Brain Researelt', 92 (1975) 89-102
89
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
D E L A Y E D M A T C H I N G 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 (Macacamulatta)
RICHARD PASSINGHAM
Department of Experimental Psychology, University of Oxford, Oxford (Great Britain) (Accepted February 2nd, 1975)
SUMMARY
Rhesus monkeys with bilateral lesions of either dorsal or ventral prefrontal cortex were tested on delayed matching for colours. The animals with dorsal frontal lesions performed as well after the operation as before, whereas those with ventral frontal lesions were severely impaired even at the shortest delay. However, the animals with dorsal frontal lesions failed to learn delayed spatial alternation. The results support the view that the monkeys with dorsal frontal lesions have an impairment in memory for spatial cues or their own movements in space.
INTRODUCTION
It has been known for nearly 40 years 11 that rhesus monkeys with bilateral lesions of prefrontal cortex fail delayed response tasks. But the reasons for this failure are still poorly understood. On these tasks the animals are required to remember for a few seconds the position where food is to be found. They might fail because they do not notice where the food is put, are distracted during the delay, confuse the position of the food on the present trial with its position on previous trials, or because they have some defect in spatial perception or memory. Since the tasks may be failed for one of many reasons it is necessary to devise tests which distinguish between these possibilities. An early series of studies investigated whether monkeys with lateral frontal lesions were impaired on delayed response and delayed alternation only when required to remember spatial cues15,16,21,z2. The results were not consistent or conclusive. It was found that the animals could learn to alternate between responding on one trial and not on the next (go-no go alternation), but failed when required to alternate between objects (object alternation)iS,21, 2~. On delayed response there was
90 suggestive evidence that the animals were better if tested with non-spatial cues 16. More recently both Buffery1 and Glick et al. 6 have found that monkeys are impaired on delayed matching for colours after lateral frontal lesions, and Fuster and Bauer 5 have reported that cooling the tissue in and around sulcus principalis produces an impairment on delayed matching. The confusion in the literature results in part from the use of large lesions which included the whole of the lateral frontal surface, since it was incorrectly assumed that the lateral frontal surface had a single function. More recently anatomicaP 3 and behaviouraF,9,17 studies have subdivided the lateral and orbital surface into areas with different though related functions. Mishkin et al. 17 have showed that if selective lesions of frontal cortex are made, rhesus monkeys with dorsal lesions including sulcus principalis are impaired on spatial but not on object alternation, whereas those with lesions of the ventrolateral and orbital surface are impaired on object as well as spatial alternation. It seemed likely, therefore, that more consistent results might be obtained for delayed response and delayed matching if selective lesions of the lateral surface were made. The present study investigates the effect of lateral and ventral frontal lesions on the performance of monkeys on non-spatial delayed matching. METHODS
Subjects
Nine rhesus monkeys (Macaca mulatta) with no previous training were used. Six were males and 3 females. At the time of operation they weighed from 4.1 to 6.0 kg.
sample key response
keys
Q
©
©
screen
,
10 c m
Fig. l. Diagram of testing panel
91 Apparatus
The animals were trained in a cage placed in a testing box such that they had direct access to a testing panel at the end of the box. The panel is illustrated in Fig. 1. The translucent Gerbrands keys were 3.3 cm in diameter. The centres of the bottom keys were separated by 15.5 cm from each other and 13.5 cm from the centre of the top key. The discriminanda were back projected onto the keys by rear-projection readout units (Industrial Electronic Engineers). Peanuts were dispensed into the food well by a Gerbrands Universal feeder. The screen could be rotated on its axle by an electric m o t o r so as to cover the 3 response keys. The interior of the box was illuminated from above by a 40 W bulb run on 140 V. A masking white noise was present. The presentation of the stimuli and reinforcement, and the movement of the screen were programmed automatically using Behavioural Research and Development logic modules. Training Pre-training
The monkeys were pre-trained to press the upper lit key as an observing response. When the animal pressed at least 3 times over 1.5 sec or more, the light on the observing response key went out and discriminanda were projected onto the two bottom keys. The animals were trained on 3 visual simultaneous discriminations: 8 vs. 1, 5 vs. 9 and 4 vs. 2. They were given 100 trials a day. Correct responses were rewarded with a peanut, and incorrect punished by the house-light being turned off for 2 sec. On 8 vs. 1 and 5 vs. 9 the animals were trained to a criterion of 90/100correct responses in one day, and on 4 vs. 2 to a criterion of 90/100 correct responses on two consecutive days. Matching - - pre-operative
The animals were then trained on matching to sample for colours (red and green) in several stages. (a) Simultaneous. First the sample colour (red or green) was presented on the observing response key. When the animal pressed at least 3 times over 1.5 sec the choice keys were illuminated, the position of the two colours being fixed so that one colour always appeared on the left and the other on the right, the sample colour still being shown on the upper key. The animals were trained to a criterion of 90/100 correct responses in two successive days. I f the animal made a mistake the trial was repeated until the animal made the correct choice (re-run correction schedule). The inter-trial interval was 5 sec during this and all other stages of matching. In the second stage the position of the colours on the response keys was randomised, and the animals were retrained to the same criterion using a re-run correction schedule. They were then tested without the correction schedule until they had performed at 90 correct over 500 trials. (b) Delay. In the next stage the animals were trained on 0 sec delay. When the
92 animal had made the observing response the sample disappeared and the colours immediately appeared on the response keys. The animals were trained without correction to a criterion of 90/100 correct responses on two successive days. (c) Titration. After completion of training at 0 sec the length of the delay was increased for each animal using a titration schedule. I f the animal made two or fewer errors out of 10 trials the delay was increased by one sec for the next 10 trials, and if the animal made 3 or more errors it was decreased by one sec. Fifty trials a day were given. Every 1000 trials the animals were retested for 100 trials on matching at 0 sec, these trials being given in one day. The delay was titrated until the animal reached a criterion of stable performance. The delay at which an animal being titrated down performed at 80 ~ correct or better was called a 'descending threshold', and the delay at which having titrated up it performed at 70 ~ incorrect or worse was called an 'ascending threshold'. The means of successive pairs of descending and ascending thresholds (75 ~ thresholds) were calculated. An animal was said to have achieved criterion when the means of two blocks of 15 mean thresholds did not differ by more than 10 ~ of the lesser, and the standard deviation of the 30 means did not exceed 2.5 sec.
Operation Operations were performed on 6 of the 9 animals within a week of their reaching criterion on delayed matching. All animals restarted testing 3 weeks after completion of pre-operative training.
Matching --post-operative The animals were first retested on delayed matching at 0 sec to a criterion of 90/100 correct responses on two successive days. The correction schedule was not used. Delay was then increased as pre-operatively and the animals retrained to the same criterion of stability.
Retention of visual discrimination The animals were then tested for retention of the visual discrimination 4 vs. 2 to the same criterion as before the operation.
