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Apparatus All the experiments were conducted with stimuli presented on a monitor with a touch-sensitive screen controlled by an IBM computer. A 20 × 28 cm Microvitec touch-sensitive monitor was used in experiment 1, tasks 1-3, and in the first preoperative assessment in experiment 2. Touches were registered when hand movements interrupted an infrared beam. A larger 41 × 29 cm Elographics touch-sensitive monitor was used in the second preoperative testing assessment and the postoperative assessment in experiment 2. The Elographics monitor uses a pressure-sensitive mechanism to register screen touches. The animals were tested in a transport cage, 30 cm from the monitor. General procedure In the first experiment six rhesus monkeys were trained preoperatively on visual pattern association (task 1). Lateral area 47/12 on the IC was then removed in three of the animals (Fig. 1), and their postoperative performance was compared with their preoperative performance and with the performance of the three controls retested after a similar interval. The two groups of monkeys were then compared on new learning of color matching to a sample (task 2). Task 2 allowed us to test whether the absence of impairment in task 1 was simply attributable to our use of a visual pattern association paradigm as opposed to the more conventional color-matching design. Finally, their performance was compared on the visual association task with longer delays (task 3).
Volume 17, Number 12, Issue of June 15, 1997 pp. 4829-4838
Copyright ©1997 Society for NeuroscienceVentral Prefrontal Cortex Is Not Essential for Working Memory
Matthew F. S. Rushworth1, Philip D. Nixon1, Madeline J. Eacott2, and Richard E. Passingham1 1 Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, United Kingdom, and 2 Department of Psychology, University of Durham Durham, DH1 3LE, United Kingdom
ABSTRACT
It is widely held that the prefrontal cortex is important for working memory. It has been suggested that the inferior convexity (IC) may play a special role in working memory for form and color (Wilson et al., 1993
Key words: prefrontal cortex; working memory; inferior convexity; area 12; area 47; object vision; positron emission tomography). We have therefore assessed the ability of monkeys with IC lesions to perform visual pattern association tasks and color-matching tasks, both with and without delay. In experiment 1, six monkeys were trained on a visual association task with delays of up to 2 sec. Conservative IC lesions that removed lateral area 47/12 in three animals had no effect on the task. Further experiments showed that these lesions had no effect on the postoperative new learning of a color-matching task with delays of up to 2 sec or versions of the visual association task involving delays of up to 8 sec. In experiment 2, larger lesions of both areas 47/12 and 45A were made in the three control animals. This lesion caused a profound deficit in the ability to relearn simultaneous color matching, but subsequent matching with delays of up to 8 sec was clearly unimpaired. We suggest that the IC may be more important for stimulus selection and attention as opposed to working memory.
INTRODUCTION
It is widely held that the prefrontal cortex is involved in working memory (Goldman-Rakic, 1987
It has recently been proposed that there is a parallel organization such that dorsal and ventral parts of the prefrontal cortex are concerned with working memory for spatial and object or form information, respectively. This proposal is based on the delay-dependent selectivities of single units in the sulcus principalis and the inferior convexity (IC), respectively, in DR tasks (Wilson et al., 1993
The fact that single units in monkeys or populations of cells in imaging studies are more active during delays need not imply that the basic function of the area is to bridge those delays. An analogy can be made with the dorsal premotor cortex, in which both single-unit studies and imaging studies have demonstrated activity related to delays that precede movement execution (Wise and Mauritz, 1985
The results are different for the sulcus principalis (area 46). It is clear that it plays some role in spatial working memory. Lesions disrupt spatial DR and DA (Mishkin, 1957
Passingham (1993)
