“Stimulus Visual,
Auditory,
E. R. JOHN Brain New
Generalization”
AND
D.
Between
and Central
Stimuli
KLEINMAN
Research Laboratories, York Medical College,
Department New York
of City
Psychiatry 10029
IN NUMEROUS STUDIES, it has been reported that during conditioning, evoked responses to the conditioned stimulus become anatomically more widespread and similar (10, 14, 16, 24, 27, 28, 35, 36, 38-40). Also, new late components appear in the evoked response (1, 3, 30, 37, 49). After acquisition of a simple conditioned response, generalization often occurs when a novel stimulus is presented. When an animal performs such a generalized behavioral response, the evoked potential waveshape elicited by the novel stimulus is a good facsimile of that usually evoked by the conditioned stimulus (48). If the animal has been differentially conditioned to discriminate between two stimuli, the waveshape evoked by a novel stimulus intermediate to those two cues depends on which behavior the animal displays during differential generalization, and is then a facsimile of that waveshape usually elicited by the differential conditioned stimulus which is the appropriate cue for the performed behavior (23). Since the wavesh ape of the evoked sponse unde r these conditions was not ::&mined by the physical characteristics of the stimulus but appeared to correlate with the behavior which was subsequently performed, we speculated that these phenomena might reflect the activation of specific memories. Further studies, involving the investigation of many possible nonspecific factors which might have been involved in such observations and utilizing computer pattern-recognition techniques to classify single evoked-response waveshapes, supported the conclusion that the brain could produce a fascimile of an ab-
Received
for
publication
Differentiated
December
17, 1973.
and
Physiology,
sent event (23). The evoked potential was found to contain exogenous processes, determined by the nature of the stimulus, and endogenous or readout processes, released by the stimulus from memory. By appropriate computer manipulations of large quantities of evoked-potential data obtained under a variety of stimulus-response contingencies, it was possible to achieve separation of these exogenous and endogenous processes. Although the absolute contribution of these processes varied greatly from region to region, both exogenous and endogenous activity were demonstrated in most brain regions (2) with a systematic quantitative relationship: the amount of endogenous activity was logarithmically proportional to the amount of exogenous activity. Microelectrode studies indicated that characteristic firing patterns in neural ensembles were correlated with the different waveshapes evoked by the differential conditioned stimuli in such experiments. Movement of chronically implanted microelectrodes revealed that those same characteristic firing patterns to a particular stimulus were found throughout anatomically extensive regions. However, at any point in these regions, two markedly different patterns of discharge were elicited by the two discriminated signals. The response of single cells to individual stimulus presentations was highly variable, but poststimulus histograms to repetitions of that stimulus always converged to the shape characteristic of the response to that signal (25, 26). In view of these findings and a body of related considerations, we proposed that the information about a conditioned stimulus was represented by the time course of nonrandom firing in anatomically ex1015
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1016
E.
R.
JOHN
AND
tensive neuronal populations, rather than by the occurrence of activity in any particular set of synaptic pathways. Activation of the memory of that sensory event and associated behavioral contingencies was assumed to reproduce the same statistical firing pattern (2 1). This theoretical formulation was based on inferences drawn from a body of electrophysiological findings observed to correlate with behavioral performance. An opportunity to test this theory directly seemed to be provided by the use of electrical stimulation of the brain in an effort to simulate the postulated release of memories about a specific differential conditioned stimulus. Significant occurrence of stimulus generalization between differentiated sensory stimuli and analogous electrical stimuli delivered directly to various brain regions or rapid transfer of differentiated response from peripheral to central stimuli or from central site to central site would constitute support for statistical it would be implausible theory because that such gross electrical excitation could fortuitously duplicate some hypothetical precise pattern of synaptic activation elaborated to represent the effects of the earlier learning experiences. A body of earlier work on stimulus generalization involving direct electrical stimulation of the brain was relevant to this undertaking. Such studies are conveniently divided into five categories: I) Stimulus generalization to brain stimuli after peripheral training. The results of such studies have been contradictory. Where stimulus generalization (SG) has been reported, initial training has either been to a minimal criterion or no differential training has been involved (9, 31, 32, 43). When high criterion levels and discriminative training have been involved, negative SG has been obtained (37, 40, 51). One of the few recent studies to address this problem was reported by Kelly et al. (29), who trained cats to discriminate between a visual stimulus plus tone versus a tone alone, using a conditioned avoidance paradigm. It should be pointed out that the discrimination involved was between the presence and the absence of a visual stimulus, rather than between the
D.
KLEINMAN
qualities of two visual stimuli. Stimulus generalization to central stimuli after peripheral training was obtained from the optic chiasm and lateral geniculate at high levels. Intermediate stimulus generalization was obtained from stimulation of the optic radiation and the superior colliculus, and very low levels of SG were obtained in response to stimulation of the visual cortex. Using high criterion levels but no discrimination training, Clark et al. (6) studied the effects of central stimulation after conditioned avoidance response training to tones of various frequencies. Good SG was observed from tone to stimulation of the cochlea, and some SG occurred when lateral lemniscal or auditorv cortex sites were stimulated. Prabably the most direct antecedent to our own studies was the work of Livanov and Korol’kova (40), who stimulated the motor cortex at 3/s after a conditioned limb-flexian response had been established to 3/s flicker, and demonstrated that such cortical stimulation elicited limb movement with the shortest response latency. 2) Stimulus generalization after training to subcortical stimulation. Most studies of generalization between subcortical loci have produced negative results (34, 45, 51). Nielson et al. (45) found some SG between the mesencephalic reticular formation (RF) and centre median or the superior colliculus, and between two levels of the medial lemniscus, but used a very low criterion (60y0). Buchwald et al. (4a) found SG between the contralateral caudate nucleus or the ventrolateral nuclei of the thalamus, after unilateral training at either site. However, generalization was not obtained to stimulation of other anatomical regions. Stutz concluded in 1968 (54) that SG does not occur between brain structures which are not functionally interrelated. This worker reported SG between parts of the limbic system. In 1970, Schuckman et al. (52) found no SG to stimulation of the contralateral lateral geniculate (LG) after training of the other geniculate, nor was there transfer to striate cortex. Conversely, no SG was observed in LG after training of striate cortex. However, SG was obtained when any striatal region was stimulated after striate cortex trainin-g.
