103:793-800, 2010. First published Dec 2, 2009; doi:10.1152/jn.00546.2009
Justin L. Vincent, Itamar Kahn, David C. Van Essen and Randy L. Buckner
You might find this additional information useful...
for this article can be found at:
67 articles, 26 of which you can access free at:
This article cites
including high-resolution figures, can be found at:
Updated information and services
can be found at:
Journal of Neurophysiology
about Additional material and information
This information is current as of March 6, 2010 .
http://www.the-aps.org/.American Physiological Society. ISSN: 0022-3077, ESSN: 1522-1598. Visit our website at
(monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2005 by the
publishes original articles on the function of the nervous system. It is published 12 times a year
Journal of Neurophysiology
on March 6, 2010
Functional Connectivity of the Macaque Posterior Parahippocampal Cortex
Justin L. Vincent,1,2Itamar Kahn,1–3David C. Van Essen,4and Randy L. Buckner1–3,5
1Department of Psychology and Center for Brain Science, Harvard University, Cambridge, Massachusetts;2Athinoula A. Martinos Center
for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts;3Howard Hughes Medical Institute;4Department
of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri; and5Departments of Psychiatry and
Radiology, 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. Functional
connectivity of the macaque posterior parahippocampal cortex. J
Neurophysiol 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 are
functionally connected to the medial temporal lobe and are active during
memory retrieval. It is unknown whether macaques have a similar
network. We examined functional connectivity in isoflurane-anesthetized
macaques to identify a network associated with posterior parahippocam-
pal cortex (PPHC). Functional connectivity was observed between the
PPHC and retrosplenial, posterior cingulate, superior temporal gyrus, and
inferior parietal cortex. PPHC correlations were distinct from regions in
parietal and temporal cortex activated by an oculomotor task. Compari-
son of macaque and human PPHC correlations revealed similarities that
suggest the temporal-parietal region identified in the macaque may share
a common lineage with human Brodmann area 39, a region thought to be
may have homologous PPHC-parietal pathways. By specifying the loca-
tion of the putative macaque homologue in parietal cortex, we provide a
target for future physiological exploration of this area’s role in mnemonic
or 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 as
the posterior cingulate and retrosplenial cortex have been
repeatedly observed with functional magnetic resonance imag-
ing (fMRI) when participants correctly recognize previously
studied items (hits) versus correctly identified new items (cor-
rect rejections). The human lateral parietal retrieval success
effect 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 a
motor response is made only to new vs. only to old items)
(Shannon and Buckner 2004). Furthermore, activation in the
human posterior parietal cortex is implicated in retrieval of
episodic details: recollection elicits a greater response than
familiarity-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 effect
remains unclear and would benefit greatly from study in the
monkey where the anatomy and physiology of the parietal cortex
is accessible. However, it is uncertain whether or not the macaque
monkey has parietal regions that are homologous to those respon-
sive during human memory-retrieval experiments. One way to
compare species using the same technique is to compare patterns
in fMRI-based functional connectivity (Biswal et al. 1995; Fox
and Raichle 2007; Van Dijk et al. 2009; Vincent et al. 2007).
Spontaneous blood oxygenation-level-dependent (BOLD) (Ogawa
et al. 1990) fluctuations reflect both direct and indirect anatomic
connectivity (Hagmann et al. 2008; Honey et al. 2009; Vincent et
al. 2007) and are correlated with fluctuations in neuronal activity
as reflected in the gamma band of the local field potential,
multiunit activity, and spiking activity (Shmuel and Leopold
2008). 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 to
facilitate comparative study of brain systems between species.
Previous studies of intrinsic functional connectivity in the
human have demonstrated that BOLD fluctuations in human
medial temporal lobe are correlated with the same regions in
posterior 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 the
so-called “default network” (Buckner et al. 2008; Vincent et al.
2006). More recently, correlations were demonstrated between
BOLD fluctuations in macaque posterior cingulate/precuneus
and bilateral lateral temporo-parietal regions that may be ana-
tomical homologues to human lateral parietal regions known to
respond during episodic memory retrieval (Margulies et al.
2009; Vincent et al. 2007).
The main goal of this study was to determine whether
macaque posterior parahippocampal cortex (PPHC) is func-
tionally correlated with regions in posterior limbic and lateral
parietal cortex and whether these regions are anatomically
distinct from the parietal regions traditionally associated with
visual-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 secondary
goal was to examine functional correlations in the posterior
cingulate/retrosplenial cortex. Hayden and colleagues (2009)
have recently shown that firing rates in the macaque posterior
cingulate are suppressed during task performance, which is
functionally similar to deactivations observed in the human
posterior cingulate and the extended default network (Buckner
et al. 2008; Gusnard and Raichle 2001; Mazoyer et al. 2001;
Shulman et al. 1997). Further, several previous human studies
suggest that the posterior cingulate is functionally connected to
many of regions that fall within the human default network
Address for reprint requests and other correspondence: J. Vincent, Harvard
University, Center for Brain Science, 52 Oxford St., Rm 280, Cambridge, MA
02138 (E-mail: email@example.com).
J Neurophysiol 103: 793–800, 2010.
First published December 2, 2009; doi:10.1152/jn.00546.2009.
7930022-3077/10 $8.00 Copyright © 2010 The American Physiological Society www.jn.org
on March 6, 2010
(e.g., Buckner et al. 2008, 2009; Grecius et al. 2009; Hagmann
et al. 2008). Therefore by seeding the macaque posterior
cingulate, we seek to explore the broader set of regions within
this functionally correlated brain network.
