Nuuropsyholowz, Vol. 23, No. 4, pp. 453 462, 1985. Printed m Great Bntam.

0028 3932185 .U.oO+O.OO c“ 1985 Pergamon Prrss Ltd.

PREFRONTAL CORTEX AND THE SEQUENCING OF MOVEMENT IN MONKEYS (MACACA kfULATTA)

R. E. PASSINGHAM

Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, U.K

(Accepted 24 January 1985)

Abstract--There have been suggestions that the prefrontal cortex may play a role in the regulation of higher-order sequences of behaviour. In this experiment monkeys were taught a sequence of three movements. After removal of either sulcus principalis or the superior prefrontal convexity monkeys were able to perform the sequence normally. After removal of arcuate cortex (areas 8 and 6) monkeys were slow to learn the task; but it is argued that their impairment may not be one ofsequencing prr se.

INTRODUCTION

THERE ARE suggestions that prefrontal cortex may play a role in the regulation of higher- order sequences of behaviour. Patients with large frontal tumours may be disorganized in their behaviour, for example in drawing or making tapping movements [23]. Monkeys with large frontal lesions are less systematic than normal monkeys in the way they search through four boxes for food [26]. Rats with medial frontal lesions are inefficient at hoarding food [17] or retrieving pups [ 191.

Both patients and monkeys have been tested on more formal tasks in which they are required to learn or reproduce motor sequences. Recently two experiments have assessed the ability of patients with frontal lesions to reproduce sequences of movement as demonstrated by the tester. KIMLJRA [16] finds that patients with left anterior lesions are impaired at reproducing three movements of the hand or mouth. KOLB and MILNER [ 181 tested patients after the removal of large portions of frontal cortex from one hemisphere. They report that patients are poor at copying manual or facial sequences after either left- or right-sided removals.

There are also three experiments in which monkeys have been trained to make a series of movements. PINTO-HAMUY and LINCK [32] and BRWY and PRIBRAM [l] trained monkeys to press panels in sequence. Three types of sequence were devised. The first is a spatial sequence in which the monkey must press three panels in a row, either with or without a colour cue to tell them where they have just pressed. The second is a non-spatial sequence in which the monkey must press three patterns in a particular order irrespective of the spatial position in which the patterns are presented. The third sequence requires the monkey to press three colours or patterns in any order so long as it does not press any particular one twice. In both experiments all the tissue on the lateral frontal surface was removed, including sulcus principalis, the superior and inferior convexity and the frontal eye fields. The monkeys were poor at relearning the spatial sequence [I], the non-spatial sequence [l] and the sequence in

which the monkey determines the order [32]. In these experiments the monkey responded in the same way to each panel, that is by

453

454 R. E. PAWNGHAM

pressing it. DEUEL [S] introduced a sequence of a different type in which the monkeys must operate three latches in order, removing a pin, turning a crank and pressing a knob. Since the latches remain in the same place from trial to trial the monkeys might learn either which latch to operate next or which position to respond to next.

DEUEL [S, 61 removed only the posterior part of the lateral frontal cortex. The lesion included both banks of the arcuate sulcus (area 8 and area 6) and the tissue on the lateral convexity in the bow of the arcuate sulcus, including the posterior one-third of sulcus principalis. The monkeys were taught the motor sequence before the operation and retested afterwards. They were markedly impaired.

The three studies mentioned, though similar in design, had very different aims. PINTO- HAMUY and LINCK [32] and BRODY and PRIBRAM Cl] were interested in the fact that after removal of prefrontal cortex including sulcus principalis monkeys fail the delayed alternation task. They suggest that the monkeys fail because they are poor at carrying out sequential tasks in general. DEUEL [5], on the other hand, was interested in the functions of the cortex in and around the arcuate sulcus lying posterior to the prefrontal region area 9. DEUEL [S]

points out that it is known that there is sensory convergence onto this region [27]; she was therefore interested in examining its role in the guidance of movement.

It is important to establish whether removal of prefrontal cortex (area 9) has any effect on the ability of a monkey to perform a sequential task if the tissue of area 8 is left intact. In the present experiment therefore either sulcus principalis, or the superior prefrontal convexity, or the arcuate region (area 8 and area 6) was removed. The monkeys were taught after surgery a motor sequence similar to that devised by DEUEL [S]. The manipulanda were modelled on those used by KIMURA [ 151 for the sequence box on which she tested neurological patients. Like the patients the monkeys had to press a button, pull a handle, and depress a lever.

