PNAS PLUS
Quantitative assessment of prefrontal cortex in
humans relative to nonhuman primates
Chad J. Donahuea,1, Matthew F. Glassera,b, Todd M. Preussc,d,e, James K. Rillingd,e,f,g,h, and David C. Van Essena,1
a
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110; bSt. Luke’s Hospital, St. Louis, MO 63017; cDivision of
Neuropharmacology and Neurologic Diseases, Emory University, Atlanta, GA 30329; dCenter for Translational Social Neuroscience, Emory University,
Atlanta, GA 30329; eYerkes National Primate Research Center, Emory University, Atlanta, GA 30329; fDepartment of Anthropology, Emory University,
Atlanta, GA 30329; gCenter for Behavioral Neuroscience, Emory University, Atlanta, GA 30329; and hDepartment of Psychiatry and Behavioral Sciences,
Emory University, Atlanta, GA 30329
Contributed by David C. Van Essen, March 22, 2018 (sent for review December 14, 2017; reviewed by Leah A. Krubitzer, Rogier Mars, and Jeroen B. Smaers)
neuroanatomy
chimpanzee
| prefrontal cortex | evolution | cortical parcellation |
Other morphometric analyses inform but do not resolve this
debate. Semendeferi et al. (19, 24) reported that although
frontal, temporal, and parietal lobes are larger in humans than in
apes, the fraction of total cortex belonging to each region is
similar across species. By contrast, studies using surface-based
interspecies registration (mapping) constrained by putative cortical homologs suggest that surface area in these regions is disproportionately larger (20-fold or more in places) in humans
compared with macaques, whereas early sensory regions (e.g.,
area V1) are expanded as little as twofold (3–5); there are also
regional differences in estimated PFC extent when comparing
marmoset, capuchin, and macaque monkeys (25). Furthermore,
cortical myelin maps derived from in vivo MRI reveal a greater
extent of lightly myelinated cortex in both association and
higher-order sensory regions in humans compared with chimpanzees and macaques, whereas species differences appear more
modest in heavily myelinated early sensorimotor regions (6).
These conflicting results and interpretations regarding PFC
scaling may largely reflect methodological differences among
studies (20, 23). One such difference is the region with which the
PFC is being compared. Bush and Allman (22) compared frontal
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C
erebral cortex varies dramatically in size and surface area
across mammals. Human cortex is the largest among primates, with a surface area roughly threefold larger than in
chimpanzees and about 10-fold larger than in the intensively
studied macaque monkey (1–6). Many studies have reported that
association cortex [prefrontal, temporal, and parietal regions
implicated in higher cognition and affect (7–9)] is disproportionately larger in humans relative to nonhuman primates
(10–16). However, other studies report different conclusions,
especially for prefrontal cortex (PFC) (17–19), resulting in
an ongoing controversy (20).
Analyses of this type are often viewed through the lens of allometry by comparing the size of a given brain region with another measure, such as overall brain size, across a range of
species. Allometric scaling implies a linear relationship when
plotting data on a logarithmically scaled plot, where the slope of
the best-fitting line may show positive (slope >1; hypermetric),
isometric (slope = 1), or negative (slope <1; hypometric) allometry. Furthermore, a significant positive deviation of a single
species from an allometric relationship would be referred to as
“exceptional” [e.g., human brain weight relative to body weight is
exceptionally large compared with other mammals (21)]. Some
studies have reported a positive allometric relationship across
primate species based on the size of the PFC and the rest of the
brain using structural volumes (18, 22). Others have compared
PFC to lower-order cortical areas and reported a deviation in
humans from the allometric trend when comparing the size of
the PFC with that of primary visual (area V1) and frontal motor
cortex (12, 23). In contrast, Gabi et al. (17) recently reported
evidence for an isometric relationship using neuronal counts for
PFC vs. other cortical regions.
www.pnas.org/cgi/doi/10.1073/pnas.1721653115
Significance
A longstanding controversy in neuroscience pertains to differences in human prefrontal cortex (PFC) compared with other
primate species; specifically, is human PFC disproportionately
large? Distinctively human behavioral capacities related to
higher cognition and affect presumably arose from evolutionary modifications since humans and great apes diverged from a
common ancestor about 6–8 Mya. Accurate determination of
regional differences in the amount of cortical gray and subcortical white matter content in humans, great apes, and Old
World monkeys can further our understanding of the link between structure and function of the human brain. Using tissue
volume analyses, we show a disproportionately large amount
of gray and white matter corresponding to PFC in humans
compared with nonhuman primates.