The present study examines the effect of IC lesions on visual pattern association and color-matching tasks. In each case stimuli were not trial unique. Postoperatively, we first tested the animals' relearning of nondelay versions of the task and assessed performance with delays only after they had reached criterion without delay. The lesions in the first experiment were conservative and focused on the anterior part of the IC, the lateral part of area 47/12 (Petrides and Pandya, 1994
Fig. 1. Lateral and ventral views of the intended lesions in the two experiments. The center diagrams show the parcellation of prefrontal anatomical areas in the macaque monkey proposed by Petrides and Pandya (1994)
[View Larger Version of this Image (33K GIF file)]
MATERIALS AND METHODS
Subjects Six rhesus macaques (Macaca mulatta) were used, aged between 2 and 4 years and weighing between 3 and 4 kg. The guidelines in Principles of Laboratory Care (National Institutes of Health publication 86-23, revised 1985) were followed. The studies were carried out under project and personal licenses from the British Home Office.Experiment 1 Task 1: visual pattern association task. The animals initially learned a simultaneous version of the task. Each trial began with the presentation of one of two cues in the center of the monitor. The cues were either blue or yellow rectangles 5 cm across and 7 cm in height. Touching the cue triggered the presentation of two response shapes on either side of the cue, all of which remained on the screen until the monkey responded. Only two response shapes were used, and both consisted of distinct black and white line patterns the same sizes as the cue shapes. One response pattern consisted of a black cross, consisting of vertical and horizontal bars, inside a white circle. The other response pattern consisted of a white-outlined, black-filled ellipse superimposed on a white, vertical bar. There was a distance of 4.5 cm between the edge of the cue shape and response shape. The correct response was determined by the color of the cue. Correct responses were rewarded with delivery of Noyes pellets or peanuts. The intertrial interval was 4 sec, unless the animal made an error, in which case it was increased to 7 sec as punishment. Touching the screen between trials was punished by doubling the intertrial interval. A rerun correction procedure was used such that the same cue was presented until the correct response was made. Response shapes were presented randomly on either side of the cue shape. Each monkey performed 100 rewarded trials every day. The monkeys were trained to a criterion of 90% correct responses for 2 consecutive days. The error score of each animal corresponded to the total error score including errors made on correction trials.
The three control animals were then used in the second experiment. Their performance on color matching to a sample was assessed on two occasions 3 weeks apart. Larger lesions of the IC, including all of areas 47/12 and 45A (Fig. 1), were then made, and the animals were retested postoperatively 3 weeks later.
Subsequently the animals were trained to perform the task with a 0 sec delay. The procedure was identical to the simultaneous presentation task, except that the cue shape did not remain on the screen while the response shapes were present. Pressing the cue shape caused it to disappear and the response shapes to reappear as before. The animals were trained to perform to a 90% correct criterion over 2 consecutive days of testing. The number of trials to reach the criterion on the simultaneous version of the task varied between ~2000 and >10,000.
The animals then learned versions of the task involving 1 and 2 sec delays between cue offset and response shape onset. The rerun correction procedure was always used. The delayed visual association task proved very difficult for some of the animals to learn; it required between just >400 trials to >12,000 trials. The animals were therefore trained to a lower criterion of 4 d at 80% correct performance on the 1 and 2 sec delay conditions.
Before surgery the animals were then retested at 0 and 2 sec delays to criteria of 80% correct performance over 4 d. Area 47/12 was then removed bilaterally in three of the animals, whereas the other three animals, matched for performance, remained as controls. Three weeks after surgery the animals were retested on simultaneous and 0 and 2 sec delay versions of the task. The same criteria were always used (simultaneous, 2 d at 90%; 0 sec, 4 d at 80%; 2 sec, 4 d at 80%).
