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

point experiments were ead i) A firmly established condjti stimulus was superimposed. on the background of the men unconditioned stimulus, t.e. the unconditioned stimul S$ applied first and the previously established conditioned lus was applied only after the effect of the unconditioned lus had become apparent. This mode of experimentation continued for several weeks or months on many dogs. T, ts were without exception uniform : the con- ditioned reflex er kept its original strength, but either weakened considerab. else disappeared altogether. The ger and the more practised the conditioned reflexes were+ Os more slowly they disappeared under this treatment,

whereas weak and recently established reflexes lost their conditioned properties very quickly. The following experiment by Dr. Solovei- chik gives an illustration of this case. The dog employed had many strongly developed alimentary conditioned reflexes, each of which gave upwards of 20 drops of saliva during 30 seconds. The establishment of a new reflex to a hissing sound was now begun. This reflex developed very quickly, and counting from the sixth application to the eleventh it gave secretions of 10, 8, 13, 9, 9 and 104 drops during 30 seconds. Altogether only eleven reinforce- ments were made, after which the conditioned stimulus of the hissing sound was superimposed upon the unconditioned. The application was repeated in this way fifty-four times in the course of thirty-two successive days. The following table shows the trial of the hissing

Salivary Secre- Time Conditioned stimulus applied tion in drops Motor reaction during 30 seconds durin 30 seconds ministration of food — 2.03 45 Hissing sound before ad- Taygstgatory ministration of food 0 eg only 5 ie eae Metronome 16 jmentary It is thus clear that the administration e unconditioned stimulus results in an inhibitory state of cortical elements on which the conditioned reflex depends—¢hese’ cortical cells becoming temporarily unresponsive to their re exciting stimulus. The above experiment does not, howeyey, tisclose the inner mechanism determining the difference in nee development of inhibition of the cortical elements in RG einforcemenht and non-reinforce- ment.

The sum of all epa of action of a positive stimulus required for the develdgment of inhibition without reinforcement is usually tapomp Aes than that of the periods of isolated action of the same stim ith reinforcement. It follows therefore that the transition KO cortical elements into an inhibitory state is not determined by the aggregate duration of the isolated stimulus. It is, however, probable that the excitation in the case of non- reinforcement persists for a long time after the cessation of the isolated action of the conditioned stimulus, while in the case of rein- forcement the excitation is curtailed from the beginning of the unconditioned stimulus. The aggregate duration of the excitation produced by the stimulus may, therefore, be the determining factor, but other explanations are possible and the matter cannot be decided without further experimentation.

The fundamental fact in all these experiments, which repeats itself time after time, is the transition sooner or later into inhibition of the state of the cortical elements acted upon by the conditioned stimulus. So far as concerns all the experimental evidence at our disposal up to the present, this- transition must be regarded as depending on a functional exhaustion of the cortical elements as a result of their activity in response to a stimulus. Such an exhaus- tion would obviously be dependent upon the duration and intensity of this activity. On the other hand it is also obvious that the process of inhibition cannot be regarded as identical with such functional auto-destruction of the cortical elements, since a state of inhibition which is initiated in an active cell spreads to other cortical elements which were not active and which were not therefore functionally exhausted.

The rate at which cortical elements become cag to inhibition in the case without reinforcement fits in with tQéyéxtreme sensitivity which they exemplify in their extreme oe constant nutrition, being, as is well known, finally and LO) rably destroyed by an arrest of the blood supply far sone any other tissue of the body. It is in complete harmo with the conception of the cerebral cortex as a signalling 4pparatus. The fact that the uncon- ditioned stimulus which is © lied induces during-its action an inhibition in the cortex iggenly an artistic finishing touch to the efficiency of the machir D nay permit myself to use the analogy of an efficient and AN signalman who after having performed his responsible d has to be provided with an immediate rest during which fie refreshed, so that he may afterwards perform © his task agaip With the same efficiency as before.