M E T H O D S
Subjects, procedures, preprocessing, and analysis are similar to a
previous report (Vincent et al. 2007). These data have been previously
published (Margulies et al. 2009; Vincent et al. 2007). Briefly, eleven
healthy adult macaque macaques (8 Macaca fascicularis; 3 M. mu-
latta) were anesthestized with isoflurane and scanned using fMRI. The
macaques were divided into two groups: data set 1 consisted of four
macaques; data set 2 consisted of eight macaques (1 macaque was
common to both groups). Data set 2 has been provided for download
at www.brainscape.org. Data were aligned to a Martin and Bowden
atlas template (Black et al. 2004; Martin and Bowden 2000; see
http://www.purl.org/net/kbmd/cyno) and preprocessed to prepare for
seed-based functional correlation analysis. Details of the procedures
are provided in a previous publication (Vincent et al. 2007) as well as
in the supplementary methods.1
Creation of regions of interest
For the group analysis of PPHC correlations in data set 2, seed regions
in the left and right PPHC were defined as voxels in and around the
posterior parahippocampal gyrus that were functionally correlated with a
posterior 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 functionally
correlated with the combined left and right PPHC seed regions. The fact
that the pC/Rsp region was defined in data set 2 as voxels correlated with
the PPHC seed region in data set 2 makes statistical interpretation of the
pC/Rsp correlations in the medial temporal lobe limited. In addition,
limitations of resolution, spatial distortion, spatial blurring, as well as our
method of defining the PPHC region make the true boundaries of the
group PPHC region ambiguous. Therefore follow-up analyses were
conducted in individual subjects. The full extent of the right PPHC was
carefully drawn on the distorted echo-planar images in three subjects
using the Martin and Bowden (2001) atlas, high-resolution magnetiza-
tion-prepared rapid gradient-echo MP-RAGE, and the high-resolution
echo-planar image (EPI) as an anatomical guide. These subject-specific
PPHC regions were then used to generate subject-specific functional
correlation maps to confirm the group map results (see Fig. 2).
For each subject and each region of interest (ROI), correlation maps
were computed as previously described (Vincent et al. 2007) by
correlating a selected regional time course against all other voxels in
the brain. Application of Fisher’s z transform (Zar 1996) yielded maps
with values at each voxel that theoretically are nearly normally
distributed over the population of subjects. Fixed effects significance
maps were created for each individual as previously described (Vin-
cent et al. 2007).
Group data were displayed over the average MP-RAGE or EPI
MRI slices (aligned to the atlas of Martin and Bowden 2000; see
http://www.purl.org/net/kbmd/cyno) or projected from volume data to
the F6 cortical surface (Vincent et al. 2007) using the Caret “enclosed
voxel” method. Individual subject data were displayed over the
individual subject’s averaged EPI MRI slices.
R E S U L T S
The left and right PPHC seed regions and their associated
correlation maps are shown in Fig. 1. Figure 1A shows the
correlation pattern for the right hemisphere PPHC seed. The top
row shows the correlation data overlaid on transverse and sagittal
sections of the average anatomy. The bottom row shows the
correlation data on lateral and medial views of the inflated F6
cortical surface. The left hemisphere PPHC correlation maps are
shown in Fig. 1B. The PPHC was functionally correlated with the
contralateral parahippocampal cortex, retrosplenial cortex, the
posterior 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 temporal
parietal cortex did not reach significance.
Figure 1C shows the results of left and right PPHC correlations
on coronal slices as well as a conjunction map showing voxels
correlated with both seed regions in red. The PPHC correlations
include parietal cortex lateral to the intraparietal sulcus on the
supramarginal and superior temporal gyrus. In the more anterior
slices, correlations were found on the superior temporal gyrus.
The correlations extended onto the inferior temporal gyrus near
V4, possibly as a consequence of spatial blurring. For better
localization, we examined correlations in individual subjects.
To further examine the location of functional correlations
between the PPHC and temporo-parietal cortex, we manually
traced the right PPHC on the T2*-weighted image in three
macaques (taken from data set 2) and computed functional
correlations using those individually drawn PPHC regions as
seeds. Figure 2 shows the individual subject maps along side
the right PPHC group correlation map. The intraparietal cortex
(IPS) and superior temporal sulcus (STS) are traced with black
lines. Overall, individuals demonstrated similar patterns of
correlation to the group map. These data demonstrate that the
PPHC correlation pattern in temporo-parietal cortex is largely
lateral to the IPS, superior to the STS, and includes the
supramarginal and superior temporal gyrus.
Portions of macaque parietal cortex are associated with
visuospatial attention and sensory-motor integration. An im-
portant question is whether or not the temporo-parietal region
we 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 the
temporo-parietal region that was correlated with the PPHC to
the 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 responses
evoked during performance of a visually guided saccadic eye
movement task in two awake, behaving macaques (Fig. 3B)
(data from Baker et al. 2006). Voxels that overlap in the two
maps are shown in yellow in Fig. 3C. There is relatively little
overlap, which indicates segregation. The only region of po-
tential overlap lies in or around dorsal-anterior MST. To
estimate the areal location of the temporo-parietal correlation
with the PPHC (Fig. 3A), the correlation data were displayed
on 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 or
near areas 7a, TPOc, and PA. Areas activated by saccadic eye
movements 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 the
regions activated by saccadic eye movements and the regions
1The online version of this article contains supplemental data.
