subdivisions and connectional networks of the lateral prefrontal cortex in the macaque monkey

Subdivisions and Connectional Networks of theLateral Prefrontal Cortex in the Macaque Monkey

Kadharbatcha S. Saleem,1,2* Brad Miller,1 and Joseph L. Price1

1Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 631102Laboratory of Neuropsychology, National Institute of Mental Health, National Institute of Health, Bethesda, Maryland 20892

ABSTRACTNeuroanatomical studies have long indicated that corti-

cocortical connections are organized in networks that

relate distinct sets of areas. Such networks have been

emphasized by development of functional imaging

methods for correlating activity across the cortex. Previ-

ously, two networks were recognized in the orbitome-

dial prefrontal cortex, the “orbital” and “medial”

networks (OPFC and MPFC, respectively). In this study,

three additional networks are proposed for the lateral

prefrontal cortex: 1) a ventrolateral network (VLPFC) in

and ventral to the principal sulcus; 2) a dorsal network

(DPFC) in and dorsal to the principal sulcus and in the

frontal pole; 3) a caudolateral network (CLPFC) in and

rostral to the arcuate sulcus and the caudal principal

sulcus. The connections of the first two networks are

described here. Areas in each network are connected

primarily with other areas in the same network, with

overlaps around the principal sulcus. The VLPFC and

DPFC are also connected with the OPFC and MPFC,

respectively. Outside the prefrontal cortex, the VLPFC

connects with specific areas related to somatic/visceral

sensation and vision, in the frontoparietal operculum,

insula, ventral bank/fundus of the superior temporal

sulcus, inferior temporal gyrus, and inferior parietal cor-

tex. In contrast, the DPFC connects with the rostral

superior temporal gyrus, dorsal bank of the superior

temporal sulcus, parahippocampal cortex, and posterior

cingulate and retrosplenial cortex. Area 45a, in caudal

VLPFC, is unique, having connections with all the net-

works. Its extrinsic connections resemble those of the

DPFC. In addition, it has connections with both auditory

belt/parabelt areas, and visual related areas. J. Comp.

Neurol. 522:1641–1690, 2014.

VC 2013 Wiley Periodicals, Inc.

INDEXING TERMS: LPFC; VLPFC; DPFC; CLPFC; OMPFC; OPFC; MPFC; superior temporal gyrus; parietal cortex; infe-

rior temporal cortex; superior temporal sulcus; insula; connections

Although the prefrontal cortex (PFC) in primates,

defined as the region rostral to the “frontal” motor

areas, does not have obvious sensory or motor roles, it

has been associated with many functions. Perhaps the

most common is “executive function,” but this vague

and ultimately unsatisfactory designation subsumes a

number of subordinate functions. Attention, spatial and

nonspatial working memory, assessment of food stimuli,

reward-guided behavior, anticipation of reward or aver-

sion, emotional behavior, and mood have all been

attributed to the PFC (Mishkin and Manning, 1978;

Levy and Goldman-Rakic, 2000; Miller, 2000; €Ong€ur

and Price, 2000; Rolls, 2000; Rushworth et al., 2005;

Petrides, 2005; Meyer et al., 2011; Noonan et al.,

2011; Rudebeck and Murray, 2011b; Price and Drevets,

2012; Passingham and Wise, 2012). Because the PFC

as a whole is large and heterogeneous, it is likely that

these and other functions are not represented evenly

across the many architectonic areas that make it up.

Instead, it may be presumed that the PFC is divided

into several networks that have distinct roles.

The development of methods that are purported to

demonstrate “functional connections” with MRI (fcMRI)

has led to the description of several corticocortical net-

works. These link widespread cortical areas in several

parts of the cortex and are presumed to underlie

Grant sponsor: National Institutes of Health; Grant number:MH70941; Grant sponsor: McDonnell Center for Higher Brain Function;Grant sponsor: National Institute of Mental Health Intramural ResearchProgram.

*CORRESPONDENCE TO: Kadharbatcha Saleem, PhD, Laboratory ofNeuropsychology, National Institute of Mental Health, 49 Convent Drive,Bldg. 49, 1B80 MSc. 4415, Bethesda, MD 20892.E-mail: [email protected]

Received June 12, 2013; Revised October 31, 2013;Accepted October 31, 2013.DOI 10.1002/cne.23498Published online November 9, 2013 in Wiley Online Library(wileyonlinelibrary.com)VC 2013 Wiley Periodicals, Inc.

The Journal of Comparative Neurology | Research in Systems Neuroscience 522:1641–1690 (2014) 1641

RESEARCH ARTICLE

Abbreviations

1–2 somatosensory areas 1 and 23a/b somatosensory areas 3a and 3b3v third ventricle4 primary motor cortex (or F1)5 superior parietal lobule area (or PE / PEa / PEc)7a caudal inferior parietal lobule area (or Opt / PG)7b rostral inferior parietal lobule area (or PFG / PF)7m medial parietal area (or PGm)7op parietal opercular area8Ad periarcuate area (or frontal eye field), dorsal subdivison8Av periarcuate area (or frontal eye field), ventral subdivison8Bd/m dorsal prefrontal area9d/m dorsal prefrontal area10mr frontal pole area10mc medial prefrontal area10o frontal pole area11l orbital prefrontal area11m orbital prefrontal area12l ventrolateral prefrontal area12m orbital prefrontal area12o orbital prefrontal area12r ventrolateral prefrontal area13a,b orbital prefrontal area13l/m orbital prefrontal area14r/c orbitomedial prefrontal area (gyrus rectus)23 posterior cingulate cortexv23 or 23v subregion of posterior cingulate cortex24a/b/c subregions of anterior cingulate cortex24a0/b0/c0 subregions of anterior cingulate cortex25 medial prefrontal area29/30 retrosplenial cortex31 posterior cingulate area32 medial prefrontal area35 area 35 of the perirhinal cortex36c area 36 of the perirhinal cortex, caudal subregion36p area 36 of the perirhinal cortex, temporal-polar subregion36r area 36 of the perirhinal cortex, rostral subregion44 ventrolateral prefrontal area45a/b ventrolateral prefrontal area46d dorsal prefrontal area46v ventrolateral prefrontal area46f ventrolateral prefrontal area46d/v caudal caudolateral prefrontal areaAAA anterior amygdaloid areaAB accessory basal nucleus of amygdalaac anterior commissureAI auditory area I, core region of the auditory cortexAIP anterior intraparietal areaAL anterior lateral, belt region of the auditory cortexamts anterior middle temporal sulcusamy amygdalaArh arcuate hypothalamic nucleusasl arcuate sulcus lower limbasu arcuate sulcus upper limbB basal nucleus of amygdalacas calcarine sulcusCC corpus callosumcd caudate nucleuscis cingulate sulcusCL caudal lateral, belt region of the auditory cortexcla claustrumclc central latocellular nucleusCLPFC caudolateral prefrontal (network) cortexCM caudomedial, belt region of the auditory cortexCOa anterior cortical nucleusCP cerebral peduncleCPB caudal parabelt region of the auditory cortexcs central sulcusDP dorsal prelunate areaDPFC dorsal prefrontal (network) cortexF1 agranular frontal area F1 (or 4)F2 agranular frontal area F2F3 agranular frontal area F3 (or SMA)F4 agranular frontal area F4F5 agranular frontal area F5F6 agranular frontal area F6 (or preSMA)F7 agranular frontal area F7FST floor of superior temporal areaG gustatory cortexGP globus pallidusHC hippocampusIa agranular insula

Iac caudal agranular insular areaIai intermediate agranular insula areaIal lateral agranular insula areaIam medial agranular insula areaIapl posterolateral agranular insula areaIapm posteromedial agranular insula areaId dysgranular insula,Ig granular insulaios inferior occipital sulcusipd infraprincipal dimpleips intraparietal sulcusL lateral nucleus of amygdalaLd lateral nucleus of amygdala, dorsal subdivision,LGN lateral geniculate nucleusLIP lateral intraparietal areaLIPd lateral intraparietal area, dorsal subdivisionLIPv lateral intraparietal area, ventral subdivisionLP lateral posterior nucleusls lateral sulcuslus lunate sulcusLv lateral nucleus of amygdala, ventral subdivision,lv lateral ventricleMD medial dorsal nucleusMDpc mediodorsal nucleus, parvicellular divisionML middle lateral, belt region of the auditory cortexMPFC medial prefrontal (network) cortexMST medial superior temporal areaMT middle temporal area,NA nucleus accumbensNBM nucleus basalis of MeynertOPf frontal opercular areaOPFC orbital prefrontal (network) cortexOpt caudal inferior parietal lobule area (or 7a)ot optic tractots occipitotemporal sulcusP pulvinarPa paraventricular nucleusPAC periamygdaloid cortexPcn paracentral nucleusPE superior parietal lobule area (or 5)PEa superior parietal lobule area (or 5)PEc superior parietal lobule area (or 5)PF rostral inferior parietal lobule area (or 7b)Pf parafascicular nucleusPFG rostral inferior parietal lobule area (or 7b)PG caudal inferior parietal lobule area (or 7a)PGm medial parietal area (or 7m)PI inferior pulvinarPi parainsular areaPL lateral pulvinarPM medial pulvinarpmts posterior middle temporal sulcusPO parieto-occipital area (or V6/V6Av)pos parieto-occipital sulcusPrCO precentral opercular areaPreSMA presupplementary motor areaps principal sulcuspu putamenPV parietal ventral areaR rostral, core region of the auditory cortexRe reunions nucleusRM rostromedial, belt region of the auditory cortexRPB rostral parabelt region of the auditory cortexrs rhinal sulcusRT rostrotemporal, core region of the auditory cortexRTL lateral rostrotemporal, belt region of the auditory cortexRTM medial rostrotemporal, belt region of the auditory cortexRTp rostrotemporal (“p” refers to polar)sas spur of the arcuate sulcusSII secondary somatosensory areaSMA supplementary motor areaSTGr rostral superior temporal gyrussts superior temporal sulcusSTSd dorsal bank of the superior temporal sulcusSTSf fundus of the superior temporal sulcusSTSv ventral bank of the superior temporal sulcusTEad dorsal subregion of anterior TETEav ventral subregion of anterior TETEOd area TEO, dorsal partTEOv area TEO, ventral partTEpd dorsal subregion of posterior TETEpv ventral subregion of posterior TE

K.S. Saleem et al.

1642 The Journal of Comparative Neurology |Research in Systems Neuroscience

specific functions (see, e.g., Power et al., 2011).

Although the relationship between these functional net-

works and anatomical connections is still uncertain,

such networks, and previous neuroanatomical analyses

of corticocortical connections (see, e.g., Pandya and

Kuypers, 1969; Jones and Powell, 1970), imply that the

cortex is a mosaic of interwoven circuits that connect

restricted cortical areas. Any region as large as the PFC

can therefore be expected to be heterogeneous in

function.

For the ventromedial or orbital and medial parts of

the PFC (OMPFC), previous neuroanatomical studies

have defined two systems or “networks.” These were

based initially on distinctions in intrinsic connections

within the OMPFC (Carmichael and Price, 1996), but

the two systems also have distinct connections with

other brain areas. The so-called orbital (OPFC) network

is connected to several sensory-related cortical areas,

such as the olfactory and taste cortices, visual-related

areas in the inferior temporal gyrus, and somatic

sensory-related areas in the insula and frontoparietal

operculum (Carmichael and Price, 1995; €Ong€ur and

Price, 2000; Saleem et al., 2008b). This network

appears to integrate multimodal sensory information,

especially related to food, and to be involved in assess-

ment of stimuli in terms of reward and/or aversion and

their relative “value” in relation to other stimuli (€Ong€ur

and Price, 2000; Padoa-Schioppa and Assad, 2006;

Rudebeck and Murray, 2011a,b). The “medial” (MPFC)

network has few sensory inputs but has substantial out-

puts to visceral control areas in the hypothalamus and

brainstem (An et al., 1998; €Ong€ur et al., 1998). It is

also interconnected with a well-defined cortical circuit

involving the anterior and posterior cingulate cortex, an

area in the rostral superior temporal gyrus and dorsal

bank of the superior temporal sulcus, and the posterior

parahippocampal cortex (Saleem et al., 2008b) as well

as limbic structures, including the amygdala, hippocam-

pus, and entorhinal cortex. This network is related to

modulation of visceral function in relation to emotion

and is critically involved in mood disorders (Drevets

et al., 1997, 1998; Mayberg et al., 1999, 2005; Price

and Drevets, 2012).