Task 2: color matching. All the animals were then taught to perform matching to a sample with color stimuli. The cue stimuli used were of two different colors not used in task 1, red and blue. The stimuli were the same sizes as those in task 1. In this task the response shapes were also red and blue bars of the same sizes and shapes as the stimulus shapes. The procedure followed the same format as task 1. A cue shape was presented on the center of the screen until touched. Subsequently, response shapes were presented on either side of the cue shape until the monkey responded. The response shapes were each of the two color bars. The correct response was to press the response shape identical in color to the cue shape. The stimuli were the same sizes and shapes as in task 1. The animals were first taught to perform simultaneous matching to a sample (SMS) and then subsequently proceeded to 0 and 2 sec delayed match (DMS) versions. In the DMS versions the cue shape was extinguished as soon as it was touched and before the response shapes were presented. A criterion of 80% correct performance was used for the simultaneous version and 0 and 2 sec delays. As before, the error score of an animal corresponded to the total error score including errors made on correction trials. Experiment 2: color matching The three animals that had served as controls took part in the second experiment. Preoperatively the animals were trained to perform color matching with delays of up to 8 sec. The colors were the same as those used in experiment 1, task 2. The stimulus size was the same as that used in experiment 1, task 3. Animals were trained to a 90% criterion (2 d) for SMS and then to an 80% criterion (4 d) in a 0 sec delay condition and a 2 sec DMS. The error score of each animal corresponded to the total error score including errors made on correction trials. This was followed by performance tests of 4 d at each delay period of 4, 6, and 8 sec. Finally there was another identical preoperative retention test after 3-4 weeks. Areas 47/12 and 45A were then removed bilaterally in all three animals. After a recovery period of 3-4 weeks the animals were retested again in an identical fashion. Surgery and histology. All surgery was carried out under sterile conditions with sodium pentobarbitone anesthesia and with the aid of a binocular operating microscope. Tissue was retracted in anatomical layers, and a bone flap was removed. The lesions were made by aspiration with a fine gauge sucker. The wound was closed in anatomical layers. At least 3 weeks were allowed for recovery before testing resumed.
Task 3: visual pattern association task with long delays. Finally all the animals relearned the visual association task with longer delays of up to 8 sec. Animals were retrained to the same criteria on simultaneous and 0 and 2 sec delay versions of the task (simultaneous, 2 d at 90%; 0 sec, 4 d at 80%; 2 sec, 4 d at 80%). Again error scores corresponded to the total error scores including errors made on correction trials. A performance test was then carried out at 4, 6, and 8 sec delays. Performance was tested by giving each animal 4 d of testing at each delay period. The animals then proceeded to the next stage of testing regardless of the level of their performance. The stimuli used in this experiment were slightly smaller than previously; the cue and response shapes were 2.5 × 3.4 cm and, consequently, farther apart (8 cm edge to edge).
When the animals had completed their testing they were anesthetized with sodium pentobarbitone and perfused with 90% saline and 10% formalin. The head was placed in a stereotaxic apparatus, and a vertical cut was made caudal to the lunate sulcus. The brains were then removed, photographed, and placed in 10% sucrose formalin until they sank. The brain was then cut at the position of the anterior commissure and cut in 50 µm coronal sections. Every fifth section was stained with cresyl violet for analysis.
Experiment 1: removal of area 47/12. As explained in the introductory remarks, the lesions in the first experiment were deliberately conservative. The intention was to include area 47/12l (Petrides and Pandya, 1994
Figure 2 shows the lesions for experiment 1. In all cases the lesions removed the lateral part of the convexity, area 47/12l. In every case there was incomplete damage to the orbital part of area 47/12, because the lesions did not extend as far as the lateral orbital sulcus (47/12o, Petrides and Pandya, 1994 
Fig. 2. Coronal cross-sections through the prefrontal cortex in animals PREF1, PREF2, and PREF3 in experiment 1. The most posterior section (top) is taken approximately 1-2 mm in front of the posterior tip of sulcus principalis (Sp). The lesion (indicated by the thick dark line joining areas of intact cortex) did not extend as far back as this section in any of the animals. The next section (second from top) is taken rostral to the last section to show the inferior ramus of the arcuate sulcus (Ai). The lesion can be seen in each animal at this level, but it is limited in extent. Its ventral limit is far from the lateral orbital sulcus (LO). The third and fourth sections from top are taken at distances one-third and two-thirds between the second section and the most anterior section (bottom) taken where the lateral ramus of the bifurcated medial orbital sulcus (MO) approaches the lateral surface. The superior ramus of the arcuate sulcus (As) is also shown. Scale bar, 1 cm.
