103:793-800, 2010. First published Dec 2, 2009;  doi:10.1152/jn.00546.2009 J NeurophysiolJustin L. Vincent, Itamar Kahn, David C. Van Essen and Randy L. Buckner

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Functional Connectivity of the Macaque Posterior Parahippocampal Cortex

Justin L. Vincent,1,2 Itamar Kahn,1–3 David C. Van Essen,4 and Randy L. Buckner1–3,5

1Department of Psychology and Center for Brain Science, Harvard University, Cambridge, Massachusetts; 2Athinoula A. Martinos Centerfor Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts; 3Howard Hughes Medical Institute; 4Departmentof Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri; and 5Departments of Psychiatry andRadiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts

Submitted 24 June 2009; accepted in final form 25 November 2009

Vincent JL, Kahn I, Van Essen DC, Buckner RL. Functionalconnectivity of the macaque posterior parahippocampal cortex. JNeurophysiol 103: 793–800, 2010. First published December 2, 2009;doi:10.1152/jn.00546.2009. Neuroimaging experiments in humans sug-gest that regions in parietal cortex and along the posterior midline arefunctionally connected to the medial temporal lobe and are active duringmemory retrieval. It is unknown whether macaques have a similarnetwork. We examined functional connectivity in isoflurane-anesthetizedmacaques to identify a network associated with posterior parahippocam-pal cortex (PPHC). Functional connectivity was observed between thePPHC and retrosplenial, posterior cingulate, superior temporal gyrus, andinferior parietal cortex. PPHC correlations were distinct from regions inparietal and temporal cortex activated by an oculomotor task. Compari-son of macaque and human PPHC correlations revealed similarities thatsuggest the temporal-parietal region identified in the macaque may sharea common lineage with human Brodmann area 39, a region thought to beinvolved in recollection. These results suggest that macaques and humansmay have homologous PPHC-parietal pathways. By specifying the loca-tion of the putative macaque homologue in parietal cortex, we provide atarget for future physiological exploration of this area’s role in mnemonicor alternative processes.

I N T R O D U C T I O N

Human posterior parietal cortex and limbic cortex are acti-vated during long-term memory retrieval (Cabeza et al. 2008;Vilberg and Rugg 2008; Wagner et al. 2005). Specifically,greater responses in human lateral parietal regions as well asthe posterior cingulate and retrosplenial cortex have beenrepeatedly observed with functional magnetic resonance imag-ing (fMRI) when participants correctly recognize previouslystudied items (hits) versus correctly identified new items (cor-rect rejections). The human lateral parietal retrieval successeffect occurs regardless of whether the stimuli are lexical,graphic, or acoustic (Henson et al. 1999; Kahn et al. 2004;Konishi et al. 2000; Leube et al. 2003; McDermott 2000;Shannon and Buckner 2004; Wheeler and Buckner 2003, 2004)and does not depend on response contingency (i.e., whether amotor response is made only to new vs. only to old items)(Shannon and Buckner 2004). Furthermore, activation in thehuman posterior parietal cortex is implicated in retrieval ofepisodic details: recollection elicits a greater response thanfamiliarity-based decisions in the absence of recollection (Ca-beza et al. 2008; Vilberg and Rugg 2008; Wagner et al. 2005).

The functional nature of the human parietal old/new effectremains unclear and would benefit greatly from study in the

monkey where the anatomy and physiology of the parietal cortexis accessible. However, it is uncertain whether or not the macaquemonkey has parietal regions that are homologous to those respon-sive during human memory-retrieval experiments. One way tocompare species using the same technique is to compare patternsin fMRI-based functional connectivity (Biswal et al. 1995; Foxand Raichle 2007; Van Dijk et al. 2009; Vincent et al. 2007).Spontaneous blood oxygenation-level-dependent (BOLD) (Ogawaet al. 1990) fluctuations reflect both direct and indirect anatomicconnectivity (Hagmann et al. 2008; Honey et al. 2009; Vincent etal. 2007) and are correlated with fluctuations in neuronal activityas reflected in the gamma band of the local field potential,multiunit activity, and spiking activity (Shmuel and Leopold2008). While there are caveats and limitations to the technique(reviewed recently in Van Dijk et al. 2009), functional connec-tivity appears sufficiently constrained by anatomic connectivity tofacilitate comparative study of brain systems between species.