Spatial reversal The animals were first trained to press the observing response key to illuminate the two response keys with white light. Presses on the left response key were rewarded. When the animal reached a criterion of 45/50 correct responses on one day, presses on the right key but not on the left were rewarded. Five successive reversals were given, each to a criterion of 45/50 correct responses on one day. Fifty trials a day were given.
Delayed alternation The animals were tested in a Wisconsin General Test Apparatus. Black plaques (7.5 cm square) covered food wells 30 cm apart, and the animals were required to
93 push the plaques to retrieve the food. They were trained for 30 trials a day on delayed alternation with a re-run correction, an opaque screen being lowered for 5 sec between trials. Training continued until the animal reached a criterion of 90/100 correct responses or until they had been tested for 1000 trials.
Matching-screen Finally the animals were retested on matching, but with the use of the automatic screen. They were first retrained on delayed matching at 0 sec without the screen to a criterion of 90/100 correct responses on two consecutive days. They were then tested with a fixed delay of 5 sec to a criterion of 80/100 correct responses over two consecutive days with 50 trials on each day. Finally, they were tested at the same delay and to the same criterion but with the automatic screen covering the keys during the delay.
DFI
DF3
VF4
VF5
VF6
Fig. 2. Reconstruction of lesions. Straight lines indicate the levels from which the cross-sections shown in Fig. 3 were taken. DF: animals with dorsal frontal lesions; VF: animals with ventral frontal lesions.
94
Groups and surgery The animals were divided into 3 groups of 3 animals. Animals in the first group were given bilateral dorsal frontal lesions (DF), those in the second bilateral ventral frontal lesions (VF), and those in the third served as unoperated controls (UC). The dorsal frontal lesions were intended to remove cortex in both banks of sulcus principalis and the dorsal convexity, the lesion extending posteriorly to within roughly 3 m m of the arcuate sulcus. The ventral frontal lesions were intended to remove cortex on the ventrolateral surface and inferior convexity, extending dorsally to within roughly 5 m m of sulcus principalis, posteriorly to within roughly 3 m m of the arcuate sulcus and ventrally to the lateral orbital sulcus. All surgery was performed with aseptic procedures and using Nembutal anaesthesia.
DF1
DF2
VF4
Fig. 3. Representative cross-sections through the lesions. DF: animals with dorsal frontal lesions; VF: animals with ventral frontal lesions.
DF1
DF3 +8.0
+6"5
+5.0
Fig. 4. Standard cross-sections through the dorsomedial nucleus of the thalamus. The areas of dense gliosis are shown in black. DF: animals with dorsal frontal lesions.
Histology At the end of the experiments the animals in the operated groups were anaesthetized with Nembutal and perfused with 0 . 9 ~ saline and 1 0 ~ formal-saline. The head was placed in a stereotaxic apparatus and a cut was made behind the thalamus in stereotaxic vertical. The brain was then removed, photographed and placed in sucrose formalin (10 ~ formalin, 30 ~ sucrose) until it sank. Fifty #m frozen sections were cut, and every tenth section stained with cresyl violet. Reconstructions of the lesions were made from sections 1 mm apart. The reconstructions of the lesions are shown in Fig. 2, and representative cross-sections in Fig. 3. The dorsal frontal lesions did not include the frontal pole, and in DF1 and DF3 the bottom of sulcus principalis was left in some sections although the tissue was almost certainly not functional. The ventral frontal lesions were small, and they did not include the frontal pole. Fig. 4 shows standard sections through the dorsomedial nucleus of the thalamus, Dense gliosis was found in the parvocellular portion is of the dorsomedial nucleus in the 3 animals with dorsal frontal lesions. No patches of dense gliosis are apparent in the dorsomedial nucleus of the 3 animals with ventral frontal lesions, but there appears to be some cell loss in the medial part of the parvocellular division of the nucleus. However, the staining of the sections was too poor and uneven to permit adequate mapping of these changes. RESULTS
Matching The titrated delays before and after operation are shown for each animal in Table I. Few animals succeeded in reaching long delays, whether because of the short inter-trial interval 1~, the method of increasing delay or some other factor. The post-
96 TABLE I D E L A Y E D
M A T C H I N G
Pre-operative (PRE) and post-operative (POST) delays at criterion and post-operative errors at 0 sec. F: failed in a 1000 trials, and the figures in brackets give the percentage correct responses in the last 100 trials. Groups
P R E (see)
POST errors at 0 see
P O S T (sec)
P O S T minus P R E (see)
Dorsal frontal 2 3 Mean
15.2 31.5 18.8
2 7 4.0
15.0 14.2 19.5 16.2
Ventral frontal 4 5 6 Mean
22.5 2.7 10.8 12.0
F (80 ~ ) F (68 ~ ) F (64 ~)
----
Unoperated control 7 8 9 Mean
10.9 7.3 7.8 8.7
3 17 7 9.0
13.0 10.0 6.1 9.7
1
9.7
5
+ 5.3 1.0
---
12.0
--
2.6
I m
m
+2.1 + 2.7 -1.7 + 1.0
o p e r a t i v e delays o f the a n i m a l s with d o r s a l f r o n t a l lesions were well within those for all a n i m a l s before o p e r a t i o n . D F 3 did n o t achieve the same level after the o p e r a t i o n as before, b u t it is unlikely t h a t this was a genuine i m p a i r m e n t since the a n i m a l ' s p e r f o r m a n c e before the o p e r a t i o n was very unstable a n d for m u c h o f the time it p e r f o r m e d at a level similar to t h a t reached after the o p e r a t i o n . On retest after the o p e r a t i o n D F 3 achieved the longest delays o f a n y animal. The a n i m a l s with ventral f r o n t a l lesions failed to regain criterion at 0 sec during 1000 trials. W h e n r e t r a i n e d on s i m u l t a n e o u s m a t c h i n g V F 5 reached a c r i t e r i o n o f 90/100 correct responses in 500 trials, V F 4 in 1700 trials a n d V F 6 failed in 2500 trials. A n analysis was m a d e o f perseverative errors before a n d after the o p e r a t i o n . T h o s e errors were analysed which occurred after a trial in which the a n i m a l h a d m a d e a correct response. I f when m a k i n g such a n e r r o r the a n i m a l went to the same c o l o u r as on the previous trial, the e r r o r was classified as perseverative for colour, a n d i f to the same side as on the previous trial the e r r o r was classified as perseverative for p o sition. T a b l e II shows the perseverative errors for a n i m a l s on 0 sec m a t c h i n g before the o p e r a t i o n , a n d for the a n i m a l s with ventral frontal lesions on 0 sec m a t c h i n g after the o p e r a t i o n . A l l a n i m a l s t e n d e d to perseverate for c o l o u r before the o p e r a t i o n b u t n o t to perseverate for position. A f t e r the o p e r a t i o n V F 6 s h o w e d an increase in p e r s e v e r a t i o n for colour, b u t the p r o p o r t i o n o f perseverative responses was still well within the range for all a n i m a l s before the operation. O u t o f the first 200 trials 60 ~ o f incorrect choices were o f one c o l o u r a n d 40 ~ o f the other. O n the o t h e r h a n d
