comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex...
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Comparative cytoarchitectonic analysis of the human andthe macaque ventrolateral prefrontal cortex andcorticocortical connection patterns in the monkey
M. Petrides1,* and D. N. Pandya2
1Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4 Canada; and Department
of Psychology, McGill University, 1205 Dr Pen®eld Avenue, Montreal, Quebec, H3A 1B1, Canada2Departments of Anatomy and Neurology, Boston University School of Medicine 02118, and Harvard Neurological Unit,
Beth Israel Hospital, Boston, Massachusetts, 02215 USA
Abstract
A comparison of the cytoarchitecture of the human and the macaque monkey ventrolateral prefrontal cortex demonstrated aregion in the monkey that exhibits the architectonic characteristic of area 45 in the human brain. This region occupies the dorsal
part of the ventrolateral prefrontal convexity just below area 9/46v. Rostroventral to area 45 in the human brain lies a large
cortical region labelled as area 47 by Brodmann. The ventrolateral component of this region extending as far as the lateral orbital
sulcus has architectonic characteristics similar to those of the ventrolateral prefrontal region labelled by Walker as area 12 in themacaque monkey. We designated this region in both the human and the monkey ventrolateral prefrontal cortex as area 47/12.
Thus, area 47/12 designates the speci®c part of the zone previously labelled as area 47 in the human brain that has the same
overall architectonic pattern as that of Walker's area 12 in the macaque monkey brain. The cortical connections of these twoareas were examined in the monkey by injecting ¯uorescent retrograde tracers. Although both area 45 and area 47/12 as de®ned
here had complex multimodal input, they could be differentiated in terms of some of their inputs. Retrograde tracers restricted to
area 47/12 resulted in heavy labelling of neurons in the rostral inferotemporal visual association cortex and in temporal limbicareas (i.e. perirhinal and parahippocampal cortex). In contrast, injections of tracers into dorsally adjacent area 45 demonstrated
strong labelling in the superior temporal gyrus (i.e. the auditory association cortex) and the multimodal cortex in the upper bank
of the superior temporal sulcus.
Introduction
Modern functional neuroimaging methods, such as positron emission
tomography and functional magnetic resonance imaging, permit the
identi®cation of changes in neuronal activity within speci®c parts of
the human cerebral cortex in relation to various cognitive processes
(e.g. Frackowiak et al., 1997; Toga & Mazziotta, 2000). As detailed
information on the connections of cortical areas and the actual
neuronal computations occurring in such areas come from experi-
mental work in the monkey, it is necessary to integrate ®ndings
emerging from functional neuroimaging studies in human subjects
with current knowledge of the anatomical/functional cortical circuits
based on studies in the monkey. In this manner, hypotheses derived
from animal research can be tested in the human brain with functional
neuroimaging. Furthermore, modulation of overall neuronal activity
observed in neuroimaging studies within speci®c cortical and
subcortical areas of human subjects during the performance of
particular cognitive tasks can be explored at the single neuron level in
monkeys performing similar tasks. In this way, one can proceed from
a statement that there is an overall change of activity in a particular
brain area in relation to a particular cognitive process to an analysis
of the actual neuronal computations occurring in that area during that
cognitive process. A major problem, however, limiting such integra-
tion stems from the fact that the available maps of the various cortical
areas of the human and the monkey brain were not the result of
studies conducted with the express aim of comparing architecture
across these two species. As a result, there are several discrepancies
in the delineations of architectonic areas between the two species due
to the application of different criteria in the de®nition of an area or
inconsistencies in the use of designations across species.
It is of historical interest to note that Brodmann (1905) in his
cytoarchitectonic map of the monkey brain labelled the frontopolar
cortex as area 12, and not as area 10 which is the designation used for
this region in his map of the human cortex (Brodmann, 1909)
(compare Fig. 1A with Fig. 2A). Brodmann used the designation
`area 10' for a large part of the ventrolateral prefrontal cortex in the
monkey (Fig. 2A). Furthermore, he did not use the designations
`area 46' and `area 45' in his cytoarchitectonic map of the monkey
brain (see Fig. 2A). Brodmann explicitly stated in his 1909 text that
his use of numbers to label areas had not been consistent across
species and that he felt particularly uncomfortable about his
parcellation of the prefrontal cortex. Indeed, these glaring discrep-
ancies in nomenclature were the main reason for the re-examination
of the monkey frontal cortex by Walker (1940), who attempted to
bring the terminology of the monkey prefrontal areas somewhat in
line with Brodmann's map of the human frontal cortex. For instance,
Walker labelled the frontopolar cortex in the monkey as area 10 (as in
Brodmann's map of the human cortex) and introduced other
*Correspondence: Dr Michael Petrides, as above.E-mail: [email protected]
Received 11 May 2002, accepted 20 May 2002
doi:10.1046/j.1460-9568.2002.02090.x
European Journal of Neuroscience, Vol. 16, pp. 291±310, 2001 ã Federation of European Neuroscience Societies
designations, such as area 46 and area 45, that Brodmann had used
for the human frontal cortex (compare Fig. 1A with Fig. 2B).
Walker's map and terminology became the basis of all modern
studies of the macaque monkey prefrontal cortex. It should be noted,
however, that Walker never compared the human and the monkey
prefrontal cortex explicitly. Thus, the criteria used by Walker to
de®ne an area in the monkey were not necessarily those used by
Brodmann to de®ne an area in the human brain.
The classical architectonic studies of the ventrolateral prefrontal
cortex of the human brain identi®ed an area 45 which occupies a
large part of the pars triangularis of the inferior frontal gyrus and an
area 47 that lies rostroventral to area 45 (Fig. 1A and B). Walker
identi®ed a part of the monkey ventrolateral prefrontal cortex as
area 45 (Fig. 2B) but only tentatively suggested that it might
correspond to area 45 of the human brain, as he had not studied
monkey and human architecture in a comparative manner (Walker,
1940; see p. 67). Other investigators, however, labelled the cortex
that Walker designated as area 45 as part of area 8 (Brodmann, 1905;
Vogt & Vogt, 1919) (Fig. 2A and C). Furthermore, a part of the
ventrolateral prefrontal cortex in the monkey was labelled as area 12
in Walker's (1940) map which is followed by all current studies of
the architecture and connections of the prefrontal cortex in the
macaque monkey (Fig. 2B). At approximately the same rostroventral
location, in the maps of the human cortex, the cortex is labelled as
FIG. 1. Cytoarchitectonic maps of the human frontal lobe as parcellated by (A) Brodmann (1909), B: Sarkissov et al. (1955) and (C) Economo & Koskinas(1925). Note that the maps of Brodmann (A) and Economo & Koskinas (C) represent not only the lateral surface but also the orbital surface of the frontal lobe.
292 M. Petrides and D. N. Pandya
ã 2001 Federation of European Neuroscience Societies, European Journal of Neuroscience, 16, 291±310
FIG. 2. Cytoarchitectonic maps of the frontal cortex of the macaque monkey as parcellated by (A) Brodmann (1905), (B) Walker (1940) and (C) Vogt &Vogt (1919).
Ventrolateral prefrontal cortex in human and monkey 293
ã 2001 Federation of European Neuroscience Societies, European Journal of Neuroscience, 16, 291±310
area 47 (Fig. 1A and B), raising the question whether some part of
the human prefrontal cortex labelled as area 47 might correspond to
area 12 in the monkey brain.
The present investigation compared the ventrolateral prefrontal
cortex of the human brain with that of the macaque monkey, the
nonhuman primate that is the most common experimental animal.
The aim of the present study was to re-examine the architecture of the
human and the monkey ventrolateral prefrontal cortex and to apply
the same criteria in delimiting architectonic areas. In addition, in the
monkey, we examined the pattern of afferent cortical connections of
the areas identi®ed on the basis of the current architectonic analysis in
order to clarify the connections of these areas and to provide further
evidence of their distinctiveness.
Materials and methods
Architectonic analysis
The detailed architectonic analysis of the ventrolateral prefrontal
cortex of the human brain was carried out from the coronal sections
(36-mm in thickness) of a brain stained with cresyl violet for
cytoarchitectonic analysis and with the Loyez stain for myeloarch-
itecture (67-year-old right-handed male). The results were then
con®rmed in another four brains in which Nissl-stained sections
through the region of interest were examined for cytoarchitecture.
These brains were cut at 36 or 10 mm at angles optimal for
cytoarchitecture.
In the monkey, the architectonic analysis was based on six brains
sectioned in the coronal plane and four brains sectioned in the
horizontal plane (36- or 40-mm sections) and stained with cresyl
violet or thionine. The architecture of the cortex lying in the lower
limb of the arcuate sulcus is poorly discriminated in standard coronal
sections because of the oblique direction of this sulcus and this is
reason for sectioning brains in the horizontal plane at an angle
perpendicular to the direction of the lower limb of the arcuate sulcus
in order to obtain sections optimal for the study of the architecture of
the cortex lying in the banks of this sulcus. These Nissl-stained
sections proved invaluable in demonstrating the details of the
architecture of this region. The architectonic boundaries were
identi®ed under low-power microscopic examination and plotted on
outlines of the brain sections. The results of this analysis were then
superimposed on drawings of the lateral and inferior surfaces of the
hemispheres. The anaesthesia and perfusion methods are described
below.
FIG. 3. Cytoarchitectonic maps of the lateral and orbital surfaces of the human (A) and macaque monkey (B) prefrontal cortex according to Petrides &Pandya (1994). The inset diagrams in B display the opened sulcus principalis and the lower limb of the arcuate sulcus to show the architectonic areas in theirbanks.
294 M. Petrides and D. N. Pandya
ã 2001 Federation of European Neuroscience Societies, European Journal of Neuroscience, 16, 291±310
Connections
The cortico-cortical connections were studied in four macaque
monkeys (macaca mulatta; weight ranging from 10 to 15 lbs) with
two different ¯uorescent tracers: a 3% solution of Diamidino Yellow
dihydrochloride (DY) (Keizer et al., 1983) and a 3% solution of Fast
Blue (FB) (Kuypers et al., 1980). In one animal, FB was injected in
the caudal part of area 45 (case 1) and DY in lateral 47/12 (case 3). In
another animal, FB was injected in the caudal part of area 47/12 (case
4) and DY in the rostral part of 47/12 (case 5). The remaining two
animals received, respectively, FB in area 45 (case 2) and DY in
area 9/46v (case 6).
The animals were initially immobilized with Ketamine and then
deeply anaesthetized with Nembutal (sodium pentobarbital,
65 mg/mL) (Sigma, St Louis, MO, USA). A craniotomy was then
performed, under aseptic surgical techniques, over the target area in
the frontal lobe. The ¯uorescent tracers were injected into different
areas of the ventrolateral frontal cortex, using the sulcal boundaries as
guides. Within each target area, two injections, 0.5 microliter in total
volume, were made. After an 8±10 day postsurgery survival period,
the animals were deeply anaesthetized with a lethal dose of sodium
pentobarbital and perfused transcardially with normal saline followed
by 4% paraformaldehyde in 0.1 M sodium cacodylate buffer (pH 7.4).
The brains were removed and prepared for frozen sectioning with the
cryoprotective method of Rosene et al. (1987). Three consecutive
series of 40-mm sections were collected and mounted on chrome-
alum coated slides. The slides were stored at 4 °C.
The presence of retrogradely labelled cells was examined by
epi¯uorescence microscopy. The distribution of labelled neurons was
plotted with an X-Y recorder driven from the stage of the microscope.
From these tracings, the distribution of labelled neurons was super-
imposed onto the lateral, medial and ventral surfaces of the brain. After
recording the distribution pattern of the labelled neurons, the sections
were stained with cresyl violet to identify the cytoarchitectonic areas
of the injection sites and the location of the labelled neurons.
All operation procedures and animal care were according to the
guidelines of the National Institute of Health and the Canadian
Council for Animal Care.
Results
Architecture
The cytoarchitecture of the ventrolateral prefrontal areas 45 and 47/
12 of the human brain will ®rst be described, followed by those of the
monkey. See Fig. 3 for the location of these areas. Although the focus
of the study was the ventrolateral prefrontal areas 45 and 47/12, we
also studied, in each brain, the immediately adjacent areas.
Area 45
Human brain
Area 45 occupies the pars triangularis of the inferior frontal gyrus
(Brodmann, 1908, 1909; Sarkissov et al., 1955; Amunts et al., 1999)
(see Fig. 1A and B). Economo & Koskinas (1925) have designated
this area as FDG (Fig. 1C). In area 45, layer III contains small to
medium pyramidal cells in its upper part and, in its lower part, has
deeply stained and densely packed large pyramidal neurons. Layer Va
contains medium pyramidal cells and layer Vb is cell-sparse,
therefore layer VI is clearly separated from Va (Figs 4 and 5). The
de®ning feature of area 45 in the human brain that distinguishes it
clearly from all adjacent areas are the clusters of large and deeply
stained pyramidal neurons that are found in the deeper part of layer
FIG. 4. Photomicrographs of cortical areas 45 and 47/12 of the human ventrolateral prefrontal cortex. The roman numerals in each photograph indicate thecortical layers. Calibration bar, 200 mm.
Ventrolateral prefrontal cortex in human and monkey 295
ã 2001 Federation of European Neuroscience Societies, European Journal of Neuroscience, 16, 291±310
FIG. 6. Photomicrographs of cortical areas 45 and 47/12 of the ventrolateral prefrontal cortex of the macaque monkey. The roman numerals in eachphotograph indicate the cortical layers. Calibration bar, 200 mm.
FIG. 5. Photomicrographs of layers III, IV and V of cortical areas 45 and 47/12 of the human ventrolateral prefrontal cortex to show closer the de®ningfeatures of these areas. The roman numerals in each photograph indicate the cortical layers. Calibration bar, 200 mm.
296 M. Petrides and D. N. Pandya
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III (i.e. IIIc) in combination with the well developed layer IV.
Area 45 can easily be delineated from the surrounding areas. The
dorsally adjacent area 9/46 shares with area 45 the well developed
layer IV, but it does not have the striking large and deeply stained
clusters of pyramidal neurons in layer IIIc that is the characteristic of
area 45. The caudally adjoining area 44 can be clearly distinguished
from area 45 because its layer IV is barely discernible in sharp
contrast to the well developed layer IV in area 45. Rostroventrally
area 45 is replaced by area 47/12 which lacks the prominent large
and deeply stained pyramids in layer IIIc and which also has a layer
IV that is less developed than that of area 45 (see below).
Monkey brain
Walker (1940) identi®ed an area in the monkey brain in the lower
limb of the arcuate sulcus that he labelled as area 45 (see Fig. 2B). In
identifying area 45 in the monkey ventrolateral prefrontal cortex
(Fig. 6), we applied the same criteria that de®ne area 45 in the human
brain, namely an area with large and deeply stained pyramidal
neurons in the deeper part of layer III in combination with a well
developed layer IV. We have observed that the area that has
characteristics similar to those of area 45 of the human brain occupies
the ventralmost part of the rostral bank of the lower limb of the
arcuate sulcus and extends onto the adjacent lateral surface for a
considerable distance. In the brains that we examined, area 45
extended as far as the infraprinciple dimple that lies below the sulcus
principalis (Figs 3, 7 and 8). The cortex above the infraprinciple
dimple, area 9/46v, was characterized by small to medium size
pyramids in layer III combined with a well developed layer IV. Thus,
as in the human brain, area 45 shared with the dorsally adjacent
area 9/46 the well developed layer IV, but was distinguished from it
by the clusters of striking large and compact neurons in the deeper
part of layer III that are so characteristic of area 45 (see Figs 6 and 8).
Rostroventrally, the transition between area 45 and 47/12 was
marked by the loss of the striking large neurons in layer IIIc and
the narrowing of layer IV (Figs 6 and 8).
We noted that, within the anterior bank of the lower limb of the
arcuate sulcus, this area is restricted to its ventralmost part. The
anterior extension of area 45, we designate as area 45A. The
posterior part, which lies in the ventral part of the rostral bank of
the lower limb of the arcuate sulcus, we designate as area 45B.
Because area 45B lies in the anterior bank of the lower limb of the
arcuate sulcus, it is poorly visualized in standard coronal sections of
the brain. We have therefore sectioned four brains at an angle
perpendicular to the direction of the lower limb of the arcuate sulcus
and studied the architecture on both the posterior and anterior banks
of the sulcus. Examination of these sections con®rmed the fact that, in
the monkey as in the human brain, area 45 with its large and deeply
stained layer IIIc neurons and well developed layer IV stands in
striking contrast with the posteriorly adjacent dysgranular cortex.
An issue of particular concern to us was the dorsal border of
area 45 within the anterior bank of the inferior limb of the arcuate
sulcus because the frontal eye ®eld as de®ned by electrical
microstimulation lies within the anterior bank of the arcuate sulcus
at the level of the sulcus principalis. Stanton et al. (1989) examined
the architecture of the cortex from which eye movements were
evoked with microstimulation within the anterior bank of the arcuate
sulcus and reported a close correlation between the frontal eye ®eld
region and the part of the anterior bank of the arcuate sulcus that
exhibits large pyramidal neurons in layer V. They pointed out that, in
the anterior bank of the arcuate sulcus, the large layer V neurons have
their highest concentration at the level of the sulcus principalis and
diminish sharply as one moves into the ventral part of the lower limb
of the arcuate sulcus, i.e. the part from where eye movements cannot
be evoked (Stanton et al., 1989). We have obtained similar results in
a recent study in which we examined the part of the anterior bank of
the arcuate cortex from where eye movements were obtained with
microstimulation (Cadoret et al. 2000). We noted that eye movements
are obtained only from the dorsal part of the anterior bank of the
inferior limb of the arcuate sulcus and that this part exhibits large
layer Va neurons. The ventral part of the arcuate sulcus from where
eye movements cannot be evoked has medium sized pyramids in
layer Va, but deeply stained large pyramids in layer IIIc in
combination with a clearly de®ned layer IV. These are the
characteristics of area 45 in the human brain and we have therefore
restricted our de®nition of area 45 in the arcuate sulcus to the
ventralmost part of this region.
Area 47/12
Human brain
In the classical maps of the human cerebral cortex, the cortical region
rostroventral to area 45 has been labelled as area 47 (Fig. 1A and B).
This area is shown to occupy the most rostral part of the inferior
frontal gyrus (pars orbitalis), extending onto the caudal half of the
orbitofrontal cortex (e.g. Beck, 1949; Sarkissov et al., 1955).
FIG. 7. Schematic reconstruction of the lateral and orbital surfaces of thefrontal lobe of a monkey on which the extent of architectonic areas 45 and47/12 are indicated. Note that the infraprincipalis dimple (IPD) has beenopened up to show that area 45 extended as far as the depth of this dimple.Area 45 extended into the anterior bank of the lower ramus of the arcuatesulcus. The line above the diagram indicates the level of the coronal sectionthat is shown in Fig. 8. AS, arcuate sulcus; CS, central sulcus; LOS, lateralorbital sulcus; SP, sulcus principalis.
Ventrolateral prefrontal cortex in human and monkey 297
ã 2001 Federation of European Neuroscience Societies, European Journal of Neuroscience, 16, 291±310
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298 M. Petrides and D. N. Pandya
ã 2001 Federation of European Neuroscience Societies, European Journal of Neuroscience, 16, 291±310
Sarkissov et al. (1955) subdivided this large region into ®ve
subdivisions. The question we examined in the present study was
whether any part of this large region may be similar in architecture
with Walker's area 12 in the monkey. Our comparative architectonic
examination indicated that the part of this region that lies rostral and
ventral to area 45 and extends as far as the lateral orbital sulcus has
architectonic features similar to those of Walker's area 12 in the
monkey (Fig. 3A). In contrast, the part of classical area 47 that
continues medial to the lateral orbital sulcus and occupies the caudal
orbitofrontal cortex has different architectonic features that are
similar to those of caudal orbitofrontal area 13 of the monkey, an area
characterized by a limbic-type dysgranular cortex (see Petrides &
Pandya, 1994). We have therefore designated the cortical region lying
rostral and ventral to area 45, continuing ventrally as far as the lateral
orbital sulcus, as area 47/12 (Fig. 3A) to denote the fact that this
particular part of the previously labelled area 47 is similar in
architecture to Walker's area 12 in the monkey brain.
The transition from area 45 to area 47/12 can be clearly de®ned.
Basically, the conspicuously large and deeply stained pyramidal
neurons in the deeper part of layer III, which are the de®ning feature of
area 45, are replaced in area 47/12 by smaller neurons (Figs 4 and 5).
Thus, in area 47/12, layer III contains small and medium pyramidal
cells in its upper part, and medium and somewhat larger pyramidal
neurons in its lower part. Another difference between area 45 and
area 47/12 is the fact that, although layer IV of area 47/12 is developed
and clearly separates layers III and V, it is not as well developed as that
of area 45. Furthermore, layers V and VI contain densely packed
medium to small pyramidal cells and these infragranular layers are
more prominent than those of adjacent area 45 (Fig. 4). The part of
area 47/12 that extends onto the orbital surface differs slightly from
the more lateral part in that layer IV is less well developed and, thus,
one can speak of a lateral and an orbital part of 47/12.
Monkey brain
In the previous cytoarchitectonic maps of the monkey prefrontal
cortex, no cortical region had been designated as area 47 (see Fig. 2).
Walker (1940), however, described an area that he labelled as area 12
at the most ventral part of the lateral frontal convexity extending, on
the orbital surface, to the lateral orbital sulcus (Fig. 2B). It should be
pointed out here that Walker's (1940) terminology of the sulci of the
frontal cortex differs from current usage and that sulcus FM in his
monkey brain is the lateral orbital sulcus. The comparability of the
monkey lateral and medial orbital sulci with those of the human brain
has recently been established (Chiavaras & Petrides, 2000).
In the present investigation in which the ventrolateral prefrontal
cortex of the monkey has been explicitly compared with that of the
human brain, it was observed that the region that Walker included in
area 12 has the same characteristics as those of the ventrolateral
prefrontal area that we have identi®ed as 47/12 (see above). We
therefore refer to this area in the monkey as area 47/12 in order to
maintain consistency between the human and the monkey frontal
cortex.
Area 47/12 in the monkey brain has a layer III that contains small
to medium-sized pyramidal neurons with a few larger neurons in its
lower part (Fig. 6). As in the human brain, the transition between
area 45 and area 47/12 is clearly marked by the disappearance of the
conspicuous densely stained and large neurons in layer IIIc that
characterize area 45 (Figs 6 and 8). Layer IV of area 47/12 is
developed and clearly separates layers III and V, but it is not as broad
as that of adjacent area 45. Again, as in the human brain, layers V and
VI are dense in comparison with those of area 45 and are not clearly
separable by the presence of a pale Vb (Fig. 6). Area 47/12 of the
monkey can be subdivided into a lateral part and an orbital part. The
orbital area 47/12 differs from the lateral area 47/12 in that it has a
slightly less developed layer IV.
In the orbital frontal cortex, area 47/12 is bordered medially by
area 13 which, both in the human and the monkey brain, is a
dysgranular type of cortex, namely layer IV is barely discernible. In
the incipient layer IV of area 13 occasional granular cells can be
detected. In contrast, area 47/12 is granular prefrontal cortex with an
identi®able layer IV. In addition, in area 13 the infragranular layers V
and VI are more prominent than the supragranular layers II and III
(Barbas & Pandya, 1989; Petrides & Pandya, 1994).
In the monkey, the differential architectonic pattern between areas
45 and 47/12 was also observed in material reacted immunohisto-
chemically for the demonstration of a neuro®lament protein (SMI32)
(Paxinos et al. 2000).
FIG. 9. Photographs of coronal sections through the injections sites for thecases studied in the present investigation. The stained sections were scannedon an Agfa ARCUS II scanner. The digital images were subsequentlyprepared using Adobe Photoshop. Arrows indicate the injection sites.Calibration bar, 5 mm.
Ventrolateral prefrontal cortex in human and monkey 299
ã 2001 Federation of European Neuroscience Societies, European Journal of Neuroscience, 16, 291±310
Connections
In the monkey, ¯uorescent tracer injections were placed in the
ventrolateral prefrontal areas 45 and 47/12 in order to see whether
they exhibit distinct connection patterns. In addition, in one case the
injection was placed in area 9/46v that borders area 45A dorsally in
order to compare the connection patterns of these two areas. The
locations of the resulting labelled neurons are described below. When
FIG. 10. Diagrammatic representation of the unfolded lateral and orbital (A) and medial (B) surfaces of the cerebral hemisphere in case 1 with FB injectionin area 45 and the distribution of the resulting labelled neurons. The sulcus principalis, the superior and inferior limbs of the arcuate sulcus, the lateral ®ssure,the superior temporal sulcus and the cingulate sulcus have been opened up to show the labelled neurons in their banks. Abbreviations as follows: AS, arcuatesulcus; CC, corpus callosum; CING S, cingulate sulcus; CS, central sulcus; IPS, intraparietal sulcus; LF, lateral ®ssure; LOS, lateral orbital sulcus; MOS,medial orbital sulcus; PS, sulcus principalis; RhF, rhinal ®ssure; STS, superior temporal sulcus.
300 M. Petrides and D. N. Pandya
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referring to architectonic divisions of the parietal and temporal
cortex, we have used the nomenclature of Pandya & Seltzer (1982),
Seltzer & Pandya (1978), Pandya & Sanides (1973) and Brodmann
(1905). For the prefrontal cortex, the architectonic parcellation of
Petrides & Pandya (1994) (Fig. 3B) will be used to describe the
location of labelled neurons. The labelled neurons were plotted on
unfolded maps of the cerebral cortex. These maps were drawn from
measurements of the extent of cortex exposed on the surface of the
brain and the cortex hidden in the banks of the sulci. Layer IV was
used to make these measurements from the coronal sections. In order
not to distort excessively, as a result of the unfolding, the overall
appearance of the cortex as viewed from the surface of the brain, we
depicted the cortex lying in the banks of the major sulci separately in
each ®gure. The sulcus principalis was used as the starting point in
unfolding the frontal cortex and was therefore represented in all the
®gures as an idealized line. In more posterior sections, the cortex was
unfolded using the midline and the Sylvian ®ssure as points of
reference. The corpus callosum, the cingulate sulcus and the midline
of the brain provided the points of reference for the measurements
used to construct the outline of the medial view of the hemisphere.
Case 1
The FB injections were placed in area 45 in the rostral bank of the
lower limb of the arcuate sulcus (Figs 9 and 10A). Rostrally, the
tracer spread onto the adjacent convexity in area 45 and, caudally, it
spread slightly into the posterior bank of the arcuate sulcus. Labelled
neurons were noted in area 9/46v and in area 46 further rostrally in
both the supragranular and infragranular layers. Ventrally, labelled
neurons could be seen in area 47/12, extending into its orbital part. In
the orbitofrontal cortex, a few labelled neurons were seen in areas 10,
11, 47/12 and 13, involving supragranular and infragranular layers.
Distinct clusters of neurons were also noted in the dorsolateral frontal
cortex, in areas 8Ad, 8B, the dorsomedial part of rostral area 6, area 9
and area 46, both in the supragranular and infragranular layers. On
the medial surface of the brain (Fig. 10B), scattered neurons were
noted in area 6, area 8B, area 9 and area 10. Labelled neurons were
also noted in area 24 of the cingulate gyrus. A distinct cluster of
neurons occurred in the lower bank and depth (24c) and the upper
bank of the cingulate sulcus, corresponding to the cingulate motor
areas. Labelled neurons were also observed in ventral area 6 and
area ProM, the peri-central operculum (SII), as well as in the insula.
In part, these somatosensory connections may have been due to the
limited spreading of the injection to the posterior bank of the arcuate
sulcus, i.e. in area 44. However, many of these connections were
replicated in Case 2 in which there was no involvement of the
posterior bank of the arcuate sulcus. It should be noted here that
connections between the ventral premotor cortex and the ventral
prearcuate region were also previously noted (Godschalk et al., 1984;
Barbas & Pandya, 1987). The connection between the ventral
prearcuate region and the posterior insula was also observed by
Mesulam & Mufson (1982).
In the parietal lobe, neurons were observed in area PG and adjacent
area POa in the lower bank of the intraparietal sulcus. Projection to
the part of the ventrolateral prefrontal cortex that is de®ned as area 45
in the present architectonic investigation was previously noted in
studies that examined injections of anterograde tracers in the inferior
parietal lobule and the adjacent lateral intraparietal sulcus (Petrides &
Pandya, 1984; Cavada & Goldman-Rakic, 1989).
A substantial number of neurons was observed in the supra-
temporal plane and the superior temporal gyrus. In the supratemporal
plane, neurons were mainly located in the cortex of the circular
sulcus, involving areas PaI and ProK, whereas in the superior
temporal gyrus distinct clusters of neurons occurred in areas TS1,
TS2, TS3, paAlt and Tpt. A large number of labelled neurons were
observed in areas TAa, TPO and PGa on the upper bank of the
superior temporal sulcus. On the lower bank of this sulcus, scattered
neurons were seen in areas TEa and FST. These inputs are consistent
with the results of investigations that examined the projections from
injections of anterograde tracers into the superior temporal gyrus
(Petrides & Pandya, 1988; Romanski et al., 1999) and the upper bank
of the superior temporal sulcus (Seltzer & Pandya, 1989). These
studies demonstrated terminations to the ventrolateral region here
de®ned as area 45, although these connections were not described as
terminating in area 45 but rather in a part of area 12.
Case 2
In case 2, the FB injections were placed in area 45, involving cortex
both on the ventrolateral convexity and in the adjacent rostral bank of
the arcuate sulcus (Figs 9 and 11A). The connections observed in
case 1 were replicated in case 2, a signi®cant difference being the
additional connections with the rostral inferotemporal cortex
(area TE) in case 2. These additional connections were probably
largely due to the limited spreading of the injection to area 47/12 (as
can be seen from the pattern of connections when area 47/12 was
injected: cases 4 and 5). In case 2, there was a signi®cant number of
labelled neurons in layers III and V in the cortex within and below the
sulcus principalis, involving areas 46, 9/46v, 47/12 and 8Av. On the
orbital surface of the frontal lobe, labelled neurons could be observed
in areas 47/12, 13, 11, 10 and 14, both in supragranular and
infragranular layers. In the dorsolateral frontal cortex, labelled
neurons in supragranular and infragranular layers could be observed,
as in case 1, in areas 8Ad, 8B, 9, 10 and 46. On the medial surface,
labelled neurons were clustered in areas 6, 8B, 9, 10 and 14, again in
both the supragranular and infragranular layers. In addition, there
were labelled cells in the anterior cingulate region in areas 32 and 24.
Caudal to the injection, the labelled neurons were located in both
banks of the lower limb of the arcuate sulcus, involving areas 45B
and 44. Labelled neurons were also observed in SII and the insula. As
in case 1, there were neurons in the supratemporal plane and the
superior temporal gyrus in layers III and V. In the supratemporal
plane, the neurons were located mainly in area PaI, Reit and ProK.
Architectonic areas TS1,TS2, TS3 (Fig. 12C), PaAlt and Tpt of the
superior temporal gyrus exhibited a substantial number of labelled
neurons in layers III and V (Fig. 11). The cortex of the upper bank of
the superior temporal sulcus displayed a large number of labelled
neurons involving all divisions of area TPO (Fig. 12B) and PGa as
well as area TAa. In the lower bank, some neurons were observed in
areas TEa and FST. In the inferotemporal region, labelled neurons
could be seen in areas TE1 and TE2. Ventromedially, a few neurons
were observed in rostral area TL as de®ned by Rosene & Pandya
(1983).
Case 3
In this case, the DY injections were placed in the lateral part of
area 47/12 (Figs 9 and 13A). There was some spreading of the
dye into the ventralmost part of area 45. Labelled neurons were
noted in area 10, area 8Av and area 45, in both the supra and
infragranular layers. On the orbital surface, a distinct cluster of
neurons was noted in areas 47/12, 13, 11, 10 and 14, in layers III
and V. In the dorsolateral frontal cortex, labelled neurons were
observed in areas 46, 8B, 9 and 10. On the medial surface, a
small cluster of neurons was seen in area 9, 10 and 14 (Fig. 13B).
Only a limited number of neurons was seen in the rostral part of
area 24 and 32. In the temporal lobe, areas Pro, TS1 and TS2
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exhibited a few labelled neurons. Labelled neurons were also
observed in areas TAa, TPO and PGa, in the upper bank of the
superior temporal sulcus. In the lower bank of this sulcus,
labelled neurons were located in areas IPa and TEa. The ventral
part of the temporal lobe had labelled neurons in area TE1 and in
the rostral part of area TL, as well as the perirhinal cortex.
Cases 4 and 5
In case 4, FB injections were placed in the caudal part of orbital
area 47/12 (Figs 9 and 14A), whereas in case 5, DY injections were
placed in the rostral part of orbital 47/12 (Figs 9 and 15A). The
pattern of labelled neurons in these two cases was similar, but with a
few differences. Labelled neurons were observed in areas 9/46v and
FIG. 11. Diagrammatic representation of the unfolded lateral and orbital (A) and medial (B) surfaces of the cerebral hemisphere in case 2 with FB injectionin area 45 and the distribution of the resulting labelled neurons. The sulcus principalis, the superior and inferior limbs of the arcuate sulcus, the lateral ®ssure,the superior temporal sulcus and the cingulate sulcus have been opened up to show the labelled neurons in their banks. Other abbreviations and conventionsas in Fig. 10.
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45, and, on the orbital surface, in areas 13 and 11 in supragranular
and infragranular layers. Only case 4 (ventrocaudal area 47/12) had
labelled neurons on the dorsolateral surface of the frontal lobe, in
areas 9 and 10 (Fig. 14A). On the medial surface, some neurons were
observed in area 9 and the cingulate areas 32 and 24, in case 4
(Fig. 14B), and only in area 24 in case 5 (Fig. 15B). Both cases
displayed neurons in area 44, as well as in the ventral part of area 6.
These connections with the ventral premotor region are consistent
with earlier studies that examined the connections of the ventral
premotor (Barbas & Pandya, 1987) or area 12 (Barbas & Pandya,
1989; Carmichael & Price, 1995). The peri-central operculum also
showed labelled neurons in both cases ± in area SII and in the insula
(Fig. 14A and 15A). In case 5 (Fig. 15A), there were also some
neurons in area PF and in the adjacent lower bank of the intraparietal
sulcus. These somatosensory-related connections are consistent with
other studies that examined the connections of this region (Barbas,
1988; Carmichael & Price, 1995).
Strong connections with the inferotemporal region were observed
in cases 4 and 5. Many labelled neurons were observed in area TEa in
the lower bank of the superior temporal sulcus, as well as in areas
TE1 and TE2. Finally, both cases had labelled neurons in the rostral
part of the perirhinal cortex, as well as in area TL of the
parahippocampal gyrus. These connections are in agreement with
earlier results by Barbas (1988) and Carmichael & Price (1995) who
also concluded that there is strong input from rostral inferotemporal
cortex to the region labelled here as area 47/12.
Case 6
In this case, the DY injections involved area 9/46v in the ventral lip
of the sulcus principalis and the adjacent cortex (Figs 9 and 16A).
Labelled cells in layers III and V were seen in area 47/12, on the
ventrolateral frontal cortex, and in areas 13 and 11, on the orbital
surface. On the medial surface, only a few cells were observed in
area 24a of the cingulate gyrus and in area 24c in the depth of the
cingulate sulcus (Fig. 16B). Posterior to the injection site on the
lateral surface, the major cluster of neurons was in ventral area 6,
area 44 and area ProM. The peri-central operculum in the upper bank
of the Sylvian ®ssure (i.e. areas 1, 2 and SII) contained a substantial
number of labelled neurons in both the supragranular and infra-
granular layers. In the insula, cells were observed in its rostral
dysgranular part. In the parietal cortex, areas PF and PFG (Fig. 12A)
displayed labelled neurons in layers III and V, these extending into
adjacent cortex in the intraparietal sulcus (area POa). These
connection patterns are in agreement with those previously reported
for this region (Barbas & Mesulam, 1985; Preuss & Goldman-Rakic,
1989).
Discussion
The present investigation compared the cytoarchitecture of the human
and the monkey ventrolateral prefrontal cortex in an attempt to de®ne
areas with similar architectonic criteria in these two primate brains.
There is no doubt that there has been considerable development of the
ventrolateral prefrontal cortical areas in the human brain (as indeed is
the case with the rest of the prefrontal cortex), but it is clear from the
present architectonic analysis that the basic architectonic plan is
similar in these two primate brains.
The issue with area 45
The ®rst issue examined in the present investigation was whether
there exists, in the macaque monkey ventrolateral prefrontal cortex, a
region that is similar in cytoarchitecture to area 45 of the human
FIG. 12. Photomicrographs showing the distribution of ¯uorescent labelled neurons in cases with injections of Fast Blue (FB) or Diamidino Yellow (DY).(A) labelled neurons in area PFG in case 6 after injection of DY in area 9/46v. (B) labelled neurons in area TPO in case 2 after injection of FB in area 45.(C) labelled neurons in area TS3 in case 2 after injection of FB in area 45. Calibration bar, 100 mm.
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ventrolateral prefrontal cortex. Walker (1940) designated as `area 45'
a part of the cortex that lies in the anterior bank of the lower limb of
the arcuate sulcus (see Fig. 2B) and tentatively suggested that it may
correspond to area 45 of the human brain. He was, however,
uncertain about this correspondence because he had not explicitly
compared monkey with human architecture (see Walker, 1940; p. 67).
In addition, he was uncertain about its limits in the arcuate sulcus
pointing out that `the upper part of it merges with area 8 without
de®nite line of demarcation' (Walker, 1940; p. 68, lines 3±5).
Furthermore, Walker characterized the region he labelled as `area 45'
as having `large pyramidal cells in the third and ®fth layers' (p. 68,
lines 1±2), whereas area 45 in the human brain is characterized by
FIG. 13. Diagrammatic representation of the unfolded lateral and orbital (A) and medial (B) surfaces of the cerebral hemisphere in case 3 with a DY injectionin area 47/12 and the distribution of the resulting labelled neurons. The sulcus principalis, the superior and inferior limbs of the arcuate sulcus, the superiortemporal sulcus and the cingulate sulcus have been opened up to show the labelled neurons in their banks. Other abbreviations and conventions as in Fig. 10.
304 M. Petrides and D. N. Pandya
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large neurons in layer III combined with medium-size pyramids in
layer V. Other investigators included the cortex that Walker
designated as area 45 as part of area 8 (Brodmann, 1905; Vogt &
Vogt, 1919; Barbas & Pandya, 1989) (Fig. 2A and 2C).
FIG. 14. Diagrammatic representation of the unfolded lateral and orbital (A) and medial (B) surfaces of the cerebral hemisphere in case 4 with FB injectionin caudal area 47/12, and the distribution of the resulting labelled neurons. The sulcus principalis, the lateral ®ssure, the superior temporal sulcus and thecingulate sulcus have been opened up to show the labelled neurons in their banks. Other abbreviations and conventions as in Fig. 10.
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More recently, the term `area 45' has sometimes been used to refer
to the ventral part of the frontal eye ®eld, from which small amplitude
saccades can be evoked with electrical microstimulation, whereas the
part of the frontal eye ®eld where large amplitude saccades can be
evoked has been referred to as caudal area 8A (Schall et al., 1995).
The frontal eye ®eld as de®ned by microstimulation is restricted to
the region of the anterior bank of the arcuate sulcus that curves
around the caudal tip of the sulcus principalis (Bruce et al., 1985;
Stanton et al., 1989; Schall et al., 1995; Cadoret et al. 2000). It is
important to note, however, that the ventral limit of the frontal eye
®eld, as de®ned by microstimulation, lies in the anterior bank of the
arcuate sulcus at a location just ventral to the caudal tip of the sulcus
FIG. 15. Diagrammatic representation of the unfolded lateral and orbital (A) and medial (B) surfaces of the cerebral hemisphere in case 5 with a DY injectionin rostral area 47/12 and the distribution of the resulting labelled neurons. The sulcus principalis, the inferior limb of the arcuate sulcus, the lateral ®ssure, thesuperior temporal sulcus and the cingulate sulcus have been opened up to show the labelled neurons in their banks. Other abbreviations and conventions as inFig. 10.
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FIG. 16. Diagrammatic representation of the unfolded lateral and orbital (A) and medial (B) surfaces of the cerebral hemisphere in case 6 with a DY injectionin area 9/46v and the distribution of the resulting labelled neurons. The sulcus principalis, the inferior limb of the arcuate sulcus, the lateral ®ssure and thecingulate sulcus have been opened up to show the labelled neurons in their banks. Other abbreviations and conventions as in Fig. 10.
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principalis. Inspection of the map of Walker (see Fig. 2B) shows that
the region labelled as `area 45' extends for a considerable distance
along the inferior limb of the arcuate sulcus, a region from which no
eye movements can be evoked with microstimulation (Stanton et al.,
1989; Cadoret et al. 2000). Thus, a large part of the region that
Walker labelled as `area 45' in the anterior bank of the inferior limb
of the arcuate sulcus clearly falls outside the `frontal eye ®eld' as
de®ned electrophysiologically.
The above considerations give rise to the following question. Is all
or part of the strip of cortex that Walker (1940) labelled as `area 45'
in the monkey arcuate cortex similar in architectonic characteristics
to area 45 in the human brain? It should be noted that, in terms of
function, no part of area 45 in the human brain has ever been viewed
as being part of the `frontal eye ®eld'. This fact suggests that it is
highly unlikely that the part of the arcuate sulcus from which eye
movements can be evoked and which has been considered to lie in the
dorsal part of the strip of cortex that Walker labelled as area 45 is
similar to area 45 of the human brain. The aim of the present study
was to examine the monkey and the human prefrontal cortex in a
strictly comparative manner to ®nd out if an area in the monkey
ventrolateral prefrontal cortex has architectonic characteristics simi-
lar to those of area 45 in the human brain. The de®nition of area 45 in
the human brain is not controversial and is agreed by all investigators
that have examined this region (Brodmann, 1908, 1909; Economo &
Koskinas, 1925; Sarkissov et al., 1955; Amunts et al., 1999). The
striking characteristic of area 45 in the human brain that differentiates
it very easily from its surrounding areas is the presence of clusters of
large deeply stained pyramidal neurons in the deeper part of layer III
(i.e. layer IIIc) combined with a well developed layer IV (see Figs 4
and 5) and medium size neurons in layer V. The well developed layer
IV distinguishes area 45 from the caudally adjacent dysgranular
area 44 where layer IV is incipient. The presence of the clusters of
conspicuous large and deeply stained pyramidal neurons in layer IIIc
distinguishes area 45 from dorsally adjacent area 9/46 where medium
size neurons are found. Rostroventrally, the border of area 45 with
area 47/12 can be marked as the point where the conspicuous and
deeply stained large pyramids in layer IIIc have virtually disappeared
(see Figs 4 and 5).
In examining the monkey ventrolateral prefrontal cortex, we
searched for an area that exhibits the distinct characteristics of
area 45 in the human brain, namely prominent, large, deeply stained
neurons in the deeper part of layer III combined with a well
developed layer IV and medium size neurons in layer V. We noted
that only the ventralmost part of the anterior bank of the lower limb
of the arcuate sulcus has architectonic characteristics similar to those
of area 45 of the human brain and that this cortex extends onto the
adjacent ventrolateral prefrontal convexity for a considerable distance
(i.e. as far as the infraprincipalis dimple) (see Figs 3B, 7 and 8). As in
the human brain, area 45 of the monkey can be distinguished,
caudally, from the dysgranular cortex, which lies in the posterior
bank of the arcuate sulcus. The transition between area 9/46 and
area 45 is marked by the appearance of the deeply stained large
pyramidal neurons in layer IIIc that are clearly more prominent and
larger than those of area 9/46 (see Fig. 8). Rostroventrally, again as
in the human brain, area 45 is succeeded by area 47/12 that has
smaller pyramidal neurons in layer IIIc (see Figs 6 and 8).
We were particularly concerned with the dorsal border of area 45
within the anterior bank of the inferior limb of the arcuate sulcus. As
pointed out above, the frontal eye ®eld region, as de®ned by low-
threshold microstimulation, lies within the anterior bank of the
arcuate sulcus in the region that curves just caudal to the sulcus
principalis. In this microstimulation-de®ned frontal eye ®eld region,
the cortex exhibits large and dense pyramidal neurons in layer V
(Stanton et al., 1989). These large layer V neurons diminish sharply
as one moves into the ventral part of the anterior bank of the inferior
limb of the arcuate sulcus, i.e. as one moves away from the region
where eye movements can be evoked (Stanton et al., 1989). In the
ventral part of the inferior limb of the arcuate sulcus that we
considered to be similar to area 45 of the human brain, one rarely
encounters the very large pyramidal neurons in layer V that are
typical in its dorsal part where the frontal eye ®eld is located. We
have included the more dorsal part of the inferior limb of the arcuate
cortex that exhibits large neurons in layer V as part of caudal area 8,
as other investigators had previously done (e.g. Brodmann, 1905;
Barbas & Pandya, 1989). Thus, it is important to note that the
ventralmost part of the anterior bank of the inferior limb of the
arcuate sulcus that we de®ned as area 45 (using the criteria of area 45
in the human brain) is distinct from the more dorsal part of the sulcus
from where short amplitude saccades are generated and which has
been considered to lie in Walker's area 45 in contrast to the part from
where large amplitude saccades are generated and which was
considered to be in caudal area 8A (Schall et al., 1995). In our
architectonic scheme, both the large and short amplitude parts of the
frontal eye ®eld would lie within subdivisions of caudal area 8.
In conclusion, area 45 in the monkey ventrolateral prefrontal
cortex, when de®ned by criteria similar to those of human area 45, is
not coincidental with the area de®ned as 45 by Walker (1940) and
does not include the part of the frontal-eye ®eld from where short
amplitude saccades are generated which was considered by some
investigators to lie in Walker's area 45 (e.g. Schall et al., 1995). We
therefore suggest that, if investigators wish to use the term area 45 for
a part of the frontal eye ®eld in the monkey brain, they should use the
term `Walker's area 45' or the `frontal eye ®eld area 45' to
distinguish it from area 45 as de®ned by criteria similar to those of
the human brain.
We injected retrograde ¯uorescent tracers into the part of the
ventrolateral prefrontal cortex of the monkey that was identi®ed in
this study as similar to area 45 of the human cortex. The pattern of
cortical inputs revealed by these injections was complex, as would be
expected for a prefrontal area, but the strong inputs from the superior
temporal gyrus (i.e. the auditory system) and the multimodal areas of
the superior temporal sulcus (Figs 10 and 11) differentiated this area
from the surrounding areas. Injections of retrograde tracers in the
dorsally adjacent area 9/46v (Fig. 16) did not reveal any inputs from
the superior temporal region. Injections of tracers in area 47/12
(Figs 13 and 14) demonstrated some input only from the anterior
portion of the superior temporal gyrus. In contrast, area 47/12 had
major inputs from the visually related rostral inferotemporal cortex
and major limbic inputs from the rhinal and parahippocampal region.
In addition, such connections from the superior temporal region were
not observed when the more dorsal part of the anterior bank of the
inferior limb of the arcuate sulcus, i.e. area 8Av, was injected with
retrograde tracers (case 3 in Petrides & Pandya, 1999), consistent
with earlier studies (Barbas & Mesulam, 1981; Schall et al., 1995).
The strong inputs from the auditory related superior temporal gyrus
and multimodal inputs from the upper bank of the superior temporal
sulcus to the monkey ventrolateral prefrontal area 45 (Figs 10 and
11), de®ned by architectonic criteria similar to those used to de®ne
human area 45, are consistent with those of an earlier study that
examined large injections of retrograde tracers in the ventrolateral
prefrontal region (Deacon, 1992). In addition, connections to the part
of the monkey ventrolateral prefrontal cortex here de®ned as similar
to human area 45 were observed in earlier studies in which
anterograde tracers were injected in the superior temporal gyrus
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(Petrides & Pandya, 1988; Romanski et al., 1999) or the superior
temporal sulcus (Seltzer & Pandya, 1989), although, naturally, these
projections were not described as terminating in area 45, as this area
had not been de®ned by the present criteria at the time these studies
were published. In these earlier studies (Petrides & Pandya, 1988;
Romanski et al., 1999), connections to the dorsal part of the
ventrolateral prefrontal cortex just ventral to the infraprincipalis
dimple, were described as being in lateral area 12 because the cortex
on the inferior convexity below the sulcus principalis was considered
to be area 12. However, as shown in the present study, the dorsal part
of the inferior convexity is occupied by area 45 as de®ned by the
criteria of the comparably named area in the human brain, whereas its
ventralmost part by area 47/12.
Although the above anatomical observations were obtained in
the monkey, they have important implications with regard to the
anatomical organization of language-related neural circuits of the
human brain. Thus, on the assumption that the connectivity of area 45
in the human brain is similar to that of the monkey, it can be
suggested that area 45 may subserve higher-order aspects of the
organization of linguistic processing. The available functional
neuroimaging data is in excellent agreement with these predictions
from the anatomical ®ndings. Whereas increases in activity in
area 44, which lies caudal to area 45, have been observed in relation
to the articulatory aspects of speech (Paulesu et al., 1993; Petrides
et al., 1993), area 45 has shown increases in activity in relation to the
retrieval of words driven by higher conceptual categories and has
been coactivated with areas of the superior temporal gyrus (e.g. Klein
et al., 1995; Petrides et al., 1995).
Furthermore, the existence of these areas in the monkey implies
that their functional contribution must not be limited to language
production and that they may play a more general and fundamental
role in cognition that was adapted to serve, also, linguistic processing
in the left hemisphere of the human brain. It has been argued that one
fundamental role of the ventrolateral prefrontal areas in cognition lies
in the control of information processing in posterior cortical areas
necessary for the active retrieval of information from memory (for a
discussion of this issue see Petrides, 1996).
The issue of area 47/12
A major issue when attempting to compare the human and the
monkey ventrolateral prefrontal cortex concerns the relationship
between area 47 of the human brain and area 12 of the monkey brain.
The designation `area 47' was used by Brodmann for a very large
zone of the human frontal cortex, extending from the ventralmost part
of the lateral prefrontal cortex to the posterior part of the orbital
frontal cortex as far as the medial orbital sulcus (Fig. 1) (Brodmann,
1908, 1909; Sarkissov et al., 1955); this area was referred to as FF by
Economo & Koskinas (1925). It is a heterogeneous region and
Sarkissov et al. (1955) subdivided it into ®ve parts. The designation
`area 47' has not been used in any of the maps of the monkey brain,
but Walker (1940) identi®ed a large area on the ventrolateral part of
the macaque frontal lobe extending onto the orbital surface which he
called area 12 (Fig. 2B). Medial to area 12, on the orbital frontal
surface, Walker (1940) identi®ed two other areas: area 13, caudally,
and area 11, rostrally.
It is important here to note that in Walker's map, area 12 occupies
the ventralmost part of the ventrolateral convexity (see Fig. 2B).
However, the term `area 12' was later used to refer to the entire
inferior convexity below the outer lip of the ventral bank of the sulcus
principalis (i.e. area 46vr of Preuss & Goldman-Rakic, 1989 or 9/46v
of Petrides & Pandya, 1994). In the present architectonic analysis, it
was evident that the region occupying the ventralmost part of the
ventrolateral prefrontal cortex and extending onto the orbital surface
that Walker labelled as area 12 characterized as having a `feeble
granular layer' (p. 76, line 8), i.e. a narrow layer IV, has
characteristics similar to those of the part of the human area 47
that lies anterior and below area 45 and which also extends as far as
the lateral orbital sulcus. We have labelled this region, in both the
human and the monkey brain, as area 47/12 (Fig. 3A and B) to
acknowledge the similarity in topography and cytoarchitecture of this
part of the frontal cortex in these two primate brains. Furthermore,
our architectonic analysis revealed that the part of Brodmann's
area 47 that extends medial to the lateral orbital sulcus in the human
brain is a dysgranular cortex that has characteristics similar to those
of the caudal orbital frontal cortex that Walker labelled as area 13 in
the monkey (see Petrides & Pandya, 1994).
Thus, the inferior convexity of the macaque monkey cortex
comprises two architectonic areas, i.e. areas 45 and 47/12, that, in the
human brain, occupy the pars triangularis and pars orbitalis of the
inferior frontal gyrus. Although both areas 47/12 and 45, as de®ned in
the present study, share many connections, there are also some major
differences. Area 47/12 maintains strong links with the rostral
inferotemporal visual association cortex and ventral limbic areas
(i.e. perirhinal cortex and rostral parahippocampal gyrus), as
compared with dorsally adjacent area 45. Furthermore, area 47/12
is not as strongly connected with the auditory superior temporal
region as area 45. The connections for area 47/12 shown in the
present study are consistent with those revealed by tracer injections in
this part of the monkey ventrolateral prefrontal cortex studied by
Barbas (1988) and Carmichael & Price (1995). It has been argued that
areas 45 and 47/12 may be part of a frontal mid-ventrolateral
executive system that is involved in active judgements on stimuli that
are coded and held in posterior association cortex and therefore this
region may be necessary for active retrieval of information from
posterior cortical association regions (Petrides 1996). Recent studies
with positron emission tomography have reported increases in
activity in this region of the cortex in various active memory
judgements on delayed matching tasks (e.g. Courtney et al., 1996;
Petrides et al. 2002) and on tasks requiring active retrieval processes
(Cadoret et al. 2001; Kostopoulos & Petrides, 2001).
The present investigation, by providing parcellations of areas of the
ventrolateral prefrontal cortex based on the same criteria in the
human and the macaque monkey brain and the connectional patterns
of these comparably identi®ed cortical areas, should facilitate the
integration of information obtained in studies of the nonhuman
primate brain with that emerging from neuroimaging work on the
functional organization of the human brain.
Acknowledgements
We thank Scott Mackey and Meg Chiavaras for excellent technical assistance.This study was supported by a grant from NSERC and CIHR. Scott Mackeyprepared Figs 4±6, 8 and 9 and Meg Chiavaras Figs 10±16.
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