In the lateral part of the PFC (LPFC), there are also

indications that relatively restricted regions have distinct

functions. Thus, in monkeys, the “ventrolateral prefrontal

cortex” (VLPFC), below the principal sulcus, has been

related to the assessment and convergence of sensory

information, including the processing of faces, visual

association, and integration of species-specific face and

vocal stimuli, and has also been thought to be involved in

object working memory and memory retrieval (Wilson

et al., 1993; O Scalaidhe et al., 1997; Asaad et al., 1998;

Levy and Goldman-Rakic, 2000; Passingham et al., 2000;

Cadoret and Petrides, 2007; Tsao et al., 2008b; Roman-

ski, 2012). The “dorsal prefrontal cortex” (DPFC) above

the principal sulcus has been thought to be involved in

self-centered functions, including behaviors that depend

on the previous actions or feelings of the individual (Pet-

rides, 2005). Finally, the “caudolateral prefrontal cortex”

(CLPFC), the region around the arcuate sulcus, and parts

of the caudal principal sulcus have been related to eye

movements (frontal eye field), attention, shape selectivity,

and working memory for spatial position (Bruce and Gold-

berg, 1985; Bruce et al., 1985; Gamlin and Yoon, 2000;

Tehovnik et al., 2000; Schall 2004; Peng et al., 2008;

Amiez and Petrides, 2009; Monosov and Thompson,

2009; Zhou and Desimone, 2011).

Several anatomical studies have documented the

connections of the LPFC with other cortical areas

(Kuypers et al., 1965; Pandya and Kuypers, 1969; Jones

and Powell, 1970; Chavis and Pandya, 1976; Barbas

and Mesulam, 1981, 1985; Kawamura and Naito, 1984;

Shiwa, 1987; Barbas, 1988; Barbas and Pandya, 1989;

Seltzer and Pandya, 1989; Ungerleider et al., 1989;

Webster et al., 1994; Romanski et al. 1999a,b). Pet-

rides and Pandya (1999, 2002, 2006, 2007), in particu-

lar, have approached this topic with several studies of

the efferent (or afferent) connections of the dorsome-

dial, ventrolateral, caudal, and rostral parts of the

LPFC. Based on these studies, Pandya and his col-

leagues have proposed that the prefrontal cortex can

be divided into two architectonic “trends,” separated

along the principal sulcus (e.g., Yeterian et al., 2012).

The dorsal trend includes the medial and dorsomedial

prefrontal surface, whereas the ventral trend includes

TF area TF of the parahippocampal cortexTFO area TFO of the parahippocampal cortexTGa agranular part of the temporal poleTGdd dysgranular part of the dorsal temporal poleTGdg granular part of the dorsal temporal poleTGsts sts part of the temporal poleTGvd ventral dysgranular part of the temporal poleTGvg ventral granular part of the temporal poleTH area TH of the parahippocampal cortexTpt temporoparietal areaV1 visual area 1 (primary visual cortex)V2 visual area 2V3v visual area 3, ventral partV4d visual area 4, dorsal part

V4t V4 transitional areaV4v visual area 4, ventral partV6 visual area 6 (or PO)V6Ad visual area 6A, dorsal divisionV6Av visual area 6A, ventral division (or PO)VA ventral anterior nucleusVAmc ventral anterior nucleus, magnocellular divisionVIP ventral intraparietal areaVLc ventral lateral caudal nucleusVLPFC ventrolateral prefrontal (network) cortexVMH ventromedial hypothalamic nucleusVPLo ventral posterior lateral oral nucleusVPM ventral posterior medial nucleus

Connections of the lateral prefrontal cortex

The Journal of Comparative Neurology | Research in Systems Neuroscience 1643

the orbital and ventrolateral surfaces. Areas within each

trend are preferentially interconnected with each other

and with similar areas in other parts of the cortex,

although substantial individual variation is reported

between areas, especially for the caudal areas of each

trend (Yeterian et al., 2012).

In this study, the intrinsic and extrinsic cortical con-

nections of the LPFC were analyzed with anterograde

and retrograde tracers in an attempt to define distinct

connectional and functional networks. Tracers were

also injected into different parts of the superior and

inferior temporal cortex that are connected with the

LPFC. Initial results on intrinsic, intra-PFC connections

suggest that there are at least three relatively distinct

networks within the dorsal, ventrolateral, and caudolat-

eral parts of the LPFC (DPFC, VLPFC, CLPFC, respec-

tively). Further analysis of the extrinsic, or extra-PFC,

corticocortical connections of the networks indicated

that each of three networks has a unique pattern of

corticocortical connections. These constitute three

functionally different cortical circuits. In addition, there

is a small ventrolateral region, just rostral to the lower

limb of the arcuate sulcus (area 45a), that has connec-

tions with all of three networks in the LPFC. Some of

the present results have been reported in abstract form

(Saleem et al., 2008a).

MATERIALS AND METHODS

Retrograde tracers were injected into subregions of

the LPFC, including the frontal pole, in adult cynomol-

gous monkeys (Macaca fascicularis). In addition, some

cases with anterograde and retrograde tracer injections

in the inferior and superior temporal cortex, which had

been prepared and used in previous studies (Saleem

et al., 2008b), were reexamined and reanalyzed in rela-

tion to the connections with the LPFC (see Table 1 for

all tracer injections). All animal protocols were reviewed

and approved by the Animal Studies Committee of

Washington University and were in compliance with the

guidelines of the NIH for the care and use of laboratory

animals.

MRI, surgery, and tracer injectionThe details of the MR imaging, anesthesia, aseptic

surgery, and tracer injections have been described by

Saleem et al. (2008b). In brief, prior to surgery, each

monkey was anesthetized (see below) and placed in an

MRI-compatible stereotaxic frame. An MRI scan was

then obtained using a 1.5-T scanner, with a receive-only

or volume coil placed over the top of the head of the

animal. Stereotaxic coordinates for each desired injec-

tion site in the PFC that were specific for each individ-

ual animal were derived without correction from the MR

images. These individual-specific coordinates were com-

pared with coordinates from the cynomolgous monkey

brain atlas of Szabo and Cowan (1984).

For the surgery and MRI scans, anesthesia was

induced by intramuscular injection of ketamine (10

mg/kg) and xylazine (0.67 mg/kg). The animals were

then intubated, and surgical anesthesia was initiated

with a gaseous mixture of oxygen, nitrous oxide, and

halothane or isofluorane. Once anesthesia had been

established, the animals were placed in a stereotaxic

apparatus, and the scalp was incised. Craniotomies

were made in the skull at the sites indicated by the ste-

reotaxic analysis. The midline was defined from the

midsagittal sinus. After surgery, a longlasting analgesic,

buprenorphine (0.1 mg/kg, i.m.), was given as the ani-

mal was brought out of anesthesia.

For most of the LPFC injections, the expected locus

of the injection was determined from the coordinates

derived from the MRI scan, an appropriate craniotomy

was made, and the principal sulcus and the arcuate sul-

cus were exposed. Similarly, for most of the inferior

and superior temporal cortical injections, the superior

TABLE 1.

Tracer Injections in the Lateral Prefrontal and Temporal

Cortex

Case No.

Area(s)

injected Tracer Figure No.

Retrograde tracer injections in VLPFC (12r, 12l, and 46v cases)1 (OM84) 12r DY 2A, 3A, 42 (OM80) 12r DY 2B3 (OM9) 12l DY 2C4 (OM87) 12l FB 2D, 3B, 55 (OM77) 46v middle FB 2E, 3C, 66 (OM76) 46v middle FB 2F7 (OM82) 46v middle CTB 2G, 3D, 78 (OM76) 46v caudal DY 2HRetrograde tracer injections in VLPFC (45a and 45b cases)9 (OM86) 45a rostral FB 3E, 8A, 910 (OM84) 45a caudal FB 3F, 8B, 1011 (OM77) 45a/b LY 3G, 8C, 11Retrograde tracer injections in DPFC (9, 10, 46d, and 8B cases)12 (OM19) 10o FB 13A13 (OM81) 46d rostral DY 13B, 14D, 1714 (OM69) 10mr FR 13C, 14E, 1815 (OM64) 10mr FB 13D, 14A, 1516 (OM64) 9d rostral DY 13E, 14B, 1517 (OM77) 9 d/m FR 13F, 14F, 1618 (OM81) 9d caudal FR 13G19 (OM85) 46d caudal/8B? FB 13H20 (OM80) 46d middle FB 13I, 14C, 1921 (OM86) 8B LY 13J, 20Anterograde and retrograde tracer injections in the temporal

cortex22 (OM59) STSd/STGr and STSv LY and BDA 12A23 (OM55) STGr DY 21A24 (OM68) STGr and belt/

parabeltDY, FB, and CTB 21B, C, D

K.S. Saleem et al.


temporal sulcus and lateral sulcus were exposed after

appropriate craniotomy. The injection sites were then

determined with reference to these sulci, together with

the stereotaxic coordinates derived from the MRI scan.

Aqueous solutions of three retrograde tracers (fast

blue [FB; Sigma, St. Louis, MO; Dr. Illing; 2%], diamidino

yellow [DY; Sigma; 4%], and cholera toxin subunit B

[CTb; List Biological, Campbell, OR; 1–2%]) and an

anterograde tracer (biotinylated dextran amine [BDA;

Molecular Probes, Eugene, OR; 10%]) and two bidirec-

tional tracers (fluoro-ruby [FR; Molecular Probes; 5% or

10%], and Lucifer yellow [LY; Molecular Probes; 5% or

10%]) were injected in each animal. The injections were

made through micropipettes with an air pressure sys-

tem. The volume of tracers injected varied between 0.1

and 1.2 ll, depending on the sensitivity of tracers. To

avoid spread of tracer into areas along the pipette

track, the micropipette was left in place for 10–20

minutes after the injection was finished. With this pro-

cedure, there was little spread of tracer into the overly-

ing cortex or white matter.

Perfusion and histological processingAfter a survival period of 2 weeks, the animals were

anesthetized with ketamine (10 mg/kg, i.m.), followed

by sodium pentobarbital (25–30 mg/kg i.v.), and per-

fused with a pH shift fixation method as described by

Carmichael and Price (1994), with slight modifications

(Saleem et al., 2008b). In this method, the animals

were first perfused transcardially with warm heparinized

saline, followed by a sequence of cold 4% paraformalde-

hyde in 0.1 M sodium acetate buffer (pH 6.5), then 4%

paraformaldehyde in 0.1 M borate buffer (pH 9.5), and

finally 4% paraformaldehyde and 10% sucrose in borate

buffer. The brain was blocked stereotaxically, removed,

photographed, and postfixed for 6 hours in the final fix-

ative/sucrose solution and then transferred through 20

and 30% sucrose in 0.1 M phosphate buffer (pH 7.2–

7.4) at 4�C.

After 3–4 days, the brain blocks were frozen in dry

ice and isopentane, and cut coronally at 50 lm thick-

ness on a sliding microtome. An alternating series of

sections was processed for each tracer, usually one

section out of 10 in each series, with 500-lm intervals

between adjacent sections. The fluorescent tracers FB

and DY were analyzed from unstained sections. BDA

was processed directly with the avidin-biotin-peroxidase

method. The other tracers, CTb, FR, and LY, were proc-

essed immunohistochemically with an avidin-biotin-

horseradish peroxidase method (Carmichael et al.,

1994; Haber et al., 2000). For these tracers, the sec-

tions were first processed to block the biotin from the

injected BDA (Avidin/Biotin Blocking Kit; Vector, Burlin-

game, CA) and then incubated for 3–3.5 days in the pri-

mary antibody (anti-CTb: List Biological; No. 703;

1:10,000–20,000; antitetramethylrhodamine [for FR]

and anti-LY: Molecular Probes; Nos. A-6397 and

A-5750; 1:1,000). The sections were then processed

with the appropriate biotinylated secondary antibody

and avidin/biotin staining kit (Vector) with diaminoben-

zidene as the chromogen (for other details see Saleem

et al., 2008b). For BDA, LY, and FR, the immunostaining

was enhanced with a silver/gold intensification method,

which made the labeled axons and cells visible with

darkfield illumination (Carmichael and Price, 1994).

Additional series of sections were processed with Nissl,

acetylcholinesterase (AChE), and myelin (Gallyas) stains,

or immunohistochemically with antibodies against par-

valbumin (Sigma.; Nos. P3171 and P3088) and a non-

phosphorylated epitope of the neurofilament protein

(recognized by the SMI-32 antibody; Sternberger Mono-

clonals, Baltimore, MD). The specificity of antibodies

against parvalbumin and SMI-32 has been described in

our previous article (Saleem et al., 2007). In brief, the

parvalbumin antibody was raised against parvalbumin

from carp muscle. It was determined to be specific by

immunoblotting (Western blot), staining specifically the

12,000-molecular-weight band that was identified as

parvalbumin by Ca binding (Sigma data sheet). The par-

valbumin has been shown to stain subpopulations of

nonpyramidal neurons (GABAergic) in the neocortex and

to label different types of neurons in subcortical struc-

tures (Jones and Hendry, 1989; Saleem and Logothetis,

2012). The SMI-32 antibody recognizes a nonphos-

phorylated epitope of neurofilament H. It was shown to

be specific by immunoblot, in which it recognizes a

double band at MW 200,000 and 180,000; this double

band merges into a single neurofilament H line on two-

dimensional blots (Sternberger and Sternberger, 1983;

Goldstein et al., 1987). The antibody has been shown

to stain a subpopulation of pyramidal cells in the neo-

cortex (see, e.g., Campbell and Morrison, 1989; Hof

and Morrison, 1995); the pattern of staining seen in

this study corresponds to well-established patterns

from many previous studies.