METHODS

Groups and suryery

The monkeys were divided into four groups, In two animals the cortex was removed bilaterally from both banks of sulcus principalis (SP). In three animals the cortex was removed bilaterally from the superior frontal convexity (SC) but the tissue of sulcus principalis was spared. This lesion extended to the midline, and an attempt was made to draw the posterior limit in front of area 8 (including the frontal eye-fields). In three other animals the tissue was removed from both banks (area 8 and area 6) of the upper limb of the arcuate sulcus (ARC); the cortex of area 8 was also removed anterior to the upper limb of the arcuate sulcus, and the cortex of area 6 was remov,ed posterior to the upper limb of the arcuate sulcus. Three monkeys served as unoperated controls.

The monkeys were tramed in other experiments 128,291. Of the three monkeys with lesions ofsulcus principalis described by PASSINGHAM [28] one (animal SP22) became ill during the present experiment and could not be tested. The monkeys were trained roughly three months after surgery.

Histolog)

A full histological report is given elsewhere ([28] for SP and SC lessons, [29] for ARC lesions). Figure 1 shows reconstructions of the lesions of a representative animal m each group. Figure 2 shows cross-sections through the lesions taken at the levels indicated by the bars in Fig. 1.

Apparatus

The monkeys were tested in a Wisconsin General Testing Apparatus. The interior was illuminated from above by a 40W bulb.

The sequence box is illustrated in Fig. 3. It measured 36 cm (length) by 14.5 cm (breadth) by 18 cm (height). On the front wall were three manipulanda, a central button (Cerbrands key, 3.3 cm in diameter), a handle to the right (6.5 cm in length, 2.5 cm in depth), and a flat lever to the left (3.5 cm in length, 2.5 cm in depth). The displacement of the manipulanda was registered by microswitches. To the right there was a door (5.5 cm in length, 5.5 cm in height) beneath the handle. The door was hinged at the top, and by opening it with the back of their hands the monkeys

SEQUENCING OF MOVEMENT 455

FIG. 1. Reconstructions of the lesions of representative animals. SP = sulcus principalis, SC = superior prefrontal convexity, ARC = arcuate. The bars show the levels at which the sections shown in Fig. 2

were taken.

SP23

SC26

ARC27

FIG. 2. Cross-sections through the lesions for the three animals shown in Fig. 1. The lesion is shown by hatching. SP = sulcus principalis, SC = superior prefrontal convexity, ARC = arcuate.

could reach a peanut placed behind it. The door could be locked with a solenoid. Even when locked a slight displacement of the door was possible, and a microswitch detected this displacement. A logic circuit (Behavioural Research and Development logic modules) determined whether the door was to remain locked or to open by release of the solenoid.

Training

The monkeys were first taught by standard shaping procedures to operate the button, handle and lever. At this stage only one of the manipulanda was available at any one time, the other two being concealed under metal covers.

456 R. E. PASSINGHAM

FIG. 3. Drawing of sequence box. The positions of the button, handle, lever and door to the foodwell are shown.

Seyuence oftwo mouemmrs. The monkeys were required to press the button, pull the handle and then open the door of the foodwell. The lever was covered up at this stage. If they did the movements in the correct order the foodwell opened as soon as they tried to lift the door. The door remained locked if the monkey had omitted one of the movements or done them in the incorrect order. The trial ended when the monkey went to the door or when it made an incorrect move (pulling the handle before pressing the button). The animals were allowed to repeat a move immediately, for example to press the button twice, but not to return to a manipulandum after operating one of the others, The monkeys were trained to a criterion of 90 out of 100 correct trials.

Sequence ofthree mowmems. The monkeys were required to press the button, pull the handle and then depress the lever. Early in training on the three sequence task the monkeys were required to register the fact that they had completed the sequence by trying the door. At this stage this only opened if the sequence had been correct. lf the monkey went to the door having made only one or two moves or having made four or more the door failed to open. It was soon found that the monkeys were confused by this; the task was equivalent to a sequence of four rather than three movements since the door had also to be operated as part of a correct sequence. The task was therefore simplified so that the solenoid audibly retracted as soon as the sequence push-pulldepress had been completed. The door now operated without the monkeys having to try it, and they were not longer penalized for going to the door too soon or too late. The trial ended when either the monkey completed the sequence correctly or made an Incorrect move. The monkeys were trained to a criterion of 90 out of 100 correct trials on this task.