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STIMULUS
GENERALIZATION
Pusakulich and Nielson (46) in 1972, Nielson (44) in 1968, and Gerken (15) in 197 I studied changes in threshold to subcortical stimuli as a function of drugs, electroconvulsive shock, or various stimulus parameters, but did not explore the questions of transfer which are of special concern to this study. 3) Stimulus generalization to cortical sites after training to cortical stimulation. There is general agreement that SG does not occur when cortical regions other than the site of training are stimulated (8, 17, 51). There is some controversy as to whether SG occurs between different sites within the same cortical area. Doty (7, S), Schuckman (50), and Schuckman and Battersby (51) agree that SG occurs when other striate cortical sites are stimulated. Schuckman et al. (52) concur in this finding. Freeman (13) failed to obtain SG to stimulation of the contralateral prepyriform cortex after training to prepyriform stimulation. Similarly, Woody and Yarowsky (60) failed to obtain SG to nearby points on the coronal-precruciate cortex after training of stimuli delivered to interspersed electrodes. It is noteworthy that the conditioned response (CR) was not dependent, in that study, on changes in the “fine structure” of the stimulus, when stimulus parameters were changed. 4) Stimulus generalization to subcortical sites after cortical training. Schuckman, Kluger, and Frumkes (52) have confirmed our earlier finding (20) that there is no SG to stimulation of the lateral geniculate after training of the visual cortex. 5) Stimulus generalization to cortical sites after subcortical training. Neider and Neff (43) reported good transfer from the inferior colliculus to the auditory cortex. Similarly, Doty (7) reported SG from lateral geniculate to optic radiations (in one monkey subjected to five test trials!). Both of these studies used low criteria and no discrimination training. Leiman (37) reported SG to stimulation of the marginal after lateral geniculate training. gyrus Schuckman, Kluger, and Frumkes (52) reported no SG from lateral geniculate to the contralateral lateral geniculate or the striate cortex, and conversely, no SG to
1017
lateral geniculate stimulation after striate training. SG was found after striate training only in other striatal areas. The studies reviewed above would more properly be termed studies of cross-modal transfer than of stimulus generalization. The various findings suggested relatively difficult access to the mechanisms established during learning which mediated conditioned responses to stimuli of one modality, when stimuli were delivered via another modality. However, in most of these earlier studies the conditioned stimulus was a sensory event of some particular quality. Little or no effort was made to construct generalization stimuli which were analogs of the original conditioned stimulus along some stimulus dimension. Under such circumstances, two possible outcomes of the search for stimulus generalization might be predicted. On one hand, if no discrimination training was involved and low criteria of learning were accepted, a broad generalization gradient might be established such that high levels of stimulus generalization were obtained. Such apparently high levels, however, might well be spurious, arising from nonspecific factors such as changes in the overall level of excitation or arousal. On the other hand, were differential conditioning established to high criteria, no stimulus generalization might be obtained because of the establishment of sharp generalization gradients. Previous results in studies of this genre seem to correspond to this pattern. Since the purpose of the brain-stimulation studies reported herein was primarily to provide a critical test of our theoretical formulations, it seemed preferable to bias our procedures against any possibility of spurious generalization, so that positive results could be construed as strong support for the theory. In the studies to be reported, accordingly, animals were trained to very high levels of discrimination between auditory or visual stimuli presented at two different repetition rates. The central stimuli utilized in tests of stimulus generalization were brief trains of electrical pulses delivered at the same repetition rates as the peripheral discriminanda, thus constituting a set of analogous signals designed to mimic the neuronal excitation postulated to rep-
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1018
resent the sensory tial training.
E. R. JOHN
stimuli
used during
AND
ini-
D. KEEINMAN The training apparatus soundproof chamber and one-way vision screen.
was was
enclosed observed
in via
a a
METHODS
Surgical Six cats were chronically implanted with 34 electrodes bilaterally located in the lateral geniculate (LG), medial geniculate (MG), visual cortex (VIS), auditory cortex (AUD), mesencephalic reticular formation (RF), intralaminar and midline thalamic nuclei (IMT), and a variety of other brain regions, using methods described elsewhere (22).
Behavioral CONTINGENCIES. Three cats were trained to press the lever on the left side of a work panel to obtain food in response to an initial stimulus at repetition rate 1, but to press the lever on the right side to obtain food if the initial stimulus occurred at repetition rate 2 (approach-approach). Three cats were trained to perform the same two differential responses to stimuli at two different repetition rates, but in order to avoid electrical shock delivered to the feet (avoidanceavoidance). Usually, 20 trials of each stimulus were presented each day, according to a modified Gellerman schedule. Sessions were sometimes lengthened if the animals working for food reward seemed particularly hungry. Foodmotivated animals were trained every weekday, fed ad libitum on Saturday, and deprived of food on Sunday to insure over 24 h of by Monday. Food reinforcement deprivation consisted of 1.5 ml of a mash made by mixing tuna and milk in a blender, and was delivered by a solenoid-operated dipper. In three cats, rate 1 was 5/s while rate 2 was 1.8/s. In three cats, rate 1 was 4/s while rate 2 was 2/s. In two cats, rate 1 was 7.7/s while rate 2 was 3.1 /s. These stimulus frequencies were counterbalanced for the various response motivations. STIMULUS-RESPONSE
APPARATUS. All procedures were carried out in a 60 x 60 x 60 cm cage with a Lucite work panel carrying two levers and dippers to deliver food. Visual stimuli were presented using a silent fluorescent tube (Iconix model 6193) mounted in the top of the cage at the rear. DC bulbs in the roof provided a moderate level of constant illumination. Thus, the visual stimuli caused a repetitive fluctuation in the level of illumination of the whole visual field of a light-adapted animal. Auditory stimuli were clicks delivered to an S-inch loudspeaker mounted in the top of the cage at the rear.
The stimulus of rate was selected as the cue lever on the right side of the all animals (CS,). Training began by presenting that stimulus at random intervals averaging 1 min, with each presentation lasting about 15 s. In approach training, at first paw movements toward the dipper and subsequently toward the nearby lever, were reinforced with food delivery. In avoidance training, weak electrical shocks to the feet were delivered every few seconds after 15 s of stimulation had elapsed, with foot shock and conditioned stimulus at first terminating as soon as the animal moved toward the lever. Gradually, more and more precise responses were required until a definite right-side leverpressing conditioned response (CR) was established. Discrete CRs were usually established in the first week of training, with several more weeks required to eliminate intertrial responses and bring CR, completely under control of cs,. At this point, the conditioned stimulus of faster repetition rate (CS,) was introduced. Animals receiving approach-approach training were presented with alternating blocks of 10 CS, and 10 CS, trials, with reinforcement withheld when the right lever was pressed in response to CS,. As the animal began to inhibit CR,, the alternating blocks of CS, and CS, were shortened until double alternation of CS, and CS, was achieved, and then a random sequence of CS, and CS, was introduced. Animals receiving avoidance-avoidance training were subjected to a very similar procedure, with initial discrimination somewhat aided by shortening the duration of CS, presentations. Establishment of this initial stage of go-no go discrimination between CS, and CS, to a 90% criterion usually took an additional month, largely because of a resurgence of spontaneous responses. During this period, the behavior of the animal was reminiscent of that seen with aperiodic reinforcement. Once go-no go discrimination between CS, and CS, was stabilized, training of CR, in reIn early stages of sponse to CS, was initiated. only CS, was presented, with CR, training, responses being shaped to the left lever on the work panel in the same way as during CR, training. CR, was usually brought under control of CS, within a few days. At that time, alternating blocks of 10 CS, and 10 CS, preintroduced, and approsentations were again DISCRIMINATION
TRAINING.
slower repetition for pressing the work panel in
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STIMULUS
GENERALIZATION
priate performance of CR, and CR, behaviors was required. As adequate discrimination behavior was established, the alternating blocks of CS, and CS, were shortened until double alternation of CS, and CS, was achieved. Up to this point training in most cats was uncomplicated, with steady improvement in performance. When random sequences of CS, and CS, were presented, with requirement of appropriate CR, and CR, performance and no self-correction permitted, severe difficulty was encountered in most animals. Although nonrandom levels of discrimination were readily achieved, the cats showed periods of perseveration of a particular CR and marked resurgence of spontaneous responses. Clear signs of frustration, such as refusal to work and sustained attempts to escape from the apparatus, were often observed. During these episodes, discrimination broke down completely and it became necessary to return to the previous stage of training. Sometimes these “neurotic” behaviors persisted with such intensity that the training procedure was suspended for weeks or even months, until the animal again became willing to work. We attributed these difficulties to some peculiar feature of the situation, possibly the particular frequencies which had been selected. After periods ranging from several months to almost a year, stable high levels of discrimination were eventually established in every animal. At this stage, discrimination appeared to be almost automatic. Movements were minimal, spontaneous responses rare or absent, and errors infrequent. PERIPHERAL-PERIPHERAL
TRANSFER
OF
TRAINING.
