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The Journal of Neuroscience, October 1, 2000, 20(19):7496-7503
Dissociable Roles of Mid-Dorsolateral Prefrontal and Anterior
Inferotemporal Cortex in Visual Working Memory
Michael
Petrides
Montreal Neurological Institute and Department of Psychology,
McGill University, Montreal, Quebec H3A 2B4, Canada
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ABSTRACT |
Functional neuroimaging in human subjects and studies of monkeys
with lesions limited to the mid-dorsolateral (MDL) prefrontal cortex
have shown that this specific region of the prefrontal cortex is
involved in visual working memory, although its precise role remains a
matter of debate. The present study compared the effect on visual
working memory of lesions restricted to the mid-dorsolateral prefrontal
cortex of the monkey with that of lesions to the anterior inferotemporal cortex, a region of the temporal cortex specialized for
visual memory. Increasing the delay during which information had to be
maintained in visual working memory impaired performance after lesions
of the anterior inferotemporal cortex, but not after mid-dorsolateral
prefrontal lesions. By contrast, increasing the number of stimuli that
had to be monitored impaired the performance of animals with
mid-dorsolateral prefrontal lesions, but not that of animals with
anterior inferotemporal lesions. This demonstration of a double
dissociation between the effects of these two lesions provides strong
evidence that the role of the mid-dorsolateral prefrontal cortex in
visual working memory does not lie in the maintenance of information
per se, but rather in the executive process of monitoring this
information. In addition, the present study demonstrated that lesions
limited to area 9, which constitutes the superior part of the
mid-dorsolateral prefrontal region, give rise to a mild impairment in
the monitoring of information, whereas lesions of the complete
mid-dorsolateral prefrontal region yield a very severe impairment.
Key words:
dorsolateral prefrontal cortex; inferotemporal cortex; visual working memory; monkey; lesions; monitoring; control process
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INTRODUCTION |
There is considerable evidence from
functional neuroimaging in human subjects (for review, see Owen, 1997 ;
D'Esposito et al., 1998; Petrides, 2000) and studies of monkeys with
lesions limited to the mid-dorsolateral (MDL) prefrontal cortex
(Petrides, 1991, 1995) that this region is involved in visual working
memory. But what precisely is the nature of the involvement of the
mid-dorsolateral prefrontal cortex in visual working memory? Does this
cortical region play a primary role in the maintenance of information
in working memory or is it involved in the executive process of keeping track (i.e., monitoring) of multiple events in working memory? It has
been argued (Petrides, 1991, 1994) that the role of the mid-dorsolateral prefrontal cortex lies in the executive process of
monitoring information in working memory.
The present investigation tested in the strictest possible manner the
above two interpretations of the nature of the impairment in visual
working memory after mid-dorsolateral prefrontal lesions. This was
achieved by manipulating the difficulty of the same visual working
memory task in two independent ways: (1) by increasing the delay, i.e.,
the time during which information must be maintained while keeping the
number of stimuli to be monitored low and constant, and (2) by
increasing the number of stimuli that must be monitored while keeping
the delay low and constant. In addition, the performance of the animals
with mid-dorsolateral prefrontal lesions was compared with that of
animals with anterior inferotemporal lesions. This lateral temporal
region is known to be the last stage in the specialized occipitotemporal system for the processing of visual pattern (object) information and has been shown to be critical for visual object memory
(Mishkin, 1982). Thus, not only was the effect of lesions to the
mid-dorsolateral prefrontal cortex tested under conditions that
independently manipulated delay and number of stimuli to be monitored,
but it was simultaneously compared with that of lesions to the part of
the cortex that is considered to be specialized for visual object memory.
The mid-dorsolateral prefrontal region can be divided into a lower
granular part in which layer IV is well developed (areas 46D and 9/46D)
and a superior dysgranular part that consists of a related type of
cortex but in which the granular layer IV is not as well developed
(area 9) (see Fig. 1). The granular part occupies the lower half of the
mid-dorsolateral prefrontal region up to and including the lip of the
sulcus principalis [for details, see Petrides and Pandya (1994,
1999)]. In the present investigation, one group of monkeys had lesions
that included both the granular and dysgranular parts of the
mid-dorsolateral prefrontal region, and another group had lesions
confined to the superior dysgranular part of this region.
The present experiment was reported at the 1998 Meeting of the Society
for Neuroscience (Petrides, 1998).
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MATERIALS AND METHODS |
Subjects and surgical procedure
The subjects were 16 adult male monkeys
(Macaca nemestrina) weighing
4.5-9.5 kg at the time of surgery. All operations were performed by
standard aseptic operating techniques for the subpial aspiration of
cortical tissue. The animals were first anesthetized with ketamine (15 mg/kg, i.m.) and then given the minimal dose of intravenous barbiturate
(Nembutal) necessary to induce a deep state of anesthesia.
Supplementary doses were administered during the operation as needed.
Antibiotics were administered postoperatively to prevent infection. All
operations were bilateral and were performed in one-stage.
There were two groups of animals with mid-dorsolateral prefrontal
lesions. Three animals had complete lesions of the mid-dorsolateral region and constituted the MDL group. These lesions were intended to
involve both the lower granular part (areas 46D and 9/46D) and the
superior dysgranular part (area 9) of the mid-dorsolateral region
(Figs. 1B,
2). Three animals had lesions that were
confined to the superior dysgranular part of the mid-dorsolateral
(SMD) prefrontal region, i.e., area 9, and these animals
constituted the SMD group (Figs. 1C,
3). Four animals served as the normal control (NC) group. In addition, three animals had lesions confined to
the posterior dorsolateral prefrontal region around the arcuate sulcus
and formed the periarcuate (PA) group (Fig.
4). These periarcuate lesions, which had
previously been shown not to impair visual working memory (Petrides,
1991, 1995), although they yield severe impairments in conditional
learning (Petrides, 1987), served as an additional operated control
group. Three monkeys [anteroventral inferotemporal (AIT) group] had
lesions confined to the anterior inferotemporal cortex, which has been
shown to play a role in visual memory (Figs.
5, 6).
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Figure 1.
A, The classic
cytoarchitectonic map of Walker (1940). Note that the dorsal part of
area 46 (dark gray dotted area), which constitutes the
granular part of the mid-dorsolateral prefrontal cortex, extends for a
considerable distance above the sulcus principalis. Area 9, which
occupies the superior part of the mid-dorsolateral prefrontal region,
exhibits a less developed granular layer IV. Walker (1940) pointed out
that the region he labeled as "area 46" is not homogeneous, but he
did not subdivide it further. For instance, dorsal area 46 that lies
within the mid-dorsolateral prefrontal region above the sulcus
principalis (dark gray dotted area) is architectonically
distinct from the sulcal part of area 46 that lines the inner part of
the sulcus principalis [for details, see Petrides and Pandya (1994,
1999)]. B, Illustration of the intended complete
mid-dorsolateral lesion (i.e., the MDL lesion). This lesion was to
include both the granular (dorsal areas 46 and 9/46) and dysgranular
(area 9) parts of the mid-dorsolateral region. In a comparative
architectonic study of the macaque and the human prefrontal cortex, we
noted that Walker's area 9 is comparable with area 9 on the superior
frontal gyrus of the human brain, whereas the dorsal part of area 46 of
Walker is comparable with dorsal areas 46 and 9/46 of the human brain
that lie on the middle frontal gyri [for details, see Petrides and
Pandya (1994, 1999)]. We therefore refer to the rostral half of
the mid-dorsolateral granular region as 46D and the caudal half as
9/46D. C, Illustration of the intended lesion to the
superior mid-dorsolateral region (i.e., the SMD lesion). This lesion
was to be restricted to area 9. AS, Arcuate sulcus;
CS, central sulcus; SP, sulcus
principalis.
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Figure 2.
Extent of the lesions of the mid-dorsal part of
the lateral frontal cortex (MDL lesions) depicted
(black) on standard diagrams of the lateral surface of
the anterior part of the brain of the monkey and on standard drawings
of coronal sections. Left hemisphere is shown on the left
side, both for the lateral surface diagrams and for the coronal
sections. The approximate stereotaxic levels for the coronal sections
shown are, from left to right, +36, +34,
+32, +30. MDL-Te, MDL-Mi, and
MDL-Mo refer to individual monkeys.
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Figure 3.
Extent of the lesions confined to the superior
part of the mid-dorsolateral prefrontal region (SMD lesions) depicted
(black) on standard diagrams of the lateral surface of
the anterior part of the brain of the monkey and on standard drawings
of coronal sections. Left hemisphere is shown on the left
side, both for the lateral surface diagrams and for the coronal
sections. The approximate stereotaxic levels for the coronal sections
shown are, from left to right, +36, +34,
+32, +30. SMD-1, SMD-2, and
SMD-3 refer to individual monkeys.
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Figure 4.
Extent of the periarcuate (PA)
lesions, i.e., the lesions of the posterior dorsolateral frontal
cortex, depicted (black) on standard diagrams of the
lateral surface of the anterior part of the brain of the monkey and on
standard drawings of coronal sections. Left hemisphere is shown on the
left side, both for the lateral surface diagrams and for
the coronal sections. The approximate stereotaxic levels for the
coronal sections shown are, from left to right, +26, +24, +22, +20.
PA-Ch, PA-Sp, and PA-Sy
refer to individual monkeys.
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Figure 5.
Schematic diagram of the lateral and inferior
surfaces of the left hemisphere of the monkey to illustrate the
location (area indicated by the dots) of the
anteroventral inferotemporal region (areas TE1 and TE2). This region
extends from the tip of the superior temporal sulcus
(STS) to the tip of the occipito-temporal sulcus
(O), excluding the perirhinal cortex along the
rhinal sulcus (Rh S). Note that the rostral part of the
STS can be viewed on both the lateral and the inferior surfaces of the
brain. The lesions of the three monkeys (AIT-1,
AIT-2, and AIT-3) that constituted this
group are shown (black) on the diagrams of the inferior
surface of the brain because only on this view can the entire extent of
this region be visualized. A, B, and
C indicate the level of the coronal sections shown in
Figure 6. AMTS, Anterior middle temporal sulcus;
AS (ir), inferior ramus of the arcuate
sulcus; AS (sr), superior ramus of the
arcuate sulcus; CS, central sulcus; IP,
intraparietal sulcus; LO, lateral orbital sulcus;
MO, medial orbital sulcus; Rh S, rhinal
sulcus; SF, Sylvian fissure; SP, sulcus
principalis; STS, superior temporal sulcus;
O, occipitotemporal sulcus.
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Figure 6.
Coronal sections through the anterior temporal
lobe to illustrate the lesions (depicted by the thick dotted
line) in the anteroventral part of the inferotemporal region in
the three monkeys (AIT-1, AIT-2, and
AIT-3) that had lesions to this region. The levels of
sections A, B, and C are
indicated in Figure 5 on the reconstructions of the inferior surfaces
of the brains of the three monkeys. Left hemisphere is shown on the
right side for the coronal sections. A,
Amygdala; AMTS, anterior middle temporal sulcus;
Rh S, rhinal sulcus; SF, Sylvian fissure;
STS, superior temporal sulcus.
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The MDL, PA, and NC groups were the same animals that had been studied
previously (Petrides, 1991, 1995). The present experiment was
administered at the end of Experiment 9 in Petrides (1995), ~3 years
after operation. The animals forming the SMD and AIT groups were
additional subjects and had a testing history similar to that of the
other groups.
MDL group. This group comprised three monkeys that were
given bilateral ablation of the mid-dorsal part of the lateral frontal cortex (Figs. 1B, 2). These lesions were
restricted within the granular (areas 46D and 9/46D) and dysgranular
(area 9) part of the mid-dorsolateral frontal region. They are referred
to here as the MDL frontal lesions because they were intended to extend from above the middle sector of the sulcus principalis to the midline.
These lesions were intended to spare the most rostral part of the
dorsolateral frontal cortex, which is part of the frontopolar cortex
(i.e., area 10), and, posteriorly, the cortex surrounding the upper
branch of the arcuate sulcus, as far as the midline (i.e., areas 8A,
8B, and rostral 6), as well as the cortex surrounding the posteriormost
part of the sulcus principalis (in the concavity of the arcuate sulcus)
that is part of area 8A, in terms of both architecture and connections
(Pandya and Kuypers, 1969; Pandya et al., 1971; Barbas and Mesulam,
1981; Petrides and Pandya, 1994, 1999). In making these lesions, great care was also taken not to damage or undercut the connections of the
inferior frontal convexity, i.e., the ventrolateral frontal cortex that
lies below the sulcus principalis.
SMD group. Three monkeys were given bilateral ablation of
the superior half of the mid-dorsolateral frontal cortex, i.e., area 9 (Figs. 1C, 3). These area 9 lesions were intended to
spare the cortex of the sulcus principalis and the granular area just above it (i.e., areas 46D and 9/46D), the most rostral part of the
dorsolateral frontal cortex, which is part of the frontopolar cortex
(i.e., area 10), and posteriorly, the cortex surrounding the upper
branch of the arcuate sulcus, as far as the midline, (i.e., areas 8A,
8B, and rostral 6).
PA group. Three animals were given a bilateral ablation of
the PA region, i.e., the posterior part of the dorsolateral frontal cortex (Fig. 4). These lesions were to include the cortex surrounding and lying within the superior ramus, the spur, and the uppermost part
of the inferior ramus of the arcuate sulcus. In other words, rostral
area 6, which lies within the posterior bank of the arcuate sulcus, and
area 8, within the anterior bank of the arcuate sulcus, were to be
removed. In making these lesions, great care was taken not to damage or
undercut the more rostrally located frontal cortex.
AIT group. Three monkeys had lesions confined to the
anterior part of the inferotemporal cortex, extending from the
rostralmost part of the superior temporal sulcus to the tip of the
occipitotemporal sulcus (Figs. 5, 6). The lesion was intended to ablate
areas TE1 and TE2, as defined by Pandya (Pandya and Yeterian, 1985). To gain access to the ventrolateral surface of the temporal lobe, the
zygomatic arch was removed, and the muscle temporalis was reflected,
permitting the opening of a large bone flap that extended to the base
of the temporal fossa.
NC group. The four monkeys that comprised this group were
not subjected to any operation.
Histological procedure
At the completion of the present and other experiments, the
operated animals were killed with an overdose of Nembutal, and their
brains were removed and fixed in a 10% formalin solution. A
macroscopic examination of the brains, which included drawings of the
lesions as seen from the surface of the brain, was carried out. Frozen
sections of the part of each brain that included the lesion were then
cut at 60 µm, and every sixth section was kept for staining with
thionin. A microscopic examination of the stained sections was
conducted, and drawings of the lesions were made (Figs. 2-6).
Testing
All testing was performed in a Wisconsin General Testing
Apparatus, which consists of a compartment where the monkey is held and
a testing area. An opaque screen can be interposed between these two
compartments to occlude the monkey's view of the testing area. The
animals were tested for 5 d during each week and were rewarded
with banana-flavored food pellets for correct responses. All animals
were highly trained on nonspatial visual self-ordered and externally
ordered working memory tasks. The precise testing history before the
present experiment of the animals comprising the MDL, PA, and NC groups
can be found in Petrides (1991, 1995). The animals comprising the SMD
and AIT groups had also received extensive testing on the same
nonspatial visual self-ordered tasks administered to the other groups.
In the nonspatial visual self-ordered tasks, the animal is faced,
during successive trials, with the same set of stimuli (e.g., objects
A, B, and C) and has to select a different one of these stimuli on each
trial until all stimuli have been selected once (Petrides, 1995). The
relative position of the stimuli changes from trial to trial to ensure
that the animal is guided by memory of the objects and not the
locations that they occupy. In other words, correct performance (i.e.,
the response leading to reward) is not to select a stimulus that had
been chosen on an earlier trial because reselection of that stimulus
would not lead to reward. Thus, training on the self-ordered tasks
teaches the monkey that the same set of stimuli will reappear on all
trials and that these stimuli must be selected only once during the
successive trials. Thus, successful performance depends on attending to
all of the stimuli in the set and carefully monitoring successive
choices (i.e., noting which stimuli from the recurring set have been
selected and which have yet to be selected). This principle was
essential for the experiment that is described below.
For the present experiment, the standard version of the self-ordered
task (Petrides, 1995) was modified so that the number of stimuli to be
monitored and the delay during which information must be maintained
could be manipulated independently. Testing consisted of a series of
pairs of presentation and test trials. The presentation trial was
identical to the first trial on the standard self-ordered task; namely,
the animal was faced with a familiar set of objects (Fig.
7). The stimuli were placed over small
white plaques that covered food wells on the test board, and under each
plaque there was a reward. The animal chose one of the objects from the
array by displacing a white plaque to obtain the reward that lay under
it. In the standard version of the self-ordered task, the same stimuli
reappear on successive trials until all are selected once. In the
present modified version, only one test trial followed the presentation
trial. On this test trial (Fig. 7), the animal was faced with the
stimulus it had chosen on the preceding presentation trial and one of
the stimuli that it had not chosen. As in all previous training of
these animals, the correct (i.e., rewarded) response on this test trial
was to select the stimulus not previously chosen.
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Figure 7.
Schematic diagram of the experimental arrangement
in the condition in which stimulus set size was manipulated. The sets
with two and four stimuli are illustrated. Note that on the
presentation trials (A), all of the stimuli
comprising the particular set are displayed in front of the monkey.
Once the animal has selected one of these objects, a test trial
(B) is administered 10 sec later, during which
the object selected is paired with one of the objects not
selected.
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In one set of conditions, the length of the delay between the
presentation trials and the test trials was varied (i.e., 10, 90, and
120 sec), but the stimulus set during the presentation trials was
always two objects. In the other set of conditions, the size of the
stimulus set was varied during the presentation trials (i.e., two,
three, four, or five objects), but the delay between the presentation
trials and the test trials was held constant at 10 sec. The order of
administration of the two parts of the experiment (set stimulus size
manipulation vs delay manipulation) was counterbalanced within each
group. Ten pairs of presentation and test trials were administered per
day. The presentation trial was initiated by the raising of an opaque
screen to display to the animal a set of small objects. In the
presentation trials of the conditions in which the size of the stimulus
set was varied, two, three, four, or five objects (depending on the
particular condition being administered) were placed in a row over
small white plaques covering food wells on the test board (Fig. 7). Each one of these objects covered a reward. The animal was allowed to
displace any one of these objects to obtain the reward that was hidden
under it, and the opaque screen was then lowered. After a delay period
of 10 sec, the opaque screen was again raised to initiate the test
trial. On the test trial, in all conditions, the monkey was faced with
only two stimuli, which were placed over the white plaques covering two
food wells of the testing board. One of these stimuli was the object
that the animal had chosen on the preceding presentation trial, and the
other was taken randomly from the stimuli that the animal had not
selected on the presentation trial. For instance, if three objects
(e.g., A, B, C) were shown on the presentation trial and the animal had chosen object A, then on the test trial the animal would be faced with
a choice between A and one of the other objects (e.g., C). Only the
stimulus not selected on the preceding presentation trial covered a
reward on the test trial (C in the example above), and the monkey was
therefore rewarded only if it selected that stimulus. Displacing the
plaque with the stimulus that had been selected on the presentation
trial did not result in reward and was scored as an error. The
left/right position of the two stimuli on the test trials was
determined randomly but with the restriction that over the 10 daily
test trials the baited object would occur an equal number of times over
the left and right positions and that no position would be baited for
more than three consecutive test trials. The animals were tested for a
total of 200 pairs of presentation and test trials per stimulus-set
condition (i.e., a total of 800 pairs of trials).
In the part of the experiment in which the length of delay was
manipulated, the testing procedure was identical to that described above, except that only two objects were presented on the presentation trial, and on the test trial the animal was faced with a choice between
the object it had chosen and the one that it had not chosen on the
preceding presentation trial. The conditions in this part of the
experiment differed only in terms of the length of the delay; i.e., the
delay between the presentation and test trials could be 10, 90, or 120 sec. The animals were tested for a total of 200 pairs of presentation
and test trials per delay condition (i.e., a total of 600 pairs of trials).
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RESULTS |
The effect of increasing the delay (from 10 to 90 sec and then to
120 sec) while keeping the number of stimuli to be monitored low (i.e.,
two stimuli) can be seen in Figure 8. The
scores of individual monkeys in the three delay conditions can be found in Table 1. Inspection of the performance
of normal animals (NC group) shows that increasing the delay was
effective in making the task more difficult for the normal animals
(p < 0.001 for 10 sec or 90 sec vs 120 sec). A
two-way ANOVA with repeated measures revealed a significant Group × Delay Interaction (F(8,22) = 6.26, p < 0.001). Further exploration of this effect with
the Newman-Keuls test revealed that in comparison with the control
animals, the group with anterior inferotemporal lesions was
significantly impaired at the 90 sec (p < 0.001) and 120 sec (p < 0.001) delays; none of
the other groups differed from the control group. Thus, the animals
with the mid-dorsolateral prefrontal lesions (MDL and SMD groups)
performed as well as the normal control animals and those with the
periarcuate lesions. Delay affected differentially only the performance
of the animals with lesions to the anterior inferotemporal cortex;
these animals performed at chance on the 120 sec delay condition.
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Figure 8.
Graph showing the mean performance of each group
across the three delays. The level of chance performance (50%) is
indicated by the horizontal dotted line.
AIT, Group with lesions to the anteroventral
inferotemporal region; MDL, group with damage to both
the lower and upper parts of the mid-dorsolateral prefrontal cortex;
NC, normal control group; PA, group with
periarcuate lesions; SMD, group with damage confined to
the superior part of the mid-dorsolateral prefrontal cortex (area
9).
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The effect of increasing the number of stimuli that the animals had to
monitor while keeping the delay short (i.e., 10 sec) is shown in Figure
9. The scores of individual monkeys can
be found in Table 2. As the size of
stimulus set from which the two test stimuli were drawn increased, the
performance of the two groups with mid-dorsolateral prefrontal lesions
deteriorated, whereas that of the animals with anterior inferotemporal
lesions and those with posterior dorsolateral prefrontal lesions (i.e., the periarcuate region) was not significantly different from the normal
control performance (Group × Stimulus Set Interaction: F(12,33) = 6.48, p < 0.001). The significance levels of the interactions reported above were
also obtained using the Greenhouse-Geisser conservative degrees of
freedom. The animals with the lesions of the complete mid-dorsolateral
prefrontal region (MDL group) were more impaired than the animals with
the lesions restricted to its upper part (SMD). In comparison with the
NC group, the MDL group was impaired at the three-stimulus set
(Newman-Keuls test, p < 0.001) and was performing at
chance at the four-stimulus (p < 0.001) and
five-stimulus set (p < 0.001). The SMD group, on the other hand, was impaired only on the five-stimulus condition (p < 0.01), and performance was still above
chance.
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Figure 9.
Graph showing mean performance of each group on
the two-, three-, four-, and five-stimulus sets. The level of chance
performance (50%) is indicated by the horizontal dotted
line. Abbreviations as in Figure 8.
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It is important to note that there was a significant drop in the
performance of the normal animals (NC group) as the stimulus set in the
presentation trials increased (p < 0.025 for
set 2 vs set 5 and p < 0.001 for set 3 vs set 5).
Clearly, this decrease in normal performance would not have occurred
had the animals attended only to the object chosen and ignored the
other stimuli. The drop in normal performance when the set increased
indicates that the earlier training on the self-ordered tasks
was effective in making the animals attend not only to the
object chosen on the presentation trials but also to the other objects
in the set that were not chosen. Thus, the animals were indeed
monitoring all stimuli in the set.
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DISCUSSION |
In the present experiment, the standard version of the
self-ordered task was modified so that the delay during which the
information must be maintained and the number of stimuli to be
monitored could be manipulated independently. In all test trials, the
monkey was faced with a choice between the object that it had selected
on the preceding presentation trial and one of the objects that it had
not selected. Thus, only the difference between the two manipulations (length of delay vs set size) can account for the observed differences in performance (Figs. 8, 9). The results demonstrated a double dissociation between the effects of lesions restricted to the mid-dorsolateral prefrontal cortex and those of the anterior
inferotemporal cortex in visual working memory. It has been shown in an
unambiguous way that the critical variable determining the impairment
in visual working memory after mid-dorsolateral prefrontal lesions is
the number of stimuli that have to be monitored, whereas the critical variable after anterior inferotemporal lesions is the length of time
during which the information must be maintained in memory. In other
words, while the anterior inferotemporal region is a neuronal module
necessary for the maintenance in memory of visual object information,
the mid-dorsolateral prefrontal region is a module necessary for the
application of an executive process that is here referred to as
monitoring of information.
Working memory, like all cognitive processing, is the result of
neuronal computations in multiple interacting brain structures. The
challenge is to specify the contribution of each of these structures.
The present dissociation is consistent with a theoretical model of the
role of several neural structures in working memory that was proposed
in the early 1990s [for details, see Petrides (1994)]. According to
this model, basic short-term memory functions, such as the temporary
storage and immediate processing of incoming and recalled information,
are the result of computations performed within sensory-specific and
multimodal parietal and temporal association areas that are the end
points in systems devoted to the processing of sensory information.
Transient neuronal firing in these posterior cortical association areas
in the absence of the original stimuli represents the maintenance of
the final stages of perceptual processing or the reactivation of
previously stored representations, i.e., in both cases memories of the
stimuli. Consistent with this view, lesions of the anterior
inferotemporal cortical region, which is the end stage in the
processing of visual object information, produced a failure to maintain
such information as delays were increased; i.e., these lesions degraded
visual short-term memory.
According to the above theoretical model, neuronal firing during the
delay in the mid-dorsolateral prefrontal region, unlike in the anterior
inferotemporal cortex, is not the maintenance of perceptual
representations per se, but rather the maintenance of symbolic coding
of the different cognitive representations (e.g., stimuli, events,
thoughts, etc.) that must be acted on for the needs of the specific
control operation (i.e., monitoring) that is performed there. The
mid-dorsolateral prefrontal neuronal activity codes symbolically the
different members of a current or an expected set of stimuli, and
interactive modulations of activity between the pools of neurons coding
the different stimuli act as markers of the current status of the
different members of the set relative to each other or the
occurrence/nonoccurrence of stimuli from the expected set. In this
manner, multiple events and their relative status in current awareness
can be monitored simultaneously. This kind of activity would be
expected to occur at the study phase of a trial in a working memory
task and would be maintained throughout the delay period so that any
changes in the status of the stimuli can be marked by further
modulations of that neuronal activity. Monitoring as defined here is
necessary for the manipulation of cognitive representations (i.e.,
high-level planning) because the sine qua non for
manipulation is the constant updating of the current relative status of
intended acts or events in working memory.
The above view of the mid-dorsolateral prefrontal cortex received
strong support from the present results. The increase in the
requirement to consider multiple stimuli simultaneously (as the
stimulus-set increased) proved devastating to the animals with
mid-dorsolateral prefrontal lesions (Fig. 9). Note that when this
monitoring requirement was minimal and delay was increased, the animals
with mid-dorsolateral prefrontal lesions, unlike those with anterior
inferotemporal lesions, were able to maintain the information in
working memory as well as the control animals. The latter finding is
consistent with earlier reports that monkeys with mid-dorsolateral
prefrontal lesions (Petrides, 1991, 1995) or even larger dorsolateral
prefrontal lesions (Bachevalier and Mishkin, 1986) performed as well as
the control animals on delayed object recognition. Thus, after
mid-dorsolateral prefrontal lesions, the problem did not lie in
selectively attending to a stimulus and ignoring others or in
processing that stimulus and then maintaining its representation during
the delay, but rather in attending to the fact that stimulus A was
selected and simultaneously noting that stimuli B, C, and D were not
selected. In other words, the mid-dorsolateral prefrontal lesions
degraded neuronal activity that is necessary to code multiple events
and their status relative to each other in current awareness.
The present results demonstrate that the maximum deficit in the
monitoring of visual nonspatial information (Fig. 9) is obtained with
rather complete lesions of the mid-dorsolateral prefrontal cortex
(i.e., the MDL lesions) that include both its granular (areas 46D and
9/46D) and dysgranular (area 9) parts (Figs. 1B, 2).
Lesions limited to the superior dysgranular part of the
mid-dorsolateral prefrontal cortex (i.e., the SMD lesions) demonstrated
a significant impairment in the five-stimulus condition and performed
as well as the control group with three stimuli (Fig. 9). These latter findings are consistent with two recent studies (Petrides, 1998; Levy
and Goldman-Rakic, 1999) in which monkeys with lesions restricted mostly to the superior part of the mid-dorsolateral prefrontal cortex
(i.e., area 9) and sparing the granular cortex just above the sulcus
principalis were shown not to be severely impaired on the nonspatial
self-ordered task with three objects.
Interestingly, in a recent study by Levy and Goldman-Rakic (1999),
monkeys with lesions limited to the cortex lining the sulcus principalis (i.e., sulcal area 46), sparing the mid-dorsolateral prefrontal region studied here, performed well on the self-ordered task
with three objects, although those monkeys were severely impaired on
spatial delayed response tasks as would be expected from the large
literature showing spatial impairments from lesions limited to the
sulcus principalis (for review, see Petrides, 1994). Thus, the effects
of lesions limited to the cortex within the sulcus principalis (i.e.,
sulcal area 46) can be dissociated from those of the cortex that lies
above the sulcus principalis (dorsal areas 46 and 9). However, the
monkeys with sulcus principalis lesions in the Levy and Goldman-Rakic
(1999) study were not tested with sets longer than three objects on the
self-ordered test, and thus it remains an open question whether animals
with such lesions would be impaired on longer sets.
The cortex in the caudal part of the sulcus principalis is part of area
8 and receives primarily visuospatial inputs from the parietal cortex
(Barbas and Mesulam, 1981, 1985; Huerta et al., 1987; Andersen et al.,
1990; Schall et al., 1995; Petrides and Pandya, 1999), and the ventral
bank of the sulcus principalis receives primarily somatosensory inputs
from the rostral parietal and the opercular parietal
region (Petrides and Pandya, 1984; Barbas and Mesulam, 1985;
Preuss and Goldman-Rakic, 1989). It has been argued previously
(Petrides, 1991, 1994; Petrides and Pandya, 1999) that lesions limited
to this part of the sulcus principalis, which receives primarily visual
and somatosensory spatial input, might result in a purely spatial
impairment (e.g., spatial delayed response tasks) and disrupt the flow
of critical spatial input into the multimodal monitoring system that
lies in the mid-dorsolateral prefrontal region above the sulcus
principalis. Because visual nonspatial input to the mid-dorsolateral
prefrontal monitoring system would be provided from the ventrolateral
prefrontal cortex (Petrides and Pandya, 1999), lesions limited to the
sulcus principalis need not affect nonspatial self-ordered tasks. Thus, if the lesions are made at the points of entry of modality-specific information into the frontal cortex, modality-specific impairments could result.
The above findings are consistent with the results of functional
neuroimaging studies in normal human subjects. Such studies have
consistently shown increases within the mid-dorsolateral prefrontal
region of the human brain during the performance of working memory
tasks whenever monitoring is taxed, regardless of the modality of the
information (for review, see Petrides, 2000). Interestingly, in a
recent study that reported a signal specifically related to the
maintenance of a spatial representation, this signal was located not in
the mid-dorsolateral prefrontal cortex but in the caudal position of
the superior frontal sulcus (Courtney et al., 1998) that most probably
corresponds to area 8 or rostral area 6 (Petrides and Pandya, 1999).
Thus, activity in the mid-dorsolateral prefrontal region is related to
monitoring within working memory, regardless of whether the information
is spatial or not (Petrides, 2000). Spatial delay-dependent activity can be selectively obtained in regions caudal to the mid-dorsolateral prefrontal region (Courtney et al., 1998).
| |
FOOTNOTES |
Received June 2, 2000; revised July 25, 2000; accepted July 25, 2000.
This study was supported by the Natural Sciences and Engineering
Council of Canada (Grant A7466). I thank K. Morris for testing the animals.
Correspondence should be addressed to Dr. Michael Petrides, Montreal
Neurological Institute, 3801 University Street, Montreal, Quebec, H3A
2B4 Canada. E-mail: petrides{at}ego.psych.mcgill.ca.
| |
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TOP
ABSTRACT
INTRODUCTION
