Time discrimination with positional responses after selective prefrontal lesions in monkeys

Brain Research, 210 (1981) 129-144

129

© Elsevier/North-Holland Biomedical Press

TIME D I S C R I M I N A T I O N W I T H POSITIONAL RESPONSES A F T E R SELECTIVE P R E F R O N T A L LESIONS IN M O N K E Y S

CARL E. ROSENKILDE*, H. ENGER ROSVOLD and MORTIMER MISHKIN Laboratory of Neuropsychology, National Institute of Health, Bethesda, Md. (U.S.A.)

(Accepted September 1lth, 1980) Key words: prefrontal cortex - - time discrimination -- positional responses - - rhesus monkey --

delayed reaction deficit

SUMMARY Monkeys with ablations of the cortex in the principal sulcus who were impaired on a spatial delayed reaction test were unimpaired on a time discrimination test in which length of time since the last trial signalled the spatial position of the correct foodwell. The finding undermines the view that the classical delayed reaction deficit after lateral prefrontal lesions reflects the loss of temporal structuring of the stream of sensory input. The result is consistent instead with the alternative view that the classical deficit reflects a spatial memory disorder. Monkeys with inferior prefrontal ablations were impaired on both spatial tasks, and on object discrimination reversal as well; analysis of their deficits indicated that they were instances of perseverative interference. Finally, monkeys with ablations of the cortex in the arcuate sulcus were not consistently impaired on any of the tasks. There is no evidence from these results that prefrontal cortex plays any role in time perception.

INTRODUCTION There is considerable evidence now in favor o f the view that the deficit in spatial delayed reactions following lesions limited to the cortex of the principal sulcus in the monkey reflects a spatial memory disorder. Monkeys with this lesion are not impaired on delayed reaction tests that are nonspatialT,1s,19,z2,2z; nor are they deficient on spatial tests that lack intratrial delaysr,16, 3s. Consequently, they have neither a global short-term memory loss nor an impairment in immediate spatial perception. Rather, * Present address: Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, N.Y. 10461 (U.S.A.).

130 their impairment appears only when spatial cues and intratrial delays are combined suggesting that they have a selective disorder in remembering spatial information6, 7,19. Although the conception of a spatial memory loss thus seems to have strong support, it is not the only current interpretation of the delayed reaction deficit after lateral prefrontal lesions. An alternative interpretation was formulated recently by Pribram and his colleagues ~5-3°,39, who have suggested that a critical factor in performance of delayed reaction tests is the proper division, or 'parsing', of the stream of stimulation to which the organism is exposed. These investigators have proposed further that the lateral prefrontal cortex plays a crucial role in this temporal structuring of the sensory stream and that it is the loss of temporal structuring after lateral prefrontal damage that is responsible for the delayed reaction impairment. The proposal was first advanced on the basis of an experiment 29 demonstrating that monkeys with lateral prefrontal lesions who had failed the traditional delayed alternation task succeeded on a variation in which temporal parsing or chunking was externally imposed by the use of alternating short and long delays. That is, the operated animals were found to alternate left (L) and right (R) responses correctly if the continuous chain of alternation was broken up into short sequences of LR LR, etc. with short delays within and longer delays between these couplets. The authors' interpretation of this finding, of course, rests on the assumption that the functional demands of the alternation task remained essentially the same in the variant as in the traditional procedure, the only change being the facilitation provided by external parsing. An alternative possibility, however, is that, at least in the case of the operated animals, external parsing altered the task qualitatively from spatial alternation to one of temporal discrimination (a long delay cueing a leftward response and a short delay cueing a rightward response), and that the animals' success reflects instead an intact temporal discrimination ability. This interpretation cannot be assessed from the data of the original experiment, since spatial and temporal cues were purposely confounded. But the interpretation can be tested if the two temporal cues are presented in random order and the animals deliberately trained to respond to one position after the shorter interval and the other position after the longer interval. In such a time discrimination task, just as in traditional delayed reaction problems, the animal must make a positional choice in the absence of an external cue at the moment of response. In the time discrimination task, however, the correct positional choice depends on the perception of a temporal cue rather than on the memory of a spatial one. According to the view that the impairment after principal sulcus lesions is confined to spatial memory, monkeys with this lesion should be unimpaired on the time discrimination task. If so, intact temporal discrimination ability would offer a simple explanation for the success of the operated animals in the parsing study. To examine this possibility, we compared time discrimination performance in animals with lesions of the cortex in the principal sulcus and animals with lesions in two adjacent prefrontal regions, the inferior convexity and the cortex in the arcuate sulcus. Since these latter two regions have been implicated in other abilities needed for the time discrimination task (conditional learningt, 9,1~,17 and positional responding 6,16,37, respectively), evaluation of their role in its performance could aid in the further specification of their functions as well.