RESULTS

No operated animal had any trouble with the two sequence task. Figure 4 gives the trials taken by each animal to learn to press the button and pull the handle before opening the

door.

SP SC ARC UC

FIG. 4. Mean trials to criterion to learn the sequence of two movements (press button, pull handle). The bars give the trials for individual animals. SP=sulcus principalis, SC=superior prefrontal

convexity. ARC =arcuate. UC = unoperated.

SEQUENCING OF MOVEMENT

2500-

2000-

Y mo-

9

F

lOOO-

500- r 01

SP

I -

SC ARC

f

F

I FI

I I I

4 UC

FIG. 5. Mean trials to criterion to learn the sequence of three movements (press button, pull handle, depress lever). The bars give the trials for individual animals. The mean for the three animals with ARC lesions is not given as two of the animals failed (F) to learn the task in 2500 trials. SP=sulcus

principalis, SC =superior prefrontal convexity, ARC = arcuate, UC = unoperated control.

The three sequence task was more difficult. Figure 5 shows the trials to criterion. The unoperated animals took a mean of 1031 trials to learn the task and made a mean of 618 errors. Neither the monkeys with lesions ofsulcus principalis nor the monkeys with lesions of the superior convexity were in any way impaired.

However, the monkeys with lesions of the arcuate area were very impaired indeed. ARC 28 passed after 2210 trials (1495 errors), but ARC 27 had not passed after 2620 trials (1582 errors) and ARC 29 had not passed after 2700 trials (1220 errors). Neither of these two animals was close to passing at the time when testing was discontinued. ARC 27 was performing at 71% correct and ARC 29 at 67% correct on the last 100 trials of testing.

An analysis was made of the last 100 errors committed by each animal on the three sequence task. These errors were classified into errors on the first move (omitting button, and operating the handle H or lever L); on the second move (omitting handle, thus producing the sequence button-handle or BH); or on the third move (omitting lever and incorrectly pressing the button again, thus producing the sequence button-handle-button or BHB). Table 1 gives the breakdown of the errors. Eight animals made over 50% of their errors on their first move, by omitting to press the button. Only two of the animals made over 50% of errors on their second move, by omitting to pull the handle before depressing the lever. No animal made many errors by returning to the button on the third move. The pattern oferrors was the same for the animals with arcuate lesions as for those in the other groups.

DISCUSSION

The sequence task posed no problems to the monkeys with lesions of the dorsolateral prefrontal cortex anterior to area 8. There is no evidence that the tissue in sulcus principalis

458 R. E. PASSINGHAM

Table 1. Percentage of errors made by the animals on the first, second and third move. The letters at the top give the incorrect responses. H = handle, L = lever,

B= button. Thus on the first move the animal made an error if it pulled the handle or depressed the lever. For more details see text.

Group 1st move 2nd move 3rd move H or L BL BHB

Unoperated control 18 19 20 Mean

Sulcus principalis 21 23 Mean

Superior convexity 24 25 26 Mean

Arcuate 27 28 29 Mean

Overall mean

85 11 4 38 61 1 83 16 1 68.7 29.3 2

71 18 11 69 27 4 70 22.5 7.5

49 38 13 30 66 4 83 19 0 54 40.3 5.7

57 43 0 65 30 5 79 20 1 67 31 2 64.5 31.5 4

or on the superior convexity is involved in the production of a fixed sequence of three movements.

The present experiment confirms the earlier finding of DEUEL [S] that a lesion of the arcuate area markedly impairs the ability of a monkey to learn a simple series of three responses. In both experiments the tissue was removed from both banks ofthe arcuate sulcus. In a later unpublished experiment HALSBAND [11] trained monkeys on the sequence task described here after the bilateral removal of either area 8 or area 6 alone. Only the monkeys with lesions in area 8 were impaired at learning the task.