Previous studies of intrinsic functional connectivity in thehuman have demonstrated that BOLD fluctuations in humanmedial temporal lobe are correlated with the same regions inposterior parietal and limbic cortex that respond during mem-ory retrieval (Vincent et al. 2006). In the human, this hip-pocampal-cortical memory system overlaps core regions of theso-called “default network” (Buckner et al. 2008; Vincent et al.2006). More recently, correlations were demonstrated betweenBOLD fluctuations in macaque posterior cingulate/precuneusand bilateral lateral temporo-parietal regions that may be ana-tomical homologues to human lateral parietal regions known torespond during episodic memory retrieval (Margulies et al.2009; Vincent et al. 2007).

The main goal of this study was to determine whethermacaque posterior parahippocampal cortex (PPHC) is func-tionally correlated with regions in posterior limbic and lateralparietal cortex and whether these regions are anatomicallydistinct from the parietal regions traditionally associated withvisual-spatial attention and sensory-motor integration (e.g.,Andersen and Buneo 2002; Colby and Goldberg 1999; Hei-lman and Gonzalez Rothi 1993; Mesulam 1999). A secondarygoal was to examine functional correlations in the posteriorcingulate/retrosplenial cortex. Hayden and colleagues (2009)have recently shown that firing rates in the macaque posteriorcingulate are suppressed during task performance, which isfunctionally similar to deactivations observed in the humanposterior cingulate and the extended default network (Buckneret al. 2008; Gusnard and Raichle 2001; Mazoyer et al. 2001;Shulman et al. 1997). Further, several previous human studiessuggest that the posterior cingulate is functionally connected tomany of regions that fall within the human default network

Address for reprint requests and other correspondence: J. Vincent, HarvardUniversity, Center for Brain Science, 52 Oxford St., Rm 280, Cambridge, MA02138 (E-mail: vincent@nmr.mgh.harvard.edu).

J Neurophysiol 103: 793–800, 2010.First published December 2, 2009; doi:10.1152/jn.00546.2009.

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(e.g., Buckner et al. 2008, 2009; Grecius et al. 2009; Hagmannet al. 2008). Therefore by seeding the macaque posteriorcingulate, we seek to explore the broader set of regions withinthis functionally correlated brain network.

M E T H O D S

Subjects, procedures, preprocessing, and analysis are similar to aprevious report (Vincent et al. 2007). These data have been previouslypublished (Margulies et al. 2009; Vincent et al. 2007). Briefly, elevenhealthy adult macaque macaques (8 Macaca fascicularis; 3 M. mu-latta) were anesthestized with isoflurane and scanned using fMRI. Themacaques were divided into two groups: data set 1 consisted of fourmacaques; data set 2 consisted of eight macaques (1 macaque wascommon to both groups). Data set 2 has been provided for downloadat www.brainscape.org. Data were aligned to a Martin and Bowdenatlas template (Black et al. 2004; Martin and Bowden 2000; seehttp://www.purl.org/net/kbmd/cyno) and preprocessed to prepare forseed-based functional correlation analysis. Details of the proceduresare provided in a previous publication (Vincent et al. 2007) as well asin the supplementary methods.1

Creation of regions of interest

For the group analysis of PPHC correlations in data set 2, seed regionsin the left and right PPHC were defined as voxels in and around theposterior parahippocampal gyrus that were functionally correlated with aposterior cingulate seed region in data set 1 (similar to Vincent et al.2006). In addition, a posterior cingulate/retrosplenial cortex (pC/Rsp)region of interest was defined in data set 2 as voxels functionallycorrelated with the combined left and right PPHC seed regions. The factthat the pC/Rsp region was defined in data set 2 as voxels correlated withthe PPHC seed region in data set 2 makes statistical interpretation of thepC/Rsp correlations in the medial temporal lobe limited. In addition,limitations of resolution, spatial distortion, spatial blurring, as well as ourmethod of defining the PPHC region make the true boundaries of thegroup PPHC region ambiguous. Therefore follow-up analyses wereconducted in individual subjects. The full extent of the right PPHC wascarefully drawn on the distorted echo-planar images in three subjectsusing the Martin and Bowden (2001) atlas, high-resolution magnetiza-tion-prepared rapid gradient-echo MP-RAGE, and the high-resolutionecho-planar image (EPI) as an anatomical guide. These subject-specificPPHC regions were then used to generate subject-specific functionalcorrelation maps to confirm the group map results (see Fig. 2).