131 MATERIALS AND METHODS

Subjects Twelve experimentally naive male monkeys (Macacamulatta), ranging in weight from 3.4 to 5.5 kg, were used in the experiment. Water was always available in their home cages, and Purina chow was given 3-7 h after the daily test session. Following preoperative acquisition of the time discrimination task, 6 monkeys received lesions of the cortex in the principal sulcus (group SP), 4 received lesions of the inferior prefrontal convexity (group IC), and 2 received lesions of the cortex in the arcuate sulcus (group SA).

Apparatus and procedure The animals were trained in a Wisconsin General Testing Apparatus located in a darkened, sound-shielded room. The illuminated test compartment contained a stationary tray with a left and a right foodwell spaced 42 cm apart. During testing, the monkey was confined in a 51 x 51 x 51 cm cage and had access to the test compartment when the interposed opaque screen was raised by the experimenter. The animals were first trained to take blanched peanut halves from open foodwells, and then from foodwells covered more and more completely by gray cardboard plaques, 7.6 x 7.6 cm. In the time discrimination task, the animal was required to discriminate between time durations of 10 and 30 sec. These durations were measured from the lowering of the opaque screen following one choice until it was raised again to permit the next. Thus, the period of time between choices served as the cue for the correct response. For approximately half the animals in each group, the left well was correct following the I0 sec period, and the right well, following the 30 sec period; for the other animals, the cue-position relation was the opposite. At the beginning of each session, the opaque screen was in the raised position and both wells were empty and uncovered. The experimenter then lowered the screen to start the temporal cue, placed the bait, and covered both wells with white plaques. Although the opaque screen prevented observation of the animal during the interresponse interval, the animal's position and orientation in the cage were always recorded at the moment the screen was raised prior to the response. A response was scored when the animal moved a plaque. No correction procedures were used. The intervals of 10 and 30 sec were each presented 15 times per day in a pseudorandom sequence until the animal reached a criterion of no more than 20 errors in 200 trials. After two weeks of rest, the animals were retrained to criterion and then operated. They were allowed two weeks to recover and were retrained again either until they reattained criterion or had received a maximum of 1500 trials. After postoperative retesting on the time discrimination, the monkeys were trained on two additional tasks - spatial delayed alternation and object discrimination reversal. These tasks were presented as diagnostic measures to insure that the lesions were behaviorally effective. In delayed alternation, the monkeys were rewarded for removing identical gray plaques alternately]from the left and the right foodwells. The

132 time between trials was always 5 sec. Each session began with one free trial in which both foodwells were baited. After an error the food was left in place and the trial repeated until the animal responded correctly. Training continued for 30 trials per day until the animals reached the criterion of 90 correct responses in 100 trials, or had received a total of 1000 trials. On this task, severe impairment was expected in both the SP and IC groups but only mild impairment in group SA 31. In object discrimination reversal, a yellow plastic bowl and a blue wooden block were presented simultaneously, each covering a foodwell. The same objects were used repetitively, their spatial position being changed from trial to trial according to a pseudorandom sequence. In the initial discrimination, the animals were rewarded for choosing the bowl until they made no more than 3 errors in 30 trials on each of two consecutive days. On the next day the reward contingencies were reversed so that the block was now correct. The animals were trained in this way for a total of 6 reversals. On this task, only group IC was expected to be impaired 31.

Surgery Soon after relearning the time discrimination task preoperatively, the animals were anesthetized with Nembutal (33 mg/kg intrahepatically) preceded by ketamine (5 mg/kg i.m.), and one-stage bilateral lesions were performed under aseptic conditions. The cortex on the lips and in the banks and depths of the principal sulcus and of the arcuate sulcus was removed in the animals of group SP and group SA, respectively. In group IC, the inferior prefrontal convexity was removed. The dorsolateral limit of this lesion was a line approximately 4 mm below and parallel to the principal sulcus, whereas the ventromedial limit was a line 8-10 mm medial to the inferior edge of the hemisphere. Posteriorly, the IC lesion included the anterior bank of the inferior arcuate sulcus on the lateral surface and extended close to the lateral fissure on the ventral surface.