After achievement of 85% or better differential performance of CR, or CR, in response to random presentations of the initial stimulus at frequency 1 or 2 (CS, or CS,), transfer of training was initiated to a different kind of stimulus delivered at the same differential repetition rate. Three animals first learned the discrimination between simultaneous flicker plus click stimuli at two different rates (A,& and A,V,) and then received transfer to flicker only at the same two rates (V, and V,). Two other animals were first trained to discriminate between A, and A,, and then received transfer of training to the visual signals V, and V,. The last animal learned to discriminate between a 600- and a 1,200-Hz tone, and then received transfer of training to two flicker signals (V, and V,). CENTRAL
STIMULATION.
ulation of the Nuclear-Chicago
brain
Direct electrical stimwas accomplished by using stimulators driving stimulus
1019
isolation units which were photically coupled (Tektronix model 2620). All system timing-was accomplished using a stimulator constructed in this laboratory, constantly monitored by a Hewlett-Packard frequency counter (model 5212A). Brain stimuli consisted of trains of 30 pulse pairs. Each pulse pair was biphasic, comprised of two segments of opposite polarity and 200 ps in duration, separated by 200 ps. The interval between pulse pairs was 5 ms. Stimuli were of constant current, regulated by the stimulus isolation units, and monitored on an oscilloscope (Tektronix model 565) using a current probe amplifier (Tektronix model 131). The electrodes in the animals’ head were connected to a subminiature socket imbedded in acrylic resin. During all training and testing procedures, a cable of Microdot mininoise wire connected this socket to a receptacle in the roof of the training apparatus. Cables from this receptacle led through the wall of the soundproof chamber to a terminal board. Connections could be made between the output of the stimulus isolation units and selected positions on this terminal board in order to stimulate particular brain regions. Other connections between positions on this terminal board and inputs of the amplifiers of a 1% channel Grass model 7 polygraph permitted simultaneous recordings to be obtained. The output of the polygraph went to a 14-channel Mnemotron tape transport so that magnetic tape recordings could be made when. desired. Results of the analysis of such recordings will be presented elsewhere. This paper will be limited to primarily behavioral observations. TRANSFER. When the animals reached a performance level of 85% accuracy in discriminating between the two different repetition rates of either auditory or visual stimuli administered in a random sequence with respect to both sensory modality and repetition rate, and when this high level of differential response was maintained in a stable fashion for several weeks, tests of generalization and transfer of training to central stimuli were initiated. The mesencephalic reticular formation (RF) was selected as the first central site for transfer of training because the widespread electrophysiological response to the peripheral CS observed after training, as well as the appearance of new late components in the evoked response, strongly suggested RF implication in the representational system storing information about the learning experiences. The first problem was to establish the appropriate intensity of current for this central stimulus. For PERIPHERAL-CENTRAL
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E. R. JOHN
1020
AND
D. KLEINMAN
this purpose, the occlusion threshold W .as determined, defined as the current level at which simultaneous presentation of phase-locked RF stimuli, together with the visual or auditory discriminanda, produced blockade of behavioral performance. The occlusion threshold, thus defined, was the amount of electrical input which disrupted adaptive behavior and therefore significantly exceeded an effective neuronal excitation. Arbitrarily, we selected some fraction of this disrupting current as the initial intensity to be used for the central conditioned stimulus. Using the training current level thus defined, a series of RF stimuli at both repetition rates was randomly interspersed among visual and auditory stimuli at both repetition rates, themselves randomized. After presentation of a number of such RF stimuli without reinforcement to test for stimulus generalization, training was initiated with reinforcement of each RF stimulus until criterion levels of discrimination were achieved. Occasionally, RF stimuli were yoked to flicker or click cues for several trials to facilitate transfer.
initiated to study both generalization and transfer of training. In each case, occlusion thresholds were determined as described above for RF stimulation. Once appropriate current levels of brain stimuli were established for each of these structures, testing of generalization and transfer of training were carried out in parallel for all four brain regions simultaneously. Each day, five trials at each stimulus repetition rate were delivered to each central site, with the order of central stimulation permuted every day. These new sites were stimulated in a sequence imbedded within a random sequence of visual, auditory, and RF discriminanda intended to maintain all previously acquired discriminations at a high level. RESULTS
Sensory-sensory
TRANSFER. After achievement of 85% criterion to such differential RF stimuli or sustained high levels of performances indicating asymptotic learning, stimulation of visual cortex, lateral geniculate, medial geniculate, intralaminar and midline thalamus were CENTRAL-CENTRAL
TABLE
1.
Initial
tjpaining, Cat 1
overtraining, Cat 2
I
transfer
In every cat, transfer to the second set of sensory discriminanda was more rapid than initial discrimination training, as shown in Table 1. If we consider the savings shown by cat I as an estimate of general facilitation of acquisition of the second task due to familiaritv with the discrimination situation, only cats 2, 3, and 6 displayed markedly more rapid transfer. Note that in cats 2, 3, and 4, a compound flicker-click stimulus was used to establish
and
transfer
i
Cat3
to other
i
-
Cat4
serzsoyy )
cues Cat 5
__Cat Q
I
+
-
Flicker plus click (4 vs. 2)
Flicker plus click (5 vs. 1.8)
Flicker plus click (5 vs. 1.8)
Click only (5 vs. 1
Click only (4 vs. 2)
Trials to discrimination criterion (2 days 2 @%>
840
1,380
500
460
540
Trials
overtraining
380
640 (4 vs. 2)
Second
discriminanda
Flicker on (4 vs. 2)
Flicker only (4 vs. 2)
Flicker only (4 vs. 2)
Flicker only (5 vs. 1.8)
Flicker only (5 vs. 1 4
Flicker only (4 vs. 2)
Trials tion
to discriminacriterion
620
120
680
Response Initial
discriminanda
Percent of original training trials required to achieve transfer Trials overtraining before RF transfer
Tone (600 vs. 1,200 Hz)
76
+
+
340
360
40
68
560
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STIMULUS
the initial discrimination. Our purpose was to facilitate both initial training and the subsequent establishment of differential responses to either flicker or click stimuli as a prelude to the study of SG to brain stimulation. To our surprise, this procedure seemed to be counterproductive. Transfer of the discrimination to flicker alone was far more difficult in those cats than we had anticipated, and was on the average slower than in cats 5 and 6 which were initially trained to discriminate clicks unaccompanied by flicker. This indicates that the auditory component of the compound flicker-click CS was so prepotent as to inhibit establishment of the flicker as a relevant cue. All of these animals showed almost immediate high levels of performance of CRs to the flicker CS when transfer of training began. Nonrandom levels of discrimination were also rapidly achieved, but achievement of criterion performance required substantial further effort. Because performance was not considered sufficiently reliable, all animals received overtraining until the discrimination seemed consistently accurate and “automatic.”
electrode placements. (Cats I and 4 are still alive.) Since the purpose of ascertaining the occlusion threshold was to select an intensity of brain stimulus appropriate for use as a CS, neither ineffectual nor disrupting, it was also important to observe whether gross movements or muscle contractions were caused. For this purpose, the brain stimuli at each current level were delivered alone as well as in conjunction with the sensory cues. Examining this procedure, it becomes apparent that tests for occlusion at current levels inadequate to cause occlusion are actually yoked transfer trials, and presentations of central stimuli intended to permit observation of gross muscular responses also constitute tests of generalization. This became obvious when we observed performance of conditioned responses to the brain stimuli alone in same cats during the procedure of establishing occlusion thresholds. Thereafter, continuous trains of brain stimuli were used to establish the occlusion threshold and select intensities of stimuli to be used for training at a given site. Training cuwen t levels On the basis of these occlusion studies, appropriate CS current intensities for each brain structure were selected for training. The intensities found most suitable for training are presented in Table 3. Note that some of these current levels somewhat exceed the intensities originally found to cause occlusion. It was found that in some cases the animals apparently adapted to stimulation and performance repeated thresholds rase. In some cases thresholds seemed to decrease with training and the current levels originally selected became excessive. In general, use of currents too low produced performance but poor dis-
Occlusion thresholds Occlusion thresholds were defined as the intensity of stimulation of a brain region which would block performance if delivered concurrently with the peripheral sensory discriminanda. These thresholds were established by delivering series of brain stimuli sequentially increasing and decreasing in intensity. Occlusion thresholds are presented in Table 2. Note that occlusion thresholds were lowest in RF except in the case of cat 4. The reason for the remarkably high value found in this cat is not understood, but may become apparent after histological identification of TABLE
2.
