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Information about movements in monkeys (Macaca mulatta) with lesions of dorsal prefrontal cortex
Brain Research, 152 (1978) 313-328 © Elsevier/North-Holland Biomedical Press
313
I N F O R M A T I O N ABOUT MOVEMENTS IN M O N K E Y S ( M A C A CA M U L A T T A ) W I T H LESIONS OF D O R S A L P R E F R O N T A L C O R T E X
RICHARD PASSINGHAM Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford OX1 3UD (Great Britain) (Accepted December 22nd, 1977)
SUMMARY It is not known on what information prefrontal cortex acts. Since it has been suggested that it might operate on information about movements, rhesus monkeys were trained on a counting task testing memory for movements. They had to tap a key until a light went out and then repeat, either immediately or after a delay, the number of presses they had made. Monkeys with lesions of dorsal prefrontal cortex were impaired on this task, unlike monkeys with lesions of sulcus principalis alone. Cortex on the dorsal prefrontal convexity appears to act on information about movements.
INTRODUCTION To understand the function of an association area it is important to know the information on which it acts. It is established that in the rhesus monkey (Macaca mulatta) there are visual inputs into inferior temporal association cortex (Von Bonin and Bailey, TE; Brodmann, 21), auditory inputs into superior temporal association cortex (TA:22), and inputs from both vision and somatic sensation into parietal association cortex (PE and PG: 5 and 7) 12,23. In line with the anatomical findings, rhesus monkeys with lesions of TE are poor at learning when required to use visual information 16, those with lesions of TA poor for auditory information 5, and those with lesions of PE and P G poor for tactile or visuospatial information 2°,z6. The anatomical connections to prefrontal association cortex appear at first sight to provide no such clues, since it receives indirect inputs from all the senses and from very many other areas of the brain 12,23. However, these projections do not all terminate in the same sub-areas of prefrontal cortex ~, and they might therefore provide clues to the functions of these sub-areas. Of particular interest are the projections into the middle third of sulcus principalis, because bilateral lesions of this tissue alone produce severe impairments in the ability of rhesus monkeys to learn the
314 spatial delayed alternation task (SDA) 2 and the related spatial delayed response task (SDR) 2s. Furthermore, it has been established that the animals only fail when required to remember where they have most recently seen or found food, and that they succeed when required to remember what object or colour they last saw or chose 17,19,z5. These results suggest that the inputs on which cortex within sulcus principalis acts must either be visuospatial information about the location of objects in spacel6, z6 or information about the movements of the animal itself, including that from kinesthesis 6. Unfortunately the anatomical evidence does not discriminate decisively between these two hypotheses. The only area behind the central sulcus from which projections have been described into the middle third of sulcus principalis is parietal area P G (7) 8. In front of the central sulcus the premotor area FB (6) projects to dorsal prefrontal cortex and into the upper bank of sulcus principalis, perhaps including the middle third of the sulcus12, 24. An area anterior to the arcuate sulcus and caudal to sulcus principalis also sends fibres into the depths and dorsal bank of the middle third of sulcus principalis 13. This area is within the frontal eyefields as mapped by electrical stimulation 27. Although projections into sulcus principalis are established from these 3 areas, our knowledge of the functions of these areas is too inadequate to tell us what information they must convey to the sulcal cortex. A large proportion of the cells in area P G (7) respond either when the monkey reaches to a particular point in space or looks in a particular directionX0,14,2L Area FB (6) receives a heavy input from area PE (5) ~ in which the majority of the cells respond to passive rotation of the joints2L Cells in the frontal eye-fields fire either when the monkey makes a saccadic eye movement, maintains orientation of its eyes, or turns its head in a specific direction 1. While the cells related to eye movements fire during the execution of the movement, those related to head turning often discharge prior to the movement 1. These electrophysiological findings do not make it clear whether the cortex in the middle third of sulcus principalis receives information about space or kinesthesis or both. It is clear that what is needed is a behavioural test which will distinguish between the two possibilities. This can be achieved with a task in which the animals must use cues produced by their own movements and in which there are no differential visuospatial cues. If the defect of monkeys with dorsal prefrontal lesions is a spatial one they should perform normally on such a task, whereas they should be impaired if they have difficulty with kinesthetic cues. Two tasks of this sort have been devised. Mishkin et al. is tested the ability of monkeys to distinguish between small and large angular displacements of a knob along a track, the starting position of the knob being varied: two animals had to grasp and move the knob with their hands, and the other 6 had to grasp it with their teeth and move it with their head. If the knob could be moved some distance the animals could find food in a food-well, whereas if it could only be moved a short way they were required not to open the food-well. Two animals with combined lesions of dorsal prefrontal and premotor cortex failed to relearn the task in 500 trials. But 4 monkeys with dorsal prefrontal lesions alone, including sulcus principalis and the anterior bank
315 of the upper limb of the arcuate sulcus, were only mildly impaired on retention of this task. However, this does not show that the failure of such animals to learn S D R and SDA could not be attributed to a difficulty in making use of kinesthetic cues, since on these tasks the monkeys are also required to remember the cues for some seconds. The other task that has been described is that used by Manning 15, in which rhesus monkeys had to press a lever until a pilot light went out. I f 64 presses were needed to turn the light off, the animals had to respond in one way, and if 32 presses were needed, they had to respond in another. One group of animals had to respond to either a red or white key, and another group to a key on the left or the right. After learning the task the animals were tested for retention 3 weeks later. All animals were then given lesions of dorsal prefrontal cortex, including sulcus principalis and the anterior bank of the upper limb of the arcuate sulcus. All but one animal took longer to relearn the task than they had on a retention test before the operation. Two questions are raised by this study. The first is: which of the various areas within dorsal prefrontal cortex must be removed to produce this impairment? It is known that monkeys with lesions of the arcuate sulcus are impaired on a conditional task on which the animal must go to the left given one cue and to the right given another 7, and it is possible that they might be impaired on other conclitional tasks such as that used by ManninglL It is of obvious importance to establish whether monkeys with lesions of sulcus principalis alone would be impaired, since it is these lesions that critically disrupt the ability of monkeys to learn SDA z and SDR 2s. The other question is whether the deficit reported by Manning 15 is severe enough to explain the failure of monkeys to learn SDA and S D R after lesions of dorsal prefrontal cortex 8 or of sulcus principalis alone2, ~8. Although some of the animals were clearly very impaired it is difficult to assess the deficit of other animals, since they were not compared with unoperated control animals. Again the impairement might have been even more severe, had a delay been imposed before the animals were allowed to report the count they had made. In the present experiment, therefore, a counting task was used which was as similar as possible to SDR. The monkeys had to press a key to turn a light off. They then had to report the number of presses they had made by repeating the same number of presses on another key. They were allowed to make their report either immediately or after delays of up to 5 sec, during which an opaque screen was lowered to prevent them from responding. Some animals were given lesions of dorsal prefrontal cortex, excluding the arcuate sulcus, and others of sulcus principalis alone. METHODS
Subjects Eight adolescent rhesus monkeys previous training.
(Macaca mulatta) were used.
They had had no
Apparatus The animals were tested in a Wisconsin General Testing Apparatus (W.G.T.A.).
316
©
©
D !
Fig. 1. Diagram of counting apparatus.