Histology Following completion of training, the animals were anesthetized and perfused transcardiatly with saline followed by 10 % formol-saline. The brains were photographed, embedded in celloidin, and cut at 25 #m in the frontal plane. Every twentieth section was mounted and stained with thionine. The extent of the cortical lesions and the thalamic degeneration are illustrated in Figs. 1-3. All lesions in group SP were restricted to the principal sulcus, with no apparent damage to surrounding regions. Three animals (SP4-6) had small amounts of intact tissue in the most anterior fifth of the sulcus, but the sparing was bilateral in only one of them (SP5). Thalamic retrograde degeneration in this group was located in the dorsolateral parvocellular part of n. medialis dorsalis. None of the animals in group IC had cortical damage outside the intended limits, but subject IC3 had a bilateral infarct of the white matter under the fundus of the inferior arcuate sulcus. Parts of the lateral orbital sulcus were spared unilaterally in subject IC1 and bilaterally in subjects IC2 and IC3. The thalamic degeneration in this group was located primarily in the medial parvocellular part of n. medialis dorsalis. In

133

+40 SP1

+35

+30

+25 ~-~

SP2

SP4

SP5

SP6 Fig. 1. Coronal sections through the lesions of the animals in group SP (principal sulcus). The borders of the ablations are indicated by dotted lines. Stereotaxic levels are approximate.

animal IC3, however, the dorsolateral parvocellular part of the nucleus was affected in addition, presumably as a result of the damage to the white matter that occurred in this case. In no case did the degeneration involve the magnocellular part of the nucleus. Some tissue was intact unilaterally in the inferior arcuate sulcus of animal SA1, but the ablation was complete in SA2. Neither of these animals sustained damage to surrounding cortical structures or to the underlying caudate nucleus. Thalamic degeneration was found at all levels in the dorsal paralamellar part of n. medialis dorsalis and in the medial part of n. ventralis lateralis (area X of Olszewski~0). At more

134 rostral levels, anterior to n. medialis dorsalis, the band o f degeneration in n. ventralis lateralis was more than doubled in width compared to that illustrated (Fig. 3). RESULTS

Time discrimination The 12 animals learned the task initially in a median o f 1870 trials (range, 1080-2310) and 578 errors (range, 361-794). The two animals in group SA were the slowest to learn preoperatively in terms o f trials to criterion (2080 and 2310,

+38

+34

+30

+25

ICl

IC2

%

IC3

IC4

0

SA1

(~-

o

S,~2 +26

+24

+22

Fig. 2. Coronal sections through the lesions of the animals in groups IC (inferior frontal convexity) and SA (arcuate sulcus). The borders of the ablations are indicated by dotted lines. Stereotaxic levels are approximate.

135 i

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Fig. 3. Retrograde degeneration in n. medialis dorsalis and n. ventralis lateralis in individual animals. Degeneration is shown in black. The stereotaxic levels are + 7 . 0 in groups SP a n d IC, and + 8 . 5 in group SA.