794J. L. VINCENT, I. KAHN, D. C. VAN ESSEN, AND R. L. BUCKNER
J Neurophysiol • VOL 103 • FEBRUARY 2010 • www.jn.org
on March 6, 2010
correlated with the PPHC. The only areas that were identified
by both analyses were area 7a (and potentially MSTda). How-
ever, the correlations with PPHC were located in a more
anterior region within area 7a, whereas the activations associ-
ated with saccadic eye movements were associated with a more
posterior region within 7a. Overall, these data suggest that the
regions correlated with the PPHC are likely to be distinct from
the regions associated with saccadic eye movements.
In humans, the hippocampal formation and posterior PPHC
are functionally correlated with regions in posterior parietal
cortex that are activated by recollection (Vincent et al. 2006).
The present analyses demonstrate that a qualitatively similar
parahippocampal-parietal network exists in macaques. To pro-
vide a more objective comparison between the two species, we
used a mapping between macaque and human cortex based on
a 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 the
surface of the human brain using anatomical and functional
landmarks (see supplementary information) and projected the
macaque PPHC functional connectivity results (collapsed
across left and right seed regions) onto the human atlas surface
functionally correlated with the contralateral medial temporal
lobe, retrosplenial cortex, posterior cingulate, and lateral tem-
poro-parietal cortex. The right (A) and left (B) PPHC seed
regions are shown in solid blue on a sagittal slice as well as the
inflated surfaces. The functional correlations are shown on
sagittal and transverse slices as well as the inflated lateral and
medial surfaces of the macaque cortex. C: left and right PPHC
correlations are shown on sequential coronal slices. A conjunc-
tion map (CONJ) shows voxels significantly correlated with
both seed regions. Correlation maps are thresholded at P ? 0.05
The posterior parahippocampal cortex (PPHC) is
are displayed on group and individual T2*-weighted MRI scans to
with the PPHC. Left: transverse and a coronal MP-RAGE slice
depicting 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 correlation
maps. The seed regions are shown above the correlations maps in
blue. Black lines trace the intraparietal sulcus (IPS) and superior
temporal sulcus (STS).
Group and individual subject PPHC correlation data
795 MACAQUE PARAHIPPOCAMPAL FUNCTIONAL CONNECTIVITY
J Neurophysiol • VOL 103 • FEBRUARY 2010 • www.jn.org
on March 6, 2010
(Supplementary Fig. S2). The deformed monkey PPHC corre-
lation map includes a region in the inferior parietal lobule plus
a smaller region in posterior cingulate/retrosplenial cortex
(Supplementary Fig. S2). For reference, we plot the estimated
borders of relevant human Brodmann areas. Based on the
results of the deformation, the regions in the macaque that were
correlated with the PPHC were in or around human Brodmann
areas 39, 31, and 23. This hypothesis, however, is dependent
on 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 functional
correlation results (Kahn et al. 2008; Vincent et al. 2006)
suggest that macaques may have regions that share a lineage
with the human default network. Further evidence for this view
comes from recent work showing that a region in the macaque
PPHC network, the posterior cingulate, shows similar func-
tional responses to the human posterior cingulate during task
performance (Hayden et al. 2009). Therefore we also examined
functional correlations associated the macaque posterior cin-
gulate/retrosplenial (pC/Rsp) cortex. The pC/Rsp was func-
tionally correlated with bilateral posterior medial temporal
lobe, 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, and
dorsal lateral prefrontal cortex (in and around areas 6, 8, 9, and
46; Fig. 4). To further examine the correlations in medial
prefrontal cortex, the data were projected onto the cortical
surface, and boundaries around functional areas were estimated
based on the schema of Ferry and colleagues (2000). The
pC/Rsp was functionally correlated with regions in and around
areas 9, 24b, 10m, 32, and 14r. Thus PPHC is functionally
correlated with a region in pC/Rsp cortex that in turn is
functionally connected with an additional set of regions
throughout the anterior cingulate and medial prefrontal cortex.
D I S C U S S I O N
This work reports the BOLD functional correlations of the
PPHC and pC/Rsp. The main finding is that specific regions
within lateral temporo-parietal, posterior cingulate, and retro-
splenial cortex are functionally correlated with the medial
temporal lobe (Fig. 1). This system was largely distinct from
the network of regions activated by a saccadic eye movement
task, which suggests that it is unlikely driven by spatial
attention or oculomotor performance (Fig. 3). Individual sub-
ject results and detailed anatomical analyses suggest that the
medial 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 between
macaque and human suggested that the parietal region corre-
lated with the PPHC in macaques might be in or around human
Brodmann area 39 (Supplementary Fig. S2). Finally, al-
though we found no direct functional connectivity between
the 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 an
intermediate (Fig. 4).
functionally correlated with the PPHC are dis-
tinct from those involved in visually guided
saccadic eye movements. PPHC functional
correlations (A and D, warm colors) as well as
activation related to visually guided saccades
(B and E, cool colors) are projected onto the
inflated (A and B) and flattened (D and E)
PPHC 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 for
the flat maps. The oculomotor activation is
largely within the superior temporal and in-
traparietal sulci whereas the temporo-parietal
region correlated with the PPHC in and around
areas 7a, PA, and TPOc.