Anothé estion arises whether there exists such a minimal period ated action of a conditioned stimulus as does not lead in bu o a progressive development of inhibition in the cortical. elements. The details of this problem are receiving a full experi- mental investigation in our laboratories at present, but there are some experiments already performed which have a probable bearing upon it. In dogs which had had for a very considerable time con- ditioned reflexes delayed by 30 seconds, and in which the conditioned stimuli still retained. their full effect, all the reflexes were transformed into almost simultaneous ones by reinforcement 1 to 2 seconds after the beginning of the conditioned, stimulus. This modification in the procedure immediately began to reflect itself on the secretory and. motor components of these reflexes, bringing about also a dis- turbance of the previous balance in strength between positive and negative conditioned reflexes. The magnitude of the positive reflexes increased considerably, while the negative reflexes were to a large extent dis-inhibited ; in other words excitation began to predominate over inhibition [experiments of Dr. Petrova and Dr. Kreps]. The following is the method used by Dr. Kreps :

The dog, in view of an especially exaggerated tendency to in- hibition, was not kept in its stand during the experiments, but was kept on the floor. Among other conditioned reflexes this dog pos- sessed a positive alimentary reflex to 132 beats per minute of a metronome, while a rate of 144 beats per minute served as the stimulus to a precise and stable differentiation. A considerable time before the experiment a conditioned inhibition had been egfablished in which flashes of a lamp acted as the conditioned i itpr to a rate of 120 beats per minute of the metronome. T onditioned - inhibition was absolute, but had not been used considerable time. All the retlexes were delayed 30 =e) These delayed conditioned alimentary reflexes were now t, ormed into simul- taneous ones, the food being presented cond only after the administration of the conditioned sti rs. The modification in the mode of reinforcement led to a d Pearanoo of the conditioned inhibition, which could not be PACAN ished in spite of. 100 applica- tions of the inhibitory Bei SEN uring 36 days. The differentia- tion of the metronome, whi iras solute before the transformation of the reflexes into simu us ones, was also dis-inhibited, and in the succeeding AG: titions which were performed within 13 days the differenttftion continued to be unsatisfactory (3 drops as against KN 7 of the positive reflex). On returning to the delay of 30, Quds with all the reflexes, the differentiation again became KO during the very first day, and the conditioned

inhibition was completely re-established after 3 days, as shown by the following table : M On transforming the reflexes again into simultaneous ones the | conditioned inhibition was almost completely dis-inhibited after ih only three repetitions of the simultaneous reinforcement. il It remains still to be determined whether in the experiments just | described, in which the conditioned stimulus is almost immediately followed by the unconditioned, there will be no tendency towards | a progressive development of inhibition with prolonged. practice, or whether the apparent vigour of the reflexes will be only temporary i and will, though much later, nevertheless be superseded by inhibition. Hand in hand with the exhaustion of the ee there goes of course their recovery. We should ex erefore, that the inhibition which appears to stand in so Qd of relation to | | functional exhaustion of the cortical eleme ould disappear with

i their functional recovery. This expec fits the case of spon- | taneous recovery of extinguished coy@ifioned reflexes which after | some interval of time return to ormal strength. Regarded [i from this point of view it R Ore easy to understand. how the | slowly developing inhibition ey petition of the reinforced condi- I tioned reflexes is sl ON a temporary return of the delayed II reflexes to their original gth when a period of very short delays is introduced or w siderable interval is made between ex- ‘Mi periments. By sh ing the period of isolated action of the con- i ditioned stim ay the one case, or by completely avoiding for a time any repetition of the excitation in the other case, the functional | exhamston e cortical elements is diminished and a better oppor- iM| tunity rded for complete recovery.