136 TABLE I Time discrimination F, failure to reach criterion within the 1500 trial limit of training. Subject

Errors

Postoperative days of perseveration *

Preoperative acquisition

Preoperative relearning

Postoperative relearmng

SP1 SP2 SP3 SP4 SP5 SP6

361 447 487 591 669 699

0 I 34 18 23 0

50 0 26 10 404F 208

30-sec foodwell

lO-sec foodwell

1 0 1 0 6 3

0 0 0 0 6 2

Total 1 0 1 0 12 5

Medians

539

10

38

1

0

1

ICI IC2 IC3 IC4

517 564 617 691

17 12 8 9

392 I 17 634F 735F

17 0 13 21

2 2 9 29

19 2 22 50

Medians

590

10

513

15.5

SAI SA2

551 794

7 0

17 109

0 I

0 0

0 1

Medians

672

4

63

0.5

0

0.5

5.5

20.5

* Defined as 23 or more responses to one foodwell in a 30 trial session (sign test, P < 0.01). respectively), b u t the 3 groups did n o t differ significantly in their p r e o p e r a t i v e scores ( K r u s k a l - W a l l i s one-way analysis o f variance, H =- 4.27 a n d 1.15 for trials a n d errors, respectively; d f 2, P ~ 0.10). O n the p r e o p e r a t i v e retention test, all m o n k e y s regained criterion with little a d d i t i o n a l training. Postoperatively, however, a n u m b e r o f animals were grossly deficient. T a b l e I shows the e r r o r scores for i n d i v i d u a l animals before a n d after surgery. I f the range o f errors in p r e o p e r a t i v e relearning is taken as the s t a n d a r d , then 4 o f the 6 animals in g r o u p SP were essentially unaffected by the surgery, whereas the two others showed a clear loss in level o f performance. Similarly, one a n i m a l in g r o u p SA was unaffected, whereas the other showed a mild effect. I n contrast, a consistent deficit was evident in the a n i m a l s o f g r o u p IC. While c o m p a r i s o n o f p o s t o p e r a t i v e error scores a m o n g the 3 groups yielded only a marginally reliable difference (H --- 4.90, d f = 2, P < 0.10), c o m p a r i s o n o f g r o u p I C with groups SP a n d SA c o m b i n e d yielded a significant deficit ( M a n n - W h i t n e y U-test, U ~-- 4 a n d 3 for trials a n d errors, respectively; two-tailed, P < 0.05). Preoperatively, all b u t one a n i m a l in each g r o u p (SP6, IC2, a n d SA2) c o m m i t t e d significantly m o r e errors to one foodwell t h a n to the other ( b i n o m i a l test, two-tailed, P -< 0.05). A n d a m o n g the 9 animals t h a t strongly preferred one side, all b u t two (SP2 a n d IC3) preferred the side that was correct after the 30 sec interval. Postoperatively, this tendency was greatly exaggerated in g r o u p IC (see T a b l e I). I f perseveration within a d a y is defined as the occurrence o f at least 23 responses to the same foodweU in a 30 trial session (sign test, P < 0.01), then the 3 m o s t i m p a i r e d animals in g r o u p I C

137 perseverated responses to the 30 sec foodwell for each of the first 13, 17, and 21 postoperative sessions, respectively. The strength of this perseverative tendency is also indicated by the accidental discovery that animals IC1 and IC3 would respond to the 30 see foodwell repetitively, 6 to 8 times in succession, after screen-closing durations of only I-2 sec each, even though the foodwell remained uncovered and empty. Initially the response resembled the plaque-pushing act, but after a few trials the animals merely reached toward the feeder without touching it. This perseverative tendency eventually reversed completely, such that all animals in group IC responded persistently instead to the 10 see foodwell, although in all animals of the group except IC4 this compensatory overshoot dissipated more quickly than the original tendency. Differences among the 3 groups in number of days of perseveration did not reach significance (H = 5.97, df ~ 2, P <: 0.10), but the median of 20 days for group IC was significantly greater than the median of only one day for the two other groups (U ---- 2, P < 0.02). In summary, ablation of the inferior prefrontal convexity produced a consistent impairment in performance that was characterized by positional perseveration. In contrast, ablation of cortex in neither the principal sulcus nor the arcuate sulcus had a reliable effect. Although two of the animals in group SP were deficient, their poor performance seemed to be related to nonsurgical factors, as described below.

Positional strategies Observations on positional strategies adopted by the animals during testing help to account for the marked differences in postoperative performance that were found both between and within groups. In the initial phase of acquisition, no particular place within the cage was favored by any animal. But in the course of training, each animal gradually stabilized its cage position so that it always initiated its instrumental response from the same place. The cage-side chosen, left or right, was idiosyncratic and unrelated to the reinforcement contingency. Body orientation was directed toward the test compartment by all animals except subject SP6, who persistently faced the right side of the cage. The following observations attest to the importance of these cage-position habits for performance on the time discrimination task. Preoperatively, subject IC3 had gradually improved performance to nearly 90 correct responses after 1000 trials, during which it had gradually assumed a constant position on the left side of the cage. The preference for this side had not quite stabilized, however, and it continued to sit occasionally on the right side of the cage, from which position it continued to commit errors. As the animal approached criterion, both its positional strategy and its response accuracy began to deteriorate. During the next few hundred trials the animal sat on the left and right sides alternately for varying periods, and then began to shift more and more frequently between the two sides until it eventually adopted the strategy of always remaining on the side that had been correct on the preceding trial, at which point it achieved criterion. The entire course of learning took 1980 trials. Thus, this subject adopted two different positional strategies in succession, each of which coincided with successful performance. Animals IC4 and SP5 likewise adopted two different positional strategies in succession prior to surgery. The first strategy for both animals was to sit on one side