Correlation mapping

For each subject and each region of interest (ROI), correlation mapswere computed as previously described (Vincent et al. 2007) bycorrelating a selected regional time course against all other voxels inthe brain. Application of Fisher’s z transform (Zar 1996) yielded mapswith values at each voxel that theoretically are nearly normallydistributed over the population of subjects. Fixed effects significancemaps were created for each individual as previously described (Vin-cent et al. 2007).

Group data were displayed over the average MP-RAGE or EPIMRI slices (aligned to the atlas of Martin and Bowden 2000; seehttp://www.purl.org/net/kbmd/cyno) or projected from volume data tothe F6 cortical surface (Vincent et al. 2007) using the Caret “enclosedvoxel” method. Individual subject data were displayed over theindividual subject’s averaged EPI MRI slices.

R E S U L T S

The left and right PPHC seed regions and their associatedcorrelation maps are shown in Fig. 1. Figure 1A shows the

correlation pattern for the right hemisphere PPHC seed. The toprow shows the correlation data overlaid on transverse and sagittalsections of the average anatomy. The bottom row shows thecorrelation data on lateral and medial views of the inflated F6cortical surface. The left hemisphere PPHC correlation maps areshown in Fig. 1B. The PPHC was functionally correlated with thecontralateral parahippocampal cortex, retrosplenial cortex, theposterior cingulate, and bilateral temporo-parietal cortex (includ-ing supramarginal gyrus and the superior temporal gyrus). Over-all, these results were similar across seed regions and hemi-spheres. However, the left PPHC correlation with left temporalparietal cortex did not reach significance.

Figure 1C shows the results of left and right PPHC correlationson coronal slices as well as a conjunction map showing voxelscorrelated with both seed regions in red. The PPHC correlationsinclude parietal cortex lateral to the intraparietal sulcus on thesupramarginal and superior temporal gyrus. In the more anteriorslices, correlations were found on the superior temporal gyrus.The correlations extended onto the inferior temporal gyrus nearV4, possibly as a consequence of spatial blurring. For betterlocalization, we examined correlations in individual subjects.

To further examine the location of functional correlationsbetween the PPHC and temporo-parietal cortex, we manuallytraced the right PPHC on the T2*-weighted image in threemacaques (taken from data set 2) and computed functionalcorrelations using those individually drawn PPHC regions asseeds. Figure 2 shows the individual subject maps along sidethe right PPHC group correlation map. The intraparietal cortex(IPS) and superior temporal sulcus (STS) are traced with blacklines. Overall, individuals demonstrated similar patterns ofcorrelation to the group map. These data demonstrate that thePPHC correlation pattern in temporo-parietal cortex is largelylateral to the IPS, superior to the STS, and includes thesupramarginal and superior temporal gyrus.

Portions of macaque parietal cortex are associated withvisuospatial attention and sensory-motor integration. An im-portant question is whether or not the temporo-parietal regionwe identified by functional connectivity with the PPHC corre-sponds with regions implicated in visual-spatial or sensory-motor functionality. To explore this issue, we compared thetemporo-parietal region that was correlated with the PPHC tothe set of regions activated by a common visual-spatial, sen-sory-motor task: visually guided saccadic eye movements.

We compared the map of PPHC functional correlations (Fig. 3A,collapsed across hemispheres) to a map of BOLD responsesevoked during performance of a visually guided saccadic eyemovement task in two awake, behaving macaques (Fig. 3B)(data from Baker et al. 2006). Voxels that overlap in the twomaps are shown in yellow in Fig. 3C. There is relatively littleoverlap, which indicates segregation. The only region of po-tential overlap lies in or around dorsal-anterior MST. Toestimate the areal location of the temporo-parietal correlationwith the PPHC (Fig. 3A), the correlation data were displayedon a cortical flat map with estimated architectonic area bound-aries overlaid (from Lewis and Van Essen 2000a) (Fig. 3D).The temporo-parietal region correlated with the PPHC is in ornear areas 7a, TPOc, and PA. Areas activated by saccadic eyemovements were in or near areas PO, MIP, VIPm, VIPl, LIPv,LIPd, 7a, MSTdp, MSTm, MSTda, MT, FST, LOP, and V3a(Fig. 3E). Overall, there are few areas that overlap between theregions activated by saccadic eye movements and the regions1 The online version of this article contains supplemental data.