They faced 2 boxes mounted on a board (left-hand box 25 cm high × 15 cm wide × 16 cm deep; right-hand box 25 cm high × 25 cm wide × 16 cm deep) (Fig. 1). On each box there was a translucent Gerbrands key 3.3 cm in diameter. The key on the animal's right could be lit with a red light and that on the left with a white light from bulbs placed behind them. Underneath the key on the right-hand box was a plastic door hinged at the top (5 × 5 cm), and by opening this with the back of their hands the animals could reach peanuts placed behind it. The door could be locked and unlocked with a solenoid, but even when locked a slight displacement of the door was possible. A microswitch detected this displacement and a logic circuit (Behavioural Research and Development logic modules) determined whether the door was then to remain locked or to open by release of the solenoid. The presentation of the stimuli and the sound of the number of presses made on each key were also controlled by the logic circuit. The interior of the W.G.T.A. was illuminated from above with a 40 W bulb run on 180 V, and a masking noise was present. Training Pre-training The monkeys were first adapted to the W.G.T.A. by giving them 3 simultaneous visual discriminations presented on plaques, black vs. white, red vs. green, and plus vs. square, all to a criterion of 90 correct choices in 100 trials. Counting - - shaping They were then adapted to the apparatus described above. First they were trained to open the door of the food-well for peanuts. They were then taught to press the left-hand key before attempting to open the food-well. I f they failed to do so, the door remained locked when they touched it, whereas if they l~ressed the key first the solenoid was released as soon as they touched the door, and the door was thus unlocked. The next stage required them to press the key on the right-hand door when the red light came on, and to continue pressing until the light went off, this requiring either one or 5 presses. At this point the white light on the left-hand key came on, and the key had to be pressed if the animal was to succeed in opening the door of the food-well.
317 Counting - - Pre-operative initial training
The animals were then trained in 3 stages to repeat on the left-hand key the number of presses that had been found necessary to turn off the red light on the right hand key. No further cue was given as to when they had pressed the left key the correct number of times, the white light remaining on until after they had attempted to open the door for the peanut. First they were tested under conditions in which a single press of the right key turned off the red light, the white light on the left-hand key coming on immediately afterwards. One or two presses of the white key were counted as correct, and enabled the animal to open the door to the food-well. If the animals failed to make any presses on the white key or made 3 or more, the door remained locked when they tried to open it. The animals were trained until they made the correct number of presses on the white key on 90/100 trials. Thirty trials were given a day. They were then trained under conditions in which 5 presses were required on the right-hand key to turn off the red light. Again the white light came on immediately on the left key, but now 5 or more presses were needed on this key to enable the animal to open the food-well. I f the animals made no press, or only one, two, 3 or 4 presses, the door would not unlock. In the third stage the animals were given successive reversals between the two previous conditions. First they were given the single press condition until they had performed correctly on 9/10 successive trials. They were then given the 5 press condition to the same criterion. Having achieved this they were reversed back to the single press condition, and so on through successive reversals, until on 9/10 reversals they had reached criterion within the 30 trials of one day's testing. The animals completed all stages of pre-training in a mean of 1267 (670-1958) trials. This is qvicker than might have been expected for a task which appears so demanding. Counting - - Pre-operative training
The animals were then tested on the final version of the task. On any trial either 1 or 5 presses turned the red light off, the number being determined randomly by use of the Gellermann schedule. I f the animals made the incorrect number of presses on the white left-hand key and thus failed to obtain food, that condition was repeated until the animal succeeded (re-run correction). The animals were trained to a criterion of 90/100 correct trials. A delay was then introduced between the time when the animal had turned off the red light and the time when it was given access to the white key. After the animal had completed the presses on the red key an opaque screen was lowered between the animal and the apparatus. The animal was therefore unable to press the white key until the screen had been raised again. The animals were trained successively at 1,2, 3, 4 and 5 sec delay, being required to reach a criterion of 45/50 correct trials at each delay in turn. A re-run correction procedure was used throughout. Having reached criterion at 5 sec delay the animals were retested at 0 sec delay to a criterion of 90/100 correct trials.
318 First operation
Operations were performed on 4 of the 8 animals within a week of their reaching criterion again at 0 sec delay. All animals restarted testing 3 weeks after finishing preoperative training. Counting - - Post-operative The animals were first retested at 0 sec delay to a criterion of 90/100 correct trials. They were then tested successively at each delay as before the operation, to a criterion of 45/50 correct trials at each delay. Delayed alternation The animals were tested on SDA in the W.G.T.A. Black plaques (7.5 sq.cm) covered food wells 30 cm apart, and the animals were required to push the plaques to retrieve peanuts. They were tested for 30 trials a day with a re-run correction, the opaque screen being lowered for 5 sec between trials. Training continued until the animals reached a criterion of 90/100 correct trials or until they had been tested for 1000 trials. Counting - - Retraining All animals were then retrained on the counting task at 0 sec and at each delay in turn. The criteria were the same as previously used. Second operation
Within a week of their reaching criterion at 5 see operations were then performed on the 4 previously unoperated animals. They restarted testing 3 weeks after completion of pre-operative training. Counting - - Post-operative These 4 animals were then retrained on the counting task exactly as before the operation. Delayed alternation - - Retest After reaching criterion on the counting task these 4 animals were retested on SDA under the same conditions as before. Groups and surgery
At the first operation dorsal prefrontal cortex (DF) was removed bilaterally in 4 animals, the remaining 4 serving as unoperated controls (UC). The dorsal prefrontal
319
DFIO
DFII
DFI2
DFI3
SPI4
SPI5
SPI6
SPI7
Fig. 2. Reconstruction of lesions. The straight lines indicate the levels from which the cross-sections shown in Fig. 3 were taken.
320
DFIO
DFII
DFI2
DFI3
SPI4
SPI5
SPI6
sPT Fig. 3. Cross-sections through lesions. The right hemisphere in shown on the left.
lesions were intended to remove the cortex in both banks of sulcus principalis and on the dorsal prefrontal convexity, the lesion extending posteriorly to within roughly 3 mm of the arcuate sulcus. All surgery was performed with aseptic procedures, with sodium pentothal as an anaesthetic. At the second operation the cortex in both banks of sulcus principalis (SP) was removed bilaterally in the 4 animals that had previously served as unoperated controls.