Data analysis and presentationof illustrations

The location and the extent of each injection site and

the spatial distribution of labeled cell bodies and axonal

varicosities were plotted from the histological sections

with a microscope digitizer system that has encoders

attached to the microscope stage and is interfaced

with a personal computer (AccuStage, Shoreview, MN).

Cortical boundaries and other landmarks were added to



these plots by camera lucida drawings of adjacent

Nissl-, parvalbumin-, AChE-, and myelin-stained sec-

tions. Each labeled cell was plotted as a single point.

The files prepared with the microscope digitizer were

transferred to Adobe Illustrator with a utility supplied

by AccuStage and then into the drawing program Can-

vas (Deneba; ACD Systems), to add the section out-

lines, boundaries between gray and white matter,

architectonic areas, and labels. To ensure that all cells

were plotted, and were not double plotted, in many

cases the sections were scanned in rows, resulting in

the appearance of rows of cells on the plots. Beyond

this, the distribution of the labeled cells was not

altered, and they retained their exact position as plot-

ted at the microscope. The maps of individual sections

were then combined to make the figures. Photomicro-

graphs to document the tracer injection sites and pat-

terns of labeling were taken with a Nikon DXM1200

CCD camera attached to the microscope, using Nikon

ACT-1 image acquisition software. The images were

transferred into Adobe Photoshop for adjustment of the

brightness and contrast to show the injection sites and

labeled axons optimally and to size the images for

inclusion into a plate.

RESULTS

Subdivisions of the LPFCBased on the observation of intrinsic and extrinsic

connections in the present study, three relatively dis-

tinct networks were recognized in the LPFC (Fig. 1A).

1) The ventrolateral prefrontal network (VLPFC) includes

the cortex ventral to the principal sulcus on the ventro-

lateral convexity of the PFC. This network consists of

areas 12r, 12l, and 46v (except for its most caudal

part, area 45a). Area 45 (45a/b) is part of the ventro-

lateral convexity but has distinct and different connec-

tions and will be considered separately. 2) The dorsal

prefrontal network (DPFC) includes cortex dorsal to the

principal sulcus, extending around the dorsomedial con-

vexity. It consists of areas 8B, 9, and 46d (except for

its most caudal part), and the frontal polar parts of

areas 10m and 10o. 3) The caudolateral prefrontal net-

work (CLPFC) that includes cortex in and rostral to the

arcuate sulcus, extending forward within the caudal por-

tion of the principal sulcus (areas 8Ad/8Av and 46d/v).

The connections that constitute CLPFC network will be

described in detail in a later publication; in this article,

the CLPFC will be described only for comparison with

the other two networks.

Note that we have chosen not to use the term dorso-

lateral prefrontal cortex or DLPFC in this study in order

to avoid confusion with the common usage of this term

to denote either the entire LPFC or specifically the

region both dorsal and ventral to the principal sulcus

(e.g., Levy and Goldman-Rakic, 2000; Wallis and Miller,

2003; Fox et al., 2012).

The architectonic areas of the LPFC (Fig. 1A) are

delineated based on the descriptions by Walker (1940),

Preuss and Goldman-Rakic (1991), and Petrides and

Pandya (1999). It is useful to consider different areas in

relation to the principal and arcuate sulci. Caudal to

the principal sulcus, area 8A (frontal eye fields) occu-

pies the rostral bank of the arcuate sulcus and the

gyrus immediately rostral to the sulcus; it is usually

divided into dorsal and ventral parts (areas 8Ad and

8Av, respectively; Petrides and Pandya, 2002). Dorsal

to the principal sulcus, areas 8B, 9, and 10 are found

from caudal to rostral on the dorsomedial convexity

(Walker, 1940). Area 9 can be further divided into 9m

on the medial wall and 9d on the dorsal surface (Preuss

and Goldman-Rakic, 1991).

The most rostral part of the PFC is occupied by area

10, which has been previously divided into a medial

subdivision (area 10m) and a rostral orbital subdivision

(area 10o; Carmichael and Price, 1994). Area 10o is in

the most rostral part of the orbital cortex and extends

around the ventral aspect of the frontal pole. Area 10m

is located on the medial wall, between areas 32 and

14, and extends rostrally around the dorsal part of the

frontal pole. The area increases in granularity rostrally,

and it can be divided into a rostral area 10mr and a

caudal area 10mc (Saleem et al., 2008b; Fig. 1B).

These areas have previously been described as part of

the MPFC; areas 10mr and 10o will also be discussed

here because these areas extend around the frontal

pole into the LPFC.

Ventral to the principal sulcus, area 12 occupies the

rostral part of the ventrolateral convexity. Carmichael

and Price (1994) divided this region into areas 12r and

12l on the lateral side and areas 12m and 12o on the

orbital surface (Fig. 1A,B). Area 45 is found in the cau-

dal aspect of the convexity, back to the inferior limb of

the arcuate sulcus (Walker, 1940), and is characterized

by having large pyramidal cells in layer III (Walker,

1940; Petrides and Pandya, 2002; see also Carmichael

and Price, 1994, for the architectonic distinction

between areas 12l and 45). Based on the comparative

cytoarchitectonic analysis in both human and nonhu-

man primates, Petrides and Pandya (1999, 2002) have

subdivided this area into 45a and 45b, on the convexity

rostral to the arcuate sulcus and in the rostroventral

bank of the sulcus, respectively (see also Gerbella

et al., 2007, for the architectonic analysis of these

areas). We adapted this subdivision in the present

study (Fig. 1). For discussion related to area 45 and

K.S. Saleem et al.


Figure 1. A: Subdivisions of the lateral prefrontal cortex (LPFC). Three relatively distinct networks (subdivisions) were recognized in LPFC

based on their intrinsic and extrinsic connections: 1) the ventrolateral prefrontal network (VLPFC; shades of yellow; which includes areas 12r,

12l, 46v/f, and 45a/b), 2) the dorsal prefrontal network (DPFC; shades of red/orange; areas 9, 46d, and 8B and also frontal pole areas 10mr

and 10o), and 3) the caudolateral prefrontal network (CLPFC; green shading; areas 8Ad/8Av and caudal most parts of 46d/v). Area 45a (pale

yellow) is a distinct region with connections different from those of other VLPFC areas. The region indicated by a question mark in the DPFC

(pale red in the midportion of 46d) may also have a pattern of connections different from the patterns of other parts of the DPFC (see Fig. 19

and related text for more detail). Note that we have chosen “DPFC” but not DLPFC (dorsolateral prefrontal cortex or network) in this study

(see page 6 in Result section). B: The architectonic subdivisions of the orbital and medial prefrontal networks in the OMPFC. The medial net-

work (MPFC) areas are indicated by red shading; and the areas of the orbital network (OPFC) are shown by yellow shading. The blue shaded

areas (areas 12o, 13a, and 13b) are connected with both networks (intermediate areas). The temporal pole is cut (dashed line) to expose the

caudal areas (Ial, Iai, and Iapm) of the orbital surface. It should be noted that, based on the extrinsic connections, the VLPFC is closely related

to OPFC network areas (yellow shaded areas in both A and B), whereas the MPFC network areas are closely related to DPFC and the frontal

pole (red shaded areas in A,B). Scale bars 5 5 mm in A (also applies to inset in A); 10 mm in B (inset).

neighboring areas in human and nonhuman primate

macaque see Petrides et al. (2012).

Area 46 is located in the both dorsal bank and ven-

tral bank of the principal sulcus and is clearly heteroge-

neous. Differences in the architectonic structure of

both banks of the principal sulcus suggest that further

subdivisions are possible in the dorsoventral axis (see

Preuss and Goldman-Rakic, 1991). We have consis-

tently noted differences in structure and connections

between the dorsal bank/lip and ventral bank/lip of

the principal sulcus and will refer to these as areas 46d

and 46v, respectively (see Fig. 1A; Saleem et al.,

2008a). Other distinctions between the fundus and dor-

sal and ventral banks of the principal sulcus may be

possible, but differences between these structures are

less consistent. As a working definition, we have

marked the fundus of the principal sulcus as 46f,

between 46d and 46v (Fig. 1A and other illustrations).

In the tables, 46f will be combined with 46v and

labeled 46v/f (e.g. see VLPFC section in Table 2).

The rostral and caudal parts of the principal sulcus

were distinguished by Petrides and Pandya (1999) as

areas 46 and 9/46d,v, respectively. Although we have

also found differences in the rostrocaudal axis, these

are less definitive, and these subdivisions will not be

explicitly delineated.

The subdivisions of areas in the orbitomedial prefron-

tal cortex (OMPFC; Fig. 1B), inferior and superior tem-

poral cortex, and other cortical areas are described and

illustrated in our previous work (Carmichael and Price,

1994; Saleem et al., 2007, 2008b; see also Saleem

and Logothetis, 2012).

Seltzer and Pandya (1978) and others (e.g., Baylis

et al., 1987) have differentiated several cytoarchitec-

tonic areas from rostral to middle parts of STS in the

rhesus monkey (Macaca mulatta): areas TAa, TPO, and

PGa in the lateral (including lip), central, and medial

part of the dorsal bank, respectively; IPa in the fundus

and very medial portion of the ventral bank; and TEa

and TEm in the medial and lateral part (including the

lip) of the ventral bank of the STS, respectively.

Although we found it useful to describe some of our

results in terms of these subdivisions, we found it diffi-

cult to define these areas precisely, especially their ros-

trocaudal borders. We therefore refer to the dorsal

bank, fundus, and ventral bank of the STS (d, f, and v,

respectively) in most descriptions.

Overview of connectionsFrom injections of retrograde tracers in all parts of

the lateral PFC, three patterns of corticocortical con-

nections within the PFC were apparent, related to the

three networks described above (VLPFC, DPFC, and

CLPFC). With a substantial degree of consistency, the

pattern of axonal label in each case corresponded to

one of these patterns. The majority of corticocortical

connections from each network are distinct from those

of the other two networks, both within the PFC and

with other parts of the cortex. The intrinsic connections

of each network (within the PFC) are generally with

other parts of the same network (see Tables 2 and 6).

Area 45a is an exception; it is connected to all three

networks (Table 4). The VLPFC is also connected to the

OPFC and the ventral premotor cortex, and the DPFC is

connected to the MPFC and the dorsal premotor

cortex.

Extrinsic connections outside the PFC link each net-

work into larger, connectionally distinct cortical cir-

cuits. The VLPFC is connected mainly to the

dysgranular insula, frontal operculum, somatic sensory-

related areas in the parietal operculum and inferior

parietal cortex, visual-related areas in the inferior tem-

poral cortex, and anterior cingulate areas (Table 3).

The DPFC is connected to the rostral part of the

superior temporal gyrus and adjacent dorsal bank of

the superior temporal sulcus (STGr/STSd), parahippo-

campal cortex, anterior and posterior cingulate, and

retrosplenial cortex (Table 6). For comparison, the

CLPFC is connected primarily with the posterior parie-

tal cortex, anterior and posterior cingulate cortex, and

caudal STS.

Ventrolateral prefrontal network (VLPFC)Area 12r, 12l, and 46v injectionsData from eight tracer injections in the VLPFC were

analyzed, four in area 12r or 12l in the ventrolateral

convexity and four in area 46v in the ventral bank and

lip of the principal sulcus (Fig. 2, Tables 2 and 3). An

additional three injections in area 45a/b were also

studied; these produced a substantially different pattern

of labeling and will be considered separately (see

below).

Intrinsic connections of the VLPFC within thePFC (Figs. 3–7, Table 2)Tracer injections in the VLPFC (except in area 45a; see

below) produced retrograde neuronal label mainly in the

VLPFC itself, in the ventral bank and lip of the principal

sulcus, and on the ventrolateral convexity (Fig. 3A–D).

In OM84-DY (Figs. 3A, 4A–E), in which an injection was

made into area 12r, labeled cells were found in ventro-

lateral areas 46v/f, 45a, 12r, 12m, and 12l. Similar pat-

terns of retrograde labeling were present in other cases

with injections in the VLPFC, but there are some differ-

ences in the detailed distribution (Table 2). For exam-

ple, in OM84-DY there are relatively fewer labeled cells

K.S. Saleem et al.


in area 12l; in contrast, OM87-FB, with an injection in

area 12l (Fig. 5E), OM77-FB, with an injection in mid-

point of area 46v (Fig. 6C), and OM82-CTb, with an

injection near the midrostrocaudal point of area 46v

(Fig. 7C,D), all have strong labeling in both areas 12l

and rostral 46v. In spite of these small variations, the

overall pattern of labeling within the VLPFC is very simi-

lar in all of these cases.

Figure 2. Location of retrograde tracers injection sites in the VLPFC (areas 12r, 12l, and 46v; A–H), shown on the lateral view of the pre-

frontal cortex, and in bright- and darkfield photomicrographs. Scale bars 5 5 mm in A–H; 1 mm in inset.