138 following the 10 sec time cues and on the other following the 30 sec time cues. However, both subjects later relinquished these tendencies, which were only partially successful, and reached criterion eventually using constant, time-invariant positions like most of the others. Following the cortical ablations, there were no changes of cage-position habit in animals SP1-4 and SAI-2, and none of these animals was affected by the surgery except the last, who was impaired only mildly. Similarly, subject SP5 responded, as before, from the right side of the cage for the first 4 postoperative sessions, during which it committed 10, 7, 4 and 2 errors, respectively, and thus nearly reattained criterion. However, the constant cage-position habit that this animal had acquired only with great difficulty preoperatively deteriorated during the next 3 sessions and, correspondingly, the number of errors increased to 8, 7, and 10, respectively. For the next 700 trials, this animal consistently responded to the right while sitting on the left, and to the left while sitting on the right, but it chose the left and right starting positions seemingly at random. Finally, during the last 300 trials of training, the animal gradually reacquired the time-dependent position habit that it had initially adopted preoperatively, a habit which now enabled it to achieve 87 correct responses in the last 100 trials. The cage position and body orientation of animal SP6 also underwent a change after surgery. Preoperatively, this monkey had consistently positioned itself on the left side of the cage facing the right wall, and had responded correctly to the right foodwell after the 10 sec time cue. Postoperatively, however, the animal often sat in the center of the cage facing the test compartment and responded incorrectly after the t0 sec time cue, i.e. to the left foodwell. It will be noted that in response to the 10 sec cue both before and after surgery the animal made the same approach movement, 45 ° to the right. But while the movement itself was the same as before, the target was now different (and incorrect) due to the changed starting position. In contrast to the foregoing results, cage-position habits acquired preoperatively were consistently disrupted by lesions of the inferior prefrontal convexity. All the animals in this group showed increased levels of activity after surgery, and in early postoperative sessions were often found to be circling when the screen was raised at the end of the time cue. As indicated earlier, 3 of these animals perseverated responses to a single side despite being randomly positioned in the cage at the moment of choice, suggesting a complete breakdown in the use of positional strategies. Partial recovery of these strategies occurred in subjects IC1 and IC2, however, both of whom reattained criterion after relearning to sit quietly during the interresponse intervals, although their positions in the cage were still somewhat irregular. In summary, the positional strategies that had been adopted by all animals preoperatively as an aid to solution of the time discrimination problem appeared to be severely disrupted by the inferior convexity lesions. In the case of the two impaired animals in group SP, by contrast, the deterioration in the use of positional strategies appeared to be related instead to idiosyncratic changes in cage-position habits similar to the changes seen in other animals before surgery.

139

Control tasks In the delayed alternation task, no animal except SA1 reached criterion within the allotted 1000 trials, providing behavioral confirmation of the effectiveness of the lesions. With the exception of IC3, however, all animals exceeded chance performance by the last 100 trials (binomial test, one-tailed, P < 0.02). These final performance levels averaged 62, 72 and 87 ~ correct for groups IC, SP, and SA, respectively. The postoperative error scores in time discrimination and delayed alternation showed a significant positive correlation in group IC (rs = + 1.00, P < 0.05) but not in group SP (rs -- ~0.43, P > 0.05). As further evidence of lesion effectiveness, group IC was found to be impaired on object discrimination reversals. Their median error score for all reversals combined was 118, compared with a median of 57 errors for the animals in the other groups (U = 3.5, one-tailed, P, < 0.05). DISCUSSION Most of the monkeys with removal of cortex in the principal sulcus were unaffected on the time discrimination task with positional responses even though they failed to learn spatial delayed alternation. Monkeys with inferior prefrontal ablations, on the other hand, were markedly impaired on both of these spatial tasks, and on nonspatial reversal as well. Finally, animals with removal of cortex in the arcuate sulcus were not reliably impaired on any of the problems. These 3 different test profiles help to define further the behavioral roles of these 3 functionally distinct prefrontal regions, each of which will be considered in turn.

