prolongation of the isolated action of the conditioned stimuli produced exactly the same pathological state (paradoxical phase) of the animal. These observations provide a brilliant example of the exquisite delicacy in the reactivity of the cortex, showing how considerable may be the effect of such minute changes in the conditions of an

The second dog, also previously mentioned,—‘‘ Braina’’—was | of an extremely inhibitable type, and the same change inke xperi- i mental conditions led to exactly opposite results. “9 dog when left in the stand without application of any stimu ckly became drowsy, with the result that not only Seas gas disappeared. but also reflexes in response to the actua istration of food. For the purpose of overcoming this drowsi des e had used the usual method of abbreviating the isolated %action of the conditioned stimulus to 4-1 second. After three w of this practice the drowsi- ness disappeared, and the dog n jook the food immediately on presentation and consumed it avidity. A prolongation of the isolated. action of the TEN stimulus to 5 seconds revealed the presence of a condition etory reflex. On continuation of the experiments with the Koljted action of 5 seconds the reflex main- tained its strength several days. After this the reflex again diminished and imal once more succumbed to drowsiness. However, it vag sufficient to prolong the conditioned stimulus

effect returned after several repetitions of the prolonged stimulus, and, what is important, it appeared within the first 5 seconds of the experiments with the isolated action of 10 seconds the animal again became drowsy and the secretory conditioned reflex again disap- peared. A further prolongation of the conditioned stimulus to 15 seconds produced a similar effect to that of the first prolongation to 10 seconds, t.e. a temporary return of the alert state and a consider- able conditioned secretion starting well within the first 5 seconds. The same sequence of events was repeated yet twice more on pro- longation of the conditioned stimulus to 20 and 25 seconds. The following is an example of an experiment :

On the next day the isolated action of the conditioned stimuli was prolonged to 20 seconds. two days’ practice with the longer interval : ohgation of the isolated action of the con- ed after a few repetitions a, temporary state the drowsiness. disappeared, and the ion reappeared, starting soon after the beginning of The latter fact shows that the enhanced secretion was not merely due to the prolongation of the period of observation but was the genuine result of a cortical excitation.

We thus see that one and the same change led to opposite effects in the two dogs : in the first it resulted in inhibition, in the second iż abolished inhibition. Most probably the difference in the effects was dependent on the fact that the first animal was alert during the experiments (i.e. in a state of cortical excitation), while the other dog was drowsy (i.e. in a state of cortical inhibition). We are constantly confronted by cases in which pathological changes in the state of the animal are brought about by some unknown secondary conditions. It has repeatedly been mentioned in the preceding lectures that conditioned reflexes to stimuli belonging to different analysers are normally of different magnitude. Remem- bering that the nervous process is considered by present-day physio- logists to be identical in all nerve fibres, and having somehow con- ceived the idea that the difference in our perception of light, sound, etc., must have some physical basis in differences of corresponding cortical elements, we were for a considerable time inclined to attribute the difference in the magnitude of the conditioned effect to individual] peculiarities of the cells of the different analysers. Reinvestigation of the whole question, as has been mentioned already, showed that the differences in the magnitude of the conditioned reactions to stimuli belonging to different analysers, depend fundamentalky upon the intensity of the stimuli themselves (p. 269). This Pyar it will be remembered, was arrived at in the following ger We knew for a long time that in a conditioned SH ODS ON ulus made up of two agencies belonging to different analysers of the stimuli almost invariably overshadows the other, as ci Xi be revealed by testing the individual components Repay y. In such a com- pound our usual auditory stimuli, in t eájority of dogs, over- shadowed visual, tactile and thermal co ents, but in a compound made up of a weakened auditory s: and a strong visual one

This observation proved the difference in response to be to fundamental differences in the cellular structure of t Wi analysers, but to the relative intensity of the individ fh Now, although the above holds good in the majority of s, in some few animals the difference in the magnitude of th €Ohditioned response to different agencies was found to be entir sent. We have already directed considerable attention to the study of this deviation, but we are not yet in a position to state definitely under what special conditions it occurs. Some of the determining conditions are, however, known. These ` special cases depend to some extent upon the general type of the nervous system of the animal—excitable or inhibitable. In the inhibitable type the usual relation between intensity of stimulus and magnitude of effect is especially obvious, occurring practically without exception otherwise than in extreme pathological states. It is true that if the period of isolated action is short there may not be any apparent difference between the effects of strong and weak stimuli, since in the initial stage the effect is practically the same in both cases ; but with a prolongation of the stimulus the secretion augments rapidly in the case of strong stimuli and only slowly in the case of weak stimuli. In the case of excitable and very greedy dogs it is, on the contrary, the abbreviation of the conditioned stimulus which helps to disclose the usual relation between the magnitudes of the effects of weak and of strong stimuli, a relation which may not be apparent when the stimuli are more prolonged.