Histology At the end of the experiments the animals were anaesthetized with Nembutal and perfused with 0.9 ~ saline, followed by Karnovsky's solution, as they were being used
321 TABLE I Pre-operative trials to criterion on counting task
Trials for delay are the sum of the trials on 1, 2, 3, 4 and 5 sec. The total trials are the sum of those for 0 sec and delay. Figures in brackets are saving scores (see text). Groups
0 sec
Delay
Total
0 Sec retest
Dorsal frontal 10 11 12 13 Mean
1047 440 443 167 523.5
1367 1820 278 493 987
2404 2260 721 657 1510.5
0 69 20 92 45.2
(1.0) (0.73) (0.91) (0.28) (0.73)
185 694 466 248 389.2
1652 909 1626 1065 1313
1837 1603 2092 1313 1711.2
0 0 28 33 15
0.0) (1.0) (0.89) (0.76) (0.91)
Unoperated 14 15 16 17 Mean
TABLE II Post-operative trials to criterion on counting task
Delay and total trials and defined in Table 1. Figures in brackets are saving scores (see text). Groups
0 Sec
Dorsal frontal 10 11 12 13 Mean
501 745 826 139 552.7
Unoperated 14 15 16 17 Mean
0 41 13 0 13.5
Delay
(0.35) (~0.26) (--0.30) (0.08) (4.03) (1.0) (0.89) (0.94) (1.0) (0.96)
1077 1291 524 832 931 246 175 783 0 301
Total
(0.11) (0.17) (~0.31) (4.25) (4.07) (0.74) (0.68) (0.35) (1.0) (0.69)
1578 2036 1350 971 1483.7 246 216 796 0 314.5
(0.21) (0.05) (---0.30) (-4).19) (--0.06) (0.76) (0.76) (0.45) (1.0) (0.74)
for a separate anatomical study. 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 thionine. Reconstructions of the lesions were made from the sections. The reconstructions of the lesions are shown in Fig. 2 and representative cross-sections in Fig. 3. The lesions were as intended, except that there was slight sparing of the depths of sulcus principalis at certain levels in some animals, e.g. DFI0, DF12 and SP16, although the remaining tissue was probably too little to be of functional significance. Both lesions led to cell
322 loss and gliosis in the parvocellular portion 22 of the dorsomedial nucleus of the thalamus, as previously described for similar lesionsT, 25. RESULTS
Counting - - Dorsal f r o n t a l
The trials to learn the counting task at 0 sec and at all delays are shown for all animals in Table I. A mean of 1611 (657-2404) trials were required to learn the task under all conditions. There was no significant difference between the performance of the animals chosen for the D F and U C groups. All animals except DF13 showed high savings on retesting at 0 sec, the mean savings score being 0.82 (0.28-1.0) (savings = test - - retest/test + retest). After the operation the animals with dorsal frontal lesions took significantly more trials to relearn the task than did the unoperated contl ol animals (Table II). This was true for the trials to relearn at 0 sec (t = 3.48, df = 6, P < 0.02), and under conditions of delay (t = 2.67, df = 6, P < 0.05), and for the total trials to relearn under all conditions (t = 4.18, df = 6, P < 0.01). Savings scores were also calculated by comparing performance at 0 sec with that for original training at 0 sec, and the trials on delay conditions and the total trials with those taken before the operation (savings ~ pre-operative - - post-operative/pre-operative + post-operative). There was no overlap between the savings scores of the two groups at 0 sec (t = 6.36, df = 6, P < 0.001), under conditions of delay (t = 4,19, df = 6, P < 0.01), or for the savings scores based on the total trials (t = 4.96, df = 6, P < 0.01). The unoperated animals showed good savings, whereas the animals with dorsal prefrontal lesions showed small or negative savings, with a mean savings score o f - - 0 . 0 6 (--0.3 to +0.21) for all trials combined. On this task two types of error are possible. The animals may incorrectly report TABLE III Per cent counting errors/counting errors + confusion errors on counting task Pre, pre-operatively; Post, post-operatively. Groups
Pre (%)
Post (%)
Post - - Pre (%)
Dorsal frontal 10 11 12 13 Mean
37.7 43.2 56.0 49.7 46.6
44.6 61.8 76.0 48.5 57.7
6.9 18.6 20.0 --1.2 11.1
Unoperated 14 15 16 17 Mean
26.9 68.4 32.2 39.7 41.8
58.6 52.5 37.8 30.0 44.7
31.7 --15.9 5.6 --9.7 2.9
323 TABLE IV
Delayed spatial alternation Trials and errors on SDA. F -- failed on 1000 trials. The per cent correct of the last 100 trials are given in brackets.
Groups
Trials
Errors
Dorsal frontal 10 11 12 13 Mean
1000 1000 1000 1000
F F F F
(39~) (72~) (68~) (52~)
521 521 454 521 504.2
Unoperated 14 15 16 17 Mean
328 463 1000 F 580
(69~)
110 193 350 209 215.5
a 1 as a 5, or a 5 as a 1, and these may be referred to as c o n f u s i o n errors. The animals may also fail to r e p o r t either a 1 or a 5, b y m a k i n g 0, 3 or 4 presses (one or two presses being allowed when r e p o r t i n g a 1 a n d m o r e t h a n 5 presses when r e p o r t i n g a 5). The latter t y p e o f e r r o r may be called a counting error. The errors, excluding c o r r e c t i o n errors, were therefore classified as confusion or c o u n t i n g errors, and the percentages are given in Table III. The two g r o u p s d o not differ significantly in the p r o p o r t i o n o f counting errors p o s t - o p e r a t i v e l y n o r in the change in the p r o p o r t i o n o f c o u n t i n g errors f r o m pre- to p o s t - o p e r a t i v e perforinance. Delayed alternation - - Dorsal frontal
When tested on learning of SDA all the animals with dorsal prefrontal lesions failed to reach criterion in 1000 trials (Table IV). Unoperated animal 16 also failed, though making fewer errors than any of the operated animals. Counting - - Sulcus principalis
On retesfing on the counting task the animals with dorsal prefrontal lesions still tended to make more errors than the unoperated animals (Table V), but the difference was not significant (t ---- 1.89, df ~ 6, P ~ 0.05) due to the continued poor performance of animal 16 in the unoperated group. After the control animals had received lesions of sulcus principalis they were not found to be obviously impaired on post-operative relearning (Table V). Animal 15 required no further trials to re-reach criterion at 0 sec and on each delay. All animals took fewer trials to relearn than the animals with dorsal prefrontal lesions had taken immediately post-operatively (Table II) or on later retesting (Table V).
324 TABLE V Pre- (Pre) and post-operative (post) trials to reach criterion on the counting task Total trials as defined in Table I. The figures given under total (Pre) are the relearning scores for the monkeys with dorsal frontal lesions of sulcus principalis. The figures under total (Post) are the postoperative relearning scores of the animals given lesions of the sulcus principalis. Groups
Total (Pre)
Dorsalfrontal 10 11 12 13 Mean
639 641 453 620 588.2
Total (Post)
m
m
Su&us principalis 14 35 15 159 16 753 17 122 Mean 267.2
273 0 355 101 182.2
TABLE VI Delayed spatial alternation Trials and errors on SDA. F = failed in 1000 trials. The percentage correct of the last 100 trials are given in brackets. Group
Trials
Sulcus principalis 14 1000 F 15 1000 F 16 1000 F 17 1000 F Mean --
Errors
(54~) (49~) (49~) (72 ~)
538 538 550 505 532.7
Delayed alternation - - Sulcus principalis The pre-operative learning scores o n S D A are given in Table IV for the a n i m a l s which later received sulcus principalis lesions. The data for post-operative relearning are shown i n Table VI. All animals failed to relearn the task i n 1000 trials. A n i m a l 16, which had previously failed to learn when unoperated, n o w made more errors t h a n previously a n d failed to p e r f o r m above chance o n the last 100 trials (49 ~ ) , whereas it was able to perform at 69 ~ before the operation. DISCUSSION The c o u n t i n g task used here differs from S D R i n only one i m p o r t a n t respect.