Cortex of the principal sulcus Temporal factors. Mastery of the time discrimination task required the animals to discriminate between a 10 see and a 30 sec interresponse interval. The absence of a reliable deficit on this problem after ablation of cortex in the principal sulcus confirms findings obtained in operant conditioning studies with D R L schedules (differential reinforcement of low rates). Performance on such schedules, which require the withholding of a response for a minimum period of time and so presumably measure timing behavior or time estimation, has also not been affected reliably by lesions in and around the principal sulcus~,14,35,36. In corroborating these earlier studies, the present demonstration of preserved time discrimination seriously undermines one current interpretation of the delayed alternation deficit after prefrontal damage. Pribram and Tubbs z9 showed that animals with lateral prefrontal damage performed efficiently on a spatial delayed alternation task in which a temporal structure was provided externally by the use of alternating long and short delays. Specifically, 15 sec delays, following which the left foodwell was baited, were alternated with 5 sec delays, following which the right foodwell was baited. The variation that had been devised was thus essentially a time discrimination task with alternating temporal cues, which the operated animals solved - - as they would be expected to on the basis of their success in the present study with randomly presented temporal cues. According to the

140 present interpretation, the use of differential delays did not facilitate delayed alternation learning; rather, it permitted solution of a qualitatively different, time discrimination, problem. The results of subsequent attempts by Pribram and his colleagues to establish that the success of operated animals on their variant of delayed alternation was indeed due to facilitation by temporal chunking do not rule out the simpler interpretation offered here. For example, as these previous investigators had predicted, a control procedure a9 that entailed an exteroceptive cue rather than temporal chunking did not 'facilitate' delayed alternation learning by operated monkeys; but that procedure would not be expected to aid performance on the basis of the present interpretation either, since it did not allow solution as a time discrimination problem. Conversely, in another control procedure 30, delayed alternation learning in impaired animals was 'facilitated', again as predicted, despite a daily reversal in the relation between the length of the delay and the position of the baited foodwell; but according to the present interpretation this task could just as easily have been solved by the operated animals as a time discrimination reversal problem. In summary, it seems unlikely from the present results that the cortex in the principal sulcus participates either in temporal discrimination or in temporal structuring. In fact, the function of this cortex probably bears no relation to temporal factors, including delay, when these are divorced from spatial factors. Spatial factors. In addition to the discrimination between 10 sec and 30 sec interresponse intervals, mastery of the time discrimination task involved the learning of a differential positional response. The absence of a reliable deficit on this task after removal of cortex in the principal sulcus corroborates previous findings6,16, 3a with other non-delay tests that entail the same response requirements. In the earlier studies, however, the correct spatial choice was signalled by a discriminative visual or auditory stimulus that continued throughout the response period. It therefore remained a possibility that the classical delayed reaction deficit after midlateral prefrontal ablations reflected a difficulty in selecting a spatial response in the absence of a concurrent exteroceptive cue. However, this possibility has now been eliminated by the finding of excellent postoperative retention in most of the animals with lesions in the principal sulcus on a test which, like delayed reaction, provides no concurrent exteroceptive cue to signal the spatial response. In the course of learning to make the correct spatial choice preoperatively, each animal slowly acquired the habit of positioning itself in the same part of the cage on every trial and of always orienting in the same direction. Departures from these constant cage-position and body-orientation habits invariably ted to a breakdown in performance. A particularly clear example of such a breakdown was observed preoperatively in animal IC3; on approaching criterion, this animal unaccountably changed its cage-position habit and then needed almost 1000 additional trials to regain criterion. The same sequence of improvement followed by deterioration was observed postoperatively in one of the two impaired animals with lesions in the principal sulcus; after nearly achieving criterion in the first few postoperative sessions, animal SP5 also suddenly altered its cage-position habit and needed 790 additional trials to regain

