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Localization of function within the dorsolateral prefrontal cortex of the rhesus monkey
EXPERIMENTAL
27,
NEUROLOGY
Localization Prefrontal
of
PATRICIA
291-304 (1970)
Function Within the Cortex of the Rhesus
S. GOLDMAN
Dorsolateral Monkey
AND H. ENCER ROSVOLD
Laboratory of Psychology, Natiortal Institute of hlmtnl Health, Bethesda, Marylaud 20314 Received
Jamtary
5, 19%
Although lateral prefrontal lesions in the monkey are known to produce impairments on spatial delayed response and spatial delayed alternation, there is some question as to whether the delay, the spatial features, or a combination of the two is the critical factor in these tests giving rise to the impairments. Accordingly, the effects of several different lateral frontal lesions were compared on two spatial tasks, one which did involve intratrial delays (delayed alternation) and one which did not (a conditional position response test). The findings indicated the existence of two functionally distinct subdivisions of the dorsolateral prefrontal cortex : one in the principal sulcus, damage to which was responsible for impaired performance on the spatial task with delay; and the other in the arcuate sulcus, removal of which was responsible for impaired performance on the spatial task without delay. These findings together with those of other investigators suggest that the cortex in the principal sulcus may be concerned with a form of spatial memory, whereas the arcuate cortex is concerned with some other, as yet unspecified function. Introduction
The area of the monkey’s lateral prefrontal cortex which extends from the midline to the lower lip of the principal s~~lcus and from the frontal pole to the arcuate sulc~~s appears to be concerned with performance on spatial tasks (6, 8). Monkeys with dorsolateral lesions of this type achieve high levels of performance on nonspatial object alternation (S), yet fail to exceed chance on spatial alternation and spatial delayed response (3). It appears, further, that within this region the principle s~~lcus is the anatomical focus for these effects since removal of the cortex in this sulcus produces a greater impairment on the spatial delayed-response tasks than that which follows partial lesions of the surrounding dorsolateral cortex (2,4. 7). Given the selective effect of dorsolateral lesionson spatial tests, the question is still unsettled as to whether the delay that is interposed in these tests between the directional cues and the directional responsesalso contributes to the impairment. Recently, for example, Stamm (lo) found that 291
292
GOLDMAN
AND
ROSVOLD
electrical stimulation of the cortex in the principal sulcus produced a marked impairment in delayed-response performance only when it was applied during the first few seconds of the delay interval. This finding seems to indicate that the delay in the spatial tasks is a source of the impairment after removal of the cortex in the principal sulcus. On the other hand, the importance of the intratrial delay is brought into question by the recent report of Lawicka, Mishkin, and Rosvold (6) that monkeys with dorsolateral removals were impaired on a conditional position response test, a spatial task without intratrial delays. One way of resolving the conflicting evidence with respect to the importance of the delay is to suppose that the spatial delayed-response task measures a memory function which has its anatomical focus in the principal sulcus, while the conditional position response task measures some other function with a different cortical representation within the dorsolateral region. The purpose of the present expriment was to explore this possibility by comparing the effects of lesions in the principal sulcus with lesions in several other subdivisions of the dorsolateral cortex on the conditional position response task and on one of the delay problems. Method
The subjects were 16 naive monkeys (Macaca ndatta) ranging in weight from 3.0-5.0 kg. All were trained on the conditional position responsetest before operation and on the basis of their learning scores were divided into four matched groups for surgery, Postoperatively, they were retested on the conditional position response test and then given training on a visual pattern discrimination and spatial delayed alternation in that order. The conditional position response test was administered in a Wisconsin General Test Apparatus (Fig. 1), containing a test tray with two recessed foodwells, located 39 cm apart. Each foodwell was covered with a wooden lid attached to the test tray by a spring hinge at the back of each well. Food pellets could be delivered into the covered wells through delivery tubes which extended from each side of the apparatus to the foodwell on that side. The apparatus was equipped with two Quam speakers (size : 2 inch; impedance: 3.2 ohms), one centered directly above and the other directly below the animal’s compartment. A Grass S-4 stimulator was used to generate a train of clicks by passing a 6-v, I-msec duration pulse at a frequency of 50/set through the identical speakers. The experimenter could activate either of the two speakersby operating switches located at the front of the apparatus. The visual discrimination and delayed-alternation tests were administered in the same apparatus except that for these tests the foodwells were covered by 3-inch square displaceable matboard plaques.
PREFRONTAL
293
CORTEX
/ > FIG. 1. Diagrammatic
representation
of the conditional
position
response
apparatus.
Conditional Position ResponseTest. A method of successiveapproximation was used to train the monkey to approach and lift open the lid which covered the foodwell at the sound made by the delivery of a food pellet. This preliminary training was terminated when the monkey performed promptly and without error in a 20-trial session in which pellets were delivered randomly to the left and right foodwells. In this and all subsequent phases of the test, the screen which separates the animal’s compartment from the testing compartment was in the raised position throughout the test session.Trials were separated by at least a 30-set interval. If intertrial responsesoccurred, the next trial was delayed at least 10 set after the last intertrial response. Intertrial responseswere kept at a low level or virtually eliminated by this procedure. After completion of this phase of training, which required from 2-7 days, directional auditory cues were introduced. The cue delivered through the speaker above the animal’s cage signaled reward on the left; the cue from the speaker below the cage signaled reward on the right. These directional cues were presented according to a quasi-random schedule. On the first day that the auditory cues were introduced, a reward was delivered to the appropriate foodwell 2 set after stimulus onset, and then on successivedays 3, 4, 5, 10, 15, and finally on the seventh and subsequentdays 20 set after stimulus onset, unless the animal responded earlier. In this early stage, the monkeys would typically
294
GOLDMAN
AND
ROSVOLD
wait for the pellet to be dropped before responding but within an average of 7 days all were responding promptly to the auditory cues alone. If the animal responded to the correct foodwell, a reward was delivered immediately and the stimulus was turned off as soon as the animal obtained the pellet. If, however, the animal responded to the incorrect foodwell, the stimulus was turned off and the trial repeated at the usual intervals until the animal corrected its response or committed a maximum of three “extra” errors. If the animal failed to correct its response within this limit, a forced correction trial was given in which the stimulus was repeated for a fifth time and the reward was delivered within 1-2 sec. Daily sessions consisted of 20 trials, not including the correction trials. Training continued until the animal performed 90 correct responses in 100 consecutive trials. Correction trials were not included in the animal’s “trials to criterion” score, but the number of extra errors made on such trials were added to errors on regular trials to give a total “errors to criterion” measure. After meeting criterion, the monkey was rested for 10 days, tested for retention to the same criterion as before, and then operated upon. After a lo-day postoperative recovery period, the animal was retested on the conditional position response test until he regained the preoperative criterion. Next he was trained on visual discrimination and then on delayed alternation, each to the criterion of 90 correct responses in 100 consecutive trials or for a maximum of 1000 trials. Vismzl DiscriPninution. A simultaneous pattern discrimination was presented for 30 trials a day by the noncorrection method. The stimuli, a plus sign and an outline square, were white paper cut-outs pasted on gray matboard plaques. Spatial Delayed Alternation. The rerun correction procedure was used to train the monkeys to displace identical gray plaques alternately from the left and right foodwells. Trials were separated by a 5-set interval. Each session began with a free trial in which both wells were baited. On subsequent trials the well not chosen on the preceding trial was baited. The animals were given 30 trials a day including correction trials. Surgery. Bilaterally symmertical lesions were made in one stage using aseptic technique and Nembutal anesthesia (40 mg/kg) . Cortical tissue was aspirated with a small-gauge sucker and hemostasis was achieved using electrocautery and cottonoid patties. The wounds were closed in anatomical layers with silk sutures. The cortex in the banks and depths of the principal sulcus was removed in four monkeys (group P) ; the remaining 12 monkeys received lesions of the cortex in the banks and depths of the arcuate sulcus (group A, n = 4) ; the dorsolateral surface excluding the cortex in the principal sulcus (group NP, n = 4) and ; the premotor area (group PM, n = 4). The NP lesion
PREFRONTAL
CORTEX
295
included all the cortex dorsal to the principal sulcus from the pole to the arcuate sulcus, including the cortex in the anterior bank of the superior branch and the upper third of the inferior ramus of that sulcus. The premotor lesion (PM) included all the cortex in the posterior bank of the arculate sulcus as well as that dorsal to the superior branch and ventral to the inferior branch of that sulcus. P, representative lesion from each group is illustrated in Fig. 2. Histology. After completion of testing, each animal was administered an overdose of Nembutal and perfused through the heart with normal saline and 10% buffered formalin. The brain was removed and photographed, embedded in celloidin, and sectioned at 25 p in the frontal plane. Every twentieth section was stained with thionine and these were used to reconstruct the lesions and to determine the locus and extent of retrograde degeneration in the thalamus. Drawings illustrating the histological findings are presented in Figs. 2 and 3. Histological
Findings
Cortical Damage in Groztp P. The removal of cortex in the principal sulcus was complete in P-l and P-4 and almost complete in P-2 and P-3. Approximately 1.5 mm and 2.0 mm of cortex in the anterior tip of the sulcus was spared in the right hemispheres of P-2 and P-3 respectively. The only notable unintended damage was sustained by P-3 and this involved a strip of cortex approximately 2.5 mm in length below the ventral lip of the principalis at the frontal pole in the left hemisphere. Co&al Damage in Gvotlfi A. The removal of cortex in the arcuate sulcus was essentially complete in A-l, A-2, and A-4. In A-l and A-2 there was slight damage to underlying white matter but neither in these cases nor in any of the other brains was there any damage to the caudate nucleus. In A-3, approximately 2 mm of cortex in the posterior “spur” which forms at the junction of the inferior and superior limbs of the arcuate sulcus was spared in the right hemisphere. Cortical Damage in Gro@ NP. The removals of three of the four NP subjects conformed reasonably well to the intended lesions. The fourth, NP-1, had an anomalous arcuate configuration in its left hemisphere: the superior ramus of this sulcus could not be located either at surgery or on histological examination. The lesion of NP-1 also differed from those of the other three NP monkeys in that the cortex in the anterior bank of the inferior limb of the arcuate was spared bilaterally. In this same animal and in one other (NP-2)) a small amount of cortex in the anterior bank of the superior limb of the arcuate was also spared unilaterally. The only other notable sparing was that of the tortes on the frontal pole of NP-4. The extent of unintended damage in this group was slight. Three of the four
296
GOLDMAN
AND
ROSVOLD
monkeys (NP-1, NP-2, and NP-3) had damage to the posterior bank of the superior limb of the arcuate at the anterior tip of this limb. This damage was present in both hemispheres of all three animals.
FIG. 2. Lateral and dorsal reconstruction of the lesions of a representative monkey from each group. Also shown are selected cross sections through these lesions. The cortical damage is shown in solid black. P, principalis; A, arcuate; NP, nonprincipalis; and PM, premotor.
PREFRONTAL
+8.5 FIG.3.
CORTEX
t7.0
Retrograde degeneration in n. medialis of the thalamus in representative animals, one stereotaxic levels. Moderate to heavy degeneration
t
5.5
dorsalis and n. ventralis from each group, at the is shown in solid black.
lateralis indicated
Covti~~~l Damage in GYOH~ PM. Three of the four removals in this group deviated from the planned lesion chiefly because they involved unintended damage to the anterior bank of the arcuate. This damage was severe in PM-3 (in the right hemisphere), moderate in PM-l (left hemisphere), and slight in PM-4 (left hemisphere). Some cortex in the posterior bank of the inferior limb of the arcuate was spared unilaterally in PM-l. PM-Z, and PM-3, and bilaterally in PM-4. The only other notable sparing was that of the posterior “spur” in the right hemisphere of PM-l. There was no apparent correlation between the extent or locus of damage and behavioral performance within any of the four groups.
298
GOLDMAN
AND
ROSVOLD
Tkalamic Degeneration. The retrograde degeneration was most marked in medialis dorsalis 1 and n. ventralis lateralis. In accord with the findings of Akert (l), the degeneration in medialis dorsalis was confined to its lateral divisions and in ventralis lateralis to area X. Moderate to heavy degeneration occurred in the parvocellular division of medialis dorsalis after removal of the cortex in the principal sulcusand in the multiformis division after the arcuate and premotor removals. Degeneration was present in both of these sections of the nucleus after the nonprincipalis lesion. The degeneration found in area X was most marked in the brains of monkeys given either arcuate or premotor lesions. A thin strip of degeneration in area X was present in the brains of the nonprincipalis group perhaps due to the damage to the depths of the arcuate sulcus; no evidence of degeneration in this area could be detected in the brains of monkeys with principal sulcus lesions. After the more posterior lesions (arcuate and premotor) there was moderate gliosis present in the internal capsule, the anterior part of n. reticularis, the lateral part of n. ventralis anterior, and parts of the intralaminar nuclei, n. paracentralis and n. centralis lateralis. Whether there was actual cell loss in these nuclei was questionable. Similar but less marked changes were noted in the nonprincipalis brains and were not apparent at all in the brains of monkeys with principalis removal alone. Results
Table 1 contains each animal’s trials and errors to criterion on the three tests. Conditional Position Response. As may be seen from the table, on the preoperative retention measures there were no differences among the four groups ; on the postoperative retention measures, however, the groups differed markedly. To analyze these effects further, a difference score, the difference between preoperative and postoperative performance, was calculated for each animal (Table 1, column 4). There was no overlap between group P and group A on the trials to criterion scores. Group P performed as well postoperatively as preoperatively ; by contrast, group A required
340-580
more
trials
to reach criterion
after
surgery
than
before.
The difference scores of the NP and PM groups, which did not differ from one another, fell in between and did not overlap with those of the other two groups. The trend of the results was the same for errors to criterion. Again the scores of group P did not overlap with those of group A. Also, the scores of group NP and group PM did not differ from one another and fell in between those of group P and group A. However, on this measure group PM did not differ on a statistical basis from either group A or group P 1 Designations
of
thalamic nuclei follow Olszewski
(9).
a The CPR For retention,
-
Preop.
0 4 0 0
0 0 9 0
0 0 0 0
0 12 0 0
E
position
21 172 58 43
67 3.5 55 40
171 294 174 134
10 71 0 0
E
60 320 260 120
340 20 120 100
420 580 340 400
40 40 0 0
T
Diff.
\‘ISUAL
1
10 59 0 0
E
21 168 58 43
67 3.5 46 41
171 294 174 134
score
DISCRIMINATION,
660 470 740 740
560 260 568 1000
840 890 780 1000
1000 1000 1000 1000
Delayed
161 130 201 211
121 100 150 406
223 235 204 422
391 515 478 490
E
ALTERNATION
180 100 120 240
120 110 2.10 250
210 80 210 120
so 300 200 160
T
Visual discrimination
74 32 57 124
37 52 99 121
73 45 93 61
26 134 97 74
E
cues early in training (see test). m the retention measures.
90 91 91 90
92 91 92 60
90 91 92 71
64 54 63 62
Last 100 trials y0 correct
alternation
AND DELAYED
on which the monkey failed to respond to the auditory were considered “errors of omission” and are retlected
60 340 260 120
340 20 140 100
420 580 340 400
____-
postop. __~
41) 140 0 0
T
RESPONSE,
Retention
response
POSITION
learning scores do not include trials however, such failures to respond
0 20 0 0
225 419 249 287
294 900 618 457
PM-1 PM-2 PM-3 PM-4
0 0 20 0
93 1.51 274 243
NP-1 NP-2 NP-3 IN P-4
225 368 691 706
295 561 241 535
A-l A-2 A-3 A-4
0 100 0 0
0 0 0 0
107 99 395 503
204 341 510 1431
T
-___-~
___-
Conditional
ON CONDITIONAL
93 257 210 222
E”
T
-. P-l P-2 P-3 P-4
Learning -__~-__-
PEHFORMANCE
TABLE
300
GOLDMAN
AND
ROSVOLD
and group NP did not differ significantly from group P. These comparisons which had been significant in the case of the trials to criterion measure did not reach statistical significance in the case of the errors to criterion measure because of the performance of PM-Z and P-2. Since both monkeys made error scores more than 1.45 standard deviations from the mean of its respective group, and because the lesions of both were comparable to those of the other monkeys in these groups, it seems reasonable to conclude that their deviant error scores were due to extraneous factors. Visuul P’attern Discrimination. As may be seen in Table I, there were no differences either in trials or errors to criterion among the four groups. This finding serves to emphasize that the deficits reported here are task specific. Delayed Alternation. Whereas on the conditional position response task the performance of group A was markedly impaired and that of group P was unimpaired, on delayed alternation the performance of the two groups was reversed: all of the monkeys in group P failed to learn the task and performed at or near chance levels throughout the 1000 trials; in contrast, three of the four group A monkeys learned delayed alternation and the fourth achieved 71% correct responses in the last 100 trials. As on the conditional position response task, the NP and PM groups did not differ from one another. The scores of all but one of the monkeys in these two groups fell well within the range of scores obtained by unoperated monkeys tested in this laboratory (12). The failure of this one monkey (NP-4) to learn the task could not be accounted for by any obvious difference between his lesion and that of the other animals in the NP group. It is of interest to note, therefore, that this animal was slow to learn the conditional position response task preoperatively and it is possible that his failure to learn delayed alternation postoperatively reflected an individual difference in learning ability rather than the effect of the lesion. If the score of this monkey is disregarded, it becomes clear that group NP as well as group PM performed delayed alternation within normal limits. Discussion
The present results provide strong evidence that the dorsolateral cortex mediates at least two dissociable functions, one having its cortical focus in the principal sulcus and the other in the arcuate sulcus. Thus, monkeys with lesions in the principal sulcus were not impaired on the conditional position response test whereas monkeys with lesions in the arcuate sulcus were severely impaired ; conversely, on delayed alternation, the animals with lesions in the principal SU~CUS failed to learn the task but those with arcuate lesions showed only a retardation in learning. The results wit12 the nonprincipalis and premotor lesions are consistent with the evidence for two
PREFRONTAL
CORTEX
301
distinct dorsolateral functions. Each of these removals included a portion of the arcuate sulcus and each produced a milder form of the conditional position response deficit than that produced by resection of the entire sulcus ; on the other hand, neither lesion included the cortex in the principal sulcus and neither produced an impairment on delayed alternation. The evidence that the dorsolateral prefrontal cortex serves more than one function confirms and extends the findings of Gross and Weiskrantz (4) and of Stepien and Stamm (11). Both sets of investigators compared the effects of removing the cortex in the principal sulcus with that of removing the dorsolateral cortex surrounding this sulcus. Both obtained results similar to those reported here : Ablation of the cortex within the principle sulcus produced a greater impairment than the nonprincipalis lesion on tasks involving delayed responses ; the nonprincipalis lesion, on the other hand, produced the greater effect on tasks which did not involve such responses. Since the arcuate sulcus appears to be the focus for the nonprincipalis effect in the present experiment, it is tempting to speculate that damage to this sulcus was responsible for the deficits following the nonprincipalis lesions in the other studies as well. However, Stepien and Stamm found no evidence of an impairment on their spatial opposition task after a lesion which was confined to the anterior bank of the arcuate, suggesting that the impairment after their larger removal is unrelated to the one on the conditional position response task found in the present experiment. Gross and Weiskrantz, on the other hand, found that the one monkey in their study that had been given a lesion limited to both banks of the arcuate sulcus was as impaired as the other monkeys with larger removals of nonprincipalis cortex. These animals, like those in the present study, were more impaired on tasks which required the discrimination of auditory cues and less impaired on delayed response than monkeys with removal of the principal sulcus alone. The data suggest that the arcuate region may be concerned with the discrimination of auditory cues and that performance on the conditional position response task in the present study was impaired by arcuate damage because it involved the discrimination of such cues. One difficulty with this interpretation, however, is that in the study by Law&&a et al,, complete dorsolateral lesions failed to affect auditory discrimination when nondirection (i.e., go-no go) responses were required. Furthermore, monkeys with arcuate ablations are impaired to some extent on delayed response and delayed alternation, neither of which involve acoustic stimuli. An explanation of the delayed-response impairments after arcuate lesions may lie in the extent to which these removals have included damage to the inferior convexity of the frontal lobes. Lesions which include the inferior convexity result in impaired performance on delayed response and delayed alternation (8) but not on the conditional position response test
302
GOLDMAN
AND
ROSVOLD
employing directional responses (6). It is possible, therefore, that the moderate impairments on delayed alternation in the present experiment and on delayed response in the Gross and Weiskrantz study were due to the removal of that part of the inferior limb of the arcuate which extends onto the inferior convexity, whereas the impairments on the conditional position response task as well as on the auditory task in the Gross and Weiskrantz study were due to the removal of the cortex in the superior ramus of this sulcus. The finding in the present experiment that the group with lesions involving only that part of the arcuate sulcus dorsal to the inferior convexity (group NP) performed normally on delayed alternation but was impaired on the conditional position response test supports this interpretation. However, still unresolved is the finding of Lawicka et al. that complete dorsolateral removals do not result in impairment on a go-no go version of an auditory discrimination task. Another possibility which must therefore be considered is that the arcuate cortex is concerned with directional responding. Both the conditional position response task and delayed alternation involve directional responses and both were impaired, even though to different degrees, by the removal of arcuate cortex. Although this suggestion does not account for the nonspatial impairment reported by Gross and Weiskrantz, the available evidence regarding arcuate function is altogether too meager to discount it entirely. While the present findings have opened up a number of possibilities regarding the function impaired by removal of cortex in the arcuate sulcus, they have narrowed the possible interpretations of the impairment produced by lesions in the principal sulcus. Historically, Jacobsen (5) viewed the effects of prefrontal lesions primarily in terms of a loss in “immediate memory.” This interpretation was never widely accepted, perhaps because it seemed to imply that a loss in immediate memory would be apparent not only on the delayed-response tasks but in all learning situations which by definition require the retention of information from day to day or even from trial to trial. Jacobsen pointed out, however, that a crucial difference between the delayed-response tests on which frontal monkeys were impaired and those tests, such as visual discrimination problems, on which they were not, was that in the former, the monkey had to recall the essential cues from recent experience whereas in the latter, the essential cues were available in the subject’s environment at the time of response. Thus, Jacobsen made a distinction between recognition and recall and proposed that monkeys with frontal lesions were impaired only in recall. While this argument deals with the objection regarding the specific effect of frontal lesions on delayed-response tests, there remains another more tacit objection to the notion of immediate memory. This objection arises from the commonly held assumption that a mem-
PREFRONTAL
CORTEX
303
ory process subserved by frontal cortex would be, by nature, supramodal, i.e., nonspecific with respect to the afferent pathways involved. Thus, Mishkin et al. (8) interpreted their finding that monkeys with dorsolateral removals achieved high levels of performance on one test of memory, object delayed alternation, as evidence against the likelihood of any memory function for the dorsolateral cortex and by implication for its midlateral focus. This argument, however, ignores the possibility that memory, like sensation, may be modality-specific (or in some way compartmentalized) and subject to selective disruption. Such a concept has long been necessary in clinical neurology to deal with the variety of amnesias and agnosias found in brain-damaged patients. Instead of considering this possibility, however, Mishkin et al. concluded from their findings that the classical frontal deficits were related to spatial rather than to mnemonic factors. This view was strongly supported by the finding of Lawicka et aE. (6) that monkeys with dorsolateral lesions were impaired on the conditional position response test, a spatial task without delays. If spatial features were critical, however, it would have to be supposed that the focal lesion of the principal sulcus which interferes so severely with performance on the spatial delay tasks, should also interere with performance on the conditional position response task. The present results have demonstrated that this is clearly not the case; furthermore, they suggest that the original deficit after dorsolateral removal reported by Lawicka et al. may be attributed to that part of the lesion involving the arcuate sulcus rather than to the inclusion of the principal sulcus. Thus, there remains no evidence that lesions of the principal sulcus produce impairments on spatial tasks other than those which also involve delays, and therefore no conclusive support for the spatial hypothesis. Just as the results of Mishkin et al. demonstrate that mnemotic factors alone cannot be responsible for the classical delayed-response impairments, the present findings demonstrate that spatial factors by themselves are also insufficient to account for these deficits. It is only when both factors are present together, as they are in spatial delayed response and spatial delayed alternation, that a lesion of the dorsolateral cortex or of the principal sulcus produces an irrecoverable impairment. By showing that the delay is critical only when it is present in spatial tasks, or conversely, that spatial features are important only when they must be recalled from recent experience, these studies provide strong evidence that the focus of the dorsolateral cortex in the principal sulcus is indeed concerned with memory, but memory specifically for spatial information. The sensory basis of spatial perception as it applies to delayed response and delayed alternation is not well understood and, perhaps, the use of the term “modality-specific” in relation to the retention of these spatial cues
304
GOLDMAN
AND
ROSVOLD
may be unwarranted. However, an analysis of the delayed-response tests in which there appear to be no salient external cues to guide behavior suggests that monkeys may learn on the basis of internal cues, i.e., by remembering their own spatially directed responses on the preceding trial (in delayed alternation) or during the baiting phase (delayed response). It seems likely that learning in these spatial tasks will turn out to depend largely on proprioceptive, i.e., response-produced cues and that it is this type of information which the frontal monkey has difficulty in remembering. The notion of immediate memory proposed here differs from that advanced by Jacobsen over 30 years ago in indicating a degree of specificity in the mnemonic process as well as in its anatomical locus which could not have been appreciated at that early stage of investigation. References 1.
2.
3. 4.
5. 6. 7. 8. 9. 10. 11.
12.
K. 1964. Comparative anatomy of the frontal cortex and thalamo-cortical connections, pp. 372-396. ZIL “The Frontal Granular Cortex and Behavior.” J. M. Warren and K. Akert [Eds.] McGraw-Hill, New York. BLUM, R. A. 1952. Effects of subtotal lesions of frontal granular cortex on delayed reaction in monkeys. A.M.A. Arch. Neural. Psychiat. 67: 375-386. GOLDMAN, P., H. E. ROSVOLD, and M. MISHKIN. 1970. Evidence for behavioral impairment following prefrontal lobectomy in the infant monkey. J. Camp. Physiol. Psychol. (in press). GROSS, C. G., and L. WEISKRANTZ. 1962. Evidence for dissociation of impairment on auditory discrimination and delayed response following lateral frontal lesions in monkeys. Exfi. New-ok 5 : 453-476. JACOBSEN, C. F. 1936. Studies of cerebral function in primates. Corn). Psychol. Monogr. 13: l-68. LAWICKA, W., M. MISHKIN, and H. E. ROSVOLD. 1966. Dissociation of impairment on auditory tasks following orbital and dorsolateral frontal lesions in monkeys. Proc. Congr. Polish Physiol. Sot., Lublin, Poland 10 : 178. MISHKIN, M. 1957. Effects of small frontal lesions on delayed aIternation in monkeys. J. Neurophysiol. 20: 615-622. MISHKIN, M., B. VEST, M. WAXLER, and H. E. ROSVOLD. 1969. A reexamination of the effects of frontal lesions on object alternation. Newopsychologia 7: 357364. OLSZEWSKI, J. 1952. “The Thalamus of the Macaca Mulatta.” Karger, Basel. STAMM, J. 1969. Electrical stimulation of monkeys’ prefrontal cortex during delayed-response performance. J. Camp. Physiol. Psychol. 67 : 535-546. STEPIEN, I., and J. STAMM. 1970. Impairment on locomotor tasks involving spatial opposition between cue and reward in frontally ablated monkeys. Acta Biologica (in press). WAXLER, M., and H. E. ROSVOLD. 1970. Delayed alternation in monkeys after removal of the hippocampus. Newopsychologia (in press). AKERT,
27,
NEUROLOGY
Localization Prefrontal
of
PATRICIA
291-304 (1970)
Function Within the Cortex of the Rhesus
S. GOLDMAN
Dorsolateral Monkey
AND H. ENCER ROSVOLD
Laboratory of Psychology, Natiortal Institute of hlmtnl Health, Bethesda, Marylaud 20314 Received
Jamtary
5, 19%
Although lateral prefrontal lesions in the monkey are known to produce impairments on spatial delayed response and spatial delayed alternation, there is some question as to whether the delay, the spatial features, or a combination of the two is the critical factor in these tests giving rise to the impairments. Accordingly, the effects of several different lateral frontal lesions were compared on two spatial tasks, one which did involve intratrial delays (delayed alternation) and one which did not (a conditional position response test). The findings indicated the existence of two functionally distinct subdivisions of the dorsolateral prefrontal cortex : one in the principal sulcus, damage to which was responsible for impaired performance on the spatial task with delay; and the other in the arcuate sulcus, removal of which was responsible for impaired performance on the spatial task without delay. These findings together with those of other investigators suggest that the cortex in the principal sulcus may be concerned with a form of spatial memory, whereas the arcuate cortex is concerned with some other, as yet unspecified function. Introduction
The area of the monkey’s lateral prefrontal cortex which extends from the midline to the lower lip of the principal s~~lcus and from the frontal pole to the arcuate sulc~~s appears to be concerned with performance on spatial tasks (6, 8). Monkeys with dorsolateral lesions of this type achieve high levels of performance on nonspatial object alternation (S), yet fail to exceed chance on spatial alternation and spatial delayed response (3). It appears, further, that within this region the principle s~~lcus is the anatomical focus for these effects since removal of the cortex in this sulcus produces a greater impairment on the spatial delayed-response tasks than that which follows partial lesions of the surrounding dorsolateral cortex (2,4. 7). Given the selective effect of dorsolateral lesionson spatial tests, the question is still unsettled as to whether the delay that is interposed in these tests between the directional cues and the directional responsesalso contributes to the impairment. Recently, for example, Stamm (lo) found that 291
292
GOLDMAN
AND
ROSVOLD
electrical stimulation of the cortex in the principal sulcus produced a marked impairment in delayed-response performance only when it was applied during the first few seconds of the delay interval. This finding seems to indicate that the delay in the spatial tasks is a source of the impairment after removal of the cortex in the principal sulcus. On the other hand, the importance of the intratrial delay is brought into question by the recent report of Lawicka, Mishkin, and Rosvold (6) that monkeys with dorsolateral removals were impaired on a conditional position response test, a spatial task without intratrial delays. One way of resolving the conflicting evidence with respect to the importance of the delay is to suppose that the spatial delayed-response task measures a memory function which has its anatomical focus in the principal sulcus, while the conditional position response task measures some other function with a different cortical representation within the dorsolateral region. The purpose of the present expriment was to explore this possibility by comparing the effects of lesions in the principal sulcus with lesions in several other subdivisions of the dorsolateral cortex on the conditional position response task and on one of the delay problems. Method
The subjects were 16 naive monkeys (Macaca ndatta) ranging in weight from 3.0-5.0 kg. All were trained on the conditional position responsetest before operation and on the basis of their learning scores were divided into four matched groups for surgery, Postoperatively, they were retested on the conditional position response test and then given training on a visual pattern discrimination and spatial delayed alternation in that order. The conditional position response test was administered in a Wisconsin General Test Apparatus (Fig. 1), containing a test tray with two recessed foodwells, located 39 cm apart. Each foodwell was covered with a wooden lid attached to the test tray by a spring hinge at the back of each well. Food pellets could be delivered into the covered wells through delivery tubes which extended from each side of the apparatus to the foodwell on that side. The apparatus was equipped with two Quam speakers (size : 2 inch; impedance: 3.2 ohms), one centered directly above and the other directly below the animal’s compartment. A Grass S-4 stimulator was used to generate a train of clicks by passing a 6-v, I-msec duration pulse at a frequency of 50/set through the identical speakers. The experimenter could activate either of the two speakersby operating switches located at the front of the apparatus. The visual discrimination and delayed-alternation tests were administered in the same apparatus except that for these tests the foodwells were covered by 3-inch square displaceable matboard plaques.
PREFRONTAL
293
CORTEX
/ > FIG. 1. Diagrammatic
representation
of the conditional
position
response
apparatus.
Conditional Position ResponseTest. A method of successiveapproximation was used to train the monkey to approach and lift open the lid which covered the foodwell at the sound made by the delivery of a food pellet. This preliminary training was terminated when the monkey performed promptly and without error in a 20-trial session in which pellets were delivered randomly to the left and right foodwells. In this and all subsequent phases of the test, the screen which separates the animal’s compartment from the testing compartment was in the raised position throughout the test session.Trials were separated by at least a 30-set interval. If intertrial responsesoccurred, the next trial was delayed at least 10 set after the last intertrial response. Intertrial responseswere kept at a low level or virtually eliminated by this procedure. After completion of this phase of training, which required from 2-7 days, directional auditory cues were introduced. The cue delivered through the speaker above the animal’s cage signaled reward on the left; the cue from the speaker below the cage signaled reward on the right. These directional cues were presented according to a quasi-random schedule. On the first day that the auditory cues were introduced, a reward was delivered to the appropriate foodwell 2 set after stimulus onset, and then on successivedays 3, 4, 5, 10, 15, and finally on the seventh and subsequentdays 20 set after stimulus onset, unless the animal responded earlier. In this early stage, the monkeys would typically
294
GOLDMAN
AND
ROSVOLD
wait for the pellet to be dropped before responding but within an average of 7 days all were responding promptly to the auditory cues alone. If the animal responded to the correct foodwell, a reward was delivered immediately and the stimulus was turned off as soon as the animal obtained the pellet. If, however, the animal responded to the incorrect foodwell, the stimulus was turned off and the trial repeated at the usual intervals until the animal corrected its response or committed a maximum of three “extra” errors. If the animal failed to correct its response within this limit, a forced correction trial was given in which the stimulus was repeated for a fifth time and the reward was delivered within 1-2 sec. Daily sessions consisted of 20 trials, not including the correction trials. Training continued until the animal performed 90 correct responses in 100 consecutive trials. Correction trials were not included in the animal’s “trials to criterion” score, but the number of extra errors made on such trials were added to errors on regular trials to give a total “errors to criterion” measure. After meeting criterion, the monkey was rested for 10 days, tested for retention to the same criterion as before, and then operated upon. After a lo-day postoperative recovery period, the animal was retested on the conditional position response test until he regained the preoperative criterion. Next he was trained on visual discrimination and then on delayed alternation, each to the criterion of 90 correct responses in 100 consecutive trials or for a maximum of 1000 trials. Vismzl DiscriPninution. A simultaneous pattern discrimination was presented for 30 trials a day by the noncorrection method. The stimuli, a plus sign and an outline square, were white paper cut-outs pasted on gray matboard plaques. Spatial Delayed Alternation. The rerun correction procedure was used to train the monkeys to displace identical gray plaques alternately from the left and right foodwells. Trials were separated by a 5-set interval. Each session began with a free trial in which both wells were baited. On subsequent trials the well not chosen on the preceding trial was baited. The animals were given 30 trials a day including correction trials. Surgery. Bilaterally symmertical lesions were made in one stage using aseptic technique and Nembutal anesthesia (40 mg/kg) . Cortical tissue was aspirated with a small-gauge sucker and hemostasis was achieved using electrocautery and cottonoid patties. The wounds were closed in anatomical layers with silk sutures. The cortex in the banks and depths of the principal sulcus was removed in four monkeys (group P) ; the remaining 12 monkeys received lesions of the cortex in the banks and depths of the arcuate sulcus (group A, n = 4) ; the dorsolateral surface excluding the cortex in the principal sulcus (group NP, n = 4) and ; the premotor area (group PM, n = 4). The NP lesion
PREFRONTAL
CORTEX
295
included all the cortex dorsal to the principal sulcus from the pole to the arcuate sulcus, including the cortex in the anterior bank of the superior branch and the upper third of the inferior ramus of that sulcus. The premotor lesion (PM) included all the cortex in the posterior bank of the arculate sulcus as well as that dorsal to the superior branch and ventral to the inferior branch of that sulcus. P, representative lesion from each group is illustrated in Fig. 2. Histology. After completion of testing, each animal was administered an overdose of Nembutal and perfused through the heart with normal saline and 10% buffered formalin. The brain was removed and photographed, embedded in celloidin, and sectioned at 25 p in the frontal plane. Every twentieth section was stained with thionine and these were used to reconstruct the lesions and to determine the locus and extent of retrograde degeneration in the thalamus. Drawings illustrating the histological findings are presented in Figs. 2 and 3. Histological
Findings
Cortical Damage in Groztp P. The removal of cortex in the principal sulcus was complete in P-l and P-4 and almost complete in P-2 and P-3. Approximately 1.5 mm and 2.0 mm of cortex in the anterior tip of the sulcus was spared in the right hemispheres of P-2 and P-3 respectively. The only notable unintended damage was sustained by P-3 and this involved a strip of cortex approximately 2.5 mm in length below the ventral lip of the principalis at the frontal pole in the left hemisphere. Co&al Damage in Gvotlfi A. The removal of cortex in the arcuate sulcus was essentially complete in A-l, A-2, and A-4. In A-l and A-2 there was slight damage to underlying white matter but neither in these cases nor in any of the other brains was there any damage to the caudate nucleus. In A-3, approximately 2 mm of cortex in the posterior “spur” which forms at the junction of the inferior and superior limbs of the arcuate sulcus was spared in the right hemisphere. Cortical Damage in Gro@ NP. The removals of three of the four NP subjects conformed reasonably well to the intended lesions. The fourth, NP-1, had an anomalous arcuate configuration in its left hemisphere: the superior ramus of this sulcus could not be located either at surgery or on histological examination. The lesion of NP-1 also differed from those of the other three NP monkeys in that the cortex in the anterior bank of the inferior limb of the arcuate was spared bilaterally. In this same animal and in one other (NP-2)) a small amount of cortex in the anterior bank of the superior limb of the arcuate was also spared unilaterally. The only other notable sparing was that of the tortes on the frontal pole of NP-4. The extent of unintended damage in this group was slight. Three of the four
296
GOLDMAN
AND
ROSVOLD
monkeys (NP-1, NP-2, and NP-3) had damage to the posterior bank of the superior limb of the arcuate at the anterior tip of this limb. This damage was present in both hemispheres of all three animals.
FIG. 2. Lateral and dorsal reconstruction of the lesions of a representative monkey from each group. Also shown are selected cross sections through these lesions. The cortical damage is shown in solid black. P, principalis; A, arcuate; NP, nonprincipalis; and PM, premotor.
PREFRONTAL
+8.5 FIG.3.
CORTEX
t7.0
Retrograde degeneration in n. medialis of the thalamus in representative animals, one stereotaxic levels. Moderate to heavy degeneration
t
5.5
dorsalis and n. ventralis from each group, at the is shown in solid black.
lateralis indicated
Covti~~~l Damage in GYOH~ PM. Three of the four removals in this group deviated from the planned lesion chiefly because they involved unintended damage to the anterior bank of the arcuate. This damage was severe in PM-3 (in the right hemisphere), moderate in PM-l (left hemisphere), and slight in PM-4 (left hemisphere). Some cortex in the posterior bank of the inferior limb of the arcuate was spared unilaterally in PM-l. PM-Z, and PM-3, and bilaterally in PM-4. The only other notable sparing was that of the posterior “spur” in the right hemisphere of PM-l. There was no apparent correlation between the extent or locus of damage and behavioral performance within any of the four groups.
298
GOLDMAN
AND
ROSVOLD
Tkalamic Degeneration. The retrograde degeneration was most marked in medialis dorsalis 1 and n. ventralis lateralis. In accord with the findings of Akert (l), the degeneration in medialis dorsalis was confined to its lateral divisions and in ventralis lateralis to area X. Moderate to heavy degeneration occurred in the parvocellular division of medialis dorsalis after removal of the cortex in the principal sulcusand in the multiformis division after the arcuate and premotor removals. Degeneration was present in both of these sections of the nucleus after the nonprincipalis lesion. The degeneration found in area X was most marked in the brains of monkeys given either arcuate or premotor lesions. A thin strip of degeneration in area X was present in the brains of the nonprincipalis group perhaps due to the damage to the depths of the arcuate sulcus; no evidence of degeneration in this area could be detected in the brains of monkeys with principal sulcus lesions. After the more posterior lesions (arcuate and premotor) there was moderate gliosis present in the internal capsule, the anterior part of n. reticularis, the lateral part of n. ventralis anterior, and parts of the intralaminar nuclei, n. paracentralis and n. centralis lateralis. Whether there was actual cell loss in these nuclei was questionable. Similar but less marked changes were noted in the nonprincipalis brains and were not apparent at all in the brains of monkeys with principalis removal alone. Results
Table 1 contains each animal’s trials and errors to criterion on the three tests. Conditional Position Response. As may be seen from the table, on the preoperative retention measures there were no differences among the four groups ; on the postoperative retention measures, however, the groups differed markedly. To analyze these effects further, a difference score, the difference between preoperative and postoperative performance, was calculated for each animal (Table 1, column 4). There was no overlap between group P and group A on the trials to criterion scores. Group P performed as well postoperatively as preoperatively ; by contrast, group A required
340-580
more
trials
to reach criterion
after
surgery
than
before.
The difference scores of the NP and PM groups, which did not differ from one another, fell in between and did not overlap with those of the other two groups. The trend of the results was the same for errors to criterion. Again the scores of group P did not overlap with those of group A. Also, the scores of group NP and group PM did not differ from one another and fell in between those of group P and group A. However, on this measure group PM did not differ on a statistical basis from either group A or group P 1 Designations
of
thalamic nuclei follow Olszewski
(9).
a The CPR For retention,
-
Preop.
0 4 0 0
0 0 9 0
0 0 0 0
0 12 0 0
E
position
21 172 58 43
67 3.5 55 40
171 294 174 134
10 71 0 0
E
60 320 260 120
340 20 120 100
420 580 340 400
40 40 0 0
T
Diff.
\‘ISUAL
1
10 59 0 0
E
21 168 58 43
67 3.5 46 41
171 294 174 134
score
DISCRIMINATION,
660 470 740 740
560 260 568 1000
840 890 780 1000
1000 1000 1000 1000
Delayed
161 130 201 211
121 100 150 406
223 235 204 422
391 515 478 490
E
ALTERNATION
180 100 120 240
120 110 2.10 250
210 80 210 120
so 300 200 160
T
Visual discrimination
74 32 57 124
37 52 99 121
73 45 93 61
26 134 97 74
E
cues early in training (see test). m the retention measures.
90 91 91 90
92 91 92 60
90 91 92 71
64 54 63 62
Last 100 trials y0 correct
alternation
AND DELAYED
on which the monkey failed to respond to the auditory were considered “errors of omission” and are retlected
60 340 260 120
340 20 140 100
420 580 340 400
____-
postop. __~
41) 140 0 0
T
RESPONSE,
Retention
response
POSITION
learning scores do not include trials however, such failures to respond
0 20 0 0
225 419 249 287
294 900 618 457
PM-1 PM-2 PM-3 PM-4
0 0 20 0
93 1.51 274 243
NP-1 NP-2 NP-3 IN P-4
225 368 691 706
295 561 241 535
A-l A-2 A-3 A-4
0 100 0 0
0 0 0 0
107 99 395 503
204 341 510 1431
T
-___-~
___-
Conditional
ON CONDITIONAL
93 257 210 222
E”
T
-. P-l P-2 P-3 P-4
Learning -__~-__-
PEHFORMANCE
TABLE
300
GOLDMAN
AND
ROSVOLD
and group NP did not differ significantly from group P. These comparisons which had been significant in the case of the trials to criterion measure did not reach statistical significance in the case of the errors to criterion measure because of the performance of PM-Z and P-2. Since both monkeys made error scores more than 1.45 standard deviations from the mean of its respective group, and because the lesions of both were comparable to those of the other monkeys in these groups, it seems reasonable to conclude that their deviant error scores were due to extraneous factors. Visuul P’attern Discrimination. As may be seen in Table I, there were no differences either in trials or errors to criterion among the four groups. This finding serves to emphasize that the deficits reported here are task specific. Delayed Alternation. Whereas on the conditional position response task the performance of group A was markedly impaired and that of group P was unimpaired, on delayed alternation the performance of the two groups was reversed: all of the monkeys in group P failed to learn the task and performed at or near chance levels throughout the 1000 trials; in contrast, three of the four group A monkeys learned delayed alternation and the fourth achieved 71% correct responses in the last 100 trials. As on the conditional position response task, the NP and PM groups did not differ from one another. The scores of all but one of the monkeys in these two groups fell well within the range of scores obtained by unoperated monkeys tested in this laboratory (12). The failure of this one monkey (NP-4) to learn the task could not be accounted for by any obvious difference between his lesion and that of the other animals in the NP group. It is of interest to note, therefore, that this animal was slow to learn the conditional position response task preoperatively and it is possible that his failure to learn delayed alternation postoperatively reflected an individual difference in learning ability rather than the effect of the lesion. If the score of this monkey is disregarded, it becomes clear that group NP as well as group PM performed delayed alternation within normal limits. Discussion
The present results provide strong evidence that the dorsolateral cortex mediates at least two dissociable functions, one having its cortical focus in the principal sulcus and the other in the arcuate sulcus. Thus, monkeys with lesions in the principal sulcus were not impaired on the conditional position response test whereas monkeys with lesions in the arcuate sulcus were severely impaired ; conversely, on delayed alternation, the animals with lesions in the principal SU~CUS failed to learn the task but those with arcuate lesions showed only a retardation in learning. The results wit12 the nonprincipalis and premotor lesions are consistent with the evidence for two
PREFRONTAL
CORTEX
301
distinct dorsolateral functions. Each of these removals included a portion of the arcuate sulcus and each produced a milder form of the conditional position response deficit than that produced by resection of the entire sulcus ; on the other hand, neither lesion included the cortex in the principal sulcus and neither produced an impairment on delayed alternation. The evidence that the dorsolateral prefrontal cortex serves more than one function confirms and extends the findings of Gross and Weiskrantz (4) and of Stepien and Stamm (11). Both sets of investigators compared the effects of removing the cortex in the principal sulcus with that of removing the dorsolateral cortex surrounding this sulcus. Both obtained results similar to those reported here : Ablation of the cortex within the principle sulcus produced a greater impairment than the nonprincipalis lesion on tasks involving delayed responses ; the nonprincipalis lesion, on the other hand, produced the greater effect on tasks which did not involve such responses. Since the arcuate sulcus appears to be the focus for the nonprincipalis effect in the present experiment, it is tempting to speculate that damage to this sulcus was responsible for the deficits following the nonprincipalis lesions in the other studies as well. However, Stepien and Stamm found no evidence of an impairment on their spatial opposition task after a lesion which was confined to the anterior bank of the arcuate, suggesting that the impairment after their larger removal is unrelated to the one on the conditional position response task found in the present experiment. Gross and Weiskrantz, on the other hand, found that the one monkey in their study that had been given a lesion limited to both banks of the arcuate sulcus was as impaired as the other monkeys with larger removals of nonprincipalis cortex. These animals, like those in the present study, were more impaired on tasks which required the discrimination of auditory cues and less impaired on delayed response than monkeys with removal of the principal sulcus alone. The data suggest that the arcuate region may be concerned with the discrimination of auditory cues and that performance on the conditional position response task in the present study was impaired by arcuate damage because it involved the discrimination of such cues. One difficulty with this interpretation, however, is that in the study by Law&&a et al,, complete dorsolateral lesions failed to affect auditory discrimination when nondirection (i.e., go-no go) responses were required. Furthermore, monkeys with arcuate ablations are impaired to some extent on delayed response and delayed alternation, neither of which involve acoustic stimuli. An explanation of the delayed-response impairments after arcuate lesions may lie in the extent to which these removals have included damage to the inferior convexity of the frontal lobes. Lesions which include the inferior convexity result in impaired performance on delayed response and delayed alternation (8) but not on the conditional position response test
302
GOLDMAN
AND
ROSVOLD
employing directional responses (6). It is possible, therefore, that the moderate impairments on delayed alternation in the present experiment and on delayed response in the Gross and Weiskrantz study were due to the removal of that part of the inferior limb of the arcuate which extends onto the inferior convexity, whereas the impairments on the conditional position response task as well as on the auditory task in the Gross and Weiskrantz study were due to the removal of the cortex in the superior ramus of this sulcus. The finding in the present experiment that the group with lesions involving only that part of the arcuate sulcus dorsal to the inferior convexity (group NP) performed normally on delayed alternation but was impaired on the conditional position response test supports this interpretation. However, still unresolved is the finding of Lawicka et al. that complete dorsolateral removals do not result in impairment on a go-no go version of an auditory discrimination task. Another possibility which must therefore be considered is that the arcuate cortex is concerned with directional responding. Both the conditional position response task and delayed alternation involve directional responses and both were impaired, even though to different degrees, by the removal of arcuate cortex. Although this suggestion does not account for the nonspatial impairment reported by Gross and Weiskrantz, the available evidence regarding arcuate function is altogether too meager to discount it entirely. While the present findings have opened up a number of possibilities regarding the function impaired by removal of cortex in the arcuate sulcus, they have narrowed the possible interpretations of the impairment produced by lesions in the principal sulcus. Historically, Jacobsen (5) viewed the effects of prefrontal lesions primarily in terms of a loss in “immediate memory.” This interpretation was never widely accepted, perhaps because it seemed to imply that a loss in immediate memory would be apparent not only on the delayed-response tasks but in all learning situations which by definition require the retention of information from day to day or even from trial to trial. Jacobsen pointed out, however, that a crucial difference between the delayed-response tests on which frontal monkeys were impaired and those tests, such as visual discrimination problems, on which they were not, was that in the former, the monkey had to recall the essential cues from recent experience whereas in the latter, the essential cues were available in the subject’s environment at the time of response. Thus, Jacobsen made a distinction between recognition and recall and proposed that monkeys with frontal lesions were impaired only in recall. While this argument deals with the objection regarding the specific effect of frontal lesions on delayed-response tests, there remains another more tacit objection to the notion of immediate memory. This objection arises from the commonly held assumption that a mem-
PREFRONTAL
CORTEX
303
ory process subserved by frontal cortex would be, by nature, supramodal, i.e., nonspecific with respect to the afferent pathways involved. Thus, Mishkin et al. (8) interpreted their finding that monkeys with dorsolateral removals achieved high levels of performance on one test of memory, object delayed alternation, as evidence against the likelihood of any memory function for the dorsolateral cortex and by implication for its midlateral focus. This argument, however, ignores the possibility that memory, like sensation, may be modality-specific (or in some way compartmentalized) and subject to selective disruption. Such a concept has long been necessary in clinical neurology to deal with the variety of amnesias and agnosias found in brain-damaged patients. Instead of considering this possibility, however, Mishkin et al. concluded from their findings that the classical frontal deficits were related to spatial rather than to mnemonic factors. This view was strongly supported by the finding of Lawicka et aE. (6) that monkeys with dorsolateral lesions were impaired on the conditional position response test, a spatial task without delays. If spatial features were critical, however, it would have to be supposed that the focal lesion of the principal sulcus which interferes so severely with performance on the spatial delay tasks, should also interere with performance on the conditional position response task. The present results have demonstrated that this is clearly not the case; furthermore, they suggest that the original deficit after dorsolateral removal reported by Lawicka et al. may be attributed to that part of the lesion involving the arcuate sulcus rather than to the inclusion of the principal sulcus. Thus, there remains no evidence that lesions of the principal sulcus produce impairments on spatial tasks other than those which also involve delays, and therefore no conclusive support for the spatial hypothesis. Just as the results of Mishkin et al. demonstrate that mnemotic factors alone cannot be responsible for the classical delayed-response impairments, the present findings demonstrate that spatial factors by themselves are also insufficient to account for these deficits. It is only when both factors are present together, as they are in spatial delayed response and spatial delayed alternation, that a lesion of the dorsolateral cortex or of the principal sulcus produces an irrecoverable impairment. By showing that the delay is critical only when it is present in spatial tasks, or conversely, that spatial features are important only when they must be recalled from recent experience, these studies provide strong evidence that the focus of the dorsolateral cortex in the principal sulcus is indeed concerned with memory, but memory specifically for spatial information. The sensory basis of spatial perception as it applies to delayed response and delayed alternation is not well understood and, perhaps, the use of the term “modality-specific” in relation to the retention of these spatial cues
304
GOLDMAN
AND
ROSVOLD
may be unwarranted. However, an analysis of the delayed-response tests in which there appear to be no salient external cues to guide behavior suggests that monkeys may learn on the basis of internal cues, i.e., by remembering their own spatially directed responses on the preceding trial (in delayed alternation) or during the baiting phase (delayed response). It seems likely that learning in these spatial tasks will turn out to depend largely on proprioceptive, i.e., response-produced cues and that it is this type of information which the frontal monkey has difficulty in remembering. The notion of immediate memory proposed here differs from that advanced by Jacobsen over 30 years ago in indicating a degree of specificity in the mnemonic process as well as in its anatomical locus which could not have been appreciated at that early stage of investigation. References 1.
2.
3. 4.
5. 6. 7. 8. 9. 10. 11.
12.
K. 1964. Comparative anatomy of the frontal cortex and thalamo-cortical connections, pp. 372-396. ZIL “The Frontal Granular Cortex and Behavior.” J. M. Warren and K. Akert [Eds.] McGraw-Hill, New York. BLUM, R. A. 1952. Effects of subtotal lesions of frontal granular cortex on delayed reaction in monkeys. A.M.A. Arch. Neural. Psychiat. 67: 375-386. GOLDMAN, P., H. E. ROSVOLD, and M. MISHKIN. 1970. Evidence for behavioral impairment following prefrontal lobectomy in the infant monkey. J. Camp. Physiol. Psychol. (in press). GROSS, C. G., and L. WEISKRANTZ. 1962. Evidence for dissociation of impairment on auditory discrimination and delayed response following lateral frontal lesions in monkeys. Exfi. New-ok 5 : 453-476. JACOBSEN, C. F. 1936. Studies of cerebral function in primates. Corn). Psychol. Monogr. 13: l-68. LAWICKA, W., M. MISHKIN, and H. E. ROSVOLD. 1966. Dissociation of impairment on auditory tasks following orbital and dorsolateral frontal lesions in monkeys. Proc. Congr. Polish Physiol. Sot., Lublin, Poland 10 : 178. MISHKIN, M. 1957. Effects of small frontal lesions on delayed aIternation in monkeys. J. Neurophysiol. 20: 615-622. MISHKIN, M., B. VEST, M. WAXLER, and H. E. ROSVOLD. 1969. A reexamination of the effects of frontal lesions on object alternation. Newopsychologia 7: 357364. OLSZEWSKI, J. 1952. “The Thalamus of the Macaca Mulatta.” Karger, Basel. STAMM, J. 1969. Electrical stimulation of monkeys’ prefrontal cortex during delayed-response performance. J. Camp. Physiol. Psychol. 67 : 535-546. STEPIEN, I., and J. STAMM. 1970. Impairment on locomotor tasks involving spatial opposition between cue and reward in frontally ablated monkeys. Acta Biologica (in press). WAXLER, M., and H. E. ROSVOLD. 1970. Delayed alternation in monkeys after removal of the hippocampus. Newopsychologia (in press). AKERT,