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correlated with the PPHC. The only areas that were identifiedby both analyses were area 7a (and potentially MSTda). How-ever, the correlations with PPHC were located in a moreanterior region within area 7a, whereas the activations associ-ated with saccadic eye movements were associated with a moreposterior region within 7a. Overall, these data suggest that theregions correlated with the PPHC are likely to be distinct fromthe regions associated with saccadic eye movements.

In humans, the hippocampal formation and posterior PPHCare functionally correlated with regions in posterior parietalcortex that are activated by recollection (Vincent et al. 2006).

The present analyses demonstrate that a qualitatively similarparahippocampal-parietal network exists in macaques. To pro-vide a more objective comparison between the two species, weused a mapping between macaque and human cortex based ona set of 29 landmarks representing known or presumed homol-ogies (supplementary information and Supplementary Fig. S1).Using this mapping, we registered the macaque brain to thesurface of the human brain using anatomical and functionallandmarks (see supplementary information) and projected themacaque PPHC functional connectivity results (collapsedacross left and right seed regions) onto the human atlas surface

FIG. 1. The posterior parahippocampal cortex (PPHC) isfunctionally correlated with the contralateral medial temporallobe, retrosplenial cortex, posterior cingulate, and lateral tem-poro-parietal cortex. The right (A) and left (B) PPHC seedregions are shown in solid blue on a sagittal slice as well as theinflated surfaces. The functional correlations are shown onsagittal and transverse slices as well as the inflated lateral andmedial surfaces of the macaque cortex. C: left and right PPHCcorrelations are shown on sequential coronal slices. A conjunc-tion map (CONJ) shows voxels significantly correlated withboth seed regions. Correlation maps are thresholded at P � 0.05(corrected).

FIG. 2. Group and individual subject PPHC correlation dataare displayed on group and individual T2*-weighted MRI scans toaid in localizing the temporo-parietal region functionally correlatedwith the PPHC. Left: transverse and a coronal MP-RAGE slicedepicting the approximate anatomy that is shown in the T2*-weighted scans to the right. Individual subject (monkeys 1–3; r �0.01) and group (n � 8; P � 0.05 corrected) PPHC correlationmaps. The seed regions are shown above the correlations maps inblue. Black lines trace the intraparietal sulcus (IPS) and superiortemporal sulcus (STS).

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(Supplementary Fig. S2). The deformed monkey PPHC corre-lation map includes a region in the inferior parietal lobule plusa smaller region in posterior cingulate/retrosplenial cortex(Supplementary Fig. S2). For reference, we plot the estimatedborders of relevant human Brodmann areas. Based on theresults of the deformation, the regions in the macaque that werecorrelated with the PPHC were in or around human Brodmannareas 39, 31, and 23. This hypothesis, however, is dependenton the validity of the cross-species registration (see DISCUSSION

and Supplementary Fig. S1).The regions functionally correlated with the medial temporal

lobe in humans overlap with regions in the default network,including the inferior parietal lobule and posterior cingulate/retrosplenial cortex (Buckner et al. 2008; Vincent et al. 2006).The similarity between macaque and human PPHC functionalcorrelation results (Kahn et al. 2008; Vincent et al. 2006)suggest that macaques may have regions that share a lineagewith the human default network. Further evidence for this viewcomes from recent work showing that a region in the macaquePPHC network, the posterior cingulate, shows similar func-tional responses to the human posterior cingulate during taskperformance (Hayden et al. 2009). Therefore we also examinedfunctional correlations associated the macaque posterior cin-gulate/retrosplenial (pC/Rsp) cortex. The pC/Rsp was func-tionally correlated with bilateral posterior medial temporallobe, parietal cortex (in and around areas 7a, LIP, and DP),medial prefrontal cortex (in and around areas 9, 14r, 10m, 24b,and 32), superior temporal sulcus, superior temporal gyrus, anddorsal lateral prefrontal cortex (in and around areas 6, 8, 9, and46; Fig. 4). To further examine the correlations in medialprefrontal cortex, the data were projected onto the corticalsurface, and boundaries around functional areas were estimated