Occlusion
thresholds
to brain
stimuli
Cat
RF
VIS
LG
1 2
45 100 80 2,400 50 100
500 500x 1,600 460 300
200 150% 150 350 250%
3 4 5 6 Values
are in microamperes.
* This
current
1021
GENERALIZATION
level
in difjerent
regions
AUD
caused
290 250 250 overt
muscular
response
MG
IMT
240 150% 600 600 600%
70 150* 1,800 350 150%
but
not occlusion.
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E.
1022
R.
JOHN
AND
crimination, whereas if currents were too high, performance was blocked. Since brain stimulation began more than 1 yr after electrode implantation, threshold changes are not reasonably attributable to histological changes around the electrode tip. Similarly, since electrodes were platinum plated and biphasic stimuli were used, these changes are not likely to be caused by stimulation per se. It seems most likely that these threshold changes relate to the establishment of new neuronal responses as a result of the conditioning process.
D.
KLEINMAN
TABLE 4. Sites where generalization occurred unreinforced stimuli -Cat
RF
VIS
LG
1
+
2% 3
+
+
+
+
+
4
+
+
5%
+
6X
+ * RF
diiqerential to
AUD
+
MG
IMT
+
+
+
+
+
+
training
preceded
testing
of other
structures.
Generalization In many brain regions, presentation of electrical stimuli at these intensities immediately resulted in performance of the differentiated conditioned response appropriate to the stimulus repetition rate. In two animals, such generalization was elicited during the search for the occlusion threshold to RF stimulation. Subsequent occlusion testing was limited to one or two trials at each intensity, and usually began at supraocclusion levels using a descending series, or used continuous trains of electrical pulses. Nonetheless, it must be conceded that in some instances a few yoked and reinforced presentations of the central stimulus occurred before performance was elicited to the brain stimulus alone. Therefore, behavioral performance thus elicited should be considered as very rapid transfer rather than as generalization in the precise meaning of the latter term. However, in some animals (particularly cat 4, who probably received most overtraining with the peripheral cues) differential generalization with no prior yoking or reinforcement was unquestionably obtained. These observations are summarized in Table 4. TABLE
Values
CurTent
3.
intensities
used for central
Transfer
As soon as generalization was observed or after current levels for brain CS were established, reinforced transfer of training began to RF stimulation. Although no data are available on the difficulty of establishing this discrimination between RF stimuli of different rates without prior training on the visual and auditory discriminations, substantial savings can be inferred from the fact that criterion levels of discrimination were achieved to RF stimuli in four of six cats within the first 100 trials, far less than were required for either the initial sensorv discrimination or the transfer of discrimination to flicker alone. The remaining two cats showed less impressive but, nonetheless, nonrandom performance within the first 200 trials. Five of the six cats showed runs of successful discrimination in the first test session with RF stimuli. Even though discrimination was by no means initially at criterion levels, all cats showed high levels of conditioned-response performance immediately when RF stimulation occurred. These results are presented in Table 5, part A. conditioned
Cat
RF
VIS
LG
1 2 3 4 5 6
60 120 60 60 40 60
320 400 200 300 250
120 100 80 240 250 100
are
in
to RF stimulation
stimuli MG 100
170 240 240
IMT 60 150 130 60 250 130
microamperes.
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STIMULUS
5.
TABLE
Peripheral-ten Cat
%CR
I
1 z 4
Total RF overtraining
B. vc
;: ;; 83 354
Concurrent
Cat 2 P %CR %D
%D
A. RF
tral
Initial Ef ;;$ 92$
and
1;: 95 36
transfer
;:i ;g 77I#I
ten tral-ten Cat
%CR
transfer
;g
GENERALIZATION
3 %D
to RF
tral Cat
stimulation 92
63
98 100 95 464
47 2” 55
‘“SOS 100 95 116
E i 76% 70$
of other
brain
1 2
26
54
s988
2
to2
:z
80 90
53 51
i Total LG 1 2 3
34 El 29 54 88 :i
47 2 58 48 68-t %z
g8 90 94
77; 82z 79$
i38 3
;i 48
100 1;: 88
48
53 57 46 62
1;: 92 91 80 1;; 72
gf: 37 56 sot gt 64
Tot a: MG 1 2 2
84 3E
64$ G6;
54 74
Total IMT 1 2 :
41 98 100 94
Total
l;os
:!:
5
%CR
after
47
--
Cat
%D
iI
to stimulation
transfer
4
%CR
1023
sensory Ei 98 E 173
Cat P %CR
%D
go” 78
46
33 57:
56
~~xx 851t
;; 347
after
33
iii;;
RF
f33P 55
60
61-f
64 94 86 54 75
Total Trials
Total N CR
41 62 49 55 52
33 65-f 54 78$ 80$ 74$
86 92 iii;:
58 72” 2
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72 6 ;: L,
56 100 35 ::
87 92 ‘808” 92
67$ 63 44: 61
58 40 E
62 70 z;:
E$
98
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%
41
93
55
49
56
%CR
%D
(1) 300 300 300 300 1,200
235 266 2278’: 1,056
discrimination
52
;;-I-
Average
%D
discrimination
70* 91x 90x loox 90x
functions
6
78 89 91
79Il.I
72t 77x
%
;i$
training
%
140 153
58
63”
200 840 300 275 250
153 162 608 203 231 :2
;77 ;; 68
F
250 1,075 ;z
816 :3;
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665 6131
58-t-
22::
:z
if 72 76 64 73 83
800 250 250 250 250
579 174 %% 212
%! 70 81 iii;
~~~ 74rt 60” 57-t k3$
795
80
63$
1,000
Discrimination training between two frequencies of flicker and of click was first established to a criterion of 85% on 2 successive days (see Table 1). After substantial overtraining on these sensory discriminations, transfer of frequency discrimination was initiated to electrical stimulation of RF. After criterion was achieved to RF stimulation, a further period of overtraining occurred to randomized sensory and RF stimulus sequences using both frequencies. Concurrent training of the other four structures was then initiated, using a Williams square to counterbalance the daily sequence. Throughout all central training, performance to the peripheral discriminanda was maintained at 80% or better, using test trial< at the beginning of each session. In certain instances, animals performed CRs after termination of the central stimulus. These responses were considered to indicate the need to adjust stimulus intensity, and were not included in the scores reported in this table. The occurrence of such “offset” CRs was as follows: cat I performed 11 CRs immediately after offset of RF stimulation, 59 CRs after offset of VIS stimulation, and 16 CRs after offset of LG stimulation; cat 5 performed 24 CRs after offset of RF stimulation and 8 CRs after offset of VIS stimulation. Because this cat became seizure prone, only 40 transfer trials to VIS and 75 transfer trials to LG could be obtained; cat 6 performed 19 CRs after offset of RF stimulation, 8 CRs after offset of LG stimulation, and 11 CRs after offset of IMT stimulation. Offset CRs usually occurred early in transfer training. *=p
Auditory,
E. R. JOHN Brain New
Generalization”
AND
D.