But it is unlikely that monkeys with lesions in area 8 do poorly because they have problems in sequencing per se. HALSBAND and PASSINGHAM [ 123 devised a non-spatial sequence task in which three movements had to be performed in order to a sing/e manipulandum. They were able to teach this task to monkeys and found that after removal of area 8 bilaterally the monkeys could still perform the task normally. Monkeys with lesions in premotor cortex (area 6) could also carry out the sequence. Presumably in the present experiment the monkeys with arcuate lesions were impaired on the sequence box because the three manipulanda were positioned in d#erent places.

It is known that after removal of area 8 monkeys are poor at tasks that require them to use visual or auditory cues at one location to guide their response to foodwells located elsewhere. For example they are poor at choosing between foodwells to their left and right on the basis of a central cue that is black or white [22] or a sound that is played above them or below [IS]. Neither of these tasks requires the animal to learn a spatial sequence, but both demand that the animal attend to several locations. Monkeys with lesions in area 8 are known to be slow in searching for targets in an array 13, 221; and they tend to neglect targets [Zl]. It is most likely

SEQUENCING OF MOVEMENT 459

that monkeys with arcuate lesions are handicapped on sequence tasks not because a sequence is required but because they must direct their attention to several points in space.

On this interpretation of the results prefrontal cortex is not taken to play a crucial role in the direction of fixed sequences of movement. It is necessary, then, to look again at the evidence quoted in the introduction since it appeared to favour some role for prefrontal cortex in the sequencing of behaviour. The studies were of two sorts, (1) observations of the

sequencing of spontaneous behaviour, whether in patients, monkeys or rats, and (2) formal experiments on the teaching of motor sequences.

In the first category LURIA [23] collected many clinical observations of the behaviour of

patients with very large frontal tumours. He was impressed by the disruption of the flow of behaviour by perseverative errors. But the lesions were too large to permit conclusions as to the functions of prefrontal as opposed to premotor cortex. LURIA et al. [24], for example, report on a patient with a large left frontal meningioma; but the patient also had a right hemiparesis. At postmortem it turned out that both premotor cortex and presumably supplementary motor cortex were involved in the lesion. Furthermore Luria tended to study patients in the acute phase of their illness. CANAVAN et al. [2] describe a patient in the weeks after the removal of a large meningioma situated dorsomedially between the two frontal lobes. In the acute phase the patient was as disorganized in her drawings and general behaviour as the patient described by LURIA et al. [24]; but the symptoms passed in only a few weeks. It is likely that the disorganization resulted from the temporary effects of oedema after the operation.

The advantage of working on animals is that discrete lesions can be made. MEYER and SETTLAGE [26] claimed that monkeys with frontal lesions were less predictable than normal monkeys in the order with which they search for food. But the lesions involved not just all the

lateral and orbital prefrontal cortex but also on the medial wall area 25 and anterior cingulate cortex, area 24, in front of the genu; and there was marked degeneration in parts of the anterior tip of the head of the caudate nucleus (as described by FRENCH and HARLOW [S]). These monkeys were hyperactive and hyperreactive [S]. Their disturbed performance may be a poor guide as to the functions of lateral prefrontal cortex.

The behaviour of rodents is disorganized after the removal of the cortex of the anterior medial wall. Both rats [17, 191 and hamsters [36] are disorderly in the way they hoard food or build a nest. But again the lesion is not a discrete one. In rodents the prefrontal cortex is divided into two sectors, on the medial surface of the frontal cortex and in the anterior part of the upper bank of the rhinal sulcus [25]. But in all studies lesions of the medial wall include the tissue on the dorsomedial shoulder of frontal cortex. DONOGHUE and WISE [7] label this area Agm. They have mapped the primary motor area MI by microstimulation in rats, and they also describe a non-primary motor area within the region AGm which they tentatively identify as MII. They suggest that this may be the equivalent of the supplementary motor cortex (part of area 6) in the monkey. PASSINGHAM et al. [30] have removed this region and find that the rats are poor at relearning a conditional motor task. The shoulder region is necessarily damaged when making a medial frontal lesion in the rat; and thus it is premature to suppose that in rodents it is prefrontal cortex that is concerned with the direction of sequential behaviour.

There are two studies in which patients with anterior lesions have been specifically taught to perform motor sequences [16, IS]. Most of the patients in KIMURA’S [ 161 study suffered from strokes or tumours. Some of the patients in the anterior group had a paralysis of the hand or arm, presumably because the lesion extended back into premotor and motor cortex.