97 TABLE II PRE-OPERAT1VE AND POST-OPERATIVE PERSEVERATIVE ERRORS FOR COLOUR AND POSITION ON MATCHING AT 0 SEe
Only those errors were analysed which followed a trial on which the animal had made the correct response. The pre-operative figures are the mean for 9 animals, and the range is given in brackets. The post-operative figures are for the 3 animals ventral frontal lesions, subjects (S) 4-6. The postoperative minus the pre-operative percentage errors are given in brackets. Pre-operative (9 animals)
Post-operative (ventral frontal)
Colour
Pos#ion
Colour
Position
75.8 (61.9 - 85.5)
51.7(39.2-61.5)
63.7(-- 6.9) 57.9 ( - - 13.5) 76.4 ( + 14.5)
71.6(+ 10.1) 68.3 ( + 18.0) 54.5 ( + 2.0)
$4 S5 S6
V F 4 a n d V F 5 showed an increase in perseverative responses to position, the p r o p o r t i o n o f such responses being outside the range for a n i m a l s before the o p e r a t i o n . In the first 200 trials V F 4 m a d e 72.7 ~ errors which were perseverative for position, a n d V F 5 68.9 ~ . F i f t y per cent o f the errors o f V F 4 on these trials were to the left, a n d 52.5 ~ o f the errors o f VF5. Visual discrimination O n p o s t - o p e r a t i v e r e t e n t i o n o f the visual d i s c r i m i n a t i o n 4 vs. 2 the m e a n trials to criterion for the 3 g r o u p s were: d o r s a l frontal 19.3, ventral f r o n t a l 76.3, u n o p e r a t e d c o n t r o l 14.0 (by an oversight UC9 was n o t retested on this task). The a n i m a l s with ventral f r o n t a l lesions t o o k significantly m o r e trials to relearn t h a n those with d o r s a l f r o n t a l lesions ( U = 0, P ~ 0.05). Spatial reversal The errors to criterion on the p o s i t i o n d i s c r i m i n a t i o n a n d on 5 reversals are shown in Fig. 5. The a n i m a l s with d o r s a l f r o n t a l lesions were n o t i m p a i r e d c o m p a r e d with u n o p e r a t e d c o n t r o l a n i m a l s on either the original d i s c r i m i n a t i o n s or the reversals. T h e a n i m a l s with ventral f r o n t a l lesions differed significantly f r o m the other two g r o u p s only on the fifth reversal (ventral f r o n t a l vs. u n o p e r a t e d c o n t r o l : U = 0, P = 0.05; ventral f r o n t a l vs. d o r s a l f r o n t a l : U = 0, P = 0.05). Delayed alternation T a b l e I I I shows the trials a n d errors to criterion on delayed alternation. A l l the a n i m a l s with d o r s a l frontal lesions failed to reach criterion in 1000 trials, a n d m a d e significantly m o r e errors t h a n the a n i m a l s in the u n o p e r a t e d c o n t r o l g r o u p ( U = 0, P = 0.05). O f the a n i m a l s with ventral f r o n t a l lesions one (VF5) was uni m p a i r e d , a n d one failed to reach criterion (VF6). One o f the a n i m a l s in the uno p e r a t e d c o n t r o l g r o u p also failed to r e a c h criterion. The errors were divided into ' c o r r e c t i o n ' a n d ' a l t e r n a t i o n ' errors. W h e n a n
98 50 45
g_ 4o e~ 35 ~
3o 25
0 ~-
20
~
15
0
5 |
I
I
I
I
I
D
1
2
3
4
5
Fig. 5. Errors to criterion on spatial discrimination (D) and 5 reversals (1-5). O, animals with dorsal frontal lesions; A, animals with ventral frontal lesions and O, unoperated control animals. TABLE III DELAYED SPATIAL ALTERNATION
Trials and errors to criterion on delayed spatial alternation. 1000F: failed to reach criterion in a 1000 trials, the percentage correct on the last 120 trials being given in brackets. Corr.: correction errors; Alt. : alternation errors. The percentage initial errors were analysed for the first 60 trials. The criterion used for correct and alternation errors was 20 ~ errors in 120 trials. F: failure to reach criterion. Group
Trials
Errors
% Initial errors
Trials to criterion
Corr.
AIt.
Corr.
Alt.
Dorsal frontal 1 1000F (72 ~ ) 2 1000F (64 ~ ) 3 1000F (42 ~ ) Mean
406 522 586 504.7
27.6 36.2 29.3 31.0
33.3 35.1 36.6 35.0
420 900 F
F F F
Ventral frontal 4 849 5 477 6 1000F (53 ~ ) Mean
287 159 438 294.7
25.9 34.5 22.0 27.5
30.2 34.2 28.6 31.0
180 120 120
660 180 F
Unoperated 7 8 9 Mean
115 390 96 200
39.6 63.8 17.2 40.2
34.3 42.8 39.6 38.6
60 240 0
300 F 300
302 1000F (66 ~ ) 369
animal made a correct response and on the next trial incorrectly went to the same side that error was termed an 'alternation' error. Alternation errors were expressed a s a p e r c e n t a g e o f t h e t r i a l s o n w h i c h t h a t e r r o r c o u l d o c c u r , t h a t is as a p e r c e n t a g e of the total daily trials minus the correction trials. After an initial incorrect response t o o n e side, c o n s e c u t i v e i n c o r r e c t r e s p o n s e s t o t h a t side w e r e c a l l e d ' c o r r e c t i o n ' e r r o r s . T h e s e w e r e e x p r e s s e d as a p e r c e n t a g e o f t h e t o t a l d a i l y t r i a l s . T h e p e r c e n t a g e
99 TABLE IV DELAYED MATCHING(WITH SCREEN) Errors on delayed matching at 0 sec, and 5 sec with and without the screen. F: failure to reach criterion in 1000 trials, the percentage correct on the last 100 trials being given in brackets. Groups
0 sec
5 sec
Dorsal frontal 1 2 3 Mean
12 8 27 15.7
29 52 18 33
Ventral frontal 4 5 6
F (84 %) F (65 %) F (69 %)
----
Unoperated 7 8 9 Mean
16 65 36 39
32 195 129 118.7
5 sec (with screen)
33 43 244 106.7
---19 82 -50.5
of correction and alternation errors did not differ significantly between the 3 groups on the first 60 trials (Table III). A criterion was set of 20 % errors in 120 trials. Animals in the ventral frontal, and unoperated control group, reached criterion on correction errors before reaching criterion on alternation. The animals with dorsal frontal lesions took significantly longer than animals in either of the other two groups to reach criterion on correction errors (dorsal frontal vs. ventral frontal: U ~- 0, P = 0.05; dorsal frontal vs. unoperated control: U = 0, P = 0.05). All three animals with dorsal frontal lesions failed to reach criterion on alternation errors, one animal failing in each of the other two groups. Matching-screen
When re-tested on delayed matching with 0 sec delay the animals with dorsal frontal lesions did not differ from those in the unoperated control group, but the monkeys with ventral frontal lesions failed to reach criterion in 1000 trials (Table IV). UC9 could not be adapted to the rotation of the screen, but DF1 and DF2 were clearly unimpaired at 5 sec with the screen compared with the other two animals in the unoperated control group. Unlike the other animals DF3 persistently pressed the sample key with its mouth, and therefore adapted less well to the rotation of the screen, since avoiding it was made more difficult. This probably accounts for the greater number of errors made by this animal. DISCUSSION
It is clear that the deficit on delayed response tasks of monkeys with lateral