Between
and Central
Stimuli
KLEINMAN
Research Laboratories, York Medical College,
Department New York
of City
Psychiatry 10029
IN NUMEROUS STUDIES, it has been reported that during conditioning, evoked responses to the conditioned stimulus become anatomically more widespread and similar (10, 14, 16, 24, 27, 28, 35, 36, 38-40). Also, new late components appear in the evoked response (1, 3, 30, 37, 49). After acquisition of a simple conditioned response, generalization often occurs when a novel stimulus is presented. When an animal performs such a generalized behavioral response, the evoked potential waveshape elicited by the novel stimulus is a good facsimile of that usually evoked by the conditioned stimulus (48). If the animal has been differentially conditioned to discriminate between two stimuli, the waveshape evoked by a novel stimulus intermediate to those two cues depends on which behavior the animal displays during differential generalization, and is then a facsimile of that waveshape usually elicited by the differential conditioned stimulus which is the appropriate cue for the performed behavior (23). Since the wavesh ape of the evoked sponse unde r these conditions was not ::&mined by the physical characteristics of the stimulus but appeared to correlate with the behavior which was subsequently performed, we speculated that these phenomena might reflect the activation of specific memories. Further studies, involving the investigation of many possible nonspecific factors which might have been involved in such observations and utilizing computer pattern-recognition techniques to classify single evoked-response waveshapes, supported the conclusion that the brain could produce a fascimile of an ab-
Received
for
publication
Differentiated
December
17, 1973.
and
Physiology,
sent event (23). The evoked potential was found to contain exogenous processes, determined by the nature of the stimulus, and endogenous or readout processes, released by the stimulus from memory. By appropriate computer manipulations of large quantities of evoked-potential data obtained under a variety of stimulus-response contingencies, it was possible to achieve separation of these exogenous and endogenous processes. Although the absolute contribution of these processes varied greatly from region to region, both exogenous and endogenous activity were demonstrated in most brain regions (2) with a systematic quantitative relationship: the amount of endogenous activity was logarithmically proportional to the amount of exogenous activity. Microelectrode studies indicated that characteristic firing patterns in neural ensembles were correlated with the different waveshapes evoked by the differential conditioned stimuli in such experiments. Movement of chronically implanted microelectrodes revealed that those same characteristic firing patterns to a particular stimulus were found throughout anatomically extensive regions. However, at any point in these regions, two markedly different patterns of discharge were elicited by the two discriminated signals. The response of single cells to individual stimulus presentations was highly variable, but poststimulus histograms to repetitions of that stimulus always converged to the shape characteristic of the response to that signal (25, 26). In view of these findings and a body of related considerations, we proposed that the information about a conditioned stimulus was represented by the time course of nonrandom firing in anatomically ex1015
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1016
E.
R.
JOHN
AND
tensive neuronal populations, rather than by the occurrence of activity in any particular set of synaptic pathways. Activation of the memory of that sensory event and associated behavioral contingencies was assumed to reproduce the same statistical firing pattern (2 1). This theoretical formulation was based on inferences drawn from a body of electrophysiological findings observed to correlate with behavioral performance. An opportunity to test this theory directly seemed to be provided by the use of electrical stimulation of the brain in an effort to simulate the postulated release of memories about a specific differential conditioned stimulus. Significant occurrence of stimulus generalization between differentiated sensory stimuli and analogous electrical stimuli delivered directly to various brain regions or rapid transfer of differentiated response from peripheral to central stimuli or from central site to central site would constitute support for statistical it would be implausible theory because that such gross electrical excitation could fortuitously duplicate some hypothetical precise pattern of synaptic activation elaborated to represent the effects of the earlier learning experiences. A body of earlier work on stimulus generalization involving direct electrical stimulation of the brain was relevant to this undertaking. Such studies are conveniently divided into five categories: I) Stimulus generalization to brain stimuli after peripheral training. The results of such studies have been contradictory. Where stimulus generalization (SG) has been reported, initial training has either been to a minimal criterion or no differential training has been involved (9, 31, 32, 43). When high criterion levels and discriminative training have been involved, negative SG has been obtained (37, 40, 51). One of the few recent studies to address this problem was reported by Kelly et al. (29), who trained cats to discriminate between a visual stimulus plus tone versus a tone alone, using a conditioned avoidance paradigm. It should be pointed out that the discrimination involved was between the presence and the absence of a visual stimulus, rather than between the
D.
KLEINMAN
qualities of two visual stimuli. Stimulus generalization to central stimuli after peripheral training was obtained from the optic chiasm and lateral geniculate at high levels. Intermediate stimulus generalization was obtained from stimulation of the optic radiation and the superior colliculus, and very low levels of SG were obtained in response to stimulation of the visual cortex. Using high criterion levels but no discrimination training, Clark et al. (6) studied the effects of central stimulation after conditioned avoidance response training to tones of various frequencies. Good SG was observed from tone to stimulation of the cochlea, and some SG occurred when lateral lemniscal or auditorv cortex sites were stimulated. Prabably the most direct antecedent to our own studies was the work of Livanov and Korol’kova (40), who stimulated the motor cortex at 3/s after a conditioned limb-flexian response had been established to 3/s flicker, and demonstrated that such cortical stimulation elicited limb movement with the shortest response latency. 2) Stimulus generalization after training to subcortical stimulation. Most studies of generalization between subcortical loci have produced negative results (34, 45, 51). Nielson et al. (45) found some SG between the mesencephalic reticular formation (RF) and centre median or the superior colliculus, and between two levels of the medial lemniscus, but used a very low criterion (60y0). Buchwald et al. (4a) found SG between the contralateral caudate nucleus or the ventrolateral nuclei of the thalamus, after unilateral training at either site. However, generalization was not obtained to stimulation of other anatomical regions. Stutz concluded in 1968 (54) that SG does not occur between brain structures which are not functionally interrelated. This worker reported SG between parts of the limbic system. In 1970, Schuckman et al. (52) found no SG to stimulation of the contralateral lateral geniculate (LG) after training of the other geniculate, nor was there transfer to striate cortex. Conversely, no SG was observed in LG after training of striate cortex. However, SG was obtained when any striatal region was stimulated after striate cortex trainin-g.