M S iments are now being performed, with the object of specially I ~\ í studying the restoration of conditioned reflexes in the case of experimental extinction, and in the case of the gradual spontaneous development of inhibition occurring in spite of reinforcement. An example of such an experiment may be taken from a research by Dr. Speransky. Amongst others the following serve as positive conditioned alimentary stimuli: beats of a metronome, intensification of the general illumination of the room, the sound of a whistle, and the appearance of a circle. The acoustic reflexes were somewhat stronger than the visual ones, giving 10 to 12 drops during 30 seconds preceding reinforcement while the visual ones gave only 6 to 8 drops. The stimuli were all applied at intervals of 10 minutes and always in the above order. In every experiment all the stimuli were repeated once or twice. Following a series of experiments of this type the next experiment would consist in stimulation by the metronome alone. Twelve successive applications were made at intervals of 10 minutes, each being reinforced. The first two applications gave 12 and 11 drops of salivary secretion respectively during their isolated action,

while the last two gave 9 drops each. It is thus seen that simple repetition of the stimulus led to a diminution in its effect by 25%. On the following day a similar experiment was conducted, but the interval between the stimuli was made very much shorter, being only’ 14 minutes. The use of such short intervals was possible onl nel in this particular dog the secretion caused by the ate t with food finished extremely quickly and, as had been fo previous determinations, well within the 14 minutes. RS variation of the experiment the reflex which measure ps on the first stimulation became diminished to 44 drops ee third stimulation (diminution by 60%), to 2 drops on oe lation (diminution by 82%); passing with more or less re A dees of 2, 5, and 7 drops, it gave on the 22nd stimulati He one drop and then no secretion at all, the dog even refaping food after the last three stimuli. When the visual “Se increased illumination of the room was applied 14 minut last stimulation by the metro- nome a reflex of 24 ‘rtp Sern was produced, and the animal took the food. A en food was given without a previous conditioned stimulus

next day a returi! made to the original method of application of all the con Anea stimuli at intervals of 10 minutes. The metronome a first stimulus to be applied and gave 64 drops. On introducing a second stimulation by the metronome as the 5th stimulus the secretion obtained was only 14 drops. Finally, intro- duced a third time as the 9th stimulus, the metronome did not produce any secretion at all. In this experiment the secretion given by the other stimuli, although slightly below normal on their first application, did not greatly diminish on repetition. The reflex to the metronome was found to be restored to its usual intensity on the following day, and now it showed no further tendency to diminish on repetition. The foregoing experiment presents many points of interest. It is seen that one and the same stimulus which is constantly reinforced and repeated many times at long intervals of time loses only little of its effect : the same stimulus when applied at short intervals of time quickly diminishes in its effect at first, then after a wave-like variation it ends by giving a complete zero of secretory and motor re- actions, the animal declining food after the conditioned stimuli. In spite of this, another and usually much weaker stimulus immediately evokes both secretory and motor effects. The fact that the animal in the stand consumed with avidity a large amount of food when not preceded by the conditioned stimulus shows that satiety of the animal played no part. Relating the effect of the beats of the metro- nome to different states of the cortical elements it must be concluded that in the case of frequent stimulation these elements get functionally exhausted and have insufficient time for recover mio that after a preliminary oscillation which may be regarded adg\gtPuggle between excitation and inhibition the cortical elemen @ass completely into inhibition.

The weaker visual stimulus sie considerably in its effect after the disappearance of ditioned reflex to the stronger stimulus of the metronom n the following day the cortical elements which are Rea, by the metronome are still not fully recovered and pass agin Ito inhibition when the stimulus is repeated. This inhibition i he same character as the internal inhibition which has beey>dgescribed in previous lectures, and it exhibits the same propaga irradiating to other cortical elements which were not pri volved. The experiment shows that the inhibition irradiatj neighbouring cortical elements standing in connection wi r conditioned stimuli leads to a diminution of their positive, effeét, exactly as was described for internal inhibition. That the tefBition in the neighbouring cortical elements is really due to { Yradiation of the primary inhibition is evidenced by the NN t*on repetition of the stimuli they do not show such a

rapid diminution in their effect as is observed in the case of the metronome. On the third day the cortical elements related to the metronome became almost entirely functionally restored. The observations described in this lecture open up many important problems, and in the first instance the question of rapidity of recovery from the inhibitory effect of different stimuli during complete rest and during activity, the effect upon this recovery of reinforcement,