The temporal and parietal regions
796J. L. VINCENT, I. KAHN, D. C. VAN ESSEN, AND R. L. BUCKNER
J Neurophysiol • VOL 103 • FEBRUARY 2010 • www.jn.org
on March 6, 2010
Limitations and caveats
Resting state functional correlation patterns measured using
fMRI 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 and
groups (e.g., Desmoiseaux et al. 2006; Van Dijk et al. 2009;
Vincent et al. 2006). While functional correlations appear to be
constrained by anatomical connectivity (Honey et al. 2009;
Margulies et al. 2009; Vincent et al. 2007), the correlation
strength 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 common
driving inputs (see Van Dijk et al. 2009 for discussion). Thus
the methods applied here provide information about large-scale
brain systems and the relationship of medial temporal struc-
tures to distributed cortical systems, but the details of anatomic
connectivity will require further exploration using direct mea-
sures of anatomic connectivity.
Functional correlations can also be modified by the cognitive
state of the participant. For example, the strength of functional
correlations can be modified by task performance (Fransson 2006;
Newton et al. 2007), sleep stage (Horovitz et al. 2009), and
anesthesia (Supplementary Figs. 4–6 of Vincent et al. 2007). The
anesthetized state of the macaques in this study may have caused
a reduction in the correlation strength between some nodes in the
PPHC and pC/Rsp correlation networks. For example, an unex-
pected finding in our study was the weak functional connectivity
between the PPHC and the medial prefrontal cortex and anterior
temporal lobe. In humans, the default network (of which PPHC
and pC/Rsp are a part) is known to exhibit significantly decreased
connectivity with the medial prefrontal cortex during loss of
consciousness characterized by deep sleep (Horovitz et al. 2009).
The present finding that the macaque medial prefrontal cortex was
not correlated with the PPHC and weakly correlated with the
pC/Rsp may be due to the anesthesia. Another possibility for the
weak or nonsignificant correlations with prefrontal and anterior
temporal regions is that the BOLD data were distorted and had
low signal in the anterior temporal lobe and the medial prefrontal
cortex. For these reasons, we are cautious when interpreting weak
or nonsignificant correlations with these anterior regions.
Supplementary Fig. S2 plots the macaque PPHC functional
correlation data on the human cortical surface using a nonlinear
monkey to human registration technique based on a previously
published schema (Denys et al. 2004) with additional land-
marks in the prefrontal cortex (Supplementary Fig. S1). Based
on the current set of landmark constraints, the temporal-
parietal region correlated with the macaque PPHC may be
functionally related to a region in the human Brodmann area
39. However, one should be cautious when drawing conclu-
sions from this analysis due to the paucity of landmarks driving
the cross-species registration in parietal cortex.
Relation to anatomical connectivity
Information about human anatomical connectivity is scarce.
Therefore other methods, including functional connectivity
mapping of spontaneous BOLD fluctuations, have been used to
study potential anatomical networks in humans. Functional
connectivity methods alone cannot unambiguously designate
functional pathways, determine the directionality of a projec-
tion, or discern whether a pathway is direct or indirect. Nev-
ertheless, despite these caveats, functional correlation mapping
has successfully generated functional and anatomical predic-
tions about the human brain. For example, we have previously
shown that the regions functionally correlated with the human
medial temporal lobe during the resting state overlapped those
regions activated by episodic memory retrieval (Vincent et al.
2006). The study of functional connectivity in the macaque is
useful for refining our understanding of the relation between
functional and anatomical connectivity. Previously we reported
similarities between functional and anatomical connectivity
maps 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 contrast
known anatomical tract tracing work in macaques in relation to
our functional correlation results from seed regions in PPHC
The PPHC is strongly anatomically connected to the poste-
rior limbic cortex. Parahippocampal cortex (area TF) has light
to moderate projections to area 29 and moderate to heavy
projections to areas 30, 23, and retrosplenial area 23v (Lavenex
et al. 2002). Morris et al. (1999) also reported that posterior
correlated with bilateral posterior medial temporal lobe, lateral temporo-
parietal cortex, superior temporal sulcus and gyrus, dorsolateral prefrontal
cortex, and medial prefrontal cortex. The seed region is shown in solid blue on
a sagittal slice. The functional correlations are shown on sagittal, transverse,
and coronal slices as well as the inflated lateral, inflated medial, and fiducial
antero-medial surfaces of the macaque brain. As can be seen from the
correlations displayed on the sagittal slice and caret surfaces, the pC/Rsp is
robustly correlated with medial prefrontal regions in and around areas 9, 24b,
10m, 32, and 14r. All correlations P ? 0.05 (corrected). Borders are adapted
from Ferry et al. (2000).
The posterior cingulate/retrosplenial (pC/Rsp) cortex is functionally
797MACAQUE PARAHIPPOCAMPAL FUNCTIONAL CONNECTIVITY
J Neurophysiol • VOL 103 • FEBRUARY 2010 • www.jn.org
on March 6, 2010
parahippocampal cortex (areas TF and TH) sends projections
to retrosplenial area 30. The parahippocampal cortex (area TF)
receives strong input from areas 30, 29l, and 29m of the
retrosplenial 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 in
both regions result in uptake in posterior cingulate area 23 and
retrosplenial cortex (areas 29 and 30). Finally, Kobayashi and
Amaral (2003, 2007) demonstrated reciprocal connections be-
tween the parahippocampal cortex and areas 23, 29, and 30.