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STIMULUS
GENERALIZATION
Pusakulich and Nielson (46) in 1972, Nielson (44) in 1968, and Gerken (15) in 197 I studied changes in threshold to subcortical stimuli as a function of drugs, electroconvulsive shock, or various stimulus parameters, but did not explore the questions of transfer which are of special concern to this study. 3) Stimulus generalization to cortical sites after training to cortical stimulation. There is general agreement that SG does not occur when cortical regions other than the site of training are stimulated (8, 17, 51). There is some controversy as to whether SG occurs between different sites within the same cortical area. Doty (7, S), Schuckman (50), and Schuckman and Battersby (51) agree that SG occurs when other striate cortical sites are stimulated. Schuckman et al. (52) concur in this finding. Freeman (13) failed to obtain SG to stimulation of the contralateral prepyriform cortex after training to prepyriform stimulation. Similarly, Woody and Yarowsky (60) failed to obtain SG to nearby points on the coronal-precruciate cortex after training of stimuli delivered to interspersed electrodes. It is noteworthy that the conditioned response (CR) was not dependent, in that study, on changes in the “fine structure” of the stimulus, when stimulus parameters were changed. 4) Stimulus generalization to subcortical sites after cortical training. Schuckman, Kluger, and Frumkes (52) have confirmed our earlier finding (20) that there is no SG to stimulation of the lateral geniculate after training of the visual cortex. 5) Stimulus generalization to cortical sites after subcortical training. Neider and Neff (43) reported good transfer from the inferior colliculus to the auditory cortex. Similarly, Doty (7) reported SG from lateral geniculate to optic radiations (in one monkey subjected to five test trials!). Both of these studies used low criteria and no discrimination training. Leiman (37) reported SG to stimulation of the marginal after lateral geniculate training. gyrus Schuckman, Kluger, and Frumkes (52) reported no SG from lateral geniculate to the contralateral lateral geniculate or the striate cortex, and conversely, no SG to
1017
lateral geniculate stimulation after striate training. SG was found after striate training only in other striatal areas. The studies reviewed above would more properly be termed studies of cross-modal transfer than of stimulus generalization. The various findings suggested relatively difficult access to the mechanisms established during learning which mediated conditioned responses to stimuli of one modality, when stimuli were delivered via another modality. However, in most of these earlier studies the conditioned stimulus was a sensory event of some particular quality. Little or no effort was made to construct generalization stimuli which were analogs of the original conditioned stimulus along some stimulus dimension. Under such circumstances, two possible outcomes of the search for stimulus generalization might be predicted. On one hand, if no discrimination training was involved and low criteria of learning were accepted, a broad generalization gradient might be established such that high levels of stimulus generalization were obtained. Such apparently high levels, however, might well be spurious, arising from nonspecific factors such as changes in the overall level of excitation or arousal. On the other hand, were differential conditioning established to high criteria, no stimulus generalization might be obtained because of the establishment of sharp generalization gradients. Previous results in studies of this genre seem to correspond to this pattern. Since the purpose of the brain-stimulation studies reported herein was primarily to provide a critical test of our theoretical formulations, it seemed preferable to bias our procedures against any possibility of spurious generalization, so that positive results could be construed as strong support for the theory. In the studies to be reported, accordingly, animals were trained to very high levels of discrimination between auditory or visual stimuli presented at two different repetition rates. The central stimuli utilized in tests of stimulus generalization were brief trains of electrical pulses delivered at the same repetition rates as the peripheral discriminanda, thus constituting a set of analogous signals designed to mimic the neuronal excitation postulated to rep-
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1018
resent the sensory tial training.
E. R. JOHN
stimuli
used during
AND
ini-
D. KEEINMAN The training apparatus soundproof chamber and one-way vision screen.
was was
enclosed observed
in via
a a
METHODS
Surgical Six cats were chronically implanted with 34 electrodes bilaterally located in the lateral geniculate (LG), medial geniculate (MG), visual cortex (VIS), auditory cortex (AUD), mesencephalic reticular formation (RF), intralaminar and midline thalamic nuclei (IMT), and a variety of other brain regions, using methods described elsewhere (22).
Behavioral CONTINGENCIES. Three cats were trained to press the lever on the left side of a work panel to obtain food in response to an initial stimulus at repetition rate 1, but to press the lever on the right side to obtain food if the initial stimulus occurred at repetition rate 2 (approach-approach). Three cats were trained to perform the same two differential responses to stimuli at two different repetition rates, but in order to avoid electrical shock delivered to the feet (avoidanceavoidance). Usually, 20 trials of each stimulus were presented each day, according to a modified Gellerman schedule. Sessions were sometimes lengthened if the animals working for food reward seemed particularly hungry. Foodmotivated animals were trained every weekday, fed ad libitum on Saturday, and deprived of food on Sunday to insure over 24 h of by Monday. Food reinforcement deprivation consisted of 1.5 ml of a mash made by mixing tuna and milk in a blender, and was delivered by a solenoid-operated dipper. In three cats, rate 1 was 5/s while rate 2 was 1.8/s. In three cats, rate 1 was 4/s while rate 2 was 2/s. In two cats, rate 1 was 7.7/s while rate 2 was 3.1 /s. These stimulus frequencies were counterbalanced for the various response motivations. STIMULUS-RESPONSE
APPARATUS. All procedures were carried out in a 60 x 60 x 60 cm cage with a Lucite work panel carrying two levers and dippers to deliver food. Visual stimuli were presented using a silent fluorescent tube (Iconix model 6193) mounted in the top of the cage at the rear. DC bulbs in the roof provided a moderate level of constant illumination. Thus, the visual stimuli caused a repetitive fluctuation in the level of illumination of the whole visual field of a light-adapted animal. Auditory stimuli were clicks delivered to an S-inch loudspeaker mounted in the top of the cage at the rear.
The stimulus of rate was selected as the cue lever on the right side of the all animals (CS,). Training began by presenting that stimulus at random intervals averaging 1 min, with each presentation lasting about 15 s. In approach training, at first paw movements toward the dipper and subsequently toward the nearby lever, were reinforced with food delivery. In avoidance training, weak electrical shocks to the feet were delivered every few seconds after 15 s of stimulation had elapsed, with foot shock and conditioned stimulus at first terminating as soon as the animal moved toward the lever. Gradually, more and more precise responses were required until a definite right-side leverpressing conditioned response (CR) was established. Discrete CRs were usually established in the first week of training, with several more weeks required to eliminate intertrial responses and bring CR, completely under control of cs,. At this point, the conditioned stimulus of faster repetition rate (CS,) was introduced. Animals receiving approach-approach training were presented with alternating blocks of 10 CS, and 10 CS, trials, with reinforcement withheld when the right lever was pressed in response to CS,. As the animal began to inhibit CR,, the alternating blocks of CS, and CS, were shortened until double alternation of CS, and CS, was achieved, and then a random sequence of CS, and CS, was introduced. Animals receiving avoidance-avoidance training were subjected to a very similar procedure, with initial discrimination somewhat aided by shortening the duration of CS, presentations. Establishment of this initial stage of go-no go discrimination between CS, and CS, to a 90% criterion usually took an additional month, largely because of a resurgence of spontaneous responses. During this period, the behavior of the animal was reminiscent of that seen with aperiodic reinforcement. Once go-no go discrimination between CS, and CS, was stabilized, training of CR, in reIn early stages of sponse to CS, was initiated. only CS, was presented, with CR, training, responses being shaped to the left lever on the work panel in the same way as during CR, training. CR, was usually brought under control of CS, within a few days. At that time, alternating blocks of 10 CS, and 10 CS, preintroduced, and approsentations were again DISCRIMINATION
TRAINING.
slower repetition for pressing the work panel in
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STIMULUS
GENERALIZATION
priate performance of CR, and CR, behaviors was required. As adequate discrimination behavior was established, the alternating blocks of CS, and CS, were shortened until double alternation of CS, and CS, was achieved. Up to this point training in most cats was uncomplicated, with steady improvement in performance. When random sequences of CS, and CS, were presented, with requirement of appropriate CR, and CR, performance and no self-correction permitted, severe difficulty was encountered in most animals. Although nonrandom levels of discrimination were readily achieved, the cats showed periods of perseveration of a particular CR and marked resurgence of spontaneous responses. Clear signs of frustration, such as refusal to work and sustained attempts to escape from the apparatus, were often observed. During these episodes, discrimination broke down completely and it became necessary to return to the previous stage of training. Sometimes these “neurotic” behaviors persisted with such intensity that the training procedure was suspended for weeks or even months, until the animal again became willing to work. We attributed these difficulties to some peculiar feature of the situation, possibly the particular frequencies which had been selected. After periods ranging from several months to almost a year, stable high levels of discrimination were eventually established in every animal. At this stage, discrimination appeared to be almost automatic. Movements were minimal, spontaneous responses rare or absent, and errors infrequent. PERIPHERAL-PERIPHERAL
TRANSFER
OF
TRAINING.