Author contributions: C.J.D., M.F.G., and D.C.V.E. designed research; C.J.D. performed
research; C.J.D., M.F.G., T.M.P., J.K.R., and D.C.V.E. analyzed data; and C.J.D., M.F.G.,
T.M.P., J.K.R., and D.C.V.E. wrote the paper.
Reviewers: L.A.K., University of California, Davis; R.M., Radboud University Nijmegen; and
J.B.S., Stony Brook University.
The authors declare no conflict of interest.
This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
Data deposition: All data related to this study are freely available via the BALSA database
(https://balsa.wustl.edu/study/zlVX).
1
To whom correspondence may be addressed. Email: donahuec@wustl.edu or vanessen@
wustl.edu.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.
1073/pnas.1721653115/-/DCSupplemental.
Published online May 8, 2018.
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Humans have the largest cerebral cortex among primates. The
question of whether association cortex, particularly prefrontal
cortex (PFC), is disproportionately larger in humans compared with
nonhuman primates is controversial: Some studies report that
human PFC is relatively larger, whereas others report a more
uniform PFC scaling. We address this controversy using MRIderived cortical surfaces of many individual humans, chimpanzees,
and macaques. We present two parcellation-based PFC delineations based on cytoarchitecture and function and show that a
previously used morphological surrogate (cortex anterior to the
genu of the corpus callosum) substantially underestimates PFC
extent, especially in humans. We find that the proportion of
cortical gray matter occupied by PFC in humans is up to 1.9-fold
greater than in macaques and 1.2-fold greater than in chimpanzees. The disparity is even more prominent for the proportion of
subcortical white matter underlying the PFC, which is 2.4-fold
greater in humans than in macaques and 1.7-fold greater than
in chimpanzees.
gray matter with remaining neocortical gray matter, whereas
Smaers et al. (23) compared the PFC with more evolutionarily
conserved, lower-order cortical regions such as primary visual
cortex (area V1). Some studies focus on volumetric differences
in cortical gray matter and/or the extent of the underlying white
matter (26), whereas others consider counts of neurons for gray
matter and nonneuronal cells for white matter (17). Most striking are differences in delineating what constitutes the PFC. A
lack of comparative architectonic or other data that could directly identify the location of homologous areas and regions has
led some investigators to instead invoke neuroanatomical proxies
for the PFC. For example, Semendeferi et al. (19) analyzed the
entire frontal lobe, whereas Smaers et al. (27) investigated cumulative frontal lobe volumes starting respectively from its anterior (prefrontal) and posterior (motor) extremes. Schoenemann
et al. (26) and Gabi et al. (17) explicitly approximated the PFC
using a morphological surrogate: cortex anterior to the genu of the
corpus callosum. However, the accuracy of this genu-based approximation has yet to be critically assessed.
Generally, “PFC” has referred to frontal lobe association cortex
lying anterior to motor and premotor regions. Many studies have
used cytoarchitectonics in efforts to objectively delineate the PFC.
Cortical layer 4 can appear granular (with a high density of small
neurons), agranular (lacking a well-defined layer 4), or dysgranular
(having a subtle layer 4 with a modest density of small neurons).