[View Larger Version of this Image (60K GIF file)]
Experiment 2: removal of areas 47/12 and 45A. The lesions were similar in the second experiment, but the intention was to include area 45A as well as area 47/12l (Petrides and Pandya, 1994
Figure 3 shows the lesions for experiment 2. The most posterior section for each animal (Fig. 3, top row) shows that the lesion extended more posteriorly in experiment 2 than it had in experiment 1 (for comparison, see the most posterior sections in Fig. 2, top row). In each case the lesion extended to the posterior end of the sulcus principalis. The second section for each animal was taken from approximately the level of the anterior tip of the inferior arcuate sulcus and shows large lesions in the lateral IC and the ventral surface as far as the lateral orbital sulcus (for comparison, see the second sections in Fig. 2). More anteriorly, in animals PREF4 and PREF5, the lesion extends as far as the lateral branch of the medial orbital sulcus. The lesion in PREF6 was smaller than in the other two animals, not quite reaching the lateral bank of the lateral orbital sulcus on the right. In PREF4 and PREF5 there was slight damage to the tissue just dorsal to the sulcus principalis at the back. 
Fig. 3. Coronal cross-sections through the prefrontal cortex in animals PREF4, PREF5, and PREF6 in experiment 2. The five sections are taken at approximately the same or slightly more posterior levels as those shown in Fig. 2. The most posterior section (top) is taken approximately 1 mm in front of the posterior tip of sulcus principalis (Sp) (there is some slight skew from the coronal plane in PREF4 and PREF5). The lesion is already present in this section in each case (compare Fig. 2, top, where there is no damage at this level). The next section (second from top) was taken at a level to include the anterior tip of the inferior arcuate sulcus (Ai) in at least one hemisphere. The lesion is extensive at this point and already extends toward the lateral orbital sulcus (LO) on the ventral surface (compare Fig. 2, second from top, where the lesion even in a slightly more anterior section is limited to part of the lateral surface). Sections third and fourth from top are taken at a one-third and two-thirds of the distance between the second section and the most anterior section taken at the point where the lateral ramus of the medial orbital sulcus (MO) approaches the lateral surface. The superior ramus of the arcuate sulcus (As) is also shown. Scale bar, 1 cm (same scale as in Fig. 2).
[View Larger Version of this Image (60K GIF file)]
Statistical comparisons Performance was assessed in two ways. Comparisons between groups were made using the nonparametric Mann-Whitney test. Where there were preoperative data, the preoperative and postoperative scores were listed and compared using a matched sample t test.
RESULTS
Experiment 1
Task 1: visual pattern association task The animals that underwent surgery were not impaired on the simultaneous task or the delayed tasks at 0 or 2 sec. Figure 4 shows the total error scores (including errors made on correction trials). Nonparametric group comparisons showed that, postoperatively, there was no significant difference between the performance of the two groups on simultaneous (U = 3.5; p = 0.6579), 0 sec delay (U = 3.0; p = 0.5127), or 2 sec delay (U = 3.0; p = 0.5127) versions. When the comparisons were made between the preoperative and postoperative scores of each individual animal, it was apparent that in all cases the animals improved after the lesion. The improvement was significant for PREF1 and PREF3 at the 0 sec delay (t = 4.80; df = 3; p = 0.017; and t = 10.23; df = 3; p = 0.002, respectively) but not at the 2 sec delay (t = 1.04; df = 6; p = 0.338; and t = 1.54; df = 6; p = 0.174, respectively). For PREF2 the improvement was not significant for delays of either 0 sec (t = 0.74; df = 3; p = 0.513) or 2 sec (t = 1.87; df = 7; p = 0.103).
Fig. 4. Visual associative task (experiment 1, task 1). The left side shows the total errors (including correction errors) each animal made in relearning to perform the visual association task with 0 and 2 sec delays. A histogram bar is shown for the control group (always on the left) and the experimental group (always on the right) for each delay time. The right side shows the error scores for relearning the task with simultaneous presentation of the sample and match choices and with 0 and 2 sec delays. Hatching indicates postoperative performance of the experimental group after the ventral prefrontal cortex has been removed from area 47/12. Bar heights indicate group mean performance;and
, performance of individual animals in the control and experimental groups, respectively.