based on the schema of Ferry and colleagues (2000). ThepC/Rsp was functionally correlated with regions in and aroundareas 9, 24b, 10m, 32, and 14r. Thus PPHC is functionallycorrelated with a region in pC/Rsp cortex that in turn isfunctionally connected with an additional set of regionsthroughout the anterior cingulate and medial prefrontal cortex.

D I S C U S S I O N

Overview

This work reports the BOLD functional correlations of thePPHC and pC/Rsp. The main finding is that specific regionswithin lateral temporo-parietal, posterior cingulate, and retro-splenial cortex are functionally correlated with the medialtemporal lobe (Fig. 1). This system was largely distinct fromthe network of regions activated by a saccadic eye movementtask, which suggests that it is unlikely driven by spatialattention or oculomotor performance (Fig. 3). Individual sub-ject results and detailed anatomical analyses suggest that themedial temporal lobe has functional connections to supramar-ginal and superior temporal gyrus in or near areas TPOc, PA,and 7a (Figs. 2 and 3). Cross-species registration betweenmacaque and human suggested that the parietal region corre-lated with the PPHC in macaques might be in or around humanBrodmann area 39 (Supplementary Fig. S2). Finally, al-though we found no direct functional connectivity betweenthe PPHC and medial prefrontal cortex, evidence for indi-rect functional connectivity with the medial prefrontal cor-tex did emerge when pC/Rsp cortex was explored as anintermediate (Fig. 4).

FIG. 3. The temporal and parietal regionsfunctionally correlated with the PPHC are dis-tinct from those involved in visually guidedsaccadic eye movements. PPHC functionalcorrelations (A and D, warm colors) as well asactivation related to visually guided saccades(B and E, cool colors) are projected onto theinflated (A and B) and flattened (D and E)surface of the right hemisphere. In addition, thePPHC correlations (red), saccade-related acti-vation (blue), and overlapping voxels (yellow)are shown in C. The flat map sections (D–F)includes temporal and parietal cortex and con-tains areal boundaries (F) that are labeled ac-cording to the schema of Lewis and Van Essen(2000a). A compass (M, medial; L, lateral; P,posterior; A, anterior) provides a reference forthe flat maps. The oculomotor activation islargely within the superior temporal and in-traparietal sulci whereas the temporo-parietalregion correlated with the PPHC in and aroundareas 7a, PA, and TPOc.

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Limitations and caveats

Resting state functional correlation patterns measured usingfMRI are consistent across acquisition sessions within a par-ticipant (Honey et al. 2009; Meindl et al. 2009; Shehzad et al.2009; Van Dijk et al. 2009) as well as across participants andgroups (e.g., Desmoiseaux et al. 2006; Van Dijk et al. 2009;Vincent et al. 2006). While functional correlations appear to beconstrained by anatomical connectivity (Honey et al. 2009;Margulies et al. 2009; Vincent et al. 2007), the correlationstrength between regions also reflects polysynaptic connectiv-ity (e.g., Habas et al. 2009; Krienen and Buckner 2009;O’Reilly et al. 2009) and may be influenced by commondriving inputs (see Van Dijk et al. 2009 for discussion). Thusthe methods applied here provide information about large-scalebrain systems and the relationship of medial temporal struc-tures to distributed cortical systems, but the details of anatomicconnectivity will require further exploration using direct mea-sures of anatomic connectivity.