Therefore our reported functional correlations between PPHC
and posterior cingulate and retrosplenial cortex are consistent
with 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 in
uptake in area 7a. In addition, Blatt and coworkers (2003)
showed that retrograde tracer injections in parahippocampal
region TF resulted in uptake in PG-Opt, which is very similar
to area 7a and is near the region that we found to be function-
ally correlated with the PPHG. In addition, Lavenex and
colleagues (2002) reported moderate to heavy anterograde
labeling in area 7 after injection in parahippocampal area TF.
Perhaps the most convincing data that area 7a is connected to
the posterior parahippocampal cortex comes from the work of
Cavada and Goldman-Rakic (1989, see Figs. 6 and 7). They
injected anterograde and retrograde tracers into parietal area 7a
and showed dense, reciprocal connections with the parahip-
pocampal cortex (particularly in TF, but including TH). When
taken in conjunction with these anatomical data, our functional
correlation data demonstrate a functional pathway between the
parahippocampal cortex and the parietal cortex in the macaque.
In addition to consistencies between functional and anatom-
ical connectivity, we also observed inconsistencies. First, the
PPHC is known to the have connections with the medial
prefrontal cortex. For example, the PPHC has both afferent and
efferent connections with areas 9, 14, 24, 25, and 32 (Blatt et
al. 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 the
medial prefrontal cortex in the monkey. Second, the PPHC is
known 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 the
most anterior (Blatt et al. 2003; Lavenex et al. 2002; Suzuki
and Amaral 1994) but also in and around MSTdp (Lewis and
Van Essen 2000b). While we observed correlations between
the PPHC and the superior temporal sulcus (Fig. 1C), we
expected the correlations to extend more anteriorly based on
previous observations. These negative observations in our data,
which we suspect to be false negatives, may be attributable to
signal dropout, distortions and/or the anesthetized state of the
animals (see Limitations and caveats).
Beyond PPHC, we also examined correlations associated
with the pC/Rsp cortex (see also Margulies et al. 2009; Vincent
et al. 2007). Correlations with the pC/Rsp were largely in
medial 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 reciprocal
connections 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 (including
area 24), superior temporal sulcus, superior temporal gyrus,
and parietal cortex (including 7a, DP, and LIP) (Kobayashi and
Amaral 2003, 2007; Morris et al. 1999). The functional con-
nectivity results were consistent with the known connectivity
of the posterior cingulate/retrosplenial cortex.
The present work makes two primary contributions to our
understanding of macaque functional anatomy. First, although
previous papers have demonstrated that the PPHC has recip-
rocal connections with retrosplenial cortex and the inferior
parietal 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 to
better understand the human brain, the present work provides a
critical bridge between the anatomical connectivity work in the
macaque 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 set
of cortical regions is more active in the passive state than
during 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 suggested
that this network is not only engaged during passive tasks but
is activated during the act of remembering (Wagner et al.
2005), thinking about the future (Schacter et al. 2008), scene
construction (Hassabis and Maguire 2007), and social cogni-
tion (Saxe and Kanwisher 2003; Vogeley and Fink 2003). An
alternative hypothesis is that the default network may involve
monitoring the external environment and is attenuated during
focused attention (Gilbert et al. 2007; Hahn et al. 2007; Raichle
et al. 2001; Shulman et al. 1997; see Buckner et al. 2008 for
are topographically similar to PPHC correlations and recollection
success effects in the human. Images display the macaque PPHC
functional correlation map (left), regions correlated with the PPHC
in the human (middle), and a convergence analysis of event-related
fMRI studies that target recollection success (right). The human
PPHC 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 as
compared with hits based preferentially on familiarity (adapted
from Wagner et al. 2005).
Macaque PPHC functional correlations in the macaque
798J. L. VINCENT, I. KAHN, D. C. VAN ESSEN, AND R. L. BUCKNER
J Neurophysiol • VOL 103 • FEBRUARY 2010 • www.jn.org
on March 6, 2010
The hallmark of the default network is task-induced deacti-
vation. In support of the hypothesis that macaques may have a
default network, covert attention suppresses neuronal re-
sponses in macaque lateral parietal area 7a (Steinmetz et al.
1994). Specifically, neurons responded more to stimuli that
appear at unattended locations than to those that appear at
attended locations. More recently, Hayden and colleagues
(2009) recorded single neurons in the macaque posterior cin-
gulate during a working memory task and demonstrated that
neurons in the posterior cingulate cortex are reliably sup-
pressed during task performance and returned to baseline levels
between trials. The network of regions functionally correlated
with the macaque parahippocampal cortex includes the poste-
rior cingulate and area 7a (Figs. 1 and 3). Because of the
functional and anatomical similarities, these macaque regions
may be homologous to regions within the human default
network. Future study of the macaque will be required to
establish functional homology. An important next step will be
to examine whether the regions here identified as functionally
correlated with the macaque PPHC are functionally deactivated
during attention demanding cognitive tasks.
The present functional connectivity results suggest that the
macaque 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 PPHC
correlation map (left) along with the human PPHC correlation
map (middle) (data from Kahn et al. 2008). Both the macaque
and human PPHC correlation maps include regions in posterior
cingulate/retrosplenial cortex and the inferior parietal lobule.