On account of the immense number of different conditions determining the different states of activity of the cortex I feel that even now the physiological analysis of many seemingly simple and well-known facts is very often far from perfect. I will describe, for example, the observations upon one of our recently acquired animals [experiments of Drs. Podkopaev and Virjikovsky}\In this case the conditioned reflexes to different agencies wer&Qevéloped with the following important variation in the usual d. The first agent to which conditioned properties were to iven was applied alter- nately with and without reinforceme food. The conditioned reflex developed comparatively qui (by the 20th application). In the case of the next stimulus the rpifforcement was given at every third application. The reflex developed even quicker than before (by the 7th application). TReJanimal became, however, extremely excited. Finally a third ont was reinforced only at every fourth application, and in thj e the conditioned reflex failed to develop and the animal b somewhat drowsy. The last stimulus was applied a total times (60 times in conjunction with food).

Let us, ha¥ing recourse to all our previous knowledge, endeavour to interpretythese facts. Why, in the last case, did the conditioned reflex fai evelop ? or, at any rate, why was it for so long delayed, if, NER / it would have developed at all? The fundamental mechanism of development of-a conditioned reflex depends upon excitation of some definite point in the cortex coincidently with a more intense excitation of some other point, probably also of the cortex, which leads to a connection being formed between these two

` points; and reversely, if such a coincident stimulation of these points is not repeated for a long time the path becomes obliterated and the connection disrupted. But when once such a path has been firmly established it remains intact without further practice, for months and years. It is obvious that under suitable conditions a new connection must be formed at the very first occurrence of the simultaneous excitation and become strengthened by every repetition. In ordinary experiments with normal dogs about twenty reinforced repetitions are required to establish the first of any conditioned reflexes experimentally produced, and this number sufficed in the first variation (alternate reinforcement) described above. In the establishment of subsequent reflexes under normal conditions only three to five repetitions are necessary, and yet in the case now under discussion (reinforcement of every fourth ap- plication) sixty repetitions produced no result. The first possible explanation is the prolongation of the interval between the separate reinforcements, but this cannot be the reason in our case since with the same intervals of time, but omitting the non-reinforced applica- tions during the intervals; the conditioned reflex invariably and quickly develops. It is obvious, therefore, that the frequ tion of the non-reinforced agent must oppose a power sistance

every new ‘stimulus which evokes the investig reflex ceases on repetition to have any effect unless the stimu as been followed up with some other reflex. Such a disap ce of, the effect is known to be due to a development of, inkibition in those cortical elements upon which the stimulus act A aca in the third variation of the experiment such an inkition might have developed on account of the application o re non-reinforced stimuli, the cortical elements never acquiri OY. the fourth, reinforced stimulus a sufficient state of excitati Cay a connection to be formed with the excited alimentary Aus elements. But although such an

interpretation seemed AigWly plausible it failed when subjected to the following experf@pntal test. When the stimulus had been repeated 240 tim times with reinforcement) a pre-established conditioned Ñ us was applied 30 seconds after the ineffective stimulus. No inhibitory after-effect. was. ever observed. Obviously, therefore, the ineffective agent could not have produced any wide- spread inhibition. It was still possible, however, that on account of prolonged practice the inhibitory effect had become extremely concentrated in a narrow region ; but neither was this explanation supported by our experiments, for when we now began to reinforce the agent at each successive application the conditioned secretory effect was already considerable at the third reinforcement, showing that the rate of development of the new conditioned reflex was maximal. We cannot, therefore, regard the stimulus as having had any definite inhibitory properties. Several further possible explana- tions have also been tested experimentally, but we have hitherto failed to disclose the nature of this phenomenon. So far, our experi- ments simply show that we have not yet gained command over all the conditions which determine the development of conditioned reflexes. The conditions enumerated in the second lecture, however sufficient they may be as regards the development of all those reflexes with which we have been accustomed to deal, nevertheless do not finally exhaust the subject, since having had all of them in our mind

