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

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  • 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. 522:16411690, 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; Ongur

    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:

    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( 2013 Wiley Periodicals, Inc.

    The Journal of Comparative Neurology | Research in Systems Neuroscience 522:16411690 (2014) 1641


  • Abbreviations

    12 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


    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; Ongur 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 (Ongur

    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; Ongur 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...


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