The earliest delineation of the PFC was Brodmann’s (15) regio
frontalis, consisting of granular frontal and orbital cortex. More
recent studies consider the PFC to include both granular and dysgranular regions of medial frontal and orbitofrontal cortex in human (28) and macaque (29) and lateral frontal cortex in both
species (30–32). Geyer (33) analyzed human premotor and prefrontal regions and reported that agranular cortex in posterior
Brodmann area 6 (premotor) transitions anteriorly to dysgranular
cortex by a graded cytoarchitectonic transition rather than by a
sharp boundary. Consistent with this hypothesis, functional neuroimaging analyses implicate some agranular as well as dysgranular
frontal lobe areas in higher cognitive function (34).
To address differences in PFC across several primate species, we
used structural MRI datasets from humans, chimpanzees, and macaque monkeys to generate cortical surface models of individual subjects, estimate cortical myelin content and thickness, and register
individuals to species-average atlases. We then utilized available data
to delineate the PFC in several ways. We present PFC delineations
based on architectonic criteria and on the callosal genu PFC approximation in all three species and on combined functional and architectonic criteria for humans and macaques. Because we analyzed only
three species, we could not create a robust nonhuman primate allometric scaling regression to evaluate whether data points for humans
are exceptional. Instead, we focus on the relative scaling of the PFC
across species compared with non-PFC cortex, area V1, and area 4.
Results
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Cytoarchitectural Designations Allow Surface-Based PFC Delineation
Across Species. Based on cytoarchitectonics, we delineated a con-
servative PFC boundary (Fig. 1, regions filled in red) that includes
granular and dysgranular frontal lobe cortex anterior to motor and
premotor cortex, as has been proposed for both humans (28, 31) and
macaques (35). However, agranular regions of medial frontal
and orbitofrontal cortex have been implicated in higher cognitive
function, and we consider it appropriate to include these areas of
frontal lobe cortex that are functionally neither motor nor premotor
in a liberal PFC delineation (Fig. 1, additional regions filled in blue).
For human cortex, we used individual-subject parcellations
from 60 unrelated subjects taken from the 210V group [the
validation group of the Human Connectome Project (HCP)
Multimodal Parcellation (HCP_MMP1.0), which used an areal
classifier that matched individual-subject feature vectors to an
initial group-average multimodal parcellation (34)]. For the
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Fig. 1. Parcellations of prefrontal cortex for human, macaque, and chimpanzee displayed on inflated (unfolded) left hemisphere surfaces cropped to
include only anterior regions for lateral (Left) and medial (Right) views of
each species. (A) Inflated human cortical surface displaying group-average
HCP_MMP1.0 parcellation. Conservative PFC includes red areas. Liberal PFC
additionally includes blue areas. (B) Inflated chimpanzee cortical surface
displaying a conservative PFC delineation based on the Bailey et al. (42)
cytoarchitectonic parcellation and maps/gradients of cortical myelin content.
(C) Inflated macaque cortical surface displaying a composite parcellation
adapted from three studies (36–38) along with conservative and liberal PFC
delineations. Figures are not to scale. Data are available at https://balsa.
wustl.edu/GrK7 (human), https://balsa.wustl.edu/px4G (chimpanzee), and
https://balsa.wustl.edu/k94P (macaque).
macaque, a pan-hemispheric composite of published parcellations (36–38) was mapped onto a species-average macaque atlas
(39) (Yerkes19) and then to the constituent 19 individuals for
morphometric analyses. This composite includes several modified areas, marked as “prime,” that reflect a combination of
previously described areas. For example, area 10′ found in dorsolateral PFC is an amalgamation of area 10 as reported by Ferry
et al. (36) and Paxinos et al. (38). Some of these areas then
Donahue et al.
Structural Cortical Features Aid in Delineating the PFC. Maps of estimated myelin content based on the T1-weighted/T2-weighted
(T1w/T2w) intensity ratio (6, 45) provide a useful architectural
marker for identifying cortical regions and areas across species.
Spatial gradients of these myelin maps can provide objective
evidence of sharply defined architectonic transitions (e.g., from
dense to moderate or light myelination; see ref. 45). Fig. 2 illustrates
myelin maps and their spatial gradients for each species in relation
to our three PFC delineations. These reveal important patterns and
correlations across measures, but the relationship to PFC boundaries is complex and differs for dorsolateral, ventrolateral, and
medial regions.