and so on. Besides these comparatively straightforward problems . there are more complex and more difficult ones. It is obvious that only certain cases of the development or disappearance of inhibition can be brought into relation with a supposed functional exhaustion and recovery of the cortical elements, and we cannot interpret in this fashion the cases of permanent and unvarying inhibitions in which the activity of the cortex is so rich—for example, all cases where an established inhibitory conditioned stimulus evokes an inhibition of the cortical elements directly and without a preceding phase of excitation—as, for instance, in the case of differentiation and conditioned inhibition. The problem presented by inhibitions of the latter type becomes still more complicated when we remember that those points of the cortex which become the centres of such direct inhibitions are never transformed into centres for excitation, even though the experiments are interrupted for weeks and months.

Internal inhibition and sleep as one and the same process with regard to their intimate mechanism. In the last lecture we arrived at the very important conclusion that under the influence of our conditioned stimuli the cortical elements invariably enter sooner or later into an inhibitory state. - With frequent repetitions of the stimuli this happens extremely quickly, and it may legitimately be regarded as an expression of the fact that the cortical elements, which represent the highest point of development of the nervous system, are extremely sensitive and therefore are functionally exhausted with comparative ease. The progressively developing inhibition, which itself cannot be regarded as a functional exhaustion, but which is a result of exhaustion, assumes the rôle of a protector of the cortical elements, preventing any excessive fatigue or dangerous functional destruction of this highly sensitive structure. During the period when the cells are in a state of inhibition, being free from activity the ical elements recover their normal state. This applies to all t lılar structures of the cortex equally, and therefore under tions in which a great number of cortical points are repeat entering into a state of excitation the whole of the cortex m xpected sooner or later to become subjected to inhibition, a state of widely spread inhibition actually does occur, e fac} in the same manner as in the case of individual Sele es ed ee and is familiar to all of us as the common and everydy) ccurrence of sleep. The complete and continuous proof of Ws contention is spread over the whole | of our twenty-five yea ork upon the hemispheres, and. at the present time no pani e physiology of the hemispheres studied by the method nditioned reflexes is bettet substantiated. Drowsiness an Sep were met with in our experimental animals from the ve ginning of our work, and we have been obliged to direct K ntion towards them continually. This, of course, has

led, to collection of an immense number of facts, which were different interpretations. However, already for many years all these varied interpretations have been fused into a final one harmonizing with all the facts at our disposal. This conclusion is, in essence, that sleep and what we call internal inhibition are one and the same process. ; The fundamental condition of the appearance and development of internal inhibition and sleep is exactly the same. It consists in the more or less prolonged or many times repeated isolated action of a conditioned stimulus producing stimulation of the cellular structures in the cortex. In all cases of internal inhibition which were discussed. in the fourth to the seventh lectures drowsiness and sleep were met with continually. In the case of extinction of a conditioned reflex some animals even at the first extinction showed not only a disappearance of the conditioned secretory and corresponding motor reaction but also a great dullness as compared with the normal state of the animal before the extinction. Repetition of extinctions, in the course of a number of days, even if all the con- ditioned stimuli were reinforced in between, led in every case to an obvious drowsiness and even sleep of the animal in its stand, though no such:symptoms had ever previously been observed. The same happens, but to a much greater extent, in the development of differen- tiation. To take an example. An animal has conditioned reflexes established to different stimuli, including one to a definite\musical tone. During the whole period of work the animal rent alert. The development of a differentiation of a tone close Py e positive one is now started, and it is noticed that durin process the animal gets drowsy. The drowsiness grad. increases, and often culminates in a deep sleep with a On relaxation of the skeletal muscles, and snoring, so to now other positive

conditioned stimuli are administered Neon by food it is necessary to stir up the animal and ro introduce the food forcibly into its mouth to initiate the act ofpating. Exactly the same thing happens in the case of develo t of long-delayed reflexes (for example, with a delay of t utes), and in the early period of our work this interfered our elena for, being not yet thoroughly familiar wit fe technique, it was impossible to obtain in some animals the r e required, on account of the development of sleep. The sam pens also in the development of conditioned inhibition, but maller extent.

fairly rapidly, which depends on non-reinforcement of the con- ditioned stimulus. In the case of the slowly developing internal - inhibitions produced by the repeated use of reinforced conditioned stimuli over a period of months or years, the development of sleep is proportionately slower and generally speaking stops short at one or other of the intermediate stages between the alert state and sleep itself, depending on the dog employed. In this respect the animals differ exactly as they differ in respect of rapidity of development of the common forms of internal inhibition.