460 K. E. PASSINGHAM

The patients of KOLB and MILNER [ 181 had undergone removal of part of frontal cortex, and diagrams are provided of the surgeon’s estimate of the size of the lobectomy. The lesions were often very extensive, and some of them, though not all, probably invade premotor cortex. Medial views are not presented and so it is not possible to assess whether supplementary motor cortex was invaded. Nonetheless there are patients, for example cases Sh.Wi and Ph.Je., who were very bad at copying hand and arm gestures even though the lesions were probably confined to prefrontal cortex.

But it is not clear that their defect is one of sequencing movements per se. DE RENZI p’t ul. [4] asked patients with left-hemisphere lesions to copy single movements and sequences of three unrelated movements. Those patients with left frontal lesions who performed badly were poor not only at copying sequences but also at copying single movements.

JASON [ 131 also tackled the issue in a study of 15 patients with left-sided vascular lesions, of whom 11 suffered from a right-sided hemiplegia. Compared with patients with right-sided lesions these patients were poor at copying from memory sequences of four gestures using the unaffected hand. Yet, as JASON [14] went on to show, these patients were impaired even if they were allowed to reproduce the gestures in any order. The problem was not that they remembered the gestures but were unsure of the order; they were poor at recalling the gestures. It is clearly important that patients with frontal lobectomies (such as those of KOLB and MILNER [lS]) be tested in the same way, so as to establish for certain whether the impairment of patients with anterior lesions is an impairment of sequencing or of recall of individual gestures when presented in a list. KOLB and MILNER [ 181 present an analysis of the errors made on the sequences of facial movements. The patients with frontal lesions made as many errors of omission or intrusion of movements from other sequences as they did order errors.

There is another way of assessing the contribution made by different cortical structures to the performance of a series of movements. ROLANI) et al. 134, 351 have measured cerebral blood flow while subjects perform a sequence of movements of the fingers. They find supplementary motor cortex to be particularly active; the rest of the prcmotor cortex increases its activity during the task but to a lesser degree [3.5]. The only region of prefrontal cortex that increases in activity significantly is a strip ofdorsal and medial frontal cortex. This is an area that was invaded in all the prefrontal lobectomies reported by KOLB and MILNER [lS]; in the present study on monkeys the superior convexity lesion also extended to the midline, though it did not include the medial surface. However, ROLANI) rt ul. [35] are inclined to discount any contribution of the dorsomedial prefrontal cortex on the grounds that this area increases its activity whatever the task a subject is given, so long as it is non- routine. It is as active. for example, when subjects do difficult visual discriminations as when they perform a sequence of finger movements 1331.

Thus on present evidence it is supplementary motor cortex and not prefrontal cortex that is directly involved in the regulation of fixed sequential movements. But that does not, of course, mean that sequential behaviour may not be disturbed by prefrontal lesions. In the study by KOLB and MILNER [ 181 the patients with frontal lobectomies did have difficulty in reproducing a series of different sequences on the basis of their memory of what they had just seen. But there are only a limited number of different gestures of the hand and arm, and even fewer of the face. Thus there was considerable interference between lists of sequences and the task was taxing. There is good evidence that after removal of prefrontal cortex monkeys and patients are poor at performing tasks which make severe demands on working memory [28]. Both have been tested on a task which required them to respond in any order to a series of

SEQUENCING OF MOVEMENT 461

items in an array without responding to any one of them more than once. After removal of

sulcus principalis monkeys tend to return to doors they have previously opened [28] and patients with frontal lesions also tend to make errors by pointing to words or pictures to which they have previously pointed [31]. As the task proceeds the list of items in working memory grows rapidly and the subject must attend carefully.

No such problem is posed if the task is just to learn a simple jixed sequence of three movements as in the present study. The task soon becomes automatic and it can then be performed without fully attending to what is being done. There is no need, as when copying movements, to attend on each trial to a novel cue, since on each occasion the sequence is the same. There is no persuasive evidence from the present study that prefrontal cortex is concerned with the constructing of such new sequences of movement. It is more likely that is

involved in the direction of actions, whether single or in sequences, when the correct action is specified by cues in working memory.

Acknow~ledgements-I am grateful to A. G. M. Canavan for helpful comments on the manuscript. The research was supported by MRC Grant 911/1/397/B.

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