After achievement of 85% or better differential performance of CR, or CR, in response to random presentations of the initial stimulus at frequency 1 or 2 (CS, or CS,), transfer of training was initiated to a different kind of stimulus delivered at the same differential repetition rate. Three animals first learned the discrimination between simultaneous flicker plus click stimuli at two different rates (A,& and A,V,) and then received transfer to flicker only at the same two rates (V, and V,). Two other animals were first trained to discriminate between A, and A,, and then received transfer of training to the visual signals V, and V,. The last animal learned to discriminate between a 600- and a 1,200-Hz tone, and then received transfer of training to two flicker signals (V, and V,). CENTRAL
STIMULATION.
ulation of the Nuclear-Chicago
brain
Direct electrical stimwas accomplished by using stimulators driving stimulus
1019
isolation units which were photically coupled (Tektronix model 2620). All system timing-was accomplished using a stimulator constructed in this laboratory, constantly monitored by a Hewlett-Packard frequency counter (model 5212A). Brain stimuli consisted of trains of 30 pulse pairs. Each pulse pair was biphasic, comprised of two segments of opposite polarity and 200 ps in duration, separated by 200 ps. The interval between pulse pairs was 5 ms. Stimuli were of constant current, regulated by the stimulus isolation units, and monitored on an oscilloscope (Tektronix model 565) using a current probe amplifier (Tektronix model 131). The electrodes in the animals’ head were connected to a subminiature socket imbedded in acrylic resin. During all training and testing procedures, a cable of Microdot mininoise wire connected this socket to a receptacle in the roof of the training apparatus. Cables from this receptacle led through the wall of the soundproof chamber to a terminal board. Connections could be made between the output of the stimulus isolation units and selected positions on this terminal board in order to stimulate particular brain regions. Other connections between positions on this terminal board and inputs of the amplifiers of a 1% channel Grass model 7 polygraph permitted simultaneous recordings to be obtained. The output of the polygraph went to a 14-channel Mnemotron tape transport so that magnetic tape recordings could be made when. desired. Results of the analysis of such recordings will be presented elsewhere. This paper will be limited to primarily behavioral observations. TRANSFER. When the animals reached a performance level of 85% accuracy in discriminating between the two different repetition rates of either auditory or visual stimuli administered in a random sequence with respect to both sensory modality and repetition rate, and when this high level of differential response was maintained in a stable fashion for several weeks, tests of generalization and transfer of training to central stimuli were initiated. The mesencephalic reticular formation (RF) was selected as the first central site for transfer of training because the widespread electrophysiological response to the peripheral CS observed after training, as well as the appearance of new late components in the evoked response, strongly suggested RF implication in the representational system storing information about the learning experiences. The first problem was to establish the appropriate intensity of current for this central stimulus. For PERIPHERAL-CENTRAL
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E. R. JOHN
1020
AND
D. KLEINMAN
this purpose, the occlusion threshold W .as determined, defined as the current level at which simultaneous presentation of phase-locked RF stimuli, together with the visual or auditory discriminanda, produced blockade of behavioral performance. The occlusion threshold, thus defined, was the amount of electrical input which disrupted adaptive behavior and therefore significantly exceeded an effective neuronal excitation. Arbitrarily, we selected some fraction of this disrupting current as the initial intensity to be used for the central conditioned stimulus. Using the training current level thus defined, a series of RF stimuli at both repetition rates was randomly interspersed among visual and auditory stimuli at both repetition rates, themselves randomized. After presentation of a number of such RF stimuli without reinforcement to test for stimulus generalization, training was initiated with reinforcement of each RF stimulus until criterion levels of discrimination were achieved. Occasionally, RF stimuli were yoked to flicker or click cues for several trials to facilitate transfer.
initiated to study both generalization and transfer of training. In each case, occlusion thresholds were determined as described above for RF stimulation. Once appropriate current levels of brain stimuli were established for each of these structures, testing of generalization and transfer of training were carried out in parallel for all four brain regions simultaneously. Each day, five trials at each stimulus repetition rate were delivered to each central site, with the order of central stimulation permuted every day. These new sites were stimulated in a sequence imbedded within a random sequence of visual, auditory, and RF discriminanda intended to maintain all previously acquired discriminations at a high level. RESULTS
Sensory-sensory
TRANSFER. After achievement of 85% criterion to such differential RF stimuli or sustained high levels of performances indicating asymptotic learning, stimulation of visual cortex, lateral geniculate, medial geniculate, intralaminar and midline thalamus were CENTRAL-CENTRAL
TABLE
1.
Initial
tjpaining, Cat 1
overtraining, Cat 2
I
transfer
In every cat, transfer to the second set of sensory discriminanda was more rapid than initial discrimination training, as shown in Table 1. If we consider the savings shown by cat I as an estimate of general facilitation of acquisition of the second task due to familiaritv with the discrimination situation, only cats 2, 3, and 6 displayed markedly more rapid transfer. Note that in cats 2, 3, and 4, a compound flicker-click stimulus was used to establish
and
transfer
i
Cat3
to other
i
-
Cat4
serzsoyy )
cues Cat 5
__Cat Q
I
+
-
Flicker plus click (4 vs. 2)
Flicker plus click (5 vs. 1.8)
Flicker plus click (5 vs. 1.8)
Click only (5 vs. 1
Click only (4 vs. 2)
Trials to discrimination criterion (2 days 2 @%>
840
1,380
500
460
540
Trials
overtraining
380
640 (4 vs. 2)
Second
discriminanda
Flicker on (4 vs. 2)
Flicker only (4 vs. 2)
Flicker only (4 vs. 2)
Flicker only (5 vs. 1.8)
Flicker only (5 vs. 1 4
Flicker only (4 vs. 2)
Trials tion
to discriminacriterion
620
120
680
Response Initial
discriminanda
Percent of original training trials required to achieve transfer Trials overtraining before RF transfer
Tone (600 vs. 1,200 Hz)
76
+
+
340
360
40
68
560
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STIMULUS
the initial discrimination. Our purpose was to facilitate both initial training and the subsequent establishment of differential responses to either flicker or click stimuli as a prelude to the study of SG to brain stimulation. To our surprise, this procedure seemed to be counterproductive. Transfer of the discrimination to flicker alone was far more difficult in those cats than we had anticipated, and was on the average slower than in cats 5 and 6 which were initially trained to discriminate clicks unaccompanied by flicker. This indicates that the auditory component of the compound flicker-click CS was so prepotent as to inhibit establishment of the flicker as a relevant cue. All of these animals showed almost immediate high levels of performance of CRs to the flicker CS when transfer of training began. Nonrandom levels of discrimination were also rapidly achieved, but achievement of criterion performance required substantial further effort. Because performance was not considered sufficiently reliable, all animals received overtraining until the discrimination seemed consistently accurate and “automatic.”
electrode placements. (Cats I and 4 are still alive.) Since the purpose of ascertaining the occlusion threshold was to select an intensity of brain stimulus appropriate for use as a CS, neither ineffectual nor disrupting, it was also important to observe whether gross movements or muscle contractions were caused. For this purpose, the brain stimuli at each current level were delivered alone as well as in conjunction with the sensory cues. Examining this procedure, it becomes apparent that tests for occlusion at current levels inadequate to cause occlusion are actually yoked transfer trials, and presentations of central stimuli intended to permit observation of gross muscular responses also constitute tests of generalization. This became obvious when we observed performance of conditioned responses to the brain stimuli alone in same cats during the procedure of establishing occlusion thresholds. Thereafter, continuous trains of brain stimuli were used to establish the occlusion threshold and select intensities of stimuli to be used for training at a given site. Training cuwen t levels On the basis of these occlusion studies, appropriate CS current intensities for each brain structure were selected for training. The intensities found most suitable for training are presented in Table 3. Note that some of these current levels somewhat exceed the intensities originally found to cause occlusion. It was found that in some cases the animals apparently adapted to stimulation and performance repeated thresholds rase. In some cases thresholds seemed to decrease with training and the current levels originally selected became excessive. In general, use of currents too low produced performance but poor dis-
Occlusion thresholds Occlusion thresholds were defined as the intensity of stimulation of a brain region which would block performance if delivered concurrently with the peripheral sensory discriminanda. These thresholds were established by delivering series of brain stimuli sequentially increasing and decreasing in intensity. Occlusion thresholds are presented in Table 2. Note that occlusion thresholds were lowest in RF except in the case of cat 4. The reason for the remarkably high value found in this cat is not understood, but may become apparent after histological identification of TABLE
2.