[View Larger Version of this Image (25K GIF file)]
Task 2: color matching There was no evidence of any impairment on the color SMS or DMS in the animals that underwent surgery when their performance was compared with that of the control group. Figure 5 shows the total error scores (including errors made on correction trials). Group comparisons showed that there was no significant difference in performance in simultaneous (U = 3.0; p = 0.5127), 0 sec delay (U = 3.0; p = 0.5127), and 2 sec delay (U = 3.0; p = 0.5127) versions of the task.
Fig. 5. Color match (experiment 1, task 2). Shown is the total number of errors (including correction errors) made in the new, postoperative learning of the color matching task with simultaneous sample and match presentation and with delays of 0 and 2 sec. Hatching indicates the performance of the experimental group with a lesion in area 47/12. Bar heights indicate group mean performance;
[View Larger Version of this Image (26K GIF file)]
Task 3: visual association task There was no evidence of any impairment in the performance of the animals that underwent surgery at even the longest delays when they were compared with the control group. Figure 6 shows the total number of errors (including errors made on correction trials) made in the first 4 d of testing for each of the delay periods. Group comparisons showed that there was no significant difference in performance at the 0 sec delay (U = 4.0; p = 0.8273), 2 sec delay (U = 1.0; p = 0.1266), 4 sec delay (U = 2.0; p = 0.2752), 6 sec delay (U = 3.0; p = 0.5127), or 8 sec delay (U = 2.0; p = 0.2752).
Fig. 6. Visual association task (experiment 1, task 3). Shown is the total number of errors (including correction errors) made by each animal during the first 400 rewarded trials of the visual association task at each delay period (0, 2, 4, 6, and 8 sec). Hatching denotes the experimental group with removal of area 47/12. Bar heights indicate group mean performance;
[View Larger Version of this Image (40K GIF file)]
It should be noted that the additional removal of area 11 in one animal, PREF3, did not have any detrimental effect on performance; PREF3 made fewer errors at every stage of all the tasks than either of the other two animals in the experimental group. Experiment 2
Figure 7 shows each monkey's color SMS performance before and after surgery. In Figure 7 the total postoperative scores (including errors made on correction trials) are compared with the first preoperative scores. The second preoperative test scores are not shown, because there was a breakdown in the first touch screen and the animals had to adapt to using a second touch screen. The performance of the animals was disrupted while they learned how to ensure that their responses were registered. By the time they had performed the preoperative retention tests at 0 and 2 sec immediately before surgery, all animals had adapted to the new monitor.
Fig. 7. Color matching task (experiment 2). The column on the left indicates the total number of errors (including correction errors) during relearning of simultaneous color matching on the first preoperative retest. The hatched column on the right indicates the relearning scores after removal of ventral prefrontal cortex areas 47/12 and 45A. Bar heights indicate the group mean performance;
[View Larger Version of this Image (28K GIF file)]
Postoperatively, all the animals made more errors during relearning of color SMS than they had made during the first preoperative test. The impairment was significant in each case, as assessed by a matched-sample t test (PREF4: df = 1; t = 93; p < 0.004; PREF5: df = 2; t = 3.30; p < 0.041; PREF6: df = 4; t = 2.31; p < 0.041).
Figure 8 shows the total number of errors (including errors in correction trials) made in obtaining the 400 rewards at each of the delay intervals. The data are shown for both preoperative tests, because preoperatively the animals had adapted to the second touch screen by the time they were given the second preoperative test. 