325 Whereas on S D R the animal must remember the spatial position of food and respond to the left or right, on this task both cues and responses are two actions which are not spatially discriminable. Rhesus monkeys with dorsal prefrontal lesions are clearly impaired on the counting task, and this defect can not be put down to a spatial disorder, such as has been suggestedg, 16,26, to account for the impairment on S D R and SDA after lesions of sulcus principalis. The issues raised are whether the focus for the deficit is in the sulcus principalis as for SDA 2 and S D R 2s, and whether the impairment is severe enough to explain the failure of monkeys with lesions of sulcus principalis to learn SDA and SDR. The monkeys with removal of the cortex in sulcus principalis were apparently not impaired, or if at all only slightly impaired, on the counting task. Animal 15 required no further trials before reaching criterion after the operation, and yet was at a chance level for 1000 trials on SDA. Although the performance of the 3 other animals cannot be compared with that of unoperated animals, it is unlikely that their performance would have been surpassed by such controls. It is true that they had been trained on the task 3 times before the operation, and were therefore highly overtrained, and it is of course possible that had they not been overtrained they would have been impaired. Nonetheless, in the absence of any evidence that pre-operative overtraining minimizes impairments after prefrontal lesion on such tasks as S D R and SDA, the most plausible hypothesis is that the focus for the deficit on the counting task is not in sulcus principalis. If so, the deficit on this task in the animals with dorsal prefrontal lesions must be the result of damage to the tissue of the dorsal or superior convexity, anterior to the arcuate sulcus. Yet animals with lesions of this area alone are able to learn SDA normally 9. The evidence therefore suggests that the ability to learn the counting task does not depend on the same tissue as does performance on SDA. The counting task is more difficult for normal monkeys to learn than either S D R or SDA. But the mean number of trials required by the animals with dorsal prefrontal lesions to relearn the task was 1484 (971-2036) with a mean savings score o f - 4 ) . 6 (--0.30 to +0.21). By comparison, 3 of the 4 animals with lesions of the sulcus principalis performed at chance after failing to relearn SDA in 1000 trials, and monkeys with dorsal prefrontal lesions including the anterior bank of the arcuate sulcus fail SDR in 1500 trials and SDA in 2000 trials s. The apparent difference in the severity of the impairment on the counting task and on SDR and SDA is the more striking when it is remembered that on the counting task an opaque screen was used, and the animals had to delay their response for up to 5 sec as on SDR and SDA. One might account for the lesser severity of the impairment found on the counting task in several ways. The animals could have cheated by using one hand when reporting a 1 and the other when reporting a 5, thus giving themselves an aid to memory. In fact no animal did this. The animals might alternatively have used cues other than kinesthetic feedback, and no attempt was made to prevent them from doing so. The animals could see their hands, as indeed they can on SDR and SDA. They might well have made some use of the sounds the keys made when pressed. A further cue available was the time it took to turn off the red light, since this was longer for 5
326 presses than for 1. It is obvious that in future studies it will be important to restrict the cues available and so to determine whether dorsal prefrontal cortex processes any information about actions or only that provided by kinesthesis. The results suggest that the deficit on SDR and SDA of monkeys with lesions in sulcus principalis is to be attributed in part to the spatial element in these tasks. However, they in no way rule out the possibility that this area of cortex may be concerned with movements, albeit movements which are discriminable in space. To locate objects with reference to itself an animal usually, though not necessarily, moves its head and eyes. If access to information about such movements was denied to the animal it might show a defect in localising things egocentrically, for example on SDR. Similarly such an animal might fail SDA because it did not know where it had seen food or what turn, whether left or right, it had last made. Although the functions of the frontal eye-fields, Brodmann area 8, are not established the evidence is at least compatible with the view that one of their functions may be to monitor head and eye movements 1. As noted earlier, an area within the eye-fields in front of the arcuate sulcus projects into the middle third of sulcus principalis 13. It is true that Mishkin et al. 18 found only a mild impairment on discrimination of head movements in monkeys with lesions including sulcus principalis. But the movements were rotations which were deliberately chosen so as not to be discriminable other than in extent. It remains quite possible that these animals might have been unable to discriminate movements of the head to the left or right. The present experiments has not settled the issue of whether monkeys with lesions of sulcus principalis fail SDR and SDA because of some difficulty in using information from their movements to the left and right in space. What it does show is that monkeys with dorsal prefrontal lesions have difficulty in using information from movements which differ in non-spatial respects. Movements may differ in their spatial coordinates, left/right, up/down, forwards/backwards and so on; or in non-spatial respects such as force, frequency, extent as studied by Mishkin et al. 18, or number as studied here and by ManninglL The present experiment differs from the others in two important respects. First, it examined the effects of delaying the animals with an opaque screen before they could make their choice. Second, it required the animals to report what movements they had made by repeating them, rather than by making some other choice. In both respects the experiment follows the conditions of SDR. It turned out that monkeys with dorsal prefrontal lesions were impaired on the counting task even when allowed to report the number of presses immediately, and that there was no evidence that they were more impaired with increasing delays. The requirement that they should execute movements proved of greater interest, since they were found to make more counting errors as well as more confusion errors. It is not that they suffered from some motor disability such that they were unable to press the keys, but rather that they often counted incorrectly. Given the evidence from Manning's study 15, that they are impaired at using information about movements, it is not surprising that they should have difficulty in counting, since counting involves a sequence of movements in which the decision whether to make a further response depends on knowledge of the number of movements already made. Counting is only one example of the many sequences of movements that an animal must make.
327 It is i n t r i g u i n g that Deuel 4 has reported that m o n k e y s with lesions of p r e m o t o r cortex, area 6, a n d the arcuate sulcus are p o o r at carrying out sequences of actions which they can correctly p e r f o r m individually. Area 6 sends projections to the dorsal frontal convexitylZ,24, the area which appears from this study to be critical for the c o u n t i n g task. It may indeed be that j u s t as other association areas work on i n f o r m a t i o n f r o m the external senses of sight, hearing a n d touch, so the i n f o r m a t i o n on which at least part of prefrontal cortex operates m a y be i n f o r m a t i o n a b o u t movements. ACKNOWLEDGEMENTS This research was supported by M.R.C. G r a n t 971/1/397/B. I a m grateful for helpful suggestions made by Dr. M. M i s h k i n d u r i n g the study.
REFERENCES 1 Bizzi, E. and Schiller, P. H., Single unit activity in the frontal eye fields of unanaesthetizedmonkeys during eye and head movements, Exp. Brain Res., 10 (1970) 151-158. 2 Butters, N. and Pandya, D. N., Retention of delayed alternation: effect of selective lesions of sulcus principalis, Science, 165 (1969) 1271-1273. 3 Chavis, D. A. and Pandya, D. N., Further observations on corticofrontal connections in the rhesus monkey, Brain Research, 117 (1976) 369-386. 4 Deuel, R. K., Loss of motor habits after cortical lesions, Neuropsyehologia, 15 (1977) 205-215. 5 Dewson, J. H., Pribram, K. H. and Lynch, J. C., Effects of ablation of temporal cortex upon speech sound discrimination in the monkey, Exp. Brain Res., 24 (1969) 579-591. 6 Gentile, A. M. and Stamm, J. S., Supplementary cues and delayed-alternation performance in frontal monkeys, J. comp. physiol. Psychol., 80 (1972) 230 237. 7 Goldman, P. S. and Rosvold, H. E., Localisation of function within dorso-lateral prefrontal cortex of the rhesus monkey, Exp. Neurol., 27 (1970) 291-304. 8 Goldman, P. S., Rosvold, H. E. and Mishkin, M., Evidence for behavioral impairment following prefrontal lobectomy in the infant monkey, J. eomp. physiol, Psychol., 70 (1970) 454-463. 9 Goldman, P. S., Rosvold, H. E., Vest, B. and Galkin, T. W,, Analysis of the delayed alternation deficit produced by dorsolateral prefrontal lesions in the rhesus monkey, J. comp. physiol. Psyehol., 77 (1971) 212-220. 10 Hyvarinen, J. and Poranen, A.,Function of the parietal association area 7 as revealed from cellular discharges in alert monkeys, Brain, 97 (1974) 673-692. 11 Jones, E. G. and Powell, T. P. S., Connexion of the somatic sensory cortex of the rhesus monkey, 1. Ipsilateral cortical connexions, Brain, 92 (1969) 477 502. 12 Jones, E. G. and Powell, T. P. S., An anatomical study of converging sensory pathways within the cerebral cortex of the monkey, Brain, 93 (1970) 793-820. 13 Kunzle, H. and Akert, K., Efferent connections of cortical area 8 (frontal eye field) in Macaca .faseicularis. A reinvest:gation using the autoradiographic technique, J. comp. Neurol., 173 (1977) 147-164. 14 Lynch, J. C., Mountcastle, V. B., Talbot, W. H. and Yin, T. C. T., Parietal lobe mechanism for directed visual attention, J. Neurophysiol., 40 (1977) 36~389. 15 Manning, F. J., Dorsolateral prefrontal lesions and discrimination of movement-produced cues by rhesus monkeys, Brain Research, in press. 16 Mishkin, M., Cortical visual areas and their interactions. In A. G. Karczmar and J. C. Eccles (Eds.), The Brain and Human Behavior, Springer-Verlag, Berlin, 1972, pp. 187-208. 17 Mishkin, M. and Manning, F. J., Non-spatial memory after selective prefrontal lesions in monkeys, Brain Research, in press. 18 Mishkin, M. Pohl, W. and Rosenkilde, C. E., Kinesthetic discrimination after prefrontal lesions in monkeys, Brain Research, 130 (1977) 163-168.