There were few labeled cells in the dorsal or caudo-

lateral subdivisions of the LPFC (DPFC and CLPFC) fol-

lowing injections in areas 12r or 12l. With injections in

area 46v, in the ventral lip of the principal sulcus, how-

ever, cells are labeled in the dorsal lip of the principal

sulcus, in area 46d (e.g., Figs. 6C, 7B). The density and

position of this label varies along the rostrocaudal

extent of 46d from case to case, but it is present in all

four available cases with injections in area 46v (Table

2). Furthermore, the label in area 46d is not found only

at the level of the injection site and therefore cannot

be attributed to diffusion of the tracer from the injec-

tion site. The labeling therefore indicates that there are

at least some connections between areas 46v and 46d

and, to that extent, some connections between the

VLPFC and DPFC.

Figure 3. Extent of intrinsic connections within the LPFC labeled by injections into different parts of the VLPFC. A–D: Injections in areas

12r, 12l, and 46v. Note that the label following these injections is confined to the VLPFC. E–G: Injections in area 45a. In these cases,

labeled cells are found in all three prefrontal networks (DPFC, CLPFC, and VLPFC). Scale bars 5 5 mm.

K.S. Saleem et al.


Figure 4. A–J: Distribution of cells in the frontal and other cortical areas that were retrogradely labeled from an injection of DY into VLPFC

area 12r (case OM84). The inset at top left shows the location of the injection site and the extent of intrinsic labeling mapped onto the

lateral view of the brain (gray-shaded area; same as Fig. 3A). The actual plottings of retrogradely labeled cells in the frontal and other cort-

ical areas are illustrated in the coronal sections A–J. Each dot represents one labeled cell; because the section was plotted in rows, the

dots appear to be aligned into lines across the cortex. The thin radial lines through the cortex indicate architectonic areal boundaries, and

the dashed line indicates layer IV. Note that cells projecting to 12r (and other VLPFC areas; see below) are located in the sensory associa-

tion areas related to vision (STSv/f and TE) and somatic sensation (OPf, Id, SII, and 7b [PFG/PF]). Also note that no auditory-related areas

are labeled after this and other VLPFC injections, except those in area 45a (see Fig. 10). For abbreviations see list. Scale bars 5 5 mm.

The injection in OM76-DY is at the caudal edge of

the VLPFC, very near the CLPFC (Fig. 2H), and this

case serves to mark the junction between these two

networks. Within the PFC, most of the neuronal label

in the case is found in other parts of the VLPFC, as

with other injections in the VLPFC. In addition, how-

ever, there are labeled cells in areas of the CLPFC,

including areas 8Ad, 8Av, and the caudal part of 46d,v

(Table 2, column H).

Elsewhere in the PFC, the experiments with injections

in the VLPFC labeled neurons in the areas of the orbital

prefrontal network, especially in rostral areas 11l, 12m,

13l, and 13m. Label in more caudal areas in the orbital

network, especially those on the rostral part of the

Figure 5. A–I: Distribution of retrogradely labeled cells in the cerebral cortex after an FB injection into VLPFC area 12l (case OM87). The

other details are the same as in Figure 4. Note that there is no labeling in the auditory core/belt/parabelt areas. Scale bars 5 5 mm.

K.S. Saleem et al.


Figure 6. A–J: Distribution of retrogradely labeled cells in the cortical and subcortical areas after an FB injection into the midportion of

area 46v (case OM77). For other details see Figure 4. Scale bars 5 5 mm.



insula (Iam, Iapm, and Ial), is more variable but is sub-

stantial in cases with strong overall labeling (see orbital

network section in Table 2).

There are almost no labeled cells in the areas of the

medial prefrontal network (areas 10m, 11m, 14c, 14r,

25, 32 or Iai; compare medial and orbital network sec-

tions in Table 2). In the caudal part of the frontal

cortex labeled neurons are found in area 44 (in the

fundus/caudal bank of the ventral limb of the

arcuate sulcus), in area PrCO on the frontal opercu-

lum, and in the ventral premotor area F5 (Figs. 3–7,

Table 2).

Figure 7. A–J: Distribution of retrogradely labeled cells in the cortical areas after CTB injection into the midportion of area 46v (case

OM82). The other details are the same as in Figure 4. Note that there is no labeling in the auditory core/belt/parabelt areas. Scale

bars 5 5 mm.

K.S. Saleem et al.


TABLE 2.

Distribution of Labeled Neurons Within the Prefrontal Cortex (Intrinsic Connections) After Injections in VLPFC Areas 12r,

12l, and 46v.



TABLE 3.

Distribution of Labeled Neurons Outside the Prefrontal Cortex (Extrinsic Connections) After Injections in VLPFC Areas 12r,

12l, and 46v.

K.S. Saleem et al.


Extrinsic connections of the VLPFC with othercortical areas (Figs. 4–7, Table 3)The experiments with injections in the VLPFC also show

a consistent pattern of extrinsic connections with corti-

cal areas outside the PFC. In general, these connec-

tions are with sensory association areas related to

somatic sensation and/or vision. As with the intrinsic

connections of the VLPFC, a major exception to this

pattern is seen only with injections in area 45a (see

below).

The constellation of connections of the VLPFC is shown

well in case OM77-FB, in which a retrograde tracer was

injected into area 46v, about midway along the ventral lip

of the principal sulcus (Figs. 2E, 6). Caudal to the frontal

cortex, most of the retrogradely labeled neurons are

found in the insula and somatic sensory related areas

(Fig. 6E–H). In particular, the dysgranular insula (Id) has

dense patches of labeled neurons through most of its

extent. There are also substantial numbers of labeled cells

in the frontal operculum (OPf), within the dorsal bank of

the lateral sulcus. The cells in OPf decrease in number

caudally, but they extend into the somatic sensory area

PV. There are very few labeled cells in area SII in this

case (Fig. 6H), but in other cases with injections in the

VLPFC area SII has substantial numbers of labeled cells

(Fig. 4H, Table 3). In the parietal cortex of OM77-FB,

labeled neurons are also found in the somatic sensory-

related area 7b (including its subdivisions PFG/PF), and in

nearby areas 7op and AIP (Fig. 6I,J, Table 3).

In the vision-related areas of the inferior temporal cortex

in OM77-FB, labeled cells are found in the ventral bank

and fundus of the superior temporal sulcus (STSv/f),

including areas IPa, PGa, and TEa/m of Seltzer and Pandya

(1978), but labeled cells are mostly absent in area TE in

the inferior temporal gyrus (Fig. 6E–H, Table 3). This is simi-

lar to other cases with injections in areas 46v and 12r. It

differs, however, from the cases with injections in area 12l

(OM9-DY and OM87-FB), in which there are fewer labeled

cells in Id and OPf and none in the parietal areas 7b and

7op (Fig. 5, Table 3). On the other hand, these cases have

more labeled neurons in the inferior temporal cortex, both

in STSv/f and in several subdivisions of area TE (TEad,

TEav, TEpd, and TEpv; Table 3).

In several cases, the labeled cells in STSf extend

from the fundus onto the medial part of STSd, in the

region identified as PGa/TPO by Seltzer and Pandya

(1978; e.g., Figs. 4E,H, 5G, 6E). These cells are not

found in the more lateral part, including the lip of the

STSd (areas TAa and TS of Seltzer and Pandya, 1978).

In the cingulate cortex, labeled cells are most consis-

tently found in the middle part of this region, in area

24a0/b0. Some cells are found in the more rostral cingu-

late region, but most of these are confined to area 24c,

within the ventral bank and fundus of the cingulate sul-

cus (Fig. 6D–H, Table 3).

In OM76-DY, in which the injection was at the bound-

ary between the VLPFC and CLPFC, a few cells were

also found in area LIP in the lateral bank of the intrapar-

ietal sulcus (Fig. 2H, Table 3). Neuronal label is not seen

in adjacent and related area 7a in this case, and no

other injection in the VLPFC produced label in these pos-

terior parietal areas. Both of these areas were consis-

tently labeled in experiments with injections in CLPFC.

Area 45a injectionsThree other, more caudal tracer injections in the VLPFC

were centered in area 45a or involved this area along

with area 45b (Fig. 8A–C). These experiments demon-

strated a pattern of intrinsic and extrinsic connections

very different from that in the experiments with more

rostral injections. They show that area 45a has exten-

sive connections with the DPFC and CLPFC as well as

the same intrinsic connections with other parts of the

VLPFC that are seen in other VLPFC injections

(although they are generally weaker). Area 45a is also

connected with cortical areas outside the PFC that are

related to the DPFC instead of the VLPFC.

An injection that was restricted to area 45b was not

available in this study. A previous study from another

group (Gerbella et al., 2010) indicates, however, that

the connections of area 45b are similar to those from

more rostral parts of the VLPFC (see discussion).

Intrinsic connections of area 45a within thePFC (Figs. 3, 9–11, Table 4)The distribution of transported label is well shown in

OM86-FB and OM84-FB, in which the tracer injections

are centered in rostral and caudal parts of area 45a,

respectively (Figs. 3E,F, 8A,B, 9, 10, Table 4). These

cases had labeled neurons in the VLPFC and in the

OPFC, although there were fewer labeled cells than in

other experiments with injections in other areas of the

VLPFC (compare orbital [OPFC] network section in

Tables 2, 4). Some labeled neurons were found in the

frontal polar part of area 10; in areas 8B, 9, and 46d of

the DPFC; and also in area 8Ad (frontal eye field) of the

CLPFC. There are almost no labeled neurons in the

medial PFC, but there are labeled cells in medial

network-associated areas 12o and Iai (Table 4). These

experiments suggest that area 45a may provide a link

for interaction between the VLPFC and other parts of

the lateral PFC.

The cases with injections in area 45a also have

labeled cells in the dorsal premotor areas F2 and F7

(e.g., Fig. 10C–E). Such connections are not seen in



most cases with injections in the VLPFC, although two

cases (OM9-DY and OM82-CTB) have labeled cells at

the border of F6 and F7 (e.g., Fig. 7D, Table 2).

Extrinsic connections of area 45a with othercortical areas (Figs. 9–11, Table 5)Caudal to the prefrontal cortex, the experiments with

injections in area 45a have relatively few or no retro-

gradely labeled cells in the somatic sensory or visually

related areas (in the Id, OPf, STSv/f, and TE) that are

connected with more rostral parts of the VLPFC (com-

pare Tables 3 and 5). Instead, there are many labeled

neurons in the superior temporal cortex, in areas that

are also connected to the DPFC (see below). OM86-FB

(Fig. 9) and OM77-LY (Fig. 11) had labeled cells in the

dorsal bank of the STS (STSd) and a few cells in the ros-

tral superior temporal gyrus (STGr). OM84-FB, with an

injection centered in caudal area 45a (Fig. 10, Table 5),

also had many cells in STSd and STGr, but in this case

many labeled cells extended into the auditory core,

medial and lateral belt, and parabelt areas caudal and

dorsal to STSd and STGr. This case had substantially

more neuronal labeling in the auditory areas than any

other case with a retrograde tracer injection in the pre-

frontal cortex. In all of the cases, the labeled cells are

found in both lateral and medial parts of STSd and

extend into STSf, including rostral parts of areas TS,

TAa, TPO, PGa, and IPa of Seltzer and Pandya (1978;

see Fig. 10F,G).

In addition to the experiments with injections in the

PFC, other cases are available from a previous study

(Saleem et al., 2008b) with injections in the parts of

Figure 8. Location of retrograde tracers injection sites in VLPFC areas 45a and 45a/b (A–C), shown on the lateral view of the prefrontal

cortex and in bright- and darkfield photomicrographs. Scale bars 5 5 mm in A–C; 2 mm in A, right panel.

K.S. Saleem et al.


Figure 9. A–J: Series of coronal sections illustrating the distribution of retrogradely labeled cells in cortical areas after an FB injection into

the rostral part of area 45a (case OM86). Note that cells that project to area 45a rostral are found in dorsal, ventrolateral, and caudolat-

eral parts of the PFC (shaded area in the inset on the top left). Outside the PFC, the labeled cells are located mainly in the STGr/STSd,

with very few cells in the auditory belt or parabelt areas. The other details are the same as in Figure 4. Scale bars 5 5 mm.



Figure 10. A–J: Distribution of retrogradely labeled cells in cortical and subcortical areas after an FB injection into the caudal part of area

45a (case OM84). Note that cells projecting to area 45a caudal are distributed in the STGr/STSd and also in the auditory belt and para-

belt regions. This case has substantially more neuronal labeling in the auditory areas than in OM86-FB (Fig. 9). For other details see Figure

4. Scale bars 5 5 mm.

K.S. Saleem et al.


Figure 11. A–J: Distribution of retrogradely labeled cells in different cortical areas after LY injection into area 45a/45b (case OM77).

Unlike other 45a injections (Figs. 9, 10), this case did not produce many labeled cells in STGr, although there are labeled cells in STSd.