Occlusion
thresholds
to brain
stimuli
Cat
RF
VIS
LG
1 2
45 100 80 2,400 50 100
500 500x 1,600 460 300
200 150% 150 350 250%
3 4 5 6 Values
are in microamperes.
* This
current
1021
GENERALIZATION
level
in difjerent
regions
AUD
caused
290 250 250 overt
muscular
response
MG
IMT
240 150% 600 600 600%
70 150* 1,800 350 150%
but
not occlusion.
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E.
1022
R.
JOHN
AND
crimination, whereas if currents were too high, performance was blocked. Since brain stimulation began more than 1 yr after electrode implantation, threshold changes are not reasonably attributable to histological changes around the electrode tip. Similarly, since electrodes were platinum plated and biphasic stimuli were used, these changes are not likely to be caused by stimulation per se. It seems most likely that these threshold changes relate to the establishment of new neuronal responses as a result of the conditioning process.
D.
KLEINMAN
TABLE 4. Sites where generalization occurred unreinforced stimuli -Cat
RF
VIS
LG
1
+
2% 3
+
+
+
+
+
4
+
+
5%
+
6X
+ * RF
diiqerential to
AUD
+
MG
IMT
+
+
+
+
+
+
training
preceded
testing
of other
structures.
Generalization In many brain regions, presentation of electrical stimuli at these intensities immediately resulted in performance of the differentiated conditioned response appropriate to the stimulus repetition rate. In two animals, such generalization was elicited during the search for the occlusion threshold to RF stimulation. Subsequent occlusion testing was limited to one or two trials at each intensity, and usually began at supraocclusion levels using a descending series, or used continuous trains of electrical pulses. Nonetheless, it must be conceded that in some instances a few yoked and reinforced presentations of the central stimulus occurred before performance was elicited to the brain stimulus alone. Therefore, behavioral performance thus elicited should be considered as very rapid transfer rather than as generalization in the precise meaning of the latter term. However, in some animals (particularly cat 4, who probably received most overtraining with the peripheral cues) differential generalization with no prior yoking or reinforcement was unquestionably obtained. These observations are summarized in Table 4. TABLE
Values
CurTent
3.
intensities
used for central
Transfer
As soon as generalization was observed or after current levels for brain CS were established, reinforced transfer of training began to RF stimulation. Although no data are available on the difficulty of establishing this discrimination between RF stimuli of different rates without prior training on the visual and auditory discriminations, substantial savings can be inferred from the fact that criterion levels of discrimination were achieved to RF stimuli in four of six cats within the first 100 trials, far less than were required for either the initial sensorv discrimination or the transfer of discrimination to flicker alone. The remaining two cats showed less impressive but, nonetheless, nonrandom performance within the first 200 trials. Five of the six cats showed runs of successful discrimination in the first test session with RF stimuli. Even though discrimination was by no means initially at criterion levels, all cats showed high levels of conditioned-response performance immediately when RF stimulation occurred. These results are presented in Table 5, part A. conditioned
Cat
RF
VIS
LG
1 2 3 4 5 6
60 120 60 60 40 60
320 400 200 300 250
120 100 80 240 250 100
are
in
to RF stimulation
stimuli MG 100
170 240 240
IMT 60 150 130 60 250 130
microamperes.
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STIMULUS
5.
TABLE
Peripheral-ten Cat
%CR
I
1 z 4
Total RF overtraining
B. vc
;: ;; 83 354
Concurrent
Cat 2 P %CR %D
%D
A. RF
tral
Initial Ef ;;$ 92$
and
1;: 95 36
transfer
;:i ;g 77I#I
ten tral-ten Cat
%CR
transfer
;g
GENERALIZATION
3 %D
to RF
tral Cat
stimulation 92
63
98 100 95 464
47 2” 55
‘“SOS 100 95 116
E i 76% 70$
of other
brain
1 2
26
54
s988
2
to2
:z
80 90
53 51
i Total LG 1 2 3
34 El 29 54 88 :i
47 2 58 48 68-t %z
g8 90 94
77; 82z 79$
i38 3
;i 48
100 1;: 88
48
53 57 46 62
1;: 92 91 80 1;; 72
gf: 37 56 sot gt 64
Tot a: MG 1 2 2
84 3E
64$ G6;
54 74
Total IMT 1 2 :
41 98 100 94
Total
l;os
:!:
5
%CR
after
47
--
Cat
%D
iI
to stimulation
transfer
4
%CR
1023
sensory Ei 98 E 173
Cat P %CR
%D
go” 78
46
33 57:
56
~~xx 851t
;; 347
after
33
iii;;
RF
f33P 55
60
61-f
64 94 86 54 75
Total Trials
Total N CR
41 62 49 55 52
33 65-f 54 78$ 80$ 74$
86 92 iii;:
58 72” 2
:i
91 94 100 1;;
67t 83T 66f 1;”
72 6 ;: L,
56 100 35 ::
87 92 ‘808” 92
67$ 63 44: 61
58 40 E
62 70 z;:
E$
98
67$
%
41
93
55
49
56
%CR
%D
(1) 300 300 300 300 1,200
235 266 2278’: 1,056
discrimination
52
;;-I-
Average
%D
discrimination
70* 91x 90x loox 90x
functions
6
78 89 91
79Il.I
72t 77x
%
;i$
training
%
140 153
58
63”
200 840 300 275 250
153 162 608 203 231 :2
;77 ;; 68
F
250 1,075 ;z
816 :3;
“,“,z 58”r 62X 64$ 64$ 63x
665 6131
58-t-
22::
:z
if 72 76 64 73 83
800 250 250 250 250
579 174 %% 212
%! 70 81 iii;
~~~ 74rt 60” 57-t k3$
795
80
63$
1,000
Discrimination training between two frequencies of flicker and of click was first established to a criterion of 85% on 2 successive days (see Table 1). After substantial overtraining on these sensory discriminations, transfer of frequency discrimination was initiated to electrical stimulation of RF. After criterion was achieved to RF stimulation, a further period of overtraining occurred to randomized sensory and RF stimulus sequences using both frequencies. Concurrent training of the other four structures was then initiated, using a Williams square to counterbalance the daily sequence. Throughout all central training, performance to the peripheral discriminanda was maintained at 80% or better, using test trial< at the beginning of each session. In certain instances, animals performed CRs after termination of the central stimulus. These responses were considered to indicate the need to adjust stimulus intensity, and were not included in the scores reported in this table. The occurrence of such “offset” CRs was as follows: cat I performed 11 CRs immediately after offset of RF stimulation, 59 CRs after offset of VIS stimulation, and 16 CRs after offset of LG stimulation; cat 5 performed 24 CRs after offset of RF stimulation and 8 CRs after offset of VIS stimulation. Because this cat became seizure prone, only 40 transfer trials to VIS and 75 transfer trials to LG could be obtained; cat 6 performed 19 CRs after offset of RF stimulation, 8 CRs after offset of LG stimulation, and 11 CRs after offset of IMT stimulation. Offset CRs usually occurred early in transfer training. *=p