141 criterion. In the other impaired animal of this group, SP6, a shift in cage position and erientation was noted from the start of postoperative training. These two operated animals did not differ from the unimpaired animals of their group in either their lesions or their learning strategies. It therefore seems likely that their drop in performance was due not to the surgery but to an instability in their cage position habits, similar to that seen in other animals before surgery. The critical importance of a constant starting position in this task suggests that the positional responses which the animals acquired with such difficulty involved two different directional movements rather than an approach to two different spatial locations. That is, the learned reaction to the discriminative time cue may have been a specific movement rather than a place response. The same interpretation applies to an earlier study 13 from this laboratory in which animals were trained to make differential positional responses to two different auditory frequency cues. It was noted in that study, too, not only that learning was extremely slow but also that correct solution depended on the adoption of a constant starting position. Thus, again, the learned reaction may have been a specific movement rather than a place response. Just the reverse seems to be true in spatial delayed reaction tests, in which it has often been demonstrated that animals need not adopt constant cage position or body orientation habits to perform successfully3,4,10,11,15,21,a0. The two different response strategies (movement vs place) that appear to be elicited in the two different types of tests are presumably related to the difference in the stimuli with which the positional responses must be associated. In both the time discrimination and tone discrimination tasks, the adoption of a directional-movement strategy could result from the use of selfproduced, possibly kinesthetic, stimuli. In spatial delayed reaction, by contrast, the adoption of a spatial-location strategy could be the consequence of cueing by exteroceptive stimuli that are in the same spatial location as the response loci. These speculations suggest that positional response learning is not a unitary process, and that further analysis may yet reveal a relationship between the 'place' form of this response and the function of the cortex in the principal sulcus. For the present, however, it must be concluded that the function of this cortical region is more closely tied to the stimulus used in spatial delayed reaction tests than it is to the response requirement. In short, the present data provide additional support for the view 6,7,19 that the classical deficit after midlateral prefrontal ablations reflects a specific disorder in remembering the predelay spatial cue.

Inferior prefrontal cortex Analysis of the preoperative distribution of errors indicated that 7 animals made significantly more errors to the 10 sec than to the 30 see time cue, whereas only two animals did the opposite. The cause of this asymmetry cannot be designated with certainty, though presumably it is related to the unique property of a time cue, which may change its signalling value in the course of a trial. That is, while the animal must be ready to move in one direction if the interresponse interval is short, it must also be prepared to shift to the other direction if that interval is extended beyond the critical duration. T h i s active shift in direction could have become anticipatory, thereby

142 resulting in the preference for the side that was correct after the longer interval, But whatever the reason for the preference, it was found to be greatly exaggerated immediately after surgery in 3 of the 4 animals given inferior prefrontal ablations. Since an exaggerated preference was not observed in the other animals that performed poorly, this preference in animals with inferior prefrontal ablations could not have been merely an effect of their poor performance, and indeed may have been the cause. This notion of perseverative interference, which has been employed to describe the impaiment of monkeys with inferior prefrontal lesions on a wide variety of tasks 1,9,12,17,3a, including the delayed alternation and object reversal tasks, accurately describes their impairment on the time discrimination task as well. Thus, not only did these animals start out with a strong preference for the 30 sec foodwell, but their preference shifted to the opposite well when the correction procedure finally took effect. Furthermore, the chance discovery in two of the animals of repeated responses at short intervals to the 30 sec foodwell even when it was uncovered and empty demonstrates that positional perseveration can be evoked by the releasing stimulus alone (raising of the opaque screen). By contrast with the notion of perseverative interference, the alternative possibilities of a disturbance in either time perception or in spatial functions, discussed above in connection with the effects of lesions in the principal sulcus, are clearly too restrictive to apply to the far-reaching consequences of inferior prefrontal damage. Cortex of the arcuate sulcus Animals with ablations of cortex in the arcuate sulcus were previously found to be markedly impaired on tasks requiring positional responses both to spatial auditory cues6, 37 and to nonspatial visual cues 16. Yet no such impairment was found with the present positional response task involving temporal cues. Apparently, an exteroceptive stimulus is necessary to reveal the impairment produced by this lesion. At the same time, lesions in the arcuate sulcus have little or no effect on the performance of spatial delayed reaction tests, as seen in both the present and earlier studies 2,6,7,a,z4. Consequently, the critical factor for elicitation of the deficit on positional response tasks after lesions in the arcuate sulcus may be the use of exteroceptive stimuli that are spatially unrelated to the response loci. If so, then the positional response learning in which the cortex of the arcuate sulcus participates may be of the type that calls for directional movements to exteroceptive cues rather than place responses. It should be noted that this is the reverse of the suggestion made above regarding the function of the tissue in the principal sulcus. ACKNOWLEDGEMENT C.E.R. is in receipt of a visiting fellowship supported by the Danish Medical Research Council.

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