328 19 Mishkin, M., Vest, B., Waxier, R. M. and Rosvold, H. E., A re-examination of the effects of frontal lesions on object alternation, Neuropsychologia, 7 (1969) 357-364. 20 Moffet, A., Ettlinger, G., Morton, H. B. and Piercy, M. F., Tactile discrimination performance in the monkey: the effect of ablation of various subdivisions of posterior parietal cortex, Cortex, 3 (1967) 5%96. 21 Mountcastle, V. B., Lynch, J. C., Georgopoulos, A., Sakata, H. and Acuna, C., Posterior parietal association cortex of the monkey: command functions for operations within extrapersonal space, J. NeurophysioL, 38 (1975) 871-908. 22 Olszewski, J., The Thalamus of the Macaca mulatta, Karger, Basel, 1952. 23 Pandya, D. N. and Kuypers, H. G. J. M., Cortico-cortical connections in the rhesus monkey, Brain Research, 13 (1969) 13-36. 24 Pandya, D. N. and Vignolo, L. A., lntra- and interhemispheric projections of the precentral, premotor and arcuate areas in the rhesus monkey, Brain Research, 26 (1971) 217-233. 25 Passingham, R. E., Delayed matching after selective prefrontal lesions in monkeys (Macaca mulatta), Brain Research, 92 (1975) 89-102. 26 Pohl, W., Dissociation of spatial discrimination deficits following frontal and parietal lesions in monkeys, J. comp. physiol., PsychoL, 82 (1973) 227-239. 27 Robinson, D. A. and Fuchs, A. F., Eye movements elicited by stimulation of frontal eye fields, J. Neurophysiol., 32 (1969) 637-648. 28 Warren, J. M. and Divac, I., Delayed response performance by rhesus monkeys with mid-principalis lesions, Psychon. Sci., 28 (1972) 146-148.
313
I N F O R M A T I O N ABOUT MOVEMENTS IN M O N K E Y S ( M A C A CA M U L A T T A ) W I T H LESIONS OF D O R S A L P R E F R O N T A L C O R T E X
RICHARD PASSINGHAM Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford OX1 3UD (Great Britain) (Accepted December 22nd, 1977)
SUMMARY It is not known on what information prefrontal cortex acts. Since it has been suggested that it might operate on information about movements, rhesus monkeys were trained on a counting task testing memory for movements. They had to tap a key until a light went out and then repeat, either immediately or after a delay, the number of presses they had made. Monkeys with lesions of dorsal prefrontal cortex were impaired on this task, unlike monkeys with lesions of sulcus principalis alone. Cortex on the dorsal prefrontal convexity appears to act on information about movements.
INTRODUCTION To understand the function of an association area it is important to know the information on which it acts. It is established that in the rhesus monkey (Macaca mulatta) there are visual inputs into inferior temporal association cortex (Von Bonin and Bailey, TE; Brodmann, 21), auditory inputs into superior temporal association cortex (TA:22), and inputs from both vision and somatic sensation into parietal association cortex (PE and PG: 5 and 7) 12,23. In line with the anatomical findings, rhesus monkeys with lesions of TE are poor at learning when required to use visual information 16, those with lesions of TA poor for auditory information 5, and those with lesions of PE and P G poor for tactile or visuospatial information 2°,z6. The anatomical connections to prefrontal association cortex appear at first sight to provide no such clues, since it receives indirect inputs from all the senses and from very many other areas of the brain 12,23. However, these projections do not all terminate in the same sub-areas of prefrontal cortex ~, and they might therefore provide clues to the functions of these sub-areas. Of particular interest are the projections into the middle third of sulcus principalis, because bilateral lesions of this tissue alone produce severe impairments in the ability of rhesus monkeys to learn the
314 spatial delayed alternation task (SDA) 2 and the related spatial delayed response task (SDR) 2s. Furthermore, it has been established that the animals only fail when required to remember where they have most recently seen or found food, and that they succeed when required to remember what object or colour they last saw or chose 17,19,z5. These results suggest that the inputs on which cortex within sulcus principalis acts must either be visuospatial information about the location of objects in spacel6, z6 or information about the movements of the animal itself, including that from kinesthesis 6. Unfortunately the anatomical evidence does not discriminate decisively between these two hypotheses. The only area behind the central sulcus from which projections have been described into the middle third of sulcus principalis is parietal area P G (7) 8. In front of the central sulcus the premotor area FB (6) projects to dorsal prefrontal cortex and into the upper bank of sulcus principalis, perhaps including the middle third of the sulcus12, 24. An area anterior to the arcuate sulcus and caudal to sulcus principalis also sends fibres into the depths and dorsal bank of the middle third of sulcus principalis 13. This area is within the frontal eyefields as mapped by electrical stimulation 27. Although projections into sulcus principalis are established from these 3 areas, our knowledge of the functions of these areas is too inadequate to tell us what information they must convey to the sulcal cortex. A large proportion of the cells in area P G (7) respond either when the monkey reaches to a particular point in space or looks in a particular directionX0,14,2L Area FB (6) receives a heavy input from area PE (5) ~ in which the majority of the cells respond to passive rotation of the joints2L Cells in the frontal eye-fields fire either when the monkey makes a saccadic eye movement, maintains orientation of its eyes, or turns its head in a specific direction 1. While the cells related to eye movements fire during the execution of the movement, those related to head turning often discharge prior to the movement 1. These electrophysiological findings do not make it clear whether the cortex in the middle third of sulcus principalis receives information about space or kinesthesis or both. It is clear that what is needed is a behavioural test which will distinguish between the two possibilities. This can be achieved with a task in which the animals must use cues produced by their own movements and in which there are no differential visuospatial cues. If the defect of monkeys with dorsal prefrontal lesions is a spatial one they should perform normally on such a task, whereas they should be impaired if they have difficulty with kinesthetic cues. Two tasks of this sort have been devised. Mishkin et al. is tested the ability of monkeys to distinguish between small and large angular displacements of a knob along a track, the starting position of the knob being varied: two animals had to grasp and move the knob with their hands, and the other 6 had to grasp it with their teeth and move it with their head. If the knob could be moved some distance the animals could find food in a food-well, whereas if it could only be moved a short way they were required not to open the food-well. Two animals with combined lesions of dorsal prefrontal and premotor cortex failed to relearn the task in 500 trials. But 4 monkeys with dorsal prefrontal lesions alone, including sulcus principalis and the anterior bank
315 of the upper limb of the arcuate sulcus, were only mildly impaired on retention of this task. However, this does not show that the failure of such animals to learn S D R and SDA could not be attributed to a difficulty in making use of kinesthetic cues, since on these tasks the monkeys are also required to remember the cues for some seconds. The other task that has been described is that used by Manning 15, in which rhesus monkeys had to press a lever until a pilot light went out. I f 64 presses were needed to turn the light off, the animals had to respond in one way, and if 32 presses were needed, they had to respond in another. One group of animals had to respond to either a red or white key, and another group to a key on the left or the right. After learning the task the animals were tested for retention 3 weeks later. All animals were then given lesions of dorsal prefrontal cortex, including sulcus principalis and the anterior bank of the upper limb of the arcuate sulcus. All but one animal took longer to relearn the task than they had on a retention test before the operation. Two questions are raised by this study. The first is: which of the various areas within dorsal prefrontal cortex must be removed to produce this impairment? It is known that monkeys with lesions of the arcuate sulcus are impaired on a conditional task on which the animal must go to the left given one cue and to the right given another 7, and it is possible that they might be impaired on other conclitional tasks such as that used by ManninglL It is of obvious importance to establish whether monkeys with lesions of sulcus principalis alone would be impaired, since it is these lesions that critically disrupt the ability of monkeys to learn SDA z and SDR 2s. The other question is whether the deficit reported by Manning 15 is severe enough to explain the failure of monkeys to learn SDA and S D R after lesions of dorsal prefrontal cortex 8 or of sulcus principalis alone2, ~8. Although some of the animals were clearly very impaired it is difficult to assess the deficit of other animals, since they were not compared with unoperated control animals. Again the impairement might have been even more severe, had a delay been imposed before the animals were allowed to report the count they had made. In the present experiment, therefore, a counting task was used which was as similar as possible to SDR. The monkeys had to press a key to turn a light off. They then had to report the number of presses they had made by repeating the same number of presses on another key. They were allowed to make their report either immediately or after delays of up to 5 sec, during which an opaque screen was lowered to prevent them from responding. Some animals were given lesions of dorsal prefrontal cortex, excluding the arcuate sulcus, and others of sulcus principalis alone. METHODS
Subjects Eight adolescent rhesus monkeys previous training.