Functional correlations can also be modified by the cognitivestate of the participant. For example, the strength of functionalcorrelations can be modified by task performance (Fransson 2006;

Newton et al. 2007), sleep stage (Horovitz et al. 2009), andanesthesia (Supplementary Figs. 4–6 of Vincent et al. 2007). Theanesthetized state of the macaques in this study may have causeda reduction in the correlation strength between some nodes in thePPHC and pC/Rsp correlation networks. For example, an unex-pected finding in our study was the weak functional connectivitybetween the PPHC and the medial prefrontal cortex and anteriortemporal lobe. In humans, the default network (of which PPHCand pC/Rsp are a part) is known to exhibit significantly decreasedconnectivity with the medial prefrontal cortex during loss ofconsciousness characterized by deep sleep (Horovitz et al. 2009).The present finding that the macaque medial prefrontal cortex wasnot correlated with the PPHC and weakly correlated with thepC/Rsp may be due to the anesthesia. Another possibility for theweak or nonsignificant correlations with prefrontal and anteriortemporal regions is that the BOLD data were distorted and hadlow signal in the anterior temporal lobe and the medial prefrontalcortex. For these reasons, we are cautious when interpreting weakor nonsignificant correlations with these anterior regions.

Supplementary Fig. S2 plots the macaque PPHC functionalcorrelation data on the human cortical surface using a nonlinearmonkey to human registration technique based on a previouslypublished schema (Denys et al. 2004) with additional land-marks in the prefrontal cortex (Supplementary Fig. S1). Basedon the current set of landmark constraints, the temporal-parietal region correlated with the macaque PPHC may befunctionally related to a region in the human Brodmann area39. However, one should be cautious when drawing conclu-sions from this analysis due to the paucity of landmarks drivingthe cross-species registration in parietal cortex.

Relation to anatomical connectivity

Information about human anatomical connectivity is scarce.Therefore other methods, including functional connectivitymapping of spontaneous BOLD fluctuations, have been used tostudy potential anatomical networks in humans. Functionalconnectivity methods alone cannot unambiguously designatefunctional pathways, determine the directionality of a projec-tion, or discern whether a pathway is direct or indirect. Nev-ertheless, despite these caveats, functional correlation mappinghas successfully generated functional and anatomical predic-tions about the human brain. For example, we have previouslyshown that the regions functionally correlated with the humanmedial temporal lobe during the resting state overlapped thoseregions activated by episodic memory retrieval (Vincent et al.2006). The study of functional connectivity in the macaque isuseful for refining our understanding of the relation betweenfunctional and anatomical connectivity. Previously we reportedsimilarities between functional and anatomical connectivitymaps in the oculomotor system as well as functional correla-tions in visual cortex and known sub-areal, retinotopic organi-zation (Vincent et al. 2007). Here we compare and contrastknown anatomical tract tracing work in macaques in relation toour functional correlation results from seed regions in PPHCand pC/Rsp.

The PPHC is strongly anatomically connected to the poste-rior limbic cortex. Parahippocampal cortex (area TF) has lightto moderate projections to area 29 and moderate to heavyprojections to areas 30, 23, and retrosplenial area 23v (Lavenexet al. 2002). Morris et al. (1999) also reported that posterior

FIG. 4. The posterior cingulate/retrosplenial (pC/Rsp) cortex is functionallycorrelated with bilateral posterior medial temporal lobe, lateral temporo-parietal cortex, superior temporal sulcus and gyrus, dorsolateral prefrontalcortex, and medial prefrontal cortex. The seed region is shown in solid blue ona sagittal slice. The functional correlations are shown on sagittal, transverse,and coronal slices as well as the inflated lateral, inflated medial, and fiducialantero-medial surfaces of the macaque brain. As can be seen from thecorrelations displayed on the sagittal slice and caret surfaces, the pC/Rsp isrobustly correlated with medial prefrontal regions in and around areas 9, 24b,10m, 32, and 14r. All correlations P � 0.05 (corrected). Borders are adaptedfrom Ferry et al. (2000).

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parahippocampal cortex (areas TF and TH) sends projectionsto retrosplenial area 30. The parahippocampal cortex (area TF)receives strong input from areas 30, 29l, and 29m of theretrosplenial cortex (Suzuki and Amaral 1994). Blatt et al.(2003) used separate retrograde tracer injections in parahip-pocampal regions TF and TH and showed that injections inboth regions result in uptake in posterior cingulate area 23 andretrosplenial cortex (areas 29 and 30). Finally, Kobayashi andAmaral (2003, 2007) demonstrated reciprocal connections be-tween the parahippocampal cortex and areas 23, 29, and 30.Therefore our reported functional correlations between PPHCand posterior cingulate and retrosplenial cortex are consistentwith known anatomical connectivity.