The parietal regions fall within an area of rapid cortical
expansion in the human compared with macaque lineage (Van
Essen and Dierker 2007) and where it is particularly difficult to
identify exact homologies.
In humans, the network correlated with the PPHC is consis-
tently activated by correct recognition (and more specifically
recollection) 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 studies
that target recollection success in the human (right) (image
from Wagner et al. 2005). The correspondences between the
human PPHC correlation map and the human recollection
success effect are clear. Based on the present macaque PPHC
results, we suggest that the human region in the inferior
parietal lobule that is functionally correlated with the PPHC
and is activated during recollection has a potential homologue
in or around macaque areas 7a, TPOc, and PA. Future studies
will be needed to determine if this macaque parietal region is
responsive 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 software
enhancements used in data analysis; and K. J. Black for providing the monkey
atlas 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 conduct
G R A N T S
This work was supported by National Institute of Mental Health Grant
R01-MH-60974 and by the Howard Hughes Medical Institute.
R E F E R E N C E S
Andersen RA, Buneo CA. Intentional maps in posterior parietal cortex. Annu
Rev Neurosci 25: 189–220, 2002.
Andreasen NC, O’Leary DS, Cizadlo T, Arndt S, Rezai K, Watkins GL,
Ponto LL, Hichwa RD. Remembering the past: two facets of episodic
memory explored with positron emission tomography. Am J Psychiatry 152:
Baker JT, Patel GH, Corbetta M, Snyder LH. Distribution of activity across
the monkey cerebral cortical surface, thalamus and midbrain during rapid,
visually guided saccades. Cereb Cortex 16: 447–459, 2006.
Binder JR, Frost JA, Hammeke TA, Bellgowan PS, Rao SM, Cox RW.
Conceptual processing during the conscious resting state: a functional MRI
study. J Cogn Neurosci 11: 80–95, 1999.
Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in
the motor cortex of resting human brain using echo-planar MRI. Magn
Reson Med 34: 537–541, 1995.
Black KJ, Koller JM, Snyder AZ, Perlmutter JS. Atlas template images for
nonhuman primate neuroimaging: baboon and macaque. Methods Enzymol
385: 91–102, 2004.
Blatt GJ, Pandya DN, Rosene DL. Parcellation of cortical afferents to three
distinct sectors in the parahippocampal gyrus of the rhesus monkey: an
anatomical and neurophysiological study. J Comp Neurol 466: 161–179,
Buckner RL, Andrews-Hanna JR, Schacter DL. The brain’s default net-
work: anatomy, function, and relevance to disease. Ann NY Acad Sci 1124:
Buckner RL, Sepulcre J, Talukdar T, Krienen FM, Liu H, Hedden T,
Andrews-Hanna JR, Sperling RA, Johnson KA. Cortical hubs revealed
by intrinsic functional connectivity: mapping, assessment of stability, and
relation to Alzheimer’s disease. J Neurosci 29: 1860–1873, 2009.
Cabeza R, Ciaramelli E, Olson IR, Moscovitch M. The parietal cortex and
episodic memory: an attentional account. Nat Rev Neurosci 9: 613–625,
Cavada C, Goldman-Rakic PS. Posterior parietal cortex in rhesus monkey: I.
Parcellation of areas based on distinctive limbic and sensory corticocortical
connections. J Comp Neurol 287: 393–421, 1989.
Colby CL, Goldberg ME. Space and attention in parietal cortex. Annu Rev
Neurosci 22: 319–349, 1999.
Damoiseaux JS, Rombouts SA, Barkhof F, Scheltens P, Stam CJ, Smith
SM, Beckmann CF. Consistent resting-state networks across healthy sub-
jects. Proc Natl Acad Sci USA 103: 13848–13853, 2006.
Denys K, Vanduffel W, Fize D, Nelissen K, Peuskens H, Van Essen D,
Orban GA. The processing of visual shape in the cerebral cortex of human
and nonhuman primates: a functional magnetic resonance imaging study.
J Neurosci 24: 2551–2565, 2004.
Ferry AT, Ongu ¨r D, An X, Price JL. Prefrontal cortical projections to the
striatum in macaque monkeys: evidence for an organization related to
prefrontal networks. J Comp Neurol 425: 447–470, 2000.
Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed
with functional magnetic resonance imaging. Nat Rev Neurosci 8: 700–711,
Fransson P. How default is the default mode of brain function? Further
evidence from intrinsic BOLD signal fluctuations. Neuropsychologia 44:
Ghatan PH, Hsieh JC, Wirse ´n-Meurling A, Wredling R, Eriksson L,
Stone-Elander S, Levander S, Ingvar M. Brain activation induced by the
perceptual maze test: a PET study of cognitive performance. Neuroimage 2:
Gilbert SJ, Dumontheil I, Simons JS, Frith CD, Burgess PW. Comment on
“Wandering minds: the default network and stimulus-independent thought.”
Science 317: 43, 2007.
Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network
activity distinguishes Alzheimer’s disease from healthy aging: evidence
from functional MRI. Proc Natl Acad Sci USA 101: 4637–4642, 2004.
Greicius MD, Supekar K, Menon V, Dougherty RF. Resting-state func-
tional connectivity reflects structural connectivity in the default mode
network. Cereb Cortex 19: 72–78, 2009.
Gusnard DA, Raichle ME. Searching for a baseline: functional imaging and
the resting human brain. Nat Rev Neurosci 2: 685–694, 2001.