It is not necessary to give any examples of individual experiments upon this transition of internal inhibition into sleep, since all our experiments abound with observations showing that internal in- hibition invariably passes into sleep unless special precautions are taken. As there is practically no stimulus of whatever strength that cannot, under certain conditions, become subjected to internal inhibition, so also there is none which cannot produce sleep. Very powerful electric shocks applied to the skin, when used as conditioned alimentary stimuli, led, after many months of use in the experi- ments of Dr. Eroféeva, to a progressively increasing internal inhibi- tion in spite of continuous reinforcement, and in the experiments of Dr. Petrova they became most effectual agents in inducing sleep. Similarly, different external agencies in their rôle of conditioned stimuli fall into an identical order of See ose regards the rapidity with which they lead to internal inhijtiom and to sleep. It was mentioned in the preceding lecture internal inhibition develops most readily with thermal and 1 eadily with auditory stimuli ; in exactly the same mannensedgp develops quickly with thermal conditioned reflexes and RQ slowly and: less frequently with auditory conditioned reflex€s.) he interference by sleep in the case of thermal conditiongd stimuli was indeed so persistent and upset the work to so grep extent that in the early period of our research I had real fia in finding collaborators who would

agree to work with the uli. | Finally, the long olated action of the conditioned stimulus was mentioned aA ctor determining the development of internal inhibition ; ii is a factor in determining the development of sleep. In sgmèđogs, while the conditioned reflex was delayed only 10 or 15 se is, the animal remained fully alert during experiments a years, but so soon as the reflex was delayed for 30 seconds drowsiness and sleep appeared. The results of this type of experiment

are often truly striking, for the quick transition from full alertness into true physiological sleep, due to this seemingly insignificant change in the experimental conditions, is amazing. Examples with variable length of delay and with variable precision of results are strewn over our work in abundance. All those methods described in the preceding lecture as retarding or abolishing that progressive growth of internal inhibition, which develops in the case of frequently repeated. conditioned reflexes not- withstanding their constant reinforcement, can be used with equal efficiency for the purpose of resisting sleep.

At this point the following question naturally arises: If sleep so closely coincides in its appearance and disappearance with internal . inhibition, how is it that the latter plays such an extremely important part during the alert state of the animal, serving for the most delicate physiological mechanism of equilibration of the higher organism with its environment ? To my mind all the facts which have been given in the preceding lectures dispose at once of the apparent contradiction. Internal inhibition during the alert state is nothing but a scattered sleep, sleep of separate groups of cellular structures ; and sleep itself is nothing but internal inhibition which is widely irradiated, extending over the whole mass of the hemispheres and involving the lower centres of the brain as well. Thus internal inhibition in the alert state of the animal represents a, regional distribution of sleep which is kept within bounds by th Noni nervous process of excitation. Such a restricting nism has been illustrated already in the lectures upon the onal mosaic of the cortex and upon its analysing activity. &

In the case of extinction the developme leep is prevented only if after extinction the conditioned. li are systematically reinforced and extinction is not repeateg tea 4ften. In differentiation of stimuli the developing internal piion which tends at first to be accompanied. by sleep—can e definitely restricted within its own analyser by inserting inhibitory conditioned stimuli between repeated. applicatio he positive conditioned stimulus. In this manner the pro of excitation which is repeatedly