In dorsolateral cortex, the heavily myelinated primary motor
cortex (area 4; Fig. 2, Top Row, outlined in black) and the
moderately myelinated premotor strip (directly anterior to area
Fig. 2. Structural features of lateral (Top and Second Rows) and medial (Third and Bottom Rows) inflated left hemisphere cortex related to delineations of
the PFC. Each primate species cortical surface displays myelin content (Top and Third Rows) and its corresponding spatial gradient (Second and Bottom Rows).
The white line overlying each map represents the group-average location of the coronal slice at the corpus callosum genu (see also Fig. 3); pink and blue lines
represent group-average conservative and liberal PFC delineations, respectively. Primary motor area 4 and primary visual area V1 are bounded by black
contours in the parietal and occipital cortex, respectively. Black bars indicate the relative scale of the group-average inflated surfaces for each species. Data
are available at https://balsa.wustl.edu/22XL.
Donahue et al.
PNAS PLUS
fined FEF (44). Given the paucity of functional data for the
chimpanzee, we focused only on a conservative PFC delineation
based on the presence of granular/dysgranular cytoarchitecture
and on myelin patterns. We identified Bailey et al. agranular
areas as motor (FA), premotor (FB and FBA), and cingulate
(LA and FL). More anterior regions were designated as PFC,
except for FDΓ, which is moderately myelinated and likely corresponds to FEF. Medially, our chimpanzee PFC delineation
includes areas FDL, FH, and FG but excludes LA and FL. (See
Supporting Information for additional details and discussion of
putative homologs. Figure S1 illustrates the chimpanzee parcellation. Tables S2 and S3 provide information and references
for areal cytoarchitecture and cognitive-related designations for human and macaque PFC areas.)
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underwent further subdivision: areas 24a, 24b, and 24c were subdivided into anterior and posterior segments (e.g., 24aa and 24ap,
respectively) based on descriptions of area 24 as dysgranular anteriorly with associated cognitive-related function transitioning to an
agranular cytoarchitecture posteriorly associated with motor function (30, 40, 41). The Bailey et al. chimpanzee architectonic parcellation (42) includes areal designations on a series of histological
section contours. We mapped areal designations from section
contours to corresponding MRI sections in an individual chimpanzee brain and from there to our surface-based chimpanzee atlas
(Supporting Information). We then drew estimated areal boundaries
on the atlas surface, aided in dorsolateral cortex by myelin maps,
cortical thickness maps, and their gradients.
For each species, an area was considered part of conservative
PFC based on cytoarchitecture and inclusion in published PFC
delineations. Areas specific to the human liberal PFC delineation include inferior frontal junction areas (IFJa/p), i/s6-8,
and 55b of the lateral frontal cortex, a/p24, 25, a32pr, d/p/s32,
and the superior frontal language area (SFL) of the medial
frontal cortex, and posterior orbitofrontal cortex (pOFC). For
the macaque, exclusively liberal PFC areas include medial
frontal areas 24aa, 24ba, 24ca, 25, and 32′ and orbitofrontal
areas 13a and 14c. The frontal eye fields are sometimes considered part of the PFC (40, 43) but were excluded here because
of their stronger association with premotor regions than with
cognitive regions in terms of moderate rather than sparse myelin
content and their functional connectivity (34). Frontal eye fields
correspond to the frontal eye field (FEF) and premotor eye field
(PEF) areas in humans; area 45b in the macaque is moderately
myelinated and overlaps with anatomically and functionally de-
Fig. 3. PFC border probability maps displayed on inflated left hemisphere atlas surfaces of the frontal lobe (Left, lateral aspect; Right, medial aspect of each
pair) overlaid on group-average sulcal depth maps. Human liberal and conservative PFC borders were created using individual subject parcellations, resulting
in pronounced intersubject variance on the group-average surface. Corresponding borders in the macaque and chimpanzee were created using a groupaverage parcellation registered to each individual subject and thus show no such variance. Black bars indicate the relative scale for the group-average
inflated surfaces. Data are available at https://balsa.wustl.edu/r7Xw (human), https://balsa.wustl.edu/xMp4 (chimpanzee), and https://balsa.wustl.edu/PMKk
(macaque).