‘we have still failed to understand the results of the experiments described above. There must exist some further condition which has up to the present been overlooked. This failure only serves to demonstrate once more the surprising extent to which, in every detail, the cortical activity is determined, ane astonishing reactivity of the cortical elements. It was, of course, obvious from the that there was no immediate possibility of attacking the c x activity of the cortex from its physico-chemical aspect. mMher did there appear to be any real hope of approaching erstanding of the cortical activity through the study of theéglefréntary properties of the nervous tissue. We have come now t that we do not possess even yet a full descriptive knowledgeyof the various aspects of this activity. Our chief task in site cortical activity at the present time i t ducing the tremendous mass of various terms of a progressively diminishing number ndamental units. This we have fully realized, we seem to be approaching our goal, but in other

must therefore con separate observati of general and ior and in some gas cases we fi urselves confronting some entirely new aspects of the cortj QXrtivity, which sometimes are within, and at other times In the beginning of the present research, on the basis of very definite but purely external signs, we distinguished three types of inhibition—external inhibition, internal inhibition, and sleep. Accumulation of further observations permitted us to fuse the Jast two types by showing that the apparent differencesare only secondary. Sleep and the various forms of internal inhibition are aspects of one and the same process, which in the one set of cases is fragmented and localized, in the other case diffused. When in the course of our further investigation of conditioned reflexes we met with the phenomenon of mutual induction, it was natural that we should perceive the similarity between negative induction and external inhibition. Hence a fundamental identity of all the three types of inhibition appeared very probable, and special efforts were directed to the collection of further evidence on the point. Some of this evidence has been given before, and fresh evidence will be added in the present lecture. In the lecture upon induction an experiment was described in which a conditioned defence reflex to a tactile stimulation of a place on the skin exerted an inhibitory after-effect upon a conditioned alimentary reflex to tactile stimulation of other places. We found reason to believe that this inhibition was in part cortical (p. 202). In the lecture upon different transition phases between the alert state and sleep it was shown that some of these phases can be observed not only during the after-effect of internal (differential) inh{bition, but also under the influence of external inhibition (p. . Ll am now in a position to add some further considerations @y avour of the identity of internal and external inhibition. W.

inclined to regard the frequent'y mentioned fact of overshad in a compound conditioned stimulus of the weaker by the Sa component as based upon external inhibition. The ae, elements belonging to the strong stimulus inhibit those of qhe“weak stimulus, and the latter, therefore, can establish only oe connection with the unconditioned centre. This theory ¿ẹ substantiated by the fact that the strengths of newly establish nditioned connections depend on the relative strengths of t Na tioned stimuli. This considera- tion obviously approximat SS more the phenomenon of external inhibition to negative grabalion in which the application of the positive conditioned sti®ẹflus reinforces, or even re-establishes, the inhibitory state of th€Dervous elements acted upon by the inhibitory stimulus. Man Ory collaborators [Drs. Mishtovt, Krjishkovsky and Leporsk: Diced that for a quick and complete establishment

of a conditioned inhibitor it is of considerable importance to choose a stimulus which is not much weaker in strength than the positive component of the combination. Recent experiments performed in this connection by Dr. Foursikov not only corroborate these obser- -` vations, but bring out the important fact that the external inhibition which on account of the investigatory reflex is produced at the first application of the new stimulus, often gradually and almost imper- ceptibly undergoes transition into the permanent conditioned inhibition. In spite of the cumulative effect of the foregoing evidence it is by no means conclusive, and I feel entitled to advance the view, that external and internal inhibition are fundamentally the same, only as a strong probability.

It was noticed in the nineteenth lecture that three different types of external stimuli lead to an inhibitory state of the cortex, namely, very weak stimuli, very strong stimuli, and unusual stimuli, and an attempt was made to give a general biological interpretation of this effect. The physiological mechanism of the effect of these stimuli is as yet obscure, neither do I find it possible to discuss the problem of inhibition in its entire range. The experimental material, although considerable, is not yet sufficient to establish any general and definite conception of the nature of inhibition and its relation to excitation. Explanations which seem to fit some one group of phenomena fail when applied to other groups.. Matty observations do not fit in with any of the theories, and N eption of the mechanism involved has had to be changed may imes in the course of our research, never entirely satisfactorily\ Here again, as in the whole of our research, we can only c and systematize facts. The fact that very powerful and ver k stimuli have a stronger tendency than medium stimuli Pour inhibition belongs to the category of unsolved problemalotfig with the mechanism of dis- inhibition, the positive effec negative stimuli in the “ ultra- paradoxical phase ” and th», negative effect of positive stimuli in the case of damage to an In many instances we fail even to see which of tha@s ena are closely related to each other and which are is and radically different. To illustrate the difficulty of su¢h qXSes I shall attempt to deal with the question of the productign of inhibition by new events or a rearrangement in the goat old events. We change, for example, the manner in whic conditioned stimulus is reinforced by food. Instead of XS automatically moving with food from behind a screen,