100 frontal lesions is not due to a single cause. Such lesions remove two areas, dorsal and ventral frontal cortex, with differing functions. Just as lesions of dorsal frontal cortex produce a deficit on spatial but not object alternation iv, so they produce a deficit on spatial delayed response 9 but not on delayed matching for colours. On the other hand lesions of ventral frontal cortex produce variable deficits on all these tasks. The results of the present study have been independently confirmed by the result of a similar study reported by Manning and Mishkin 14 in which monkeys with lesions of sulcus principalis were found to be unimpaired on delayed matching for colours or objects, whereas monkeys with lesions of the inferior convexity were markedly impaired on these tasks. The impairment reported in previous studies as a result of lesions 1,6 or cooling 5 of lateral frontal cortex can be attributed to interference with the function of the ventrolateral surface. Different explanations must be given for the deficit of monkeys with dorsal and ventral frontal lesions on delayed response tasks. Of the possible reasons for failure only some are plausible. There is little evidence that the animals fail to attend to the pre-delay cues. The claim by Finan 4, that the animals performed better on delayed response if their attention was drawn to these cues by allowing them to remove food from the correct food-well before the delay, was not confirmed by Passingham ~9 for monkeys with dorsal or ventral and orbital lesions. Similarly increased activity, which could disrupt mediating responses during the delay, does not appear to account for the defect. Passingham ~9found that animals with dorsal or ventral and orbital lesions failed delayed response, but they did not cross the midline during the delay on significantly more trials than control animals. Finally, although lowering an opaque screen during the delay makes delayed response tasks more difficult for all animals, it does not appear likely that it is the cause of the deficit in animals with frontal lesions. Treichler 23 found a deficit on delayed alternation given without a screen to monkeys with lateral frontal lesions, and in the present study the animals with dorsal frontal lesions were not impaired on delayed matching with a screen, and the animals with ventral frontal lesions were impaired on delayed matching without a screen. The results support the suggestion of Goldman et a l ) that monkeys with dorsal frontal lesions are impaired only when required to remember spatial cues or their own movements in space. The lack of impairment of these animals on spatial reversal in the present study is not consistent with previous findings ~,9. It is possible that the inconsistency results from the use in this study of an observing response or from the fact that a screen was not used. On delayed spatial alternation normal animals learn the correction schedule before the alternation schedule and yet the animals with dorsal frontal lesions were impaired in learning the correction schedule. Whether these animals are impaired only on those spatial tasks on which there is interference from trial to trial remains to be established. Animals with ventral frontal lesions are impaired whether or not the cues are spatial. They were impaired on retention of a visual discrimination as reported in other studiesS, 20. On spatial reversal the animals were only slightly, if at all, impaired, contrary to previous findings2, 9. However, Butters et a l ) have also reported a lack
101 of i m p a i r m e n t o n object reversal in a n i m a l s with lesions of the inferior convexity even t h o u g h other studies have shown a n i m p a i r m e n t 1°. The reason for the inconsistency of these results is n o t clear. The a n i m a l s with ventral frontal lesions were i m p a i r e d o n delayed m a t c h i n g even at 0 sec delay. It has been shown that delayed m a t c h i n g is a task o n which there is considerable interference for all a n i m a l s from trial to trial. Two out of 3 of the a n i m a l s increased their perseverative errors to p o s i t i o n after the operation, b u t it is unclear whether this increase is the result or the cause of their i m p a i r m e n t . Nonetheless it remains a plausible hypothesis that m o n k e y s with ventral frontal lesions m a y fail delayed response tasks because of their tendency to perseverate as d e m o n s t r a t e d on other tasks2,10. ACKNOWLEDGMENTS This research was supported b y M . R . C . G r a n t G 971/1/397/B. I a m grateful to Mr. I. Hughes a n d Miss M. M c A n u l t y for assistance with the histology, a n d to Dr. A. Cowey for c o m m e n t s o n a n early draft of this paper.
REFERENCES 1 BUFEERY,A. W. R., Attention and retention following frontal and temporal lesions in the monkey, APA Proc., (1965) 104. 2 BUTTER,C. M., Perseveration in extinction and in discriminationreversal tasks following selective frontal ablations in Macaca mulatta, PhysioL Behav., 4 (1969) 163-171. 3 BUTTERS,N., BUTTER,C. M., ROSEN,J., ANDSTEIN,D., Behavioural effects of sequential and onestage ablations of orbital prefrontal cortex in the monkey, Exp. NeuroL, 39 (1973) 204-214. 4 FINAN,J. L., Delayed response with pre-delay reinforcement in monkeys after the removal of the frontal lobes, Amer. J. PsychoL, 55 (1942) 202-214. 5 FUSTER,J. M., AND BAUER,R. H., Visual short-term memory deficit from hypothermia of frontal cortex, Brain Research, 81 (1974) 393-400. 6 GLICK,S. D., GOLDFARB,T. L., AND JARVIK,M. E., Recovery of delayed matching performance following lateral frontal lesions in monkeys, Commun. Behav. Biol., 3 (1969) 299-303. 7 GOLDMAN,P. S.. AND ROSVOLD,H. E., Localisation of function within the dorsolateral cortex of the rhesus monkey, Exp. NeuroL, 27 (1970) 291-304. 8 GOLDMAN, P. S., ROSVOLD, H. E., AND MISHKIN, M., Evidence for behavioural impairment following prefrontal lobectomy in the infant monkey, J. comp.physiol. Psychol., 70 (1970) 454-463. 9 GOLDMAN,P. S., ROSVOLD,H. E., VEST,B., AND GALKIN,Z. W., Analysis of the delayed-alternation deficit produced by dorsolateral prefrontal lesions in the rhesus monkey, J. comp. physiol. PsychoL, 73 (1971) 212-220. 10 IVERSEN,S. D., ANDMISHKIN,M., Perseverative interference in monkeys following selective lesions of the inferior prefrontal convexity, Exp. Brain Res., 11 (1970) 376-386. i1 JACOBSEN,C. F., The functions of the frontal association areas in monkeys, Comp. Psychol. Monogr., 13 (1936) 3-60. 12 JARRARD,L. E., AND MOISE, S. L., Short-term memory in the monkey. In L. E. JARRARD(Ed.), Cognitive Processes of Non-ttuman Primates, Academic Press, New York, 1971, pp. 1-24. 13 JOHNSON, T. N., ROSVOLD, H. E., AND MISHKIN, M., Projections from behaviourally defined sectors of the prefrontal cortex to the basal ganglia, septum and diencephalon of the monkey, Exp. NeuroL, 21 (1968) 20-34. 14 MANNING, F. J., AND MISHKIN, M., Nonspatial Memory after Selective Prefrontal Lesions in Monkeys, paper read at Eastern Psychol. Assoc., U.S.A., 1975.