4; mainly green in human; green and yellow in chimpanzee,
mainly orange-yellow in macaque) provide useful landmarks
across species. In the macaque, the thickness map and its gradient were also useful, particularly for posterior area 4 (Supporting Information). In all three species, a myelin gradient ridge
(Fig. 2, Second Row) runs along part of the anterior border of
area 4. Anterior to this premotor/primary motor gradient ridge is
another gradient ridge. In the human, this anterior gradient ridge
aligns well with the liberal PFC border. In the macaque, both
conservative and liberal PFC borders run in the general vicinity
of the anterior myelin gradient ridges, but the correlation is not
good for either. The border of chimpanzee conservative PFC
follows the ridge closely in this region.
In ventrolateral and ventral regions, lightly myelinated PFC in
all three species is adjoined by even more lightly myelinated
cortex in the anterior insula (Fig. 2, Top Row, indigo and black)
and orbitofrontal cortex (Fig. 2, Third Row). However, the most
prominent myelin gradient does not coincide with published
architectonic PFC delineations [also, in the macaque and chimpanzee datasets, orbitofrontal cortex was not as accurately segmented owing to localized signal dropout and distortion of T1w
relative to T2w images]. In medial cortex, the PFC is lightly
myelinated dorsally and very lightly myelinated ventrally in all
three species, but none of them shows a clear myelin gradient
running along the PFC boundary. Thus, there are strong crossspecies similarities in myelin maps in and near the PFC, but only
in the dorsolateral PFC of human and chimpanzee do we con-
sider myelin gradients strongly informative about PFC borders.
Cortical thickness maps and their gradients were of limited utility
for delineating PFC borders (Fig. S4).
Genu-Based Morphological Surrogate Underestimates PFC Extent.
Fig. 3 illustrates the range of individual variation in the location of liberal, conservative, and genu-based PFC borders as
defined for each species. Probability maps indicate most (yellow)
and least (black) common locations of each border.
Important species differences are revealed by comparing
parcellation-based PFC delineations (both liberal and conservative) with genu-based PFC approximations (Fig. 3, Bottom
Row). In dorsolateral frontal cortex, the macaque and chimpanzee genu-based PFC border runs somewhat anterior to the
moderately myelinated region adjacent to premotor cortex,
mostly anterior to the conservative delineation. By visual inspection, the genu-based delineation in the human more substantially underestimates PFC spatial extent compared with both
liberal and conservative delineations. This observation is evaluated quantitatively in the next section.
Human PFC Is Absolutely and Relatively Large Compared with
Nonhuman Primates. Table 1 reports the mean volume for total
cortical gray matter, primary visual area V1, and primary motor
area 4 and mean volumes relating to PFC delineations, along
with SDs. These volumes were calculated for both hemispheres
of each individual subject and then were averaged. Also provided
Table 1. Cortical gray matter volumes across species
Gray matter, cm3
Species
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Human (n = 60)
Chimpanzee (n = 29)
Macaque (n = 19)
Total volume
Genu-based PFC (%)
Conservative PFC (%)
Liberal PFC (%)
Area V1 (%)
Area 4 (%)
512 ± 55
134 ± 13
34.4 ± 2.9
77.2 ± 11 (15)
18.5 ± 2.6 (14)
3.34 ± 0.5 (10)
105 ± 13 (21)
23.2 ± 2.4 (17)
4.4 ± 0.5 (13)
131 ± 16 (26)
14.0 ± 2.0 (2.72)
7.5 ± 0.8 (5.63)
3.3 ± 0.4 (10.7)
11.2 ± 1.6 (2.18)
8.1 ± 1.2 (6.04)
1.4 ± 0.2 (4.46)
4.8 ± 0.6 (14)
Mean volumes of human, chimpanzee, and macaque cortical gray matter for entire cortex; genu-based, conservative, and liberal delineations of prefrontal
cortex; primary visual area V1, and primary motor area 4, as well as SDs. Percentages in parentheses are percentages of total cortical gray matter volume. See
Dataset S1 for additional measures.