Exactly the same is ved in the case of conditioned inhibition and inhibition of Gejay. -In all these cases if the experiment is conducted with thought drowsiness and sleep appear only as phasic event uring the time when the physiological demarcation between the areas of excitation and inhibition is not yet\fully estab- lished. However, as soon as the conditions of the experiments lead. to a prevalence of inhibition sleep again reappears. The following is a striking example : In the lecture upon the functional mosaic a dog was mentioned in which a tone served. as the stimulus to a positive conditioned reflex, while twenty neighbouring tones up and down the scale were differentiated. as stimuli for negative conditioned reflexes. This animal was never inclined. to drowsiness or sleep when a balance was maintained between the number of repetitions of the positive and negative conditioned stimuli, and under these conditions the dog always gave full reflexes to the applications of the positive stimulus. As soon, however, as the inhibitory tones were used several times in succession, the dog quickly fell into such profound sleep that even most powerful extraneous stimuli failed to awaken it. When a return was made to the interposition of the negative conditioned stimuli between applications of the positive one, sleep was never observed to develop. In this respect, such experiments as have already been mentioned in connection with the mosaic character of cortical functions—especially those with the use of tactile stimuli—are very instructive. In spite of a tendency of tactile conditioned stimuli to favour the development of drowsiness and sleep, the dog used by Dr. Koupalov never exhibited any signs of drowsiness, although a conditioned tactile mosaig was practised in this dog for over two years (p. 223). This SY ioul due to the inhibition being constantly limited and ch oe in its irradiation by the antagonistic excitatory process. An r Ne ecthed of combat- ing any wide irradiation of inhibition js €\Sncrease the number of positive conditioned stimuli, and so the spread of inhibition from its initial points of develop

also bears on this subject, i re complicated. A long-delayed alimentary reflex to a met e was being developed without the previous establishment imultaneous reflex: the length of the delay was 3 minute g several days the dog became more and more drowsy, and. INY y fell into a state of profound sleep. Obviously the inhibition developed. during the first period of action of the metronom s so powerful that it prevented the development of the pha Coj excitation which normally precedes reinforcement. Five iene were now used to develop further alimentary KS reflexes—these agencies together with the original

stimulus were allowed to act for only 5 seconds before reinforcement. Drowsiness quickly disappeared and all the reflexes developed with ease. The delay before reinforcement was now gradually extended in all six reflexes by 5 seconds each day. Corresponding with the increase in delay before reinforcement the latent period of the reflexes became longer, and finally without any interference of sleep six long- delayed reflexes became firmly established, all with a preliminary period of inhibition of 1-14 minutes. The process of excitation, originating in six different points of the cortex, allowed the inhibi- tion to develop only gradually, limiting it both in time and space and. preventing the development of sleep.

To the same group as the last belong some further observations which were made in only a few dogs, all of them very easily subjected to inhibition. These dogs developed drowsiness and sleep simply on account of limitation of movements when placed in the stand. Sleep could be avoided, at least for some length of time, by conducting the experiments with the animals free upon the floor. It is probable that under the latter condition stimuli originating within the motor apparatus and the skin provided fairly regular foci of excitation within the cortex which counteracted to some extent any wide irradiation of conditioned inhibition. However, another factor of probably greater importance also undoubtedly played a part, and to this we shall return later.

What has been shown to take place in the cortical legos with respect to the development of internal inhibition under influence of conditioned stimuli, can be observed to the sa wtent in the case of stimulation of the cortical elements by s which have no special conditioned physiological significanc s has previously been mentioned, among the different r the investigatory reflex has a special importance. mm. as a point d'appui in the cells of the cortex as well as in th er parts of the brain. In the normal animal the reflex is undoubtedly produced with the active co-operation of the cortex. This is supported by the exquisite sensitivity of the reflex, for it J ked by any minutest change’ in the environment. This is AP pon only through the presence of the higher analysing Q y of the cerebral cortex and is wholly unattainable by the T e of the brain alone. The investigatory reflex, as we know,@avariably weakens on repetition, and finally disappears altog Der Special experiments conducted in my laboratory by, (<n Popov showed that the disappearance