102 15 MISHKIN, M., AND PRIBRAM,K. H., Analysis of the effects of frontal lesions in monkey. I. Variations of delayed alternation, J. comp. physiol. PsychoL, 48 (1955) 492-495. 16 MISHKIN, M., AND PRIBRAM, K. H., Analysis of the effects of frontal lesions in monkey. II. Variation of delayed response, J. comp. physiol. Psychol., 49 (1956) 36-40. 17 MISHKIN, M., VEST, B., WAXLER, R. M., AND ROSVOLD, H. E., A re-examination of the effects of frontal lesions on object alternation, Neuropsychology, 7 (1969) 357-364. 18 OLSZEWSKI,J., The Thalamus of the Macaca mulatta, Karger, Basel, 1952. 19 PASSINGHAM,R. E., Behavioural Changes after Lesions of Frontal Granular Cortex in Monkeys (Macaca mulatta}, Unpublished P h . D . Thesis, London University, 1971. 20 PASSINGHAM,R. E., Visual discrimination learning after selective prefrontal ablations in monkeys ( Macaca mulatta) , Neuropsychology, 10 (1972) 27-30. 21 PRIBRAM,K. H., A further experimental analysis of the behavioural defect that follows injury to the primate frontal cortex, Exp. NeuroL, 3 (1961) 432-466. 22 PR1BRAM, K. H., AND MISHKIN, M., Analysis of the effects of frontal lesions in monkey. III. Object alternation, J. comp. physiol. PsychoL, 49 (1956) 41-45. 23 TREICHLER,F. R., The influence of delay interval on severity of the spatial alternation deficit in frontal monkeys, Cortex, 7 (1971) 143-151.
89
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
D E L A Y E D M A T C H I N G 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 (Macacamulatta)
RICHARD PASSINGHAM
Department of Experimental Psychology, University of Oxford, Oxford (Great Britain) (Accepted February 2nd, 1975)
SUMMARY
Rhesus monkeys with bilateral lesions of either dorsal or ventral prefrontal cortex were tested on delayed matching for colours. The animals with dorsal frontal lesions performed as well after the operation as before, whereas those with ventral frontal lesions were severely impaired even at the shortest delay. However, the animals with dorsal frontal lesions failed to learn delayed spatial alternation. The results support the view that the monkeys with dorsal frontal lesions have an impairment in memory for spatial cues or their own movements in space.
INTRODUCTION
It has been known for nearly 40 years 11 that rhesus monkeys with bilateral lesions of prefrontal cortex fail delayed response tasks. But the reasons for this failure are still poorly understood. On these tasks the animals are required to remember for a few seconds the position where food is to be found. They might fail because they do not notice where the food is put, are distracted during the delay, confuse the position of the food on the present trial with its position on previous trials, or because they have some defect in spatial perception or memory. Since the tasks may be failed for one of many reasons it is necessary to devise tests which distinguish between these possibilities. An early series of studies investigated whether monkeys with lateral frontal lesions were impaired on delayed response and delayed alternation only when required to remember spatial cues15,16,21,z2. The results were not consistent or conclusive. It was found that the animals could learn to alternate between responding on one trial and not on the next (go-no go alternation), but failed when required to alternate between objects (object alternation)iS,21, 2~. On delayed response there was
90 suggestive evidence that the animals were better if tested with non-spatial cues 16. More recently both Buffery1 and Glick et al. 6 have found that monkeys are impaired on delayed matching for colours after lateral frontal lesions, and Fuster and Bauer 5 have reported that cooling the tissue in and around sulcus principalis produces an impairment on delayed matching. The confusion in the literature results in part from the use of large lesions which included the whole of the lateral frontal surface, since it was incorrectly assumed that the lateral frontal surface had a single function. More recently anatomicaP 3 and behaviouraF,9,17 studies have subdivided the lateral and orbital surface into areas with different though related functions. Mishkin et al. 17 have showed that if selective lesions of frontal cortex are made, rhesus monkeys with dorsal lesions including sulcus principalis are impaired on spatial but not on object alternation, whereas those with lesions of the ventrolateral and orbital surface are impaired on object as well as spatial alternation. It seemed likely, therefore, that more consistent results might be obtained for delayed response and delayed matching if selective lesions of the lateral surface were made. The present study investigates the effect of lateral and ventral frontal lesions on the performance of monkeys on non-spatial delayed matching. METHODS
Subjects
Nine rhesus monkeys (Macaca mulatta) with no previous training were used. Six were males and 3 females. At the time of operation they weighed from 4.1 to 6.0 kg.
sample key response
keys
Q
©
©
screen
,
10 c m
Fig. l. Diagram of testing panel
91 Apparatus
The animals were trained in a cage placed in a testing box such that they had direct access to a testing panel at the end of the box. The panel is illustrated in Fig. 1. The translucent Gerbrands keys were 3.3 cm in diameter. The centres of the bottom keys were separated by 15.5 cm from each other and 13.5 cm from the centre of the top key. The discriminanda were back projected onto the keys by rear-projection readout units (Industrial Electronic Engineers). Peanuts were dispensed into the food well by a Gerbrands Universal feeder. The screen could be rotated on its axle by an electric m o t o r so as to cover the 3 response keys. The interior of the box was illuminated from above by a 40 W bulb run on 140 V. A masking white noise was present. The presentation of the stimuli and reinforcement, and the movement of the screen were programmed automatically using Behavioural Research and Development logic modules. Training Pre-training
The monkeys were pre-trained to press the upper lit key as an observing response. When the animal pressed at least 3 times over 1.5 sec or more, the light on the observing response key went out and discriminanda were projected onto the two bottom keys. The animals were trained on 3 visual simultaneous discriminations: 8 vs. 1, 5 vs. 9 and 4 vs. 2. They were given 100 trials a day. Correct responses were rewarded with a peanut, and incorrect punished by the house-light being turned off for 2 sec. On 8 vs. 1 and 5 vs. 9 the animals were trained to a criterion of 90/100correct responses in one day, and on 4 vs. 2 to a criterion of 90/100 correct responses on two consecutive days. Matching - - pre-operative
The animals were then trained on matching to sample for colours (red and green) in several stages. (a) Simultaneous. First the sample colour (red or green) was presented on the observing response key. When the animal pressed at least 3 times over 1.5 sec the choice keys were illuminated, the position of the two colours being fixed so that one colour always appeared on the left and the other on the right, the sample colour still being shown on the upper key. The animals were trained to a criterion of 90/100 correct responses in two successive days. I f the animal made a mistake the trial was repeated until the animal made the correct choice (re-run correction schedule). The inter-trial interval was 5 sec during this and all other stages of matching. In the second stage the position of the colours on the response keys was randomised, and the animals were retrained to the same criterion using a re-run correction schedule. They were then tested without the correction schedule until they had performed at 90 correct over 500 trials. (b) Delay. In the next stage the animals were trained on 0 sec delay. When the
92 animal had made the observing response the sample disappeared and the colours immediately appeared on the response keys. The animals were trained without correction to a criterion of 90/100 correct responses on two successive days. (c) Titration. After completion of training at 0 sec the length of the delay was increased for each animal using a titration schedule. I f the animal made two or fewer errors out of 10 trials the delay was increased by one sec for the next 10 trials, and if the animal made 3 or more errors it was decreased by one sec. Fifty trials a day were given. Every 1000 trials the animals were retested for 100 trials on matching at 0 sec, these trials being given in one day. The delay was titrated until the animal reached a criterion of stable performance. The delay at which an animal being titrated down performed at 80 ~ correct or better was called a 'descending threshold', and the delay at which having titrated up it performed at 70 ~ incorrect or worse was called an 'ascending threshold'. The means of successive pairs of descending and ascending thresholds (75 ~ thresholds) were calculated. An animal was said to have achieved criterion when the means of two blocks of 15 mean thresholds did not differ by more than 10 ~ of the lesser, and the standard deviation of the 30 means did not exceed 2.5 sec.