The other details are the same as in Figures 4. For abbreviations see list. Scale bars 5 5 mm.



TABLE 4.

Distribution of Labeled Neurons Within the Prefrontal Cortex (Intrinsic Connections) After Injections in Areas 45a and

45a/b.

K.S. Saleem et al.


TABLE 5.

Distribution of Labeled Neurons Outside the Prefrontal Cortex (Extrinsic Connections) after Injections in Areas 45a and 45a/b.



the superior and inferior temporal cortex areas that

have labeled cells following tracer injections in the

PFC. In particular, in case OM59, there are two

anterograde tracer injections in the STSd/STGr (LY)

and in STSv (BDA; Fig. 12). The injection in STSd/

STGr resulted in substantial axonal label in area 45a,

whereas the injection in STSv produced axonal label

in overlapping parts of area 45a, together with label

in areas 12l, 45b, and 46v. These confirm the previ-

ously described connections from STSd/STGr to area

45a (Figs. 9–11) as well as the connections from

STSv to area 12l (Fig. 5) and other parts of the VLPFC

(Table 3).

Dorsal prefrontal network (DPFC; includingfrontal pole)Area 9d/m, 46d, and 10mr/10o injectionsTen experiments are available in which injections of ret-

rograde axonal tracers were made into the DPFC. Four

of the injections are at the frontal pole (Fig. 13A–D;

OM19-FB in area 10o ventrally, OM81-DY in rostral

Figure 12. Projections from superior and inferior temporal cortex to PFC. A,B: Distribution of anterogradely labeled axonal varicosities in

the lateral PFC after an LY injection (red) into the dorsal bank of STS/STGr junction (STSd/ STGr) and a BDA injection (blue) into the ven-

tral bank of the STS (STSv). In A the rostral part of the STS is opened on the lateral view of the brain to show the location and extent of

the injection sites in the STSd/STGr and STSv. The distribution of LY and BDA labeling in B is obtained from Figures 18 and 19 of Saleem

et al. (2008b). Note the complementary distribution of terminals in the lateral PFC, with some overlap in area 45a after the superior and

inferior temporal cortex injections. Scale bars 5 5 mm.

K.S. Saleem et al.


Figure 13. Location of retrograde tracers injection sites in the DPFC (areas 9, 10, 46d, and 8B; A–J), shown on the lateral view of the pre-

frontal cortex and in bright- and darkfield photomicrographs. Dashed outline in C,F indicate the core region of the injection site. Scale

bars 5 5 mm in A–J; 2 mm in insets.



area 46d, OM69-FR and OM64-FB in area 10mr dor-

sally). Three injections are in area 9 (Fig. 13E–G;

OM64-DY and OM81-FR in 9d and OM77-FR in both 9d

and 9m). Two injections are in area 46d (Fig. 13H,I;

OM85-FB more caudally, overlapping the border

between areas 46d and 8B; OM80-FB in mid-46d at the

dorsal lip of the principal sulcus). Finally, one injection

was placed in area 8B (Fig. 13J; OM86-LY).

Intrinsic connections of the DPFC within thePFC (Figs. 14–20, Table 6)The distribution of retrogradely labeled neurons in all of

these cases indicates a consistent pattern of connec-

tions, which is markedly different from the pattern seen

with injections in VLPFC (compare Tables 2 and 6). In

the lateral PFC, there are substantial numbers of

labeled neurons around the injection site and in other

parts of the DPFC. This pattern is well illustrated in

case OM64, which had two injections in the DPFC, FB

in area 10mr, and DY in area 9d (Figs. 13D,E, 14A,B,

15). From both injections there is label in areas 9 and

10. In area 46d, the label was concentrated in the ros-

tral to middle lip, bank, and fundus of the principal sul-

cus; it did not extend into the caudal part of the

sulcus. Similar patterns are seen in other cases

with injections in area 10o/mr, 9d, 46d, and 8B

(OM77-FR, OM81-DY, and OM69-FR; Figs. 16–18,

Table 6).

Figure 14. Extent of intrinsic connections within the lateral PFC labeled by injections into different parts of the DPFC (areas 9d/m, 10mr,

and 46d). Note that the labeled cells following these injections are found in other parts of DPFC (A–F) as well as in caudal VLPFC areas

45a/b in some cases (D–F). Scale bars 5 5 mm.

K.S. Saleem et al.


In addition to this label in the DPFC, most of the

(7/10) cases also had labeled neurons in area 45a,

and possibly 45b (e.g., OM77-FR, Fig. 16, Table 6).

This fits with the observations noted above, that injec-

tions in area 45a labeled cells in the DPFC. Again, it

indicates that area 45a, though located in the caudal

Figure 15. A–K: Distribution of cells in the frontal and other cortical areas that were retrogradely labeled from an injection of FB into

10mr (blue dots) and DY in 9d rostral (red dots; case OM64). Other details are the same as in Figure 4. Note that cells projecting to

10mr and 9d rostral (and other DPFC areas; see below) are located in the rostral superior temporal gyrus (STGr), dorsal bank of the supe-

rior temporal sulcus (STSd), and auditory related areas in the caudal superior temporal gyrus. This distribution is very different from that

seen with injections in the VLPFC cases. For abbreviations see list. Scale bars 5 5 mm.



part of the VLPFC, is specifically connected with the

DPFC.

Most other parts of the VLPFC contained few if

any labeled cells from injections in the DPFC. In

many cases, however, labeled neurons were found in

the ventral bank of the principal sulcus (e.g., OM80-

FB; Fig. 19C,D), confirming the connections across

the principal sulcus described above. With injections

in the caudal part of DPFC, there were also a vari-

able number of labeled cells in area 8Ad and

Figure 16. A–J: Distribution of retrogradely labeled cells in the cerebral cortex after an FR injection into dorsomedial portion of caudal

area 9 (9d/m; case OM77). The other details are the same as in Figure 4. Scale bars 5 5 mm.

K.S. Saleem et al.


the dorsal premotor areas F2/F7 (Table 6, columns

F–J).

Cases with injections in area 9d, 9m, 10m, and 10o

have substantial numbers of labeled neurons in areas

of the MPFC. This included not only areas 10mc and

32 but also areas 11m, 14r/c and 13b on the gyrus

rectus at the medial edge of the orbital cortex and

areas Iai and 12o in the caudolateral part of the orbital

cortex (Figs. 15, 16, 18; Table 6). The injections in

area 46d did not label cells in the medial network

areas on the medial wall of the hemisphere, although

they did have cells in the related area 12o and/or Iai

Figure 17. A–K: Distribution of retrogradely labeled cells after DY injection into rostral portion of area 46d or frontal pole (case OM81).

For other details see Figure 4. Scale bars 5 5 mm.



(Figs. 17D, 19E, Table 6, columns H–J). There were

only very few labeled cells in the areas of the OPFC in

the central part of the orbital cortex, although small

numbers of labeled cells were found in area 13m or

13l in some cases.

Extrinsic connections of DPFC with other corti-cal areas (Figs. 15–18, Table 7)Outside the PFC, the distribution of retrogradely labeled

neurons from the injections in the DPFC is remarkably

consistent and is very different from that seen with

Figure 18. A–J: Distribution of retrogradely labeled cells in the cortical and subcortical areas after FR injection into the frontal pole area

10mr (case OM69). The other details are the same as in Figure 4. Scale bars 5 5 mm.

K.S. Saleem et al.


injections in the VLPFC. In almost all cases, there are

substantial numbers of labeled cells in the rostral part

of the superior temporal gyrus (STGr) and the dorsal

bank of the superior temporal sulcus (STSd), but there

are no labeled cells in the sensory association areas of

the insula, frontal operculum, or inferior temporal cortex

(Table 7). The cells are concentrated in the lateral part

of STSd (area TAa of Seltzer and Pandya, 1978), with

few if any in the medial part of STSd (area TPO).

In a few cases, especially those with injections

near the frontal pole, the labeled cells extended dor-

sally into the auditory-related parabelt or belt areas

caudal and dorsal to the STGr (e.g., OM64-FB and

DY, Fig. 15G; OM81-DY, Fig. 17G; OM69-FR, Figs.

18E–H, Table 7). In all of these cases, however, the

density of the label is greater in the STGr and/or

STSd and decreases markedly as it extends into the

auditory areas.

Figure 19. A–J: Distribution of retrogradely labeled cells in the cerebral cortex after an FB injection into midportion of area 46d (case

OM80). Unlike other DPFC cases, this injection labeled more cells in the medial parietal and parieto-occipital areas but not in the

auditory-related areas in STG. The other details are the same as in Figure 4. Scale bars 5 5 mm.



The other cortical areas in which labeled neurons

were found after injections in DPFC were the posterior

parahippocampal (areas TF and TH), the posterior cin-

gulate (areas 23 and v23), and retrosplenial (areas

29/30) cortices (Table 7). Areas TF and TH were espe-

cially labeled with injections in area 9d/m (Figs. 15I,

Figure 20. A–J: Distribution of retrogradely labeled cells after LY injection into area 8B (case OM86). The other details are the same as in

Figure 4. Scale bars 5 5 mm.

K.S. Saleem et al.


16G). The label in the posterior cingulate cortex was

found in virtually every case, but the distribution dif-

fered slightly among the subdivisions. In most DPFC

cases, there was also label in the rostral cingulate

area 24, but there were few if any cells in the middle

cingulate area 240.

Exceptional cases in DPFC (Figs. 19 and 20,Table 7)Although most of the cases with injections in the DPFC

have remarkably consistent patterns of retrograde neu-

ronal labeling, two cases produced variant patterns of

label. OM80-FB (Figs. 13I, 19), with an injection in the

TABLE 6.

Distribution of Labeled Neurons Within the Prefrontal Cortex (Intrinsic Connections) After Injections in DPFC and Frontal

Pole Areas 8B, 9, 10, and 46d.



midportion of area 46d, differed from other DPFC cases

in that labeled cells were not seen in the STGr/STSd

but were found in the medial parietal area 7m (or area

PGm), area 31, and the parieto-occipital areas V6Ad

and V6Av (or area PO; Fig. 19G–J). This distribution of

labeling was not seen in any of the other DPFC cases

in this study. A possible explanation is that the midpor-

tion of the dorsal bank of the principal sulcus (indicated

by a question mark in Fig. 1A) is a distinct area with

connections different from those of the cortex rostral,

dorsal, and caudal to it. This is supported by the pat-

tern of label in the LPFC in available cases that have

TABLE 7.

Distribution of Labeled Neurons Outside the Prefrontal Cortex (Extrinsic Connections) After Injections in DPFC and Frontal

Pole Areas 8B, 9, 10, and 46d.

K.S. Saleem et al.


tracer injections in STGr (Fig. 12; OM59-LY; see also

Figs. 6F,G, 15A,B in Saleem et al., 2008b). None of

these cases has transported label in the midportion of

area 46d, in the dorsal lip of the principal sulcus.

OM86-LY, with an injection in area 8B (Fig. 20), also

had only a few if any labeled cells in STGr/STSd or in

the posterior parietal area 7a, which is usually labeled

only from the CLPFC. Because LY is a bidirectional

tracer, however, in this case it was possible to see that

there were anterogradely labeled axons in STGr/STSd

and areas 7m, retrosplenial cortex (29/30), and parie-

tooccipital area V6Ad/v. There is relatively little label

outside the PFC in this case, and the paucity of retro-

grade cellular label in STGr/STSd may be due to a low

efficacy of the tracer injection. Petrides and Pandya

(1999) reported a comparable experiment with a some-

what larger tracer injection in area 8B, which had a pat-

tern of labeling similar to that seen in OM86-LY but

with more label in STSd and area 7a (their areas TPO

and Opt, respectively).

Connections within the STG (Fig. 21)The results described above indicate that the STGr/

STSd region provides a major input to the DPFC net-

work, and it has previously been shown to provide to

the MPFC network (Saleem et al., 2008b). Because the

STG as a whole is usually presumed to have an auditory

function, an important question is whether there are

connections between the auditory-defined belt/parabelt

areas and STGr/STSd. Experiments were therefore per-

formed and analyzed that have tracer injections into

either the belt/parabelt areas or the STGr (OM55 DY;

OM68 DY, FB, and CTB; Fig. 21A–D). The results indi-

cate that neurons labeled from an injection in STGr are

distributed mostly throughout the STGr/STSd but also

extend caudally and dorsally to overlap the edge of the

rostral and caudal parabelt (RPB and CPB, respectively;

see Fig. 21A,B). Conversely, after injections in the belt/

parabelt, retrogradely labeled neurons are most densely

distributed in the core/belt/parabelt but also extend

rostrally and ventrally to overlap the STGr/STSd (see

Fig. 21C,D).

Laminar distribution of labeled cellsAlthough detailed cell counts were not made, inspection

of the plots of retrogradely labeled neurons indicates

that labeled cells were generally distributed in both

superficial and deep layers of the cortex (see discus-

sion below). Little indication of any more specific lami-

nar organization was found, except the connections

from medial temporal lobe areas 28 and TF/TH. In

these areas, the labeled neurons were distributed

mostly in the deep layers after injections in DPFC area

9d/m (Fig. 16F,G) and frontal pole area 10mr (Fig.