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Donahue et al.
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Scaling Relative to Primary Visual and Motor Areas. To quantify how
the PFC has scaled relative to more evolutionarily conserved
cortical areas, we analyzed primary visual cortex (area V1) and
primary motor cortex (area 4) in terms of their cortical gray
matter volume, surface area, and cortical thickness in humans,
chimpanzees, and macaques (see Fig. 2 for delineations, Dataset
S1 for detailed measures, and Supporting Information for
additional methodological details).
In humans, chimpanzees, and macaques, respectively, the
mean V1 volume was 14.0 ± 2 cm3, 7.5 ± 0.8 cm3, and 3.3 ±
0.4 cm3; the surface area was 69.7 ± 9.4 cm2, 47.2 ± 4.7 cm2, and
21.6 ± 1.8 cm2; and the cortical thickness was 2.0 ± 0.1 mm, 2.0 ±
0.2 mm, and 1.8 ± 0.1 mm. The PFC volume is similar to that of
V1 in the macaque but is severalfold larger than V1 in the
chimpanzee and is up to ninefold larger than V1 in humans.
Surface area followed a similar trend: PFC surface area is
White matter, cm3
Species
Human (n = 60)
Chimpanzee (n = 29)
Macaque (n = 19)
Total volume
Genu-based PFC (%)
443 ± 62
119 ± 12
21.8 ± 2.5
52.3 ± 10.2 (12)
8.5 ± 1.9 (7)
1.1 ± 0.2 (5)
Volumes of human, chimpanzee, and macaque subcortical white matter for
entire cortex and genu-based delineations of PFC. PFC percentages in parentheses are relative to total volume. See Dataset S1 for additional measures.
similar to that of V1 in the macaque but is up to 1.8-fold
greater than V1 in chimpanzees and is sixfold greater in humans.
For primary motor area 4 in humans, chimpanzees, and macaques,
respectively, the mean volume was 11.2 ± 1.6 cm3, 8.1 ± 1.2 cm3, and
1.4 ± 0.2 cm3; the surface area was 39.4 ± 5.4 cm2, 25.6 ± 3.1 cm2,
and 5.3 ± 0.5 cm2; and the cortical thickness was 2.8 ± 0.1 mm, 2.6 ±
0.2 mm, and 2.9 ± 0.1 mm. Comparisons with PFC gray matter
volumes in humans and chimpanzees shows a trend similar to that for
area V1, as the PFC is roughly 12-fold larger than area 4 in humans
and is threefold greater than area 4 in chimpanzees. However, macaque area 4 is only 42% of the V1 volume, and its PFC volume is
threefold greater than that of area 4.
White Matter Volumes. Table 2 reports the total volume of subcortical white matter for each species along with volumes of
white matter anterior to the genu-based PFC proxy, which is the
only parcellation having a well-defined posterior extent of PFC
white matter and hence amenable to analysis of white matter
volumes. Total white matter volumes for humans, chimpanzees,
and macaques were on average 443 ± 62 cm3, 119 ± 12 cm3, and
21.8 ± 2.5 cm3, respectively (see Dataset S1 for additional
measures).
The ratio of total white matter to gray matter volume is similar
in the human and chimpanzee (0.87 and 0.89, respectively),
considerably greater than that for the macaque (0.63), indicating
a 35–40% relative increase in the total white matter-to-gray
matter ratio in humans and chimpanzees relative to the macaque. Genu-based PFC white matter-to-gray matter ratios are
0.68 in human, 0.46 in chimpanzee, and 0.33 in macaque. Analyzed differently, PFC white matter is a larger fraction of total
white matter in humans (12%) than in chimpanzees (7%) or
macaques (5%). This 2.4-fold relative difference in PFC white
Fig. 4. Log-scale plots comparing PFC gray and white matter volume with reference values across species (macaques, diamonds; chimpanzees, squares;
humans, circles). (A) Volumes of conservative PFC (red), non-PFC (black), and area V1 (green) gray matter plotted against total cortical gray matter volume.