Operation Operations were performed on 6 of the 9 animals within a week of their reaching criterion on delayed matching. All animals restarted testing 3 weeks after completion of pre-operative training.
Matching --post-operative The animals were first retested on delayed matching at 0 sec to a criterion of 90/100 correct responses on two successive days. The correction schedule was not used. Delay was then increased as pre-operatively and the animals retrained to the same criterion of stability.
Retention of visual discrimination The animals were then tested for retention of the visual discrimination 4 vs. 2 to the same criterion as before the operation.
Spatial reversal The animals were first trained to press the observing response key to illuminate the two response keys with white light. Presses on the left response key were rewarded. When the animal reached a criterion of 45/50 correct responses on one day, presses on the right key but not on the left were rewarded. Five successive reversals were given, each to a criterion of 45/50 correct responses on one day. Fifty trials a day were given.
Delayed alternation The animals were tested in a Wisconsin General Test Apparatus. Black plaques (7.5 cm square) covered food wells 30 cm apart, and the animals were required to
93 push the plaques to retrieve the food. They were trained for 30 trials a day on delayed alternation with a re-run correction, an opaque screen being lowered for 5 sec between trials. Training continued until the animal reached a criterion of 90/100 correct responses or until they had been tested for 1000 trials.
Matching-screen Finally the animals were retested on matching, but with the use of the automatic screen. They were first retrained on delayed matching at 0 sec without the screen to a criterion of 90/100 correct responses on two consecutive days. They were then tested with a fixed delay of 5 sec to a criterion of 80/100 correct responses over two consecutive days with 50 trials on each day. Finally, they were tested at the same delay and to the same criterion but with the automatic screen covering the keys during the delay.
DFI
DF3
VF4
VF5
VF6
Fig. 2. Reconstruction of lesions. Straight lines indicate the levels from which the cross-sections shown in Fig. 3 were taken. DF: animals with dorsal frontal lesions; VF: animals with ventral frontal lesions.
94
Groups and surgery The animals were divided into 3 groups of 3 animals. Animals in the first group were given bilateral dorsal frontal lesions (DF), those in the second bilateral ventral frontal lesions (VF), and those in the third served as unoperated controls (UC). The dorsal frontal lesions were intended to remove cortex in both banks of sulcus principalis and the dorsal convexity, the lesion extending posteriorly to within roughly 3 m m of the arcuate sulcus. The ventral frontal lesions were intended to remove cortex on the ventrolateral surface and inferior convexity, extending dorsally to within roughly 5 m m of sulcus principalis, posteriorly to within roughly 3 m m of the arcuate sulcus and ventrally to the lateral orbital sulcus. All surgery was performed with aseptic procedures and using Nembutal anaesthesia.
DF1
DF2
VF4
Fig. 3. Representative cross-sections through the lesions. DF: animals with dorsal frontal lesions; VF: animals with ventral frontal lesions.
DF1
DF3 +8.0
+6"5
+5.0
Fig. 4. Standard cross-sections through the dorsomedial nucleus of the thalamus. The areas of dense gliosis are shown in black. DF: animals with dorsal frontal lesions.
Histology At the end of the experiments the animals in the operated groups were anaesthetized with Nembutal and perfused with 0 . 9 ~ saline and 1 0 ~ formal-saline. The head was placed in a stereotaxic apparatus and a cut was made behind the thalamus in stereotaxic vertical. The brain was then removed, photographed and placed in sucrose formalin (10 ~ formalin, 30 ~ sucrose) until it sank. Fifty #m frozen sections were cut, and every tenth section stained with cresyl violet. Reconstructions of the lesions were made from sections 1 mm apart. The reconstructions of the lesions are shown in Fig. 2, and representative cross-sections in Fig. 3. The dorsal frontal lesions did not include the frontal pole, and in DF1 and DF3 the bottom of sulcus principalis was left in some sections although the tissue was almost certainly not functional. The ventral frontal lesions were small, and they did not include the frontal pole. Fig. 4 shows standard sections through the dorsomedial nucleus of the thalamus, Dense gliosis was found in the parvocellular portion is of the dorsomedial nucleus in the 3 animals with dorsal frontal lesions. No patches of dense gliosis are apparent in the dorsomedial nucleus of the 3 animals with ventral frontal lesions, but there appears to be some cell loss in the medial part of the parvocellular division of the nucleus. However, the staining of the sections was too poor and uneven to permit adequate mapping of these changes. RESULTS
Matching The titrated delays before and after operation are shown for each animal in Table I. Few animals succeeded in reaching long delays, whether because of the short inter-trial interval 1~, the method of increasing delay or some other factor. The post-
96 TABLE I D E L A Y E D
M A T C H I N G
Pre-operative (PRE) and post-operative (POST) delays at criterion and post-operative errors at 0 sec. F: failed in a 1000 trials, and the figures in brackets give the percentage correct responses in the last 100 trials. Groups
P R E (see)
POST errors at 0 see
P O S T (sec)
P O S T minus P R E (see)
Dorsal frontal 2 3 Mean
15.2 31.5 18.8
2 7 4.0
15.0 14.2 19.5 16.2
Ventral frontal 4 5 6 Mean
22.5 2.7 10.8 12.0
F (80 ~ ) F (68 ~ ) F (64 ~)
----
Unoperated control 7 8 9 Mean
10.9 7.3 7.8 8.7
3 17 7 9.0
13.0 10.0 6.1 9.7
1
9.7
5
+ 5.3 1.0
---
12.0
--
2.6
I m
m
+2.1 + 2.7 -1.7 + 1.0