18G,H; see also Kondo et al., 2005, their Fig. 14A for

the projections from area 28 to medial prefrontal

network).

In some cases, the labeled neurons in some architec-

tonic areas within and outside the prefrontal cortex

(orbitofrontal and STS areas) appeared to be in superfi-

cial layers (2–3) and gradually moved to the deep

layers (5–6) in the adjacent sections, or vice versa, pos-

sibly because of the tangential plane of sections

through cortical gyri (e.g., see labeled neurons in cen-

tral orbital area 13m in Fig. 5D,E). This pattern was

also reported previously for the distribution of antero-

gradely labeled terminals in the temporal cortex (see

the connections from area TEav to STS in Saleem et al.,

2000, their Fig. 10, top right).

DISCUSSION

The results presented here, based on analysis of 24

axonal tracer injections in 14 monkeys, indicate that

the areas on the lateral surface of the PFC can be

divided into three distinct networks, in the dorsal, ven-

trolateral, and caudal parts of this large cortical region.

Areas in each of these networks are preferentially con-

nected to other areas within the same part of the PFC

and to a distinctive set of areas elsewhere in the cere-

bral cortex. In addition, area 45a in the ventrolateral

part of the PFC is a special region that is connected

across all three PFC networks and has a unique set of

extrinsic connections outside the PFC. A second unique

region may exist in the midrostrocaudal part of area

46d (in the dorsal bank/lip of the principal sulcus), but

there is not currently sufficient evidence for a definitive

definition of this area.

These results expand previous observations on the

OMPFC that recognized two networks, which were

termed the “orbital” and “medial” prefrontal networks

(although neither corresponds solely to the orbital or

medial cortical surface; Carmichael and Price, 1996;

Saleem et al., 2008b). The areas within each network

are preferentially interconnected by intrinsic connec-

tions (Carmichael and Price, 1996) and have distinct

and selective connections to other cortical and subcort-

ical structures (€Ong€ur et al., 1998; An et al., 1998;

Ferry et al., 2000; Kondo et al., 2003, 2005; Hsu and

Price 2007; Saleem et al., 2008b). Perhaps the most

striking observation in the current study is that VLPFC

and DPFC networks are very similar in their connections

to the orbital and medial networks (OPFC and MPFC),

respectively. The combined MPFC/DPFC and OPFC/

VLPFC networks are similar to previously proposed dor-

sal and ventral architectonic “trends” in the prefrontal



Figure 21. Intrinsic connections within the temporal cortex (shaded area), illustrated on the lateral view of the brain. The distribution of

retrogradely labeled cells in the rostrocaudal part of the superior temporal gyrus (STGr, RPB, and CPB), dorsal bank of the superior tempo-

ral sulcus (STSd), and supratemporal plane (core and belt) after DY injections into STGr (A,B), and FB and CTB injections into rostral belt/

parabelt junction (C,D). The lateral sulcus is opened to show the core and belt areas in the supratemporal plane. The STS is also opened

to show the dorsal, fundus, and ventral banks (d, f, and v, respectively). The actual distribution of cells (dots) is also indicated in selected

coronal slices in the right panel. For abbreviations see list. Scale bars 5 5 mm.

K.S. Saleem et al.


cortex (Yeterian et al., 2012). The interpretation pro-

posed here differs in that area 45a is considered a

unique area and that the caudal part of the PFC has

been separated out as the CLPFC network, which is

especially connected with the posterior parietal cortex

(Saleem et al., 2008a).

It should be emphasized that each of the networks is

composed of a number of architectonic areas, each of

which has its own distinctive characteristics, especially

as shown by architectonic differences. Presumably

there are also functional differences between areas

within each network, although in most cases these

have not yet been defined. In spite of these differences,

there is remarkable consistency in the connections of

areas within a network, particularly in relation to con-

nections with regions outside the PFC. Such consis-

tency appears to indicate that each network as a whole

is involved in the same general function (e.g., sensory-

motor integration vs. self-referential functions), although

individual areas may function in relation to different

aspects of that general function (see below for further

discussion).

The absence of a clear laminar organization in the

pattern of retrogradely labeled cells is initially surpris-

ing, because of previous reports of differential laminar

patterns in projections between prefrontal areas, espe-

cially between areas postulated to be at different hier-

archical levels (Barbas and Rempel-Clower, 1997;

Rempel-Clower and Barbas, 2000). Several factors may

explain this discrepancy, however. The most striking

patterns previously reported were in the lamination of

axonal terminations. Almost all of the experiments

reported here used retrograde tracers, so we cannot

make any statement about laminar patterns of axonal

termination. In addition, we did not make counts of

cells in different layers, so it is possible that more

subtle quantitative differences in lamination were over-

looked. Finally, most of the connections reported in this

study were between areas that would have been con-

sidered to be at higher levels, so differences may not

be as clearcut.

VLPFC networkThe VLPFC, which extends from the ventral bank of

the principal sulcus onto the ventrolateral convexity,

has extrinsic connections that are similar to those of

the orbital network areas. These connections are gener-

ally with cortical regions that are involved in sensory

processing or integration (Fig. 22). Thus, there are

strong connections with the dysgranular insula (Id) and

the frontal opercular area (OPf), which in some cases

extend caudally into areas PV and SII in the lateral sul-

cus. These areas are related to tactile, somatic sensory,

and visceral afferent processing in primates (Robinson

and Burton, 1980; Cusick et al., 1989; Krubitzer et al.,

1995; Burton et al., 1995, 2008; Disbrow et al., 2000;

Kaas and Collins, 2003; Fitzgerald et al., 2004; Eickhoff

et al., 2010). Other connections are with the ventral

bank/fundus of the superior temporal sulcus (STSv/f),

and the inferior temporal area TE that are involved in

the visual discrimination and recognition of objects and

faces (Tanaka, 1996; Janssen et al., 2000; Tsao et al.,

2003, 2008a; Op de Beeck et al., 2008; Ungerleider

and Bell, 2011; Kravitz et al., 2013). On the motor side,

there are connections to the ventral premotor area F5

and to a lesser extent with the dorsal premotor areas

F6/F7 (area F7 corresponds to the supplementary eye

field) and with parietal areas 7b (PFG/PF) and AIP (see

also Borra et al., 2011; Gerbella et al., 2013). These

areas are themselves interconnected and appear to

function in somatosensory, visual, and motor interac-

tions for goal-directed motor acts and sensory-motor

transformations for grasping of objects (Jennerod et al.,

1995; Sakata et al., 1995; Murata et al., 2000; Rozzi

et al., 2008; Kravitz et al., 2011). Connections were not

found between the VLPFC and posterior parietal areas

LIP and 7a, although relatively strong connections were

found between these areas and the CLPFC (Saleem

et al., 2008a).

Connections of areas 12r, 12l, and 46vAlthough the visually related inputs to the VLPFC (12r,

12l, and 46v) originate from the inferotemporal cortex

(IT), the present data indicate that these projections do

not arise equally from all parts of IT or terminate evenly

throughout the VLPFC. Projections to areas 12r, 12l, and

46v all arise in the ventral bank and fundus of the rostral

STS (STSv/f). In contrast, the rostral or caudal subre-

gions of TE (areas TEad, TEav, TEpd, and TEpv; see

Table 3) project primarily to area 12l. This difference pre-

sumably reflects functional distinctions. For example,

Janssen et al. (2000) found that, whereas neurons in

both STSv and TE (TEad) respond to and are selective

for two-dimensional (2D) shapes, many more of the neu-

rons in STSv are selective for 3D shape than in area

TEad.

Somatic sensory inputs terminate throughout the

VLPFC but have a relatively diverse origin. The most

obviously somatic sensory projections are from areas

PV and SII, areas that have been clearly established as

responding to somatic sensory stimuli, with connections

to primary somatic sensory cortex or thalamus (see,

e.g., Robinson and Burton, 1980; Krubitzer et al.,

1995). The strongest connection to the VLPFC, how-

ever, is with areas Id and OPf, rostral to areas SII and

PV. The nature of somatic sensory information



Figure 22. Summary diagram of the connections of VLPFC (areas 12r, 12l, and 46v), illustrated on the inflated medial, lateral, and ventral

views of the macaque brain. The strength of the connections is indicated by different shades of purple (see key in the figure). Note that

these areas are connected to the orbitofrontal (“orbital network” areas) and other VLPFC areas 44, 45a, and 45b within the prefrontal cor-

tex and sensory association areas related to somatic sensation and/or vision outside the prefrontal cortex (see Discussion for more

detail). For abbreviations see list.

K.S. Saleem et al.


represented is unclear because there have been few

reported physiological recordings in these areas. Many

of the studies that explored the opercular areas have

used anesthetized animals, and it is possible that neu-

rons in the OPf respond to relatively complex stimuli

and are not responsive in anesthetized animals. Various

physiological and anatomical data suggest that area Id

may process visceral afferent activity related to the

state of the body (Craig, 2009). This will be discussed

below in a section on the functional significance of the

VLPFC network.

It is notable that none of the VLPFC areas is con-

nected with auditory association cortex in the superior

temporal gyrus and supratemporal plane, except for the

special case of area 45a (see below). Even when cells

were labeled in STSd following VLPFC injections, they

were in the very medial part of the sulcus (area PGa

and TPO of Seltzer and Pandya, 1978), where visual

responses but not auditory responses have been

reported (Baylis et al., 1987).

The present findings of VLPFC connections with tem-

poral, parietal, and insular cortical areas are consistent

with previous descriptions (Barbas, 1988; Seltzer and

Pandya, 1989; Petrides and Pandya, 2002; Borra et al.,

2011; Gerbella et al., 2010, 2013; see also Cavada and

Goldman-Rakic, 1989; Rozzi et al., 2006; Borra et al.,

2008), although many of these studies used large injec-

tions that obscured the connectional patterns and

made the interpretation more difficult. As a group,

these studies have been interpreted to show a varied

set of different connections, without an attempt to

identify cortical networks.

Petrides and Pandya (2002) described the connec-

tions of the VLPFC, including areas 45, 12l (their 47/

12), and 46v (their 9/46v), as part of a series of stud-

ies on all parts of the PFC. For all of the VLPFC areas,

they reported complex multimodal inputs, which varied

with the target prefrontal area. Area 12l (47/12) was

shown to be primarily connected to STSv and anterior

area TE, whereas area 46v (9/46v) was related to areas

Id, the frontal operculum, SII, and the inferior part of

the intraparietal sulcus, in the region of areas 7b and

AIP. Both of these areas were also strongly intercon-

nected with other VLPFC areas. Area 45 was reported

to have the most complex connections, interacting with

extensive parts of the DPFC as well as the VLPFC; out-

side the PFC, its major connection was with the STGr/

STSd and auditory association areas (their Fig. 10). All

of these results are in excellent agreement with the

observations presented here (see below for a discus-

sion of area 45a).

In two recent studies, Luppino and his colleagues

examined the connections of areas 12r and 46v, with

the use of many small, well placed tracer injections

(Borra et al., 2011; Gerbella et al., 2013). Their delinea-

tion of area 12r was somewhat larger than that used in

this study, so their most caudal injections in this area

impinged on our area 12l (Borra et al., 2011). Conse-

quently, they reported that the middle portion of area

12r was related to somatic sensory/visceral afferent

areas in Id, the frontal operculum, and area SII as well

as the STSv. Conversely, the more caudal region (our

12l) was connected primarily to the visually related

regions STSv and anterior TE, without connections to

the insular or opercular areas. Interestingly, they found

that the most rostral part of area 12r has a third pat-

tern of connections, primarily with the fundus of the

STS.

Similar patterns emerged from their study of area

46v, with variation along the principal sulcus from ros-

tral to caudal (Gerbella et al., 2013). The mid- to rostral

part of 46v was shown to have its main extrinsic con-

nection (outside the PFC) with the STSv/f. In the mid-

to caudal part of 46v, this pattern of connections

shifted to the insular and opercular areas. Finally, the

most caudal part of area 46v showed a very different

pattern, with connections to the posterior STS and the

posterior parietal area LIP, areas that are related to

hand–eye interaction and attention. This pattern corre-

sponds to our results for the caudal part of area 46

that is part of the CLPFC network.