The PPHC is anatomically connected to the lateral temporo-parietal cortex. Suzuki and Amaral (1994, Fig. 15) demon-strated that retrograde tracer injections into area TF result inuptake in area 7a. In addition, Blatt and coworkers (2003)showed that retrograde tracer injections in parahippocampalregion TF resulted in uptake in PG-Opt, which is very similarto area 7a and is near the region that we found to be function-ally correlated with the PPHG. In addition, Lavenex andcolleagues (2002) reported moderate to heavy anterogradelabeling in area 7 after injection in parahippocampal area TF.Perhaps the most convincing data that area 7a is connected tothe posterior parahippocampal cortex comes from the work ofCavada and Goldman-Rakic (1989, see Figs. 6 and 7). Theyinjected anterograde and retrograde tracers into parietal area 7aand showed dense, reciprocal connections with the parahip-pocampal cortex (particularly in TF, but including TH). Whentaken in conjunction with these anatomical data, our functionalcorrelation data demonstrate a functional pathway between theparahippocampal cortex and the parietal cortex in the macaque.

In addition to consistencies between functional and anatom-ical connectivity, we also observed inconsistencies. First, thePPHC is known to the have connections with the medialprefrontal cortex. For example, the PPHC has both afferent andefferent connections with areas 9, 14, 24, 25, and 32 (Blatt etal. 2003; Lavenex et al. 2002; Kondo et al. 2005; Saleem et al.2008; Suzuki and Amaral 1994). We did not observe signifi-cant correlations between our group PPHC seed region and themedial prefrontal cortex in the monkey. Second, the PPHC isknown to have connections with anterior temporal cortex.Specifically, the PPHC has both afferent and efferent connec-tions with dorsal superior temporal sulcus, in particular in themost anterior (Blatt et al. 2003; Lavenex et al. 2002; Suzukiand Amaral 1994) but also in and around MSTdp (Lewis andVan Essen 2000b). While we observed correlations betweenthe PPHC and the superior temporal sulcus (Fig. 1C), weexpected the correlations to extend more anteriorly based onprevious observations. These negative observations in our data,

which we suspect to be false negatives, may be attributable tosignal dropout, distortions and/or the anesthetized state of theanimals (see Limitations and caveats).

Beyond PPHC, we also examined correlations associatedwith the pC/Rsp cortex (see also Margulies et al. 2009; Vincentet al. 2007). Correlations with the pC/Rsp were largely inmedial prefrontal cortex, dorsolateral prefrontal cortex, supe-rior temporal sulcus, superior temporal gyrus, parietal cortex,and posterior parahippocampal cortex. Posterior cingulate/ret-rosplenial cortex (including areas 23, 29, and 30) has reciprocalconnections with the hippocampal formation and PPHC (in-cluding TF and TH), the dorsolateral prefrontal cortex (includ-ing areas 9, 10, 11, and 46), medial prefrontal cortex (includingarea 24), superior temporal sulcus, superior temporal gyrus,and parietal cortex (including 7a, DP, and LIP) (Kobayashi andAmaral 2003, 2007; Morris et al. 1999). The functional con-nectivity results were consistent with the known connectivityof the posterior cingulate/retrosplenial cortex.

The present work makes two primary contributions to ourunderstanding of macaque functional anatomy. First, althoughprevious papers have demonstrated that the PPHC has recip-rocal connections with retrosplenial cortex and the inferiorparietal lobule (including area 7a), we extend those observa-tions by demonstrating that the spontaneous BOLD fluctua-tions in PPHC, retrosplenial cortex, and 7a are robustly corre-lated. Second, as macaque studies are conducted primarily tobetter understand the human brain, the present work provides acritical bridge between the anatomical connectivity work in themacaque and the functional connectivity and functional acti-vation literature in the human (Fig. 5).