o p e r a t i v e delays o f the a n i m a l s with d o r s a l f r o n t a l lesions were well within those for all a n i m a l s before o p e r a t i o n . D F 3 did n o t achieve the same level after the o p e r a t i o n as before, b u t it is unlikely t h a t this was a genuine i m p a i r m e n t since the a n i m a l ' s p e r f o r m a n c e before the o p e r a t i o n was very unstable a n d for m u c h o f the time it p e r f o r m e d at a level similar to t h a t reached after the o p e r a t i o n . On retest after the o p e r a t i o n D F 3 achieved the longest delays o f a n y animal. The a n i m a l s with ventral f r o n t a l lesions failed to regain criterion at 0 sec during 1000 trials. W h e n r e t r a i n e d on s i m u l t a n e o u s m a t c h i n g V F 5 reached a c r i t e r i o n o f 90/100 correct responses in 500 trials, V F 4 in 1700 trials a n d V F 6 failed in 2500 trials. A n analysis was m a d e o f perseverative errors before a n d after the o p e r a t i o n . T h o s e errors were analysed which occurred after a trial in which the a n i m a l h a d m a d e a correct response. I f when m a k i n g such a n e r r o r the a n i m a l went to the same c o l o u r as on the previous trial, the e r r o r was classified as perseverative for colour, a n d i f to the same side as on the previous trial the e r r o r was classified as perseverative for p o sition. T a b l e II shows the perseverative errors for a n i m a l s on 0 sec m a t c h i n g before the o p e r a t i o n , a n d for the a n i m a l s with ventral frontal lesions on 0 sec m a t c h i n g after the o p e r a t i o n . A l l a n i m a l s t e n d e d to perseverate for c o l o u r before the o p e r a t i o n b u t n o t to perseverate for position. A f t e r the o p e r a t i o n V F 6 s h o w e d an increase in p e r s e v e r a t i o n for colour, b u t the p r o p o r t i o n o f perseverative responses was still well within the range for all a n i m a l s before the operation. O u t o f the first 200 trials 60 ~ o f incorrect choices were o f one c o l o u r a n d 40 ~ o f the other. O n the o t h e r h a n d
97 TABLE II PRE-OPERAT1VE AND POST-OPERATIVE PERSEVERATIVE ERRORS FOR COLOUR AND POSITION ON MATCHING AT 0 SEe
Only those errors were analysed which followed a trial on which the animal had made the correct response. The pre-operative figures are the mean for 9 animals, and the range is given in brackets. The post-operative figures are for the 3 animals ventral frontal lesions, subjects (S) 4-6. The postoperative minus the pre-operative percentage errors are given in brackets. Pre-operative (9 animals)
Post-operative (ventral frontal)
Colour
Pos#ion
Colour
Position
75.8 (61.9 - 85.5)
51.7(39.2-61.5)
63.7(-- 6.9) 57.9 ( - - 13.5) 76.4 ( + 14.5)
71.6(+ 10.1) 68.3 ( + 18.0) 54.5 ( + 2.0)
$4 S5 S6
V F 4 a n d V F 5 showed an increase in perseverative responses to position, the p r o p o r t i o n o f such responses being outside the range for a n i m a l s before the o p e r a t i o n . In the first 200 trials V F 4 m a d e 72.7 ~ errors which were perseverative for position, a n d V F 5 68.9 ~ . F i f t y per cent o f the errors o f V F 4 on these trials were to the left, a n d 52.5 ~ o f the errors o f VF5. Visual discrimination O n p o s t - o p e r a t i v e r e t e n t i o n o f the visual d i s c r i m i n a t i o n 4 vs. 2 the m e a n trials to criterion for the 3 g r o u p s were: d o r s a l frontal 19.3, ventral f r o n t a l 76.3, u n o p e r a t e d c o n t r o l 14.0 (by an oversight UC9 was n o t retested on this task). The a n i m a l s with ventral f r o n t a l lesions t o o k significantly m o r e trials to relearn t h a n those with d o r s a l f r o n t a l lesions ( U = 0, P ~ 0.05). Spatial reversal The errors to criterion on the p o s i t i o n d i s c r i m i n a t i o n a n d on 5 reversals are shown in Fig. 5. The a n i m a l s with d o r s a l f r o n t a l lesions were n o t i m p a i r e d c o m p a r e d with u n o p e r a t e d c o n t r o l a n i m a l s on either the original d i s c r i m i n a t i o n s or the reversals. T h e a n i m a l s with ventral f r o n t a l lesions differed significantly f r o m the other two g r o u p s only on the fifth reversal (ventral f r o n t a l vs. u n o p e r a t e d c o n t r o l : U = 0, P = 0.05; ventral f r o n t a l vs. d o r s a l f r o n t a l : U = 0, P = 0.05). Delayed alternation T a b l e I I I shows the trials a n d errors to criterion on delayed alternation. A l l the a n i m a l s with d o r s a l frontal lesions failed to reach criterion in 1000 trials, a n d m a d e significantly m o r e errors t h a n the a n i m a l s in the u n o p e r a t e d c o n t r o l g r o u p ( U = 0, P = 0.05). O f the a n i m a l s with ventral f r o n t a l lesions one (VF5) was uni m p a i r e d , a n d one failed to reach criterion (VF6). One o f the a n i m a l s in the uno p e r a t e d c o n t r o l g r o u p also failed to r e a c h criterion. The errors were divided into ' c o r r e c t i o n ' a n d ' a l t e r n a t i o n ' errors. W h e n a n
98 50 45
g_ 4o e~ 35 ~
3o 25
0 ~-
20
~
15
0
5 |
I
I
I
I
I
D
1
2
3
4
5
Fig. 5. Errors to criterion on spatial discrimination (D) and 5 reversals (1-5). O, animals with dorsal frontal lesions; A, animals with ventral frontal lesions and O, unoperated control animals. TABLE III DELAYED SPATIAL ALTERNATION
Trials and errors to criterion on delayed spatial alternation. 1000F: failed to reach criterion in a 1000 trials, the percentage correct on the last 120 trials being given in brackets. Corr.: correction errors; Alt. : alternation errors. The percentage initial errors were analysed for the first 60 trials. The criterion used for correct and alternation errors was 20 ~ errors in 120 trials. F: failure to reach criterion. Group
Trials
Errors
% Initial errors
Trials to criterion
Corr.
AIt.
Corr.
Alt.
Dorsal frontal 1 1000F (72 ~ ) 2 1000F (64 ~ ) 3 1000F (42 ~ ) Mean
406 522 586 504.7
27.6 36.2 29.3 31.0
33.3 35.1 36.6 35.0
420 900 F
F F F
Ventral frontal 4 849 5 477 6 1000F (53 ~ ) Mean
287 159 438 294.7
25.9 34.5 22.0 27.5
30.2 34.2 28.6 31.0
180 120 120
660 180 F
Unoperated 7 8 9 Mean
115 390 96 200
39.6 63.8 17.2 40.2
34.3 42.8 39.6 38.6
60 240 0
300 F 300
302 1000F (66 ~ ) 369
animal made a correct response and on the next trial incorrectly went to the same side that error was termed an 'alternation' error. Alternation errors were expressed a s a p e r c e n t a g e o f t h e t r i a l s o n w h i c h t h a t e r r o r c o u l d o c c u r , t h a t is as a p e r c e n t a g e of the total daily trials minus the correction trials. After an initial incorrect response t o o n e side, c o n s e c u t i v e i n c o r r e c t r e s p o n s e s t o t h a t side w e r e c a l l e d ' c o r r e c t i o n ' e r r o r s . T h e s e w e r e e x p r e s s e d as a p e r c e n t a g e o f t h e t o t a l d a i l y t r i a l s . T h e p e r c e n t a g e
99 TABLE IV DELAYED MATCHING(WITH SCREEN) Errors on delayed matching at 0 sec, and 5 sec with and without the screen. F: failure to reach criterion in 1000 trials, the percentage correct on the last 100 trials being given in brackets. Groups
0 sec
5 sec
Dorsal frontal 1 2 3 Mean
12 8 27 15.7
29 52 18 33
Ventral frontal 4 5 6
F (84 %) F (65 %) F (69 %)
----
Unoperated 7 8 9 Mean
16 65 36 39
32 195 129 118.7
5 sec (with screen)
33 43 244 106.7
---19 82 -50.5
of correction and alternation errors did not differ significantly between the 3 groups on the first 60 trials (Table III). A criterion was set of 20 % errors in 120 trials. Animals in the ventral frontal, and unoperated control group, reached criterion on correction errors before reaching criterion on alternation. The animals with dorsal frontal lesions took significantly longer than animals in either of the other two groups to reach criterion on correction errors (dorsal frontal vs. ventral frontal: U ~- 0, P = 0.05; dorsal frontal vs. unoperated control: U = 0, P = 0.05). All three animals with dorsal frontal lesions failed to reach criterion on alternation errors, one animal failing in each of the other two groups. Matching-screen
When re-tested on delayed matching with 0 sec delay the animals with dorsal frontal lesions did not differ from those in the unoperated control group, but the monkeys with ventral frontal lesions failed to reach criterion in 1000 trials (Table IV). UC9 could not be adapted to the rotation of the screen, but DF1 and DF2 were clearly unimpaired at 5 sec with the screen compared with the other two animals in the unoperated control group. Unlike the other animals DF3 persistently pressed the sample key with its mouth, and therefore adapted less well to the rotation of the screen, since avoiding it was made more difficult. This probably accounts for the greater number of errors made by this animal. DISCUSSION
It is clear that the deficit on delayed response tasks of monkeys with lateral
100 frontal lesions is not due to a single cause. Such lesions remove two areas, dorsal and ventral frontal cortex, with differing functions. Just as lesions of dorsal frontal cortex produce a deficit on spatial but not object alternation iv, so they produce a deficit on spatial delayed response 9 but not on delayed matching for colours. On the other hand lesions of ventral frontal cortex produce variable deficits on all these tasks. The results of the present study have been independently confirmed by the result of a similar study reported by Manning and Mishkin 14 in which monkeys with lesions of sulcus principalis were found to be unimpaired on delayed matching for colours or objects, whereas monkeys with lesions of the inferior convexity were markedly impaired on these tasks. The impairment reported in previous studies as a result of lesions 1,6 or cooling 5 of lateral frontal cortex can be attributed to interference with the function of the ventrolateral surface. Different explanations must be given for the deficit of monkeys with dorsal and ventral frontal lesions on delayed response tasks. Of the possible reasons for failure only some are plausible. There is little evidence that the animals fail to attend to the pre-delay cues. The claim by Finan 4, that the animals performed better on delayed response if their attention was drawn to these cues by allowing them to remove food from the correct food-well before the delay, was not confirmed by Passingham ~9 for monkeys with dorsal or ventral and orbital lesions. Similarly increased activity, which could disrupt mediating responses during the delay, does not appear to account for the defect. Passingham ~9found that animals with dorsal or ventral and orbital lesions failed delayed response, but they did not cross the midline during the delay on significantly more trials than control animals. Finally, although lowering an opaque screen during the delay makes delayed response tasks more difficult for all animals, it does not appear likely that it is the cause of the deficit in animals with frontal lesions. Treichler 23 found a deficit on delayed alternation given without a screen to monkeys with lateral frontal lesions, and in the present study the animals with dorsal frontal lesions were not impaired on delayed matching with a screen, and the animals with ventral frontal lesions were impaired on delayed matching without a screen. The results support the suggestion of Goldman et a l ) that monkeys with dorsal frontal lesions are impaired only when required to remember spatial cues or their own movements in space. The lack of impairment of these animals on spatial reversal in the present study is not consistent with previous findings ~,9. It is possible that the inconsistency results from the use in this study of an observing response or from the fact that a screen was not used. On delayed spatial alternation normal animals learn the correction schedule before the alternation schedule and yet the animals with dorsal frontal lesions were impaired in learning the correction schedule. Whether these animals are impaired only on those spatial tasks on which there is interference from trial to trial remains to be established. Animals with ventral frontal lesions are impaired whether or not the cues are spatial. They were impaired on retention of a visual discrimination as reported in other studiesS, 20. On spatial reversal the animals were only slightly, if at all, impaired, contrary to previous findings2, 9. However, Butters et a l ) have also reported a lack
101 of i m p a i r m e n t o n object reversal in a n i m a l s with lesions of the inferior convexity even t h o u g h other studies have shown a n i m p a i r m e n t 1°. The reason for the inconsistency of these results is n o t clear. The a n i m a l s with ventral frontal lesions were i m p a i r e d o n delayed m a t c h i n g even at 0 sec delay. It has been shown that delayed m a t c h i n g is a task o n which there is considerable interference for all a n i m a l s from trial to trial. Two out of 3 of the a n i m a l s increased their perseverative errors to p o s i t i o n after the operation, b u t it is unclear whether this increase is the result or the cause of their i m p a i r m e n t . Nonetheless it remains a plausible hypothesis that m o n k e y s with ventral frontal lesions m a y fail delayed response tasks because of their tendency to perseverate as d e m o n s t r a t e d on other tasks2,10. ACKNOWLEDGMENTS This research was supported b y M . R . C . G r a n t G 971/1/397/B. I a m grateful to Mr. I. Hughes a n d Miss M. M c A n u l t y for assistance with the histology, a n d to Dr. A. Cowey for c o m m e n t s o n a n early draft of this paper.
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