Volumes of area 4 are plotted with solid magenta markers without a corresponding linear fit. (B) PFC gray matter volume plotted against the volume of the
primary visual cortex. Blue, red, and black markers indicate liberal, conservative, and genu-based PFC delineations, respectively. (C) Genu-based PFC white
matter volume plotted against total white matter volume. For all panels, solid lines represent the best fit using mean macaque, chimpanzee, and human data
points; dotted lines represent 95% CIs.
Donahue et al.
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Table 2. Subcortical white matter volumes across species
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(in parentheses) is the percentage of each PFC region of interest
(ROI) and cortical area volume relative to total volume of the
neocortex (see Supporting Information for individual variance in
percentage values and Dataset S1 for additional measures).
After averaging the left and right hemispheres, computed
mean gray matter volumes were 512 ± 55 cm3, 134 ± 13 cm3, and
34.4 ± 2.9 cm3 for human, chimpanzee, and macaque, respectively, indicating that the volume of human cortical gray
matter is 15-fold greater than that in the macaque and roughly
fourfold greater than that in the chimpanzee. Mean surface areas
were 1,843 ± 196 cm2 for humans, 599 ± 53 cm2 for chimpanzees,
and 193 ± 13 cm2 for macaques; mean cortical thicknesses were
2.7 ± 0.1 mm, 2.6 ± 0.1 mm, and 2.0 ± 0.1 mm, respectively (SDs
are of means across subjects).
As shown by our two parcellation-based delineations, the
proportion of PFC gray matter volume is up to 1.9-fold greater in
humans compared with macaques (26% vs. 14% for the liberal
delineation; 21% vs. 13% for the conservative delineation) and
1.2-fold greater compared with chimpanzees (21% vs. 17% for
the conservative delineation). The genu-based PFC approximation shows a more moderate species difference, constituting 15%
of human cortical gray matter volume compared with 14% in the
chimpanzee and 10% in the macaque. Cortical volume computed using the genu-based proxy for PFC underestimates the
parcellation-based delineations in all three species but most
prominently in humans.
matter between humans and macaques (12% vs. 5%) markedly exceeds the 1.5-fold difference in the genu-based gray
matter volumes.
PFC Exhibits Positive Allometric Scaling for Humans and Nonhuman
Primates. Fig. 4 illustrates several logarithmically scaled com-
parisons that represent the size of the PFC across species relative
to reference measures. To assess the differential scaling of different cortical regions, we plotted the volumes of PFC gray
matter, non-PFC gray matter, area V1, and area 4 against the
volume of total cortical gray matter (Fig. 4A). We additionally
compared PFC gray matter with the more evolutionarily conserved area V1 (Fig. 4B) and compared PFC white matter with
total white matter (Fig. 4C).
When using total cortical gray matter as a reference (Fig. 4A),
the scaling of conservative PFC gray matter as defined by the
regression line through the mean macaque, chimpanzee, and
human data points exhibits positive allometry (slope of 1.18;
95% CI 1.16–1.18). Additionally, this regression of PFC across
total cortex appears steeper than that of other comparators: nonPFC cortex (slope of 0.97; 95% CI 0.96–0.97) and visual area V1
(slope of 0.53; 95% CI 0.49–0.54). Analysis of covariance
(ANCOVA) across the three regression slopes indicated they
are significantly different from one another (Supporting Information). Interestingly, data for area 4 across the three species
deviate markedly from an allometric fit (linear on a log–log plot).