Habas C, Kamdar N, Nguyen D, Prater K, Beckmann CF, Menon V,
Greicius MD. Distinct cerebellar contributions to intrinsic connectivity
networks. J Neurosci 29: 8586–8594, 2009.
799MACAQUE PARAHIPPOCAMPAL FUNCTIONAL CONNECTIVITY
J Neurophysiol • VOL 103 • FEBRUARY 2010 • www.jn.org
on March 6, 2010
Hagmann P, Cammoun L, Gigandet X, Meuli R, Honey CJ, Wedeen VJ, Download full-text
Sporns O. Mapping the structural core of human cerebral cortex. PLoS Biol
6: e159, 2008.
Hahn B, Ross TJ, Stein EA. Cingulate activation increases dynamically with
response speed under stimulus unpredictability. Cereb. Cortex 17: 1664–
Hassabis D, Maguire EA. Deconstructing episodic memory with construc-
tion. Trends Cogn Sci 11: 299–306, 2007.
Hayden BY, Smith DV, Platt ML. Electrophysiological correlates of default-
mode processing in macaque posterior cingulate cortex. Proc Natl Acad Sci
USA 106: 5948–5953, 2009.
Heilman KM, Gonzalez Rothi LJ. Apraxia. In: Clinical Neuropsychology,
edited by Heilman KM, Valenstein E. Oxford, UK: Oxford Univ. Press,
1993, p. 141–163.
Henson RN, Rugg MD, Shallice T, Josephs O, Dolan RJ. Recollection and
familiarity in recognition memory: an event-related functional magnetic
resonance imaging study. J Neurosci 19: 3962–3972, 1999.
Honey CJ, Sporns O, Cammoun L, Gigandet X, Thiran JP, Meuli R,
Hagmann P. Predicting human resting-state functional connectivity from
structural connectivity. Proc Natl Acad Sci USA 106: 2035–2040, 2009.
Horovitz SG, Braun AR, Carr WS, Picchioni D, Balkin TJ, Fukunaga M,
Duyn JH. Decoupling of the brain’s default mode network during deep
sleep. Proc Natl Acad Sci USA 106: 11376–11381, 2009.
Kahn I, Andrews-Hanna JR, Vincent JL, Snyder AZ, Buckner RL.
Distinct cortical anatomy linked to subregions of the medial temporal lobe
revealed by intrinsic functional connectivity. J Neurophysiol 100: 129–139,
Kahn I, Davachi L, Wagner AD. Functional-neuroanatomic correlates of
recollection: implications for models of recognition memory. J Neurosci 24:
Kobayashi Y, Amaral DG. Macaque monkey retrosplenial cortex. II. Cortical
afferents. J Comp Neurol 466: 48–79, 2003.
Kobayashi Y, Amaral DG. Macaque monkey retrosplenial cortex. III. Cor-
tical efferents. J Comp Neurol 502: 810–833, 2007.
Kondo H, Saleem KS, Price JL. Differential connections of the perirhinal and
parahippocampal cortex with the orbital and medial prefrontal networks in
macaque monkeys. J Comp Neurol 493: 479–509, 2005.
Konishi S, Wheeler ME, Donaldson DI, Buckner RL. Neural correlates of
episodic retrieval success. Neuroimage 12: 276–286, 2000.
Krienen FM, Buckner RL. Segregated fronto-cerebellar circuits revealed by
intrinsic functional connectivity. Cereb Cortex 19: 2485–2497, 2009.
Lavenex P, Suzuki WA, Amaral DG. Perirhinal and parahippocampal cor-
tices of the macaque monkey: projections to the neocortex. J Comp Neurol
447: 394–420, 2002.
Leube DT, Erb M, Grodd W, Bartels M, Kircher TT. Successful episodic
memory retrieval of newly learned faces activates a left fronto-parietal
network. Brain Res Cogn Brain Res 18: 97–101, 2003.
Lewis JW, Van Essen DC. Mapping of architectonic subdivisions in the
macaque monkey, with emphasis on parieto-occipital cortex. J Comp Neurol
428: 79–111, 2000a.
Lewis JW, Van Essen DC. Corticocortical connections of visual, sensorimo-
tor, and multimodal processing areas in the parietal lobe of the macaque
monkey. J Comp Neurol 428: 112–137, 2000b.
Margulies DS, Vincent JL, Kelly C, Lohmann G, Uddin LQ, Biswal BB,
Villringer A, Castellanos FX, Milham MP, Petrides M. Precuneus shares
intrinsic functional architecture in humans and monkeys. Proc Natl Acad Sci
USA 106: 20069–20074, 2009.
Martin RF, Bowden D. Primate Brain Maps: Structure of the Macaque Brain.
Amsterdam: Elsevier, 2000.
Mazoyer B, Zago L, Mellet E, Bricogne S, Etard O, Houde ´ O, Crivello F,
Joliot M, Petit L, Tzourio-Mazoyer N. Cortical networks for working
memory and executive functions sustain the conscious resting state in man.
Brain Res Bull 54: 287–298, 2001.
McDermott KB, Jones TC, Petersen SE, Lageman SK, Roediger HL 3rd.
Retrieval success is accompanied by enhanced activation in anterior pre-
frontal cortex during recognition memory: an event-related fMRI study. J
Cogn Neurosci 12: 965–976, 2000.