Connections of area 45aArea 45a stands out from the other parts of the VLPFC

(12r, 12l, and 46v; compare Figs. 23 and 22), in that it

has substantial intrinsic connections with areas in the

other subdivisions of the PFC (DPFC and CLPFC) as

well as with those of the VLPFC. Furthermore, the

extrinsic connections of area 45a with cortical areas

outside the PFC resemble the connections of the DPFC

network (see below). In particular, there are strong con-

nections with areas STGr/STSd, which are seen with

dorsal prefrontal areas but not with other ventrolateral

prefrontal areas. These connections extend more cau-

dally in the temporal cortex than the connections of

most of the DPFC areas (with the exception of the fron-

tal pole), to involve the auditory association areas in

the belt and parabelt region. This study has confirmed

the previous reports of connections of area 45a, both

within and outside the PFC (Petrides and Pandya 2002;

Saleem et al., 2008b; Gerbella et al., 2010). Another

study by Romanski et al. (1999a, their Fig. 9) also

agrees with the present results, although the architec-

tonic delineation of area 45 in their maps is slightly dif-

ferent from ours. In their study, a tracer injection in

area 12vl, which is anterior to area 45 in their map (but



Figure 23. Summary diagram of the connections of VLPFC area 45a. Other details are the same as Figure 22. Note that this area demon-

strated patterns of intrinsic and extrinsic connections very different from those of the other VLPFC areas. It is connected to all the subdi-

visions of the LPFC and the auditory-related areas in the supratemporal plane and superior temporal gyrus (core, belt, parabelt, and STGr)

and the dorsal bank of the STS (STSd). See Discussion for more detail.

K.S. Saleem et al.


partially overlaps with areas 45a, 12l, and 12o on the

orbital cortex as defined in the present study) labeled

both terminals and neurons in the auditory belt and

parabelt areas as well as the upper bank of the STS.

Complementary experiments with injections in the ros-

tral belt areas of the auditory cortex labeled axon termi-

nals in areas 12vl, 45, and medial part of 12o

(Romanski et al., 1999b, see their Fig. 3e). It is impor-

tant to note that injections into area 12l (ventral to

area 45a; Fig. 5) in the present study did not label any

cells in the auditory association areas but only cells in

the inferior temporal cortex (area TE and STSv). Further-

more, an anterograde tracer injection that involved area

STGr/STSd in our previous study produced dense ter-

minal labeling in the medial part of 12o and in 45a but

very sparse labeling in 12l (Fig. 12; see also Fig. 18D,E

in Saleem et al., 2008b).

There may be further organization in the input from

superior temporal cortex to area 45a. We found that

the rostral part of area 45a receives projections mainly

from STSd, whereas the caudal part (just anterior to

the ventral limb of the arcuate sulcus) receives input

from the auditory association areas (belt and parabelt)

in STG as well as STSd. These results suggest func-

tional subdivisions within area 45a.

At least a portion of area 45a also receives inputs

from visually related areas in STSv (Fig. 12; see also

Petrides and Pandya, 2002; Saleem et al., 2008b; Ger-

bella et al., 2010). The cells in STSd that project to

area 45a also extend substantially into the medial part

(areas PGa and TPO of Seltzer and Pandya, 1978),

where visual responses have been reported (Baylis

et al., 1987). Such observations, especially the conver-

gence of visual and auditory inputs, indicate that area

45a is a functionally distinct region. Recordings that

seem to correspond to 45a have found convergent

responses to visual and auditory stimuli in individual

neurons; the auditory responses were particularly to

species-specific calls (Sugihara et al., 2006; Romanski,

2012), and visual responses to face stimuli have also

been found (Wilson et al., 1993; O’Scalaidhe et al.,

1997; Tsao et al., 2008b). It is worth noting that the

area identified by Romanski and colleagues (1999a,b;

2012) in rhesus macaques is reported to be just rostral

to area 45a. Regardless of terminology, it seems proba-

ble that these areas coincide, but this remains to be

conclusively determined.

In any case, area 45a and the region around it

appear to be involved in vocal and facial communica-

tion between monkeys. It is fascinating to speculate

that area 45a may be a precursor for the language-

related areas found in the caudal ventrolateral PFC in

humans (Kelly et al., 2010; Petrides et al., 2012).

Area 45b may be more similar to other parts of

VLPFC than area 45a. Although we do not have an

injection restricted to area 45b, experiments with injec-

tions in the temporal cortex showed that the visual

area STSv projects to 45b (Fig. 12; see also Fig. 19E of

Saleem et al., 2008b). In addition, Gerbella et al.

(2010) showed that tracer injections restricted to area

45b labeled cells in the STSv and in several parts of TE,

but not in the STGr/STSd or the auditory belt and para-

belt areas. However, based on reports of direct connec-

tions of 45b with 8A and LIP (Gerbella et al., 2010), it

is possible that further work will indicate that area 45b

is also related to CLPFC.

Functional significance of the VLPFC networkThe areas of the VLPFC network (except 45a) are inter-

connected with the orbital network (OPFC), and both

networks have a very similar pattern of extrinsic con-

nections with several sensory processing areas, includ-

ing the insular and opercular areas for somatic

sensation and inferior temporal areas for vision; in the

case of the OPFC, there are also multisensory inputs

from the perirhinal cortex (Carmichael and Price, 1995;

Kondo et al., 2005; Saleem et al., 2008b). The two net-

works are also connected with ventral premotor areas

(Carmichael and Price, 1995; Saleem et al., 2008b; cur-

rent study). It is reasonable to suggest that both net-

works have a similar function, which is related in some

way to integration of multisensory stimuli and possibly

the promotion of appropriate motor responses. The

major difference between the OPFC and the VLPFC is

that the OPFC has strong connections with the primary

olfactory cortex and the gustatory cortex (Carmichael

et al., 1994; Carmichael and Price, 1995), which are

not found with the VLPFC. Although the OPFC network

therefore appears to be involved in processing food-

related stimuli, it is more likely that the VLPFC is

related to nonfood stimuli.

In the case of the orbital network, there is now sub-

stantial data indicating that it serves to assess the rela-

tive value of sensory objects, as well as playing a

central role in reward processing (Hikosaka and Wata-

nabe, 2000; Rolls, 2000; Schultz et al., 2000; Padoa-

Schioppa and Assad, 2006; Noonan et al., 2011; Rude-

beck and Murray, 2011a). Presumably, the VLPFC plays

a similar role in object assessment. Such a role implies

that the networks receive information both about the

sensory nature of the stimuli and about their affective

quality that could serve as the basis of a judgment that

the stimuli are rewarding or aversive.

It is readily apparent that areas such as PV and SII

may provide somatic sensory information, whereas

areas STSv and TE presumably provide visual



information about objects that are to be assessed, just

as the primary olfactory and gustatory cortex provide

the OPFC with information about flavor. The source of

positive or negative affective information is less appa-

rent. Among the connections that have been identified,

the most likely source of such information is the dys-

granular cortex in the rostral and central part of the

insula. This cortical region appears to receive taste/vis-

ceral afferents that could provide information about the

state of the body (Cechetto and Saper, 1987; Saper

et al., 2002; Scott, 2011), and it has substantial limbic

connections with the amygdala (Amaral and Price,

1984; Price and Drevets, 2010). It has been suggested

that activity in the insula underlies “body sense,” or

how we “feel about ourselves” (Craig, 2009, 2011).

Such sensibility could well provide the affective signals

that are needed for analysis of value. The most basic

element of reward in a phylogenetic sense is the avail-

ability of adequate food and warmth, and to be in safe

surroundings, factors that are signaled by visceral

afferents.

There has also been a considerable amount of atten-

tion to the anterior insula as a “control” area for behav-

iors (Nelson et al., 2010; Power and Petersen, 2013). In

humans, the anterior insula is among the most fre-

quently activated regions across a wide variety of fMRI

studies, involving many task situations (Nelson, et al.,

2010). It is not clear exactly what this human area cor-

responds to in monkeys, but it is likely to include the

posterior agranular and the anterior dysgranular insular

regions. It is possible that in phylogenetically earlier

animals this region was an area in which visceral affer-

ent information was evaluated and that in primates it

has evolved into a structure for more complex repre-

sentation of bodily sensibility and wellbeing. From the

current study, it is notable that the anterior insula has

such substantial and specific connections with the

orbital and VLPFC networks.

DPFC networkThe DPFC network includes cortex on the dorsal part

of the medial hemispheric surface above the cingulate

sulcus and cortex on the dorsolateral surface, dorsal to

and including the dorsal bank of the principal sulcus. It

also includes the frontal pole. It does not include the

cortex around the caudal end of the principal sulcus or

in the rostral bank of the arcuate sulcus, however, which

is part of the CLPFC network and has axonal connec-

tions distinctly different from the DPFC network. There is

some terminological confusion between these regions, at

least in part because the region around the caudal end

of the principal sulcus has often been referred to as the

“dorsolateral” PFC or DLPFC (e.g., Levy and Goldman-

Rakic, 2000; Wallis and Miller, 2003; Fox et al., 2012);

because of this confusion, we have not used the term

“dorsolateral” in referring to the DPFC.

The axonal connections of the DPFC network are simi-

lar to those of the “medial PFC network,” including inter-

connections with the STGr/STSd in the rostral temporal

cortex, the posterior cingulate/retrosplenial cortex, and

the posterior parahippocampal cortex (Fig. 24; see also

Saleem et al., 2008b; their Fig. 22B). Furthermore, just

as different areas within the DPFC network are intercon-

nected with each other, they are also connected to

areas within the MPFC network. The major difference in

the connections of the MPFC and DPFC networks is that

the MPFC network has stronger connections with limbic

structures such as the amygdala, entorhinal cortex, and

hippocampal formation. The MPFC network also has

stronger outputs to the hypothalamus and periaqueduc-

tal gray than most parts of the DPFC, although area 9

has relatively substantial projections to these visceral

control regions (€Ong€ur et al., 1998; An et al., 1998).

Our results agree well with previous studies of the

connections of the DFPC, although the interpretations

have differed. The earliest studies with axonal tracer

methods (Barbas and Mesulam, 1985; Barbas and Pan-

dya, 1989) used relatively large injections and inter-

preted the results in terms of phylogenetic “streams”

from supposedly less well differentiated orbital and

medial “paralimbic” cortex to supposedly more devel-

oped cortex in the region of the arcuate sulcus. None-

theless, these studies identified the major targets of

the DPFC (e.g., in the rostral STG and STS region; Bar-

bas and Mesulam, 1985).

Three other studies have provided more detailed

descriptions. Petrides and Pandya (1999) described five

experiments with retrograde tracer injections in areas

8b, 9d, and 46d (including their area 9/46d) plus three

more caudal injections. The distribution of labeled cells

is very similar to that reported here. In all of the cases

with injections in the DPFC (as defined here), most of

the labeled connections within the PFC were with other

parts of the DPFC, the MPFC, and area 45a. The con-

nections outside the PFC were mainly with the posterior

cingulate cortex, the STG/STSd region, and the poste-

rior parahippocampal cortex (areas TF and TH). A sec-

ond article by Petrides and Pandya (2007) described

seven cases with large tracer injections in the rostral

PFC, the results of which again correspond closely to

the results of the present study. The major connections

of the frontal pole (area 10) and area 9 were reported

to be with the posterior cingulate cortex and with the

rostral part of the superior temporal gyrus and sulcus.

Interestingly, the only one of their cases in which the

labeling clearly extended into the auditory belt/parabelt

K.S. Saleem et al.


Figure 24. Summary diagram of the connections of DPFC and frontal pole (areas 9, 10, and 46d). Note that these areas are connected to

the medial prefrontal (“medial network” areas), auditory-related areas in the rostral superior temporal gyrus, dorsal bank of the STS

(STSd), parahippocampal cortex (TF/TH), cingulate cortex (23/24), and retrosplenial cortex (29/30).



(their areas TS2 and TS3) was a large injection directly

in the frontal pole (their case 1).

In a third study, Romanski et al. (1999a) analyzed

possible auditory projections to the PFC from the STG,

based on 16 experiments with tracer injections in sev-

eral parts of the PFC. The tracer used was horseradish

peroxidase (WGA-HRP, or fluorescent tracers), and many

of the injections were large, invaded the white matter,

and crossed areal boundaries, making them difficult to

interpret. Connections from the STG were identified in

11 of the cases, especially those with injections that

involved areas of the DPFC and MPFC. In eight cases,

the pattern of labeling was reported to include the para-

belt. Among these, six injections were in or near the

frontal pole (area 10o/10mr) or area 45a, areas that

were identified in the present study as connected to the

parabelt; another was in area 8A. Therefore, although it

is difficult to make a precise comparison, there is rela-

tively good agreement in the data between the Roman-

ski et al. study and the present study.

Auditory inputs to the PFCIt is generally thought that there are auditory inputs to

the PFC (see, e.g., Kaas and Hackett, 2000), although

many of the details on the precise origin and areas of

termination of such connections have been somewhat

vague. Many of these can now be filled in, but ques-

tions remain, and the functional nature of the input(s)

is still uncertain. The key points are that there are con-

nections with both defined parabelt areas and the

“auditory-related area” in the rostral superior temporal

cortex (STGr and possibly STSd) and that these possibly

different projections are distributed in distinct patterns

to different parts of the PFC.