Relation to the default network

A “default mode” of human brain function (Raichle et al.2001) was proposed from the observation that a particular setof cortical regions is more active in the passive state thanduring performance of most attention demanding tasks (An-dreasen et al. 1995; Binder et al. 1999; Buckner et al. 2008;Ghatan et al. 1995; Mazoyer et al. 2001; McKiernan et al.2003; Shulman et al. 1997). Additional research has suggestedthat this network is not only engaged during passive tasks butis activated during the act of remembering (Wagner et al.2005), thinking about the future (Schacter et al. 2008), sceneconstruction (Hassabis and Maguire 2007), and social cogni-tion (Saxe and Kanwisher 2003; Vogeley and Fink 2003). Analternative hypothesis is that the default network may involvemonitoring the external environment and is attenuated duringfocused attention (Gilbert et al. 2007; Hahn et al. 2007; Raichleet al. 2001; Shulman et al. 1997; see Buckner et al. 2008 fordiscussion).

FIG. 5. Macaque PPHC functional correlations in the macaqueare topographically similar to PPHC correlations and recollectionsuccess effects in the human. Images display the macaque PPHCfunctional correlation map (left), regions correlated with the PPHCin the human (middle), and a convergence analysis of event-relatedfMRI studies that target recollection success (right). The humanPPHC correlation data were computed from an anatomically de-fined seed region in the left hemisphere (adapted from Kahn et al.2008). The recollection success effect is defined as greater activa-tion during retrieval associated with a high level of recollection ascompared with hits based preferentially on familiarity (adaptedfrom Wagner et al. 2005).

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The hallmark of the default network is task-induced deacti-vation. In support of the hypothesis that macaques may have adefault network, covert attention suppresses neuronal re-sponses in macaque lateral parietal area 7a (Steinmetz et al.1994). Specifically, neurons responded more to stimuli thatappear at unattended locations than to those that appear atattended locations. More recently, Hayden and colleagues(2009) recorded single neurons in the macaque posterior cin-gulate during a working memory task and demonstrated thatneurons in the posterior cingulate cortex are reliably sup-pressed during task performance and returned to baseline levelsbetween trials. The network of regions functionally correlatedwith the macaque parahippocampal cortex includes the poste-rior cingulate and area 7a (Figs. 1 and 3). Because of thefunctional and anatomical similarities, these macaque regionsmay be homologous to regions within the human defaultnetwork. Future study of the macaque will be required toestablish functional homology. An important next step will beto examine whether the regions here identified as functionallycorrelated with the macaque PPHC are functionally deactivatedduring attention demanding cognitive tasks.

Future directions

The present functional connectivity results suggest that themacaque has a potential homologue of the human hippocam-pal-cortical memory network (Greicius et al. 2004; Kahn et al.2008; Vincent et al. 2006). Figure 5 shows the macaque PPHCcorrelation map (left) along with the human PPHC correlationmap (middle) (data from Kahn et al. 2008). Both the macaqueand human PPHC correlation maps include regions in posteriorcingulate/retrosplenial cortex and the inferior parietal lobule.The parietal regions fall within an area of rapid corticalexpansion in the human compared with macaque lineage (VanEssen and Dierker 2007) and where it is particularly difficult toidentify exact homologies.

In humans, the network correlated with the PPHC is consis-tently activated by correct recognition (and more specificallyrecollection) of previously studied items (Cabeza et al. 2008;Vilberg and Rugg 2008; Wagner et al. 2005). Figure 5, right,shows a convergence analysis of event-related fMRI studiesthat target recollection success in the human (right) (imagefrom Wagner et al. 2005). The correspondences between thehuman PPHC correlation map and the human recollectionsuccess effect are clear. Based on the present macaque PPHCresults, we suggest that the human region in the inferiorparietal lobule that is functionally correlated with the PPHCand is activated during recollection has a potential homologuein or around macaque areas 7a, TPOc, and PA. Future studieswill be needed to determine if this macaque parietal region isresponsive to long-term memory-based recognition judgments.

A C K N O W L E D G M E N T S

We thank W. Suzuki for valuable discussion; J. Harwell for Caret softwareenhancements used in data analysis; and K. J. Black for providing the monkeyatlas target. We thank G. H. Patel, M. D. Fox, A. Z. Snyder, J. T. Baker, J. M.Zempel, L. H. Snyder, M. Corbetta, and M. E. Raichle for helping to conductthese experiments.

G R A N T S

This work was supported by National Institute of Mental Health GrantR01-MH-60974 and by the Howard Hughes Medical Institute.

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