McKiernan KA, Kaufman JN, Kucera-Thompson J, Binder JR. A para-
metric manipulation of factors affecting task-induced deactivation in func-
tional neuroimaging. J Cogn Neurosci 15: 394–408, 2003.
Meindl T, Teipel S, Elmouden R, Mueller S, Koch W, Dietrich O, Coates
U, Reiser M, Glaser C. Test-retest reproducibility of the default-mode
network in healthy individuals. Hum Brain Mapp In press.
Mesulam MM. Spatial attention and neglect: parietal, frontal and cingulate
contributions to the mental representation and attentional targeting of salient
extrapersonal events. Philos Trans R Soc Lond B Biol Sci 354: 1325–1346,
Morris R, Petrides M, Pandya DN. Architecture and connections of retro-
splenial area 30 in the rhesus monkey (Macaca mulatta). Eur J Neurosci 11:
Newton AT, Morgan VL, Gore JC. Task demand modulation of steady-state
functional connectivity to primary motor cortex. Hum Brain Mapp 28:
Ogawa S, Lee TM, Kay AR, Tank DW. Brain magnetic resonance imaging
with contrast dependent on blood oxygenation. Proc Natl Acad Sci USA 87:
O’Reilly JX, Beckmann CF, Tomassini V, Ramnani N, Johansen-Berg H.
Distinct and overlapping functional zones in the cerebellum defined by
resting state functional connectivity. Cereb Cortex In press.
Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shul-
man GL. A default mode of brain function. Proc Natl Acad Sci USA 98:
Saleem KS, Kondo H, Price JL. Complementary circuits connecting the
orbital and medial prefrontal networks with the temporal, insular, and
opercular cortex in the macaque monkey. J Comp Neurol 506: 659–693,
Saxe R, Kanwisher N. People thinking about thinking people: the role of the
temporo-parietal junction in “theory of mind.” NeuroImage 19: 1835–1842,
Schacter DL, Addis DR, Buckner RL. Episodic simulation of future events:
concepts, data, and applications. Ann NY Acad Sci 1124: 39–60, 2008.
Shannon BJ, Buckner RL. Functional-anatomic correlates of memory re-
trieval that suggest nontraditional processing roles for multiple distinct
regions within posterior parietal cortex. J Neurosci 24: 10084–10092, 2004.
Shehzad Z, Kelly AM, Reiss PT, Gee DG, Gotimer K, Uddin LQ, Lee SH,
Margulies DS, Roy AK, Biswal BB, Petkova E, Castellanos FX, Milham
MP. The resting brain: unconstrained yet reliable. Cereb Cortex 19: 2209–
Shmuel A, Leopold DA. Neuronal correlates of spontaneous fluctuations in
fMRI signals in monkey visual cortex: implications for functional connec-
tivity at rest. Hum Brain Mapp 29: 751–761, 2008.
Shulman GL, Fiez JA, Corbetta M, Buckner RL, Miezin FM, Raichle ME,
Petersen SE. Common blood flow changes across visual tasks. II. Decreases
in cerebral cortex. J Cogn Neurosci 9: 648–663, 1997.
Steinmetz MA, Connor CE, Constantinidis C, McLaughlin JR. Covert
attention suppresses neuronal responses in area 7a of the posterior parietal
cortex. J Neurophysiol 72: 1020–1023, 1994.
Suzuki WA, Amaral DG. Perirhinal and parahippocampal cortices of the
macaque monkey: cortical afferents. J Comp Neurol 350: 497–533, 1994.
Van Dijk KR, Hedden T, Venkataraman A, Evans KC, Lazar SW,
Buckner RL. Intrinsic functional connectivity as a tool for human connec-
tomics: theory, properties, and optimization. J Neurophysiol 2009, Epub.
Van Essen DC, Dierker DL. Surface-based and probabilistic atlases of
primate cerebral cortex. Neuron 56: 209–225, 2007.
Vilberg KL, Rugg MD. Memory retrieval and parietal cortex: a review of
evidence from a dual-process perspective. Neuropsychologia 46: 1787–
Vincent JL, Patel GH, Fox MD, Snyder AZ, Baker JT, Van Essen DC,
Zempel JM, Snyder LH, Corbetta M, Raichle ME. Intrinsic functional
architecture in the anesthetized monkey brain. Nature 447: 83–86, 2007.
Vincent JL, Snyder AZ, Fox MD, Shannon BJ, Andrews JR, Raichle ME,
Buckner RL. Coherent spontaneous activity identifies a hippocampal-
parietal memory network. J Neurophysiol 96: 3517–3531, 2006.
Vogeley K, Fink GR. Neural correlates of the first-person-perspective. Trends
Cogn Sci 7: 38–42, 2003.
Wagner AD, Shannon BJ, Kahn I, Buckner RL. Parietal lobe contributions
to episodic memory retrieval. Trends Cogn Sci 9: 445–453, 2005.
Wheeler ME, Buckner RL. Functional dissociation among components of
remembering: control, perceived oldness, and content. J Neurosci 23:
Wheeler ME, Buckner RL. Functional-anatomic correlates of remembering
and knowing. NeuroImage 21: 1337–1349, 2004.
Zar JH. Biostatistical Analysis. Upper Saddle River, NJ: Prentice-Hall, 1996.
800J. L. VINCENT, I. KAHN, D. C. VAN ESSEN, AND R. L. BUCKNER
J Neurophysiol • VOL 103 • FEBRUARY 2010 • www.jn.org
on March 6, 2010