As discussed above, there is good agreement that

the rostral parabelt projects both to the frontal pole

(area 10mr/10o) and to a region in the caudal part of

the VLPFC; in our observations and those of Gerbella

et al. (2010), this latter region corresponds to area

45a. As discussed above, area 45a is an intriguing can-

didate for a monkey communication area that might be

related to the prefrontal language areas in humans. The

role of the auditory input to the frontal pole is not

known. From perhaps the only study with awake mon-

keys that recorded specifically from the frontal pole,

Wise and his colleagues reported that neurons in the

frontal pole “encode chosen goals at feedback time

and nothing else” (Tsujimoto et al., 2010). If this is so,

auditory input would be needed if the chosen goal

includes evocation of a call or other vocalization.

Areas STGr/STSd, rostral and ventral to the auditory

belt/parabelt areas, project to area 45a and the frontal

pole but also project much more widely to the DPFC

and MPFC. The evidence linking STGr/STSd to auditory

function is much less strong and direct than for the

auditory parabelt areas. This question would seem to

depend on two additional, related questions. 1) Are

there corticocortical connections from the core, belt, or

parabelt to STGr/STSd? 2) Can reliable auditory

responses or activation be found outside the auditory

core/belt/parabelt regions? The answer to both ques-

tions appears to be a qualified yes, although the evi-

dence is not as definitive as one would like.

A study by Hackett et al. (1998) placed tracer injec-

tions in several parts of the auditory parabelt. Although

the focus of the study was connections within the

defined auditory areas, they reported “isolated patches

of labeled cells in the STS and rostral STG” following

the most rostral injections in the parabelt. In the pres-

ent study, we found that tracer injections in STGr or

the rostral parabelt produced label mainly in the

injected area but that there was overlap between the

zone labeled from the STGr and that labeled from the

rostral parabelt.

Most of the neurophysiological studies that have

recorded responses to auditory stimuli have been con-

centrated in the supratemporal plane and in belt/para-

belt areas in the middle to caudal STG. For example, a

recent study (Kikuchi et al., 2010) on responses to

complex auditory stimuli, including monkey calls, was

restricted to areas within the lateral sulcus. In part this

may be due to the difficulty of getting an electrode into

more lateral areas in unanesthetized monkeys, but it

leaves a gap in the published data on STGr/STSd.

Neurophysiological studies of STSd have mostly

stressed the polysensory nature of the region and have

referred to it as the superior temporal polysensory area

(STP). Cells in the STP respond differentially to several

modalities and are also responsive to motion-related

stimuli (Bruce et al., 1981; Heitanen and Perrett, 1993;

Oram et al., 1993; Oram and Parrett, 1996). The exact

boundaries of the STP are not well defined, but it is

said to correspond to areas TPO and PGa of Seltzer

and Pandya (1978; see also Heitanen and Perrett,

1993), which occupy the very medial part of the STSd.

Most studies on STP have also reported units in the

medial part of the STSd (see, e.g., Heitanen and Per-

rett, 1993; Oram and Perrett, 1996). The area that we

have referred as STGr/STSd occupies the more lateral

part and lip of STSd and the adjacent surface of the

STG. It is likely, therefore, that the cortical area that is

connected to MPFC and DPFC is separate from the

STP. From one of the few comprehensive studies of

this region, Baylis et al. (1987) reported responsive

neurons in many areas within the STS; almost all of the

areas responded mainly to visual stimuli, including all

K.S. Saleem et al.


parts of STSv/f and area TPO in the medial part of

STSd. Only the lateral part of STSd (their area TAa) and

STGr (their area TS) had substantial responses to both

visual and auditory stimuli. A particularly useful study

was reported by Poremba and Mishkin (2007), who

used the 2-deoxyglucose method of labeling metabol-

ically (and synaptically) active brain areas to compare

areas activated by auditory stimuli on one side of the

cortex with areas in the contralateral hemisphere that

had been deafferented by cutting the auditory pathways

and commissures. Their study indicates that the entire

STG is activated in the “hearing” hemisphere and deac-

tivated in the “deaf” hemisphere. A close examination

of their illustrated data, however, shows that the pri-

mary auditory area and the belt and parabelt regions

are strongly affected, whereas the STGr/STSd region is

affected to a substantially lesser degree (see their Figs.

3, 7). The activation seen in STGr/STSd was in isolated

columns; that in the core/belt/parabelt was more

continuous.

Taken together, all of these observations suggest

that STGr/STSd may not be exclusively or primarily

related to audition but may be more fully involved in a

related function, such as communication or vocalization.

In this respect, it is notable that an earlier study from

this laboratory that defined cortical projections to the

midbrain periaqueductal gray (PAG) showed that these

arise from STGr/STSd as well as from most of the

areas of the MPFC and DPFC (An et al., 1998). The

PAG and the MPFC have long been recognized as sites

where stimulation can evoke vocalization in monkeys

(for review see Jurgens, 2009). The PAG appears to

function through coordinating control of laryngeal

motorneurons and other vocalization-related nuclei in

the caudal brainstem. The PAG also coordinates behav-

ioral and autonomic responses to stress, especially pain

(Keay and Bandler, 2001), and it is likely that the role

of the PAG in vocalization is related to its general role

in relation to stress. The MPFC/DPFC appears to pro-

vide cortical modulation of this stress response (see

below), and it may be suggested that STGr/STSd con-

tributes to this function.

Functional significance of DPFC networkRelation to default mode networkTaken together, the DPFC, MPFC, and their connected

cortical areas (STGr/STSd, posterior cingulate and para-

hippocampal cortices), as defined in monkeys, closely

resemble the network identified in humans as the

“default mode network” (DMN). As analyzed with func-

tional imaging methods, the DMN is active under rest-

ing conditions and decreases its activity under most

active test conditions (Raichle et al., 2001; Raichle and

Snyder, 2007). The core regions of the DMN in humans

are the posterior cingulate cortex and adjacent precu-

neus and the medial and dorsal prefrontal cortex, which

match the combined MPFC and DPFC in monkeys, and

the posterior cingulate region to which they are con-

nected. Other cortical regions that are usually included

in the DMN are the parietal/temporal/occipital junction

region, the rostral part of the middle temporal gyrus,

and the entorhinal and parahippocampal cortices. The

only one of these regions that does not appear to cor-

respond to a part of the MPFC/DPFC network and con-

nected cortical areas in monkeys is the parietal/

temporal/occipital junction region. Although the middle

temporal gyrus region in humans does not immediately

correspond to the STGr/STSd region in monkeys, this

may be because of expansion of the temporal cortex in

humans, which produces a middle temporal gyrus that

is not present in monkeys. The visual association areas

in the inferior temporal cortex in monkeys have moved

onto the ventral surface of the temporal lobe in humans

(Denys et al., 2004; Orban et al., 2004; Tsao et al.,

2008a). It may be suggested that the middle temporal

gyrus has developed from an expansion of the cortex in

the STS, such that the STGr/STSd in monkeys is repre-

sented in the middle temporal gyrus in humans.

Although the function of the DMN is still unclear, it has

been implicated in self-referential functions, among

others (Gusnard et al., 2001; Gusnard, 2005). Mood is

a prime example of such functions, and areas within

the DMN have been frequently implicated in mood dis-

orders, especially areas in the MPFC, rostral and ventral

to the genu of the corpus callosum (Sheline et al.,

2009; Price and Drevets, 2010, 2012; Holtzheimer

et al., 2012). Petrides has presented evidence that that

the DPFC is involved in a different type of self-

referential function, namely, monitoring previous behav-

ior as a guide to subsequent choices (Petrides et al.,

2002; Petrides, 2005).

The function of the middle temporal gyrus in humans

has been unclear. Recently, however, Kanwisher and

her colleagues have reported a new method of analyz-

ing fMRI data in individual subjects that allows the

demonstration of language-related activation in an

extended strip along the middle temporal gyrus (Feder-

enko et al., 2010). This language-related strip includes

the rostral part of the gyrus that is part of the DMN

and may correspond to the STGr/STSd in monkeys.

Convergent region around principal sulcusThe three networks of the lateral PFC (DPFC, VLPFC,

and CLPFC) all extend into the principal sulcus, with

the DPFC largely in the dorsal bank, the VLPFC in the

ventral bank, and the CLPFC in the caudal part of the



sulcus. The extrinsic connections of these parts of the

sulcus are distinct, but intrinsic corticocortical connec-

tions suggest that there is considerable interaction

within the principal sulcus. Most of the local connec-

tions of PFC networks are restricted to other areas of

the same network, but there are substantial connec-

tions between the dorsal and the ventral banks of the

principal sulcus, linking the DPFC and VLPFC networks.

Similarly, experiments with injections in areas of the

CLPFC show that there are connections with more ros-

tral parts of the principal sulcus.

A recent study of neuronal responses in the dorsal

and ventral banks of the principal sulcus suggests how

this might work (Cai and Padoa-Schippo, 2014). As

mentioned above, previous work had shown that neu-

rons in the OPFC network function in assessment of

stimuli by encoding the relative value of offered

rewards (Padoa-Schioppa and Assad, 2006). Given the

similarities and connections between the OPFC and

VLPFC networks, it would be expected that neurons in

the VLPFC might show similar responses. Indeed, neu-

rons were found that respond to the relative value of

stimuli in the ventral bank of the principal sulcus.

Remarkably, the same types of responses were also

found in the dorsal bank, although at a longer average

latency (see also Kennerly et al., 2009), suggesting that

the activity was processed in the VLPFC network and

then relayed to the DPFC networks. Presumably, the

two networks use the activity for different purposes,

but this remains to be determined.

Correlation with other speciesFor rats, there is evidence for the existence of orbital

and medial PFC networks similar to those defined for

monkeys, although they are substantially less complex

(Floyd et al., 2000, 2001). The medial PFC of monkeys

has obvious correlation with medial agranular frontal

areas in rats, and several small areas in the dorsal

bank of the rostral rhinal sulcus of rats appear to corre-

spond to areas in the orbital cortex of monkeys. On the

other hand, there are considerable questions about

whether the granular areas in the lateral PFC of prima-

tes exist in rodents (Preuss, 1995, 2000). Functionally,

it has been suggested that the agranular medial PFC in

rodents has a function similar to that of much of the

granular cortex of the primate lateral PFC, but anatomi-

cally the two regions are very different. There is virtu-

ally no granular frontal cortex in rodents. The current

finding that the DPFC and VLPFC networks have similar

connections to the MPFC and OPFC networks, respec-

tively, suggests a possible solution to this question.

That is, the dorsal and ventral parts of the primate lat-

eral PFC might have developed phylogenetically by elab-

oration and expansion of the medial and orbital

networks in some precursor species. The functions rep-

resented in two networks in rodents would then be

spread over larger regions, which would develop novel

structural and functional characteristics as they become

further subdivided. In that sense, the medial PFC in

rodents would be expected to have some of the func-

tions of the lateral PFC in primates, but these would be

much less well developed and would be combined with

functions that are represented primarily by the MPFC

network in primates.

The suggestion that the DPFC has developed out of

the MPFC and the VLPFC out of the OPFC is very simi-

lar to a longstanding proposal by Pandya and his col-

leagues for dorsal and ventral streams or trends of

phylogenetic development of the PFC (see Yeterian

et al., 2012). Their “dorsal architectonic trend” corre-

sponds largely to the combined MPFC and DPFC net-

works, and their “ventral architectonic trend” is similar

to the combined OPFC and VLPFC networks. There are

several differences in the detailed definition of these

systems (for example, the MPFC network includes

some areas along the medial and lateral edges of the

orbital cortical surface), but the major difference is that

the CLPFC is included in the dorsal and ventral trends,

whereas we have separated it out as a distinct system.

A corollary of this argument is that the PFC in

humans is essentially an expansion and elaboration of

the same networks found in monkeys. This cannot be

determined at present, but it is notable that the same

architectonic areas found in the orbital and medial pre-

frontal cortices of monkeys can be identified in humans

(€Ong€ur et al., 2003), and these can be used to outline

the MPFC and OPFC networks. Petrides and colleagues

(2012) have also proposed correlated architectonic

maps for the LPFC for monkeys and humans, although

these maps are not sufficiently detailed to account for

the subdivisions defined in this study. The presence of

the DMN in the dorsal as well as ventral parts of the

MPFC in humans (see above) suggests that the MPFC

and DPFC networks are present in humans and that

they are located mostly on the medial wall and dorsal

convexity of the hemisphere. It is reasonable to expect

that the VLPFC network is located on the ventrolateral

convexity, but it is difficult to delineate it precisely. If

area 45a is indeed part of a communication system, it

is likely to have expanded substantially with the devel-

opment of language areas in the LPFC.

ACKNOWLEDGMENTSWe thank Hieu Van Luu, Abhisek C. Kandai, and Sze-

chuan Suen for their excellent technical assistance and

Colin Reveley for providing inflated brain images. We also

K.S. Saleem et al.


thank two anonymous reviewers for useful comments on

the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors have no conflicts of interest.

ROLE OF AUTHORS

All authors were involved in this study. Study concept

and design: KSS, JLP. Acquisition of data: KSS, BM, JLP.

Analysis and interpretation of data: KSS, BM, JLP. Draft-

ing of the article: KSS, JLP.

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