a measured amount of food is now delivered mechanically into a stationary plate. Many dogs after this change persistently decline the food, and all conditioned reflexes disappear. This, of course, is a case of inhibition, but what explanation can be suggested as to its mechanism ? It may be compared with an observation discussed in the thirteenth lecture where a change in the sequence of a series of conditioned stimuli led in some animals to a more or less pro- found inhibition of the entire conditioned activity—an inhibition which lasted for several days, notwithstanding that a return was made to the previous order of stimulation. What happens here with a small number of conditioned stimuli can well be imagined to take

. place in respect to the entire environment. Constant repetitions of external events. in a stereotyped order may lead to a definite stereotyped pattern of activity in the cortex, each new distribution of the stimuli now producing a disturbance in the pattern of the cortical activity, leading to inhibition in exactly the same manner as in our experiments with alteration in the sequence of the conditioned stimuli. This comparison does not, however, explain the mechanism of the development of inhibition in this particular case. Was it a result of the investigatory reflex due to the change in environment, or are the investigatory reflex and this very prolonged inhibition two independent phenomena? In favour of the first supposition the fact can be advanced that in very inhjbitable dogs the investigatory reflex exercises an extraordinaril gripneed inhibitory after-effect. XS

The whole subject of conditioned reflexes has, continuously growing and expanding during the ty-five years of its existence. The present lecture should sh the reader the exceptional difficulties we still meet with. ee difficulties, though some of them now seem trivial, res ed us throughout ; even in‘our comparatively early mat we still find scope for revision, and for the correction of di nt, sometimes important, errors. I shall discuss one of which was discovered and corrected in repeating some ol iments during the preparation of these lectures, and anoth ich is still beng investigated.

In the fourth lectur C% different modes of re-establishment of extinguished Go reflexes were described. In the first, spontaneous. recovery acourred after a longer or shorter interval of rest ; such rec Sy was slow in developing, but stable. In the second, quick eOr was brought about with the help of reinforce- ment by the underlying unconditioned reflex. In the third, quick recovery was effected through the introduction of some extraneous reflex. The recoveries in the last two cases were described as fundamentally differing from one another, since the former was not only rapid, but also stable, whereas the latter, though equally quick, was only temporary—vanishing with the disappearance of the extraneous reflex and its after-effect, when the inhibition would again acquire its full intensity and maintain itself until the final recovery occurred spontaneously, just as if no extraneous stimulus had ever intervened. The term “ dis-inhibition” was therefore applied only to the latter case. The difficulty of interpreting the mechanism of this difference was immediately recognized. Recently during experiments upon some new aspects of the relation between the conditioned and the unconditioned stimulus these old observa- tions were repeated, and found to be inaccurate [experiments of Dr. Podkopaev].

The recovery of an extinguished conditioned reflex is found in both cases to be temporary—in the case of the special reinforcing agent as well as under the influence of an extraneous reflex. In both cases the extinguished conditioned stimulus recovers its positive effect only for a time, then the positive effect again disappears, recovery occurring spontaneously. When the extinguished con- ditioned: reflex is alimentary while the extraneous qne is a defence reflex based.on acid, the extent and duration re disinhibition can be seen with great ease and regularity t dentical which- ever method of restoration is employed. experiments were conducted on two dogs, and they entirely boratea one another. I shall describe the experiments on o the dogs in detail. On extinguishing the conditioned ali reflex to a metronome it was found that the reflex remaine zero for 20 minutes counting from the last non-reinforced gestion of the conditioned stimulus. Then spontaneously the reflex bégan slowly to recover, reaching at the thirtieth minute 40% s original value. After a fresh extinc- tion to the first zer onditioned stimulus was immediately reinforced, but it ain found twenty minutes later to give a