Fig. 8. Color matching with delays (experiment 2). Shown is the total number of errors (including correction errors) made during the first 400 rewarded trials at each delay (0, 2, 4, 6, and 8 sec) during the two preoperative tests and the postoperative test (hatched bar). Bar heights indicate group mean performance;
[View Larger Version of this Image (47K GIF file)]
The effect of the lesion was assessed by comparing the number of errors made in relearning the task with the criterion at 0 and 2 sec delays and the number of errors made during the attainment of 400 rewards (4 d of testing) on the performance testing at 0, 2, 4, 6, and 8 sec delays. Postoperatively all the animals made more errors in relearning the task on 0 sec delay trials than they had during the second preoperative test. However, the impairment was only significant in PREF5, as assessed by a matched sample t test (df = 3; t = 4.91; p = 0.08). It was not significant for either of the other animals (PREF4: df = 3; t = 1.03; p = 0.191; PREF6: df = 3; t = 0.36; p = 0.37), and as a group they performed similarly to the animals on the second occasion. All animals relearned the task in the minimum period of 4 d of testing as they had done before surgery.
There was no evidence of a delay-dependent deficit, because postoperative performance did not decline at longer delays (2, 4, 6, and 8 sec). Postoperative group performance at the longer delays was always within the range of both the first and second preoperative test group performances. Although PREF5 always performed worse than on either preoperative test, PREF4 and PREF6 sometimes performed better and sometimes worse than before surgery.
DISCUSSION
The anatomy of the inferior convexity
We did not observe any delay-dependent defects after IC lesions. On the contrary, in the second experiment, SMS was profoundly impaired, but the imposition of delays, after initial relearning, caused no more difficulty than preoperatively (Figs. 7, 8).
It might be argued that the lesion was not selective enough to affect just DMS but leaving SMS intact. If the lesions were made any smaller, however, as in the first experiment, not only was there no deficit on any of the simultaneous presentation tasks, but there was no deficit on any of the delay trials either (Figs. 4, 5, 6).
The small prefrontal lesions were made in the first experiment because we were concerned that previous reports of nondelay impairments (Iversen and Mishkin, 1970 The inferior convexity and working memory
According to Goldman-Rakic (1987
Our results suggest that previously reported deficits on DMS after IC lesions may actually reflect a problem in relearning the matching task, and that the delay may not have been crucial. Passingham (1975)
The results are consistent with previous reports of IC lesions causing impairments on nondelay tasks. Passingham (1975)
Kowalska et al. (1991)
Furthermore, it should be noted that the impairments caused by IC lesions are not restricted to tasks with color or form stimuli. Spatial delayed response is also disrupted by IC lesions (Iversen and Mishkin, 1970 Human ventral prefrontal cortex and working memory
Parts of the human ventrolateral and dorsolateral prefrontal cortices (VLPFC and DLPFC, respectively) are homologous to the macaque IC and DLPFC (Petrides and Pandya, 1994
Fig. 9. Peak regional cerebral blood flow changes in the human prefrontal cortex during matching tasks. Summarized are positron emission tomography studies in which the Tailarach and Tournoux (1988) coordinate system has been used. Peaks from both hemispheres are plotted onto the same figures. A, There are clear foci of activation in the VLPFC during form and face DMS and other working memory tasks (). Other foci, however, clearly fall into the DLPFC (
). 1, From Petrides et al. (1993)
[View Larger Version of this Image (17K GIF file)]
There is evidence that a part of DLPFC is also important for nonspatial working memory tasks (Petrides et al., 1993
The human VLPFC also resembles the monkey IC in that its role is not restricted to form, face, and color tasks; it is also concerned with spatial matching tasks whether they involve delays (Jonides et al., 1993 Conclusion
In summary, the results suggest that the DLPFC and the IC are not parallel working memory mechanisms, with the DLPFC operating on spatial input and the IC operating on visual inputs (Goldman-Rakic, 1987
FOOTNOTES
Received Oct. 18, 1996; revised March 18, 1997; accepted March 27, 1997.
This work was supported by a Wellcome program grant. We thank M. Brown and D. French for technical assistance and C. Healey Yorke for histological processing.
Correspondence should be addressed to Matthew Rushworth, Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford OX1 3UD, UK.
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