Area 4 volume is similar to that of V1 in humans and chimpanzees but is much smaller than that in the macaque (Discussion). When, instead, the evolutionarily conserved visual area
V1 is used as a reference (Fig. 4B), the PFC scales with even
greater positive allometry (slope of 2.21; 95% CI 2.05–2.24).
Finally, PFC white matter scaled with total white matter volume
with positive allometry (slope of 1.27; 95% CI 1.26–1.31).
Discussion
Using a cortical surface-based approach, we have presented a
comparative delineation and analysis of frontal association cortex in humans, chimpanzees, and macaques. In addressing a
longstanding controversy, we report strong evidence for a greater
proportion of human PFC gray matter volume compared with
two nonhuman primates and an even greater species difference
for PFC white matter volume.
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Prefrontal Cortex Can Be Delineated Using Cytoarchitectonic and
Functional Criteria. Our criteria for areal inclusion in the PFC
entailed judgment calls based on the preponderance of available
evidence. Our conservative criteria relating to granular/dysgranular cytoarchitecture, although guided by evidence in the literature, is not a simple consensus view. Our liberal delineations
in the human and macaque (areas reported to have agranular
cytoarchitecture) entailed subjective assessments regarding what
cognitive task contrast activation or other functional information
relative to neighbors warrants inclusion. A notable exception to
these criteria across species is the exclusion of frontal eye fields:
area FEF in humans, 45b in macaques, and FDΓ in chimpanzees.
While these areas are cytoarchitecturally granular/dysgranular
and receive thalamic inputs primarily from the mediodorsal
(MD) nucleus, their functional relationship to eye movement led
to our placing them in the premotor category as opposed to
cognitive-related PFC [see Supporting Information and Supplementary neuroanatomical results in Glasser et al. (34)]. Additionally, some areas in the macaque composite parcellation (e.g.,
anterior and posterior subdivisions of areas 24a, 24b, and 24c)
might reasonably be reassigned to account for a gradient in
cytoarchitecture, primarily in areas that extend posteriorly into
densely myelinated cortex. However, plausible alternative
choices for PFC extent in any of the species would not negate our
main conclusion that the relative size of the PFC in the human
E5188 | www.pnas.org/cgi/doi/10.1073/pnas.1721653115
lineage is larger than that in nonhuman primates. For example,
inclusion of frontal eye field areas FEF and 45b in humans and
macaques (0.52% of cortical gray matter volume in humans and
0.47% in the macaque; Dataset S1) would not materially affect
our conclusions. For chimpanzees, the lack of functional imaging data limited our analysis to conservative and genu-based
PFC delineations, which were guided by the Bailey et al. (42)
cytoarchitectural atlas in terms of cytoarchitecture and plausibility of putative cortical homologs. These putative homologies
were based on descriptions of cytoarchitecture and are by no
means conclusive; however, they allowed a first-order comparison with humans and macaques. Explicit regional boundaries,
however, were drawn based on visual inspection and comparison
of maps of cortical myelin content, cortical thickness, and their
associated spatial gradients (indicative of areal transitions)
across species. Nevertheless, our candidate chimpanzee PFC
boundary between premotor and prefrontal cortex warrants further analysis using modern architectonic and/or imaging methods.
Besides the architectonic, functional, and morphological criteria invoked in our study, other types of information have been
proposed for delineating the PFC in various mammalian species.
These include the distribution of dopaminergic projections and a
prominent level of projections from the MD nucleus of the
thalamus (46–48). Neither of these metrics, however, has been
shown to be adequately specific to provide strong diagnostic
criteria for delineating the PFC (32, 40): Dopaminergic projections are prominent throughout the primate brain and are not
demonstrably overrepresented in granular frontal cortex (49, 50)
compared with more posterior neocortex. Similarly, MD thalamic projections, while particularly prevalent in granular frontal
cortex and thus a meaningful guide, are also present across the
precentral motor region as well as more posterior regions (51).
Human PFC Volume Is Disproportionately Large. We used a surfacebased approach (1, 2, 4) derived from structural MRI to generate
our analysis of cortical volumes. Our sample