(Macaca mulatta) were used.
They had had no
Apparatus The animals were tested in a Wisconsin General Testing Apparatus (W.G.T.A.).
316
©
©
D !
Fig. 1. Diagram of counting apparatus.
They faced 2 boxes mounted on a board (left-hand box 25 cm high × 15 cm wide × 16 cm deep; right-hand box 25 cm high × 25 cm wide × 16 cm deep) (Fig. 1). On each box there was a translucent Gerbrands key 3.3 cm in diameter. The key on the animal's right could be lit with a red light and that on the left with a white light from bulbs placed behind them. Underneath the key on the right-hand box was a plastic door hinged at the top (5 × 5 cm), and by opening this with the back of their hands the animals could reach peanuts placed behind it. The door could be locked and unlocked with a solenoid, but even when locked a slight displacement of the door was possible. A microswitch detected this displacement and a logic circuit (Behavioural Research and Development logic modules) determined whether the door was then to remain locked or to open by release of the solenoid. The presentation of the stimuli and the sound of the number of presses made on each key were also controlled by the logic circuit. The interior of the W.G.T.A. was illuminated from above with a 40 W bulb run on 180 V, and a masking noise was present. Training Pre-training The monkeys were first adapted to the W.G.T.A. by giving them 3 simultaneous visual discriminations presented on plaques, black vs. white, red vs. green, and plus vs. square, all to a criterion of 90 correct choices in 100 trials. Counting - - shaping They were then adapted to the apparatus described above. First they were trained to open the door of the food-well for peanuts. They were then taught to press the left-hand key before attempting to open the food-well. I f they failed to do so, the door remained locked when they touched it, whereas if they l~ressed the key first the solenoid was released as soon as they touched the door, and the door was thus unlocked. The next stage required them to press the key on the right-hand door when the red light came on, and to continue pressing until the light went off, this requiring either one or 5 presses. At this point the white light on the left-hand key came on, and the key had to be pressed if the animal was to succeed in opening the door of the food-well.
317 Counting - - Pre-operative initial training
The animals were then trained in 3 stages to repeat on the left-hand key the number of presses that had been found necessary to turn off the red light on the right hand key. No further cue was given as to when they had pressed the left key the correct number of times, the white light remaining on until after they had attempted to open the door for the peanut. First they were tested under conditions in which a single press of the right key turned off the red light, the white light on the left-hand key coming on immediately afterwards. One or two presses of the white key were counted as correct, and enabled the animal to open the door to the food-well. If the animals failed to make any presses on the white key or made 3 or more, the door remained locked when they tried to open it. The animals were trained until they made the correct number of presses on the white key on 90/100 trials. Thirty trials were given a day. They were then trained under conditions in which 5 presses were required on the right-hand key to turn off the red light. Again the white light came on immediately on the left key, but now 5 or more presses were needed on this key to enable the animal to open the food-well. I f the animals made no press, or only one, two, 3 or 4 presses, the door would not unlock. In the third stage the animals were given successive reversals between the two previous conditions. First they were given the single press condition until they had performed correctly on 9/10 successive trials. They were then given the 5 press condition to the same criterion. Having achieved this they were reversed back to the single press condition, and so on through successive reversals, until on 9/10 reversals they had reached criterion within the 30 trials of one day's testing. The animals completed all stages of pre-training in a mean of 1267 (670-1958) trials. This is qvicker than might have been expected for a task which appears so demanding. Counting - - Pre-operative training
The animals were then tested on the final version of the task. On any trial either 1 or 5 presses turned the red light off, the number being determined randomly by use of the Gellermann schedule. I f the animals made the incorrect number of presses on the white left-hand key and thus failed to obtain food, that condition was repeated until the animal succeeded (re-run correction). The animals were trained to a criterion of 90/100 correct trials. A delay was then introduced between the time when the animal had turned off the red light and the time when it was given access to the white key. After the animal had completed the presses on the red key an opaque screen was lowered between the animal and the apparatus. The animal was therefore unable to press the white key until the screen had been raised again. The animals were trained successively at 1,2, 3, 4 and 5 sec delay, being required to reach a criterion of 45/50 correct trials at each delay in turn. A re-run correction procedure was used throughout. Having reached criterion at 5 sec delay the animals were retested at 0 sec delay to a criterion of 90/100 correct trials.
318 First operation
Operations were performed on 4 of the 8 animals within a week of their reaching criterion again at 0 sec delay. All animals restarted testing 3 weeks after finishing preoperative training. Counting - - Post-operative The animals were first retested at 0 sec delay to a criterion of 90/100 correct trials. They were then tested successively at each delay as before the operation, to a criterion of 45/50 correct trials at each delay. Delayed alternation The animals were tested on SDA in the W.G.T.A. Black plaques (7.5 sq.cm) covered food wells 30 cm apart, and the animals were required to push the plaques to retrieve peanuts. They were tested for 30 trials a day with a re-run correction, the opaque screen being lowered for 5 sec between trials. Training continued until the animals reached a criterion of 90/100 correct trials or until they had been tested for 1000 trials. Counting - - Retraining All animals were then retrained on the counting task at 0 sec and at each delay in turn. The criteria were the same as previously used. Second operation
Within a week of their reaching criterion at 5 see operations were then performed on the 4 previously unoperated animals. They restarted testing 3 weeks after completion of pre-operative training. Counting - - Post-operative These 4 animals were then retrained on the counting task exactly as before the operation. Delayed alternation - - Retest After reaching criterion on the counting task these 4 animals were retested on SDA under the same conditions as before. Groups and surgery
At the first operation dorsal prefrontal cortex (DF) was removed bilaterally in 4 animals, the remaining 4 serving as unoperated controls (UC). The dorsal prefrontal
319
DFIO
DFII
DFI2
DFI3
SPI4
SPI5
SPI6
SPI7
Fig. 2. Reconstruction of lesions. The straight lines indicate the levels from which the cross-sections shown in Fig. 3 were taken.
320
DFIO
DFII
DFI2
DFI3
SPI4
SPI5
SPI6
sPT Fig. 3. Cross-sections through lesions. The right hemisphere in shown on the left.
lesions were intended to remove the cortex in both banks of sulcus principalis and on the dorsal prefrontal convexity, the lesion extending posteriorly to within roughly 3 mm of the arcuate sulcus. All surgery was performed with aseptic procedures, with sodium pentothal as an anaesthetic. At the second operation the cortex in both banks of sulcus principalis (SP) was removed bilaterally in the 4 animals that had previously served as unoperated controls.
Histology At the end of the experiments the animals were anaesthetized with Nembutal and perfused with 0.9 ~ saline, followed by Karnovsky's solution, as they were being used
321 TABLE I Pre-operative trials to criterion on counting task
Trials for delay are the sum of the trials on 1, 2, 3, 4 and 5 sec. The total trials are the sum of those for 0 sec and delay. Figures in brackets are saving scores (see text). Groups
0 sec
Delay
Total
0 Sec retest
Dorsal frontal 10 11 12 13 Mean
1047 440 443 167 523.5
1367 1820 278 493 987
2404 2260 721 657 1510.5
0 69 20 92 45.2
(1.0) (0.73) (0.91) (0.28) (0.73)
185 694 466 248 389.2
1652 909 1626 1065 1313
1837 1603 2092 1313 1711.2
0 0 28 33 15
0.0) (1.0) (0.89) (0.76) (0.91)
Unoperated 14 15 16 17 Mean
TABLE II Post-operative trials to criterion on counting task
Delay and total trials and defined in Table 1. Figures in brackets are saving scores (see text). Groups
0 Sec
Dorsal frontal 10 11 12 13 Mean
501 745 826 139 552.7
Unoperated 14 15 16 17 Mean
0 41 13 0 13.5
Delay
(0.35) (~0.26) (--0.30) (0.08) (4.03) (1.0) (0.89) (0.94) (1.0) (0.96)
1077 1291 524 832 931 246 175 783 0 301
Total
(0.11) (0.17) (~0.31) (4.25) (4.07) (0.74) (0.68) (0.35) (1.0) (0.69)
1578 2036 1350 971 1483.7 246 216 796 0 314.5
(0.21) (0.05) (---0.30) (-4).19) (--0.06) (0.76) (0.76) (0.45) (1.0) (0.74)
for a separate anatomical study. 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 thionine. Reconstructions of the lesions were made from the sections. The reconstructions of the lesions are shown in Fig. 2 and representative cross-sections in Fig. 3. The lesions were as intended, except that there was slight sparing of the depths of sulcus principalis at certain levels in some animals, e.g. DFI0, DF12 and SP16, although the remaining tissue was probably too little to be of functional significance. Both lesions led to cell
322 loss and gliosis in the parvocellular portion 22 of the dorsomedial nucleus of the thalamus, as previously described for similar lesionsT, 25. RESULTS
Counting - - Dorsal f r o n t a l
The trials to learn the counting task at 0 sec and at all delays are shown for all animals in Table I. A mean of 1611 (657-2404) trials were required to learn the task under all conditions. There was no significant difference between the performance of the animals chosen for the D F and U C groups. All animals except DF13 showed high savings on retesting at 0 sec, the mean savings score being 0.82 (0.28-1.0) (savings = test - - retest/test + retest). After the operation the animals with dorsal frontal lesions took significantly more trials to relearn the task than did the unoperated contl ol animals (Table II). This was true for the trials to relearn at 0 sec (t = 3.48, df = 6, P < 0.02), and under conditions of delay (t = 2.67, df = 6, P < 0.05), and for the total trials to relearn under all conditions (t = 4.18, df = 6, P < 0.01). Savings scores were also calculated by comparing performance at 0 sec with that for original training at 0 sec, and the trials on delay conditions and the total trials with those taken before the operation (savings ~ pre-operative - - post-operative/pre-operative + post-operative). There was no overlap between the savings scores of the two groups at 0 sec (t = 6.36, df = 6, P < 0.001), under conditions of delay (t = 4,19, df = 6, P < 0.01), or for the savings scores based on the total trials (t = 4.96, df = 6, P < 0.01). The unoperated animals showed good savings, whereas the animals with dorsal prefrontal lesions showed small or negative savings, with a mean savings score o f - - 0 . 0 6 (--0.3 to +0.21) for all trials combined. On this task two types of error are possible. The animals may incorrectly report TABLE III Per cent counting errors/counting errors + confusion errors on counting task Pre, pre-operatively; Post, post-operatively. Groups
Pre (%)
Post (%)
Post - - Pre (%)
Dorsal frontal 10 11 12 13 Mean
37.7 43.2 56.0 49.7 46.6
44.6 61.8 76.0 48.5 57.7
6.9 18.6 20.0 --1.2 11.1
Unoperated 14 15 16 17 Mean
26.9 68.4 32.2 39.7 41.8
58.6 52.5 37.8 30.0 44.7
31.7 --15.9 5.6 --9.7 2.9
323 TABLE IV
Delayed spatial alternation Trials and errors on SDA. F -- failed on 1000 trials. The per cent correct of the last 100 trials are given in brackets.
Groups
Trials
Errors
Dorsal frontal 10 11 12 13 Mean
1000 1000 1000 1000
F F F F
(39~) (72~) (68~) (52~)
521 521 454 521 504.2
Unoperated 14 15 16 17 Mean
328 463 1000 F 580
(69~)
110 193 350 209 215.5
a 1 as a 5, or a 5 as a 1, and these may be referred to as c o n f u s i o n errors. The animals may also fail to r e p o r t either a 1 or a 5, b y m a k i n g 0, 3 or 4 presses (one or two presses being allowed when r e p o r t i n g a 1 a n d m o r e t h a n 5 presses when r e p o r t i n g a 5). The latter t y p e o f e r r o r may be called a counting error. The errors, excluding c o r r e c t i o n errors, were therefore classified as confusion or c o u n t i n g errors, and the percentages are given in Table III. The two g r o u p s d o not differ significantly in the p r o p o r t i o n o f counting errors p o s t - o p e r a t i v e l y n o r in the change in the p r o p o r t i o n o f c o u n t i n g errors f r o m pre- to p o s t - o p e r a t i v e perforinance. Delayed alternation - - Dorsal frontal
When tested on learning of SDA all the animals with dorsal prefrontal lesions failed to reach criterion in 1000 trials (Table IV). Unoperated animal 16 also failed, though making fewer errors than any of the operated animals. Counting - - Sulcus principalis
On retesfing on the counting task the animals with dorsal prefrontal lesions still tended to make more errors than the unoperated animals (Table V), but the difference was not significant (t ---- 1.89, df ~ 6, P ~ 0.05) due to the continued poor performance of animal 16 in the unoperated group. After the control animals had received lesions of sulcus principalis they were not found to be obviously impaired on post-operative relearning (Table V). Animal 15 required no further trials to re-reach criterion at 0 sec and on each delay. All animals took fewer trials to relearn than the animals with dorsal prefrontal lesions had taken immediately post-operatively (Table II) or on later retesting (Table V).
324 TABLE V Pre- (Pre) and post-operative (post) trials to reach criterion on the counting task Total trials as defined in Table I. The figures given under total (Pre) are the relearning scores for the monkeys with dorsal frontal lesions of sulcus principalis. The figures under total (Post) are the postoperative relearning scores of the animals given lesions of the sulcus principalis. Groups
Total (Pre)
Dorsalfrontal 10 11 12 13 Mean
639 641 453 620 588.2
Total (Post)
m
m
Su&us principalis 14 35 15 159 16 753 17 122 Mean 267.2
273 0 355 101 182.2
TABLE VI Delayed spatial alternation Trials and errors on SDA. F = failed in 1000 trials. The percentage correct of the last 100 trials are given in brackets. Group
Trials
Sulcus principalis 14 1000 F 15 1000 F 16 1000 F 17 1000 F Mean --
Errors
(54~) (49~) (49~) (72 ~)
538 538 550 505 532.7
Delayed alternation - - Sulcus principalis The pre-operative learning scores o n S D A are given in Table IV for the a n i m a l s which later received sulcus principalis lesions. The data for post-operative relearning are shown i n Table VI. All animals failed to relearn the task i n 1000 trials. A n i m a l 16, which had previously failed to learn when unoperated, n o w made more errors t h a n previously a n d failed to p e r f o r m above chance o n the last 100 trials (49 ~ ) , whereas it was able to perform at 69 ~ before the operation. DISCUSSION The c o u n t i n g task used here differs from S D R i n only one i m p o r t a n t respect.
325 Whereas on S D R the animal must remember the spatial position of food and respond to the left or right, on this task both cues and responses are two actions which are not spatially discriminable. Rhesus monkeys with dorsal prefrontal lesions are clearly impaired on the counting task, and this defect can not be put down to a spatial disorder, such as has been suggestedg, 16,26, to account for the impairment on S D R and SDA after lesions of sulcus principalis. The issues raised are whether the focus for the deficit is in the sulcus principalis as for SDA 2 and S D R 2s, and whether the impairment is severe enough to explain the failure of monkeys with lesions of sulcus principalis to learn SDA and SDR. The monkeys with removal of the cortex in sulcus principalis were apparently not impaired, or if at all only slightly impaired, on the counting task. Animal 15 required no further trials before reaching criterion after the operation, and yet was at a chance level for 1000 trials on SDA. Although the performance of the 3 other animals cannot be compared with that of unoperated animals, it is unlikely that their performance would have been surpassed by such controls. It is true that they had been trained on the task 3 times before the operation, and were therefore highly overtrained, and it is of course possible that had they not been overtrained they would have been impaired. Nonetheless, in the absence of any evidence that pre-operative overtraining minimizes impairments after prefrontal lesion on such tasks as S D R and SDA, the most plausible hypothesis is that the focus for the deficit on the counting task is not in sulcus principalis. If so, the deficit on this task in the animals with dorsal prefrontal lesions must be the result of damage to the tissue of the dorsal or superior convexity, anterior to the arcuate sulcus. Yet animals with lesions of this area alone are able to learn SDA normally 9. The evidence therefore suggests that the ability to learn the counting task does not depend on the same tissue as does performance on SDA. The counting task is more difficult for normal monkeys to learn than either S D R or SDA. But the mean number of trials required by the animals with dorsal prefrontal lesions to relearn the task was 1484 (971-2036) with a mean savings score o f - 4 ) . 6 (--0.30 to +0.21). By comparison, 3 of the 4 animals with lesions of the sulcus principalis performed at chance after failing to relearn SDA in 1000 trials, and monkeys with dorsal prefrontal lesions including the anterior bank of the arcuate sulcus fail SDR in 1500 trials and SDA in 2000 trials s. The apparent difference in the severity of the impairment on the counting task and on SDR and SDA is the more striking when it is remembered that on the counting task an opaque screen was used, and the animals had to delay their response for up to 5 sec as on SDR and SDA. One might account for the lesser severity of the impairment found on the counting task in several ways. The animals could have cheated by using one hand when reporting a 1 and the other when reporting a 5, thus giving themselves an aid to memory. In fact no animal did this. The animals might alternatively have used cues other than kinesthetic feedback, and no attempt was made to prevent them from doing so. The animals could see their hands, as indeed they can on SDR and SDA. They might well have made some use of the sounds the keys made when pressed. A further cue available was the time it took to turn off the red light, since this was longer for 5
326 presses than for 1. It is obvious that in future studies it will be important to restrict the cues available and so to determine whether dorsal prefrontal cortex processes any information about actions or only that provided by kinesthesis. The results suggest that the deficit on SDR and SDA of monkeys with lesions in sulcus principalis is to be attributed in part to the spatial element in these tasks. However, they in no way rule out the possibility that this area of cortex may be concerned with movements, albeit movements which are discriminable in space. To locate objects with reference to itself an animal usually, though not necessarily, moves its head and eyes. If access to information about such movements was denied to the animal it might show a defect in localising things egocentrically, for example on SDR. Similarly such an animal might fail SDA because it did not know where it had seen food or what turn, whether left or right, it had last made. Although the functions of the frontal eye-fields, Brodmann area 8, are not established the evidence is at least compatible with the view that one of their functions may be to monitor head and eye movements 1. As noted earlier, an area within the eye-fields in front of the arcuate sulcus projects into the middle third of sulcus principalis 13. It is true that Mishkin et al. 18 found only a mild impairment on discrimination of head movements in monkeys with lesions including sulcus principalis. But the movements were rotations which were deliberately chosen so as not to be discriminable other than in extent. It remains quite possible that these animals might have been unable to discriminate movements of the head to the left or right. The present experiments has not settled the issue of whether monkeys with lesions of sulcus principalis fail SDR and SDA because of some difficulty in using information from their movements to the left and right in space. What it does show is that monkeys with dorsal prefrontal lesions have difficulty in using information from movements which differ in non-spatial respects. Movements may differ in their spatial coordinates, left/right, up/down, forwards/backwards and so on; or in non-spatial respects such as force, frequency, extent as studied by Mishkin et al. 18, or number as studied here and by ManninglL The present experiment differs from the others in two important respects. First, it examined the effects of delaying the animals with an opaque screen before they could make their choice. Second, it required the animals to report what movements they had made by repeating them, rather than by making some other choice. In both respects the experiment follows the conditions of SDR. It turned out that monkeys with dorsal prefrontal lesions were impaired on the counting task even when allowed to report the number of presses immediately, and that there was no evidence that they were more impaired with increasing delays. The requirement that they should execute movements proved of greater interest, since they were found to make more counting errors as well as more confusion errors. It is not that they suffered from some motor disability such that they were unable to press the keys, but rather that they often counted incorrectly. Given the evidence from Manning's study 15, that they are impaired at using information about movements, it is not surprising that they should have difficulty in counting, since counting involves a sequence of movements in which the decision whether to make a further response depends on knowledge of the number of movements already made. Counting is only one example of the many sequences of movements that an animal must make.
327 It is i n t r i g u i n g that Deuel 4 has reported that m o n k e y s with lesions of p r e m o t o r cortex, area 6, a n d the arcuate sulcus are p o o r at carrying out sequences of actions which they can correctly p e r f o r m individually. Area 6 sends projections to the dorsal frontal convexitylZ,24, the area which appears from this study to be critical for the c o u n t i n g task. It may indeed be that j u s t as other association areas work on i n f o r m a t i o n f r o m the external senses of sight, hearing a n d touch, so the i n f o r m a t i o n on which at least part of prefrontal cortex operates m a y be i n f o r m a t i o n a b o u t movements. ACKNOWLEDGEMENTS This research was supported by M.R.C. G r a n t 971/1/397/B. I a m grateful for helpful suggestions made by Dr. M. M i s h k i n d u r i n g the study.
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