comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex...

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Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey M. Petrides 1, * and D. N. Pandya 2 1 Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4 Canada; and Department of Psychology, McGill University, 1205 Dr Penfield Avenue, Montreal, Quebec, H3A 1B1, Canada 2 Departments 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 a region 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 the macaque 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 specific 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 two areas were examined in the monkey by injecting fluorescent retrograde tracers. Although both area 45 and area 47/12 as defined 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 limbic areas (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 identification of changes in neuronal activity within specific 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 findings 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 specific 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 definition 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 ª Federation of European Neuroscience Societies

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Page 1: Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey

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

Page 2: Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey

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

Page 3: Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey

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

Page 4: Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey

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

Page 5: Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey

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

Page 6: Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey

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

ã 2001 Federation of European Neuroscience Societies, European Journal of Neuroscience, 16, 291±310

Page 7: Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey

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

Page 8: Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey

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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

Page 9: Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey

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.

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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.

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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.

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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

308 M. Petrides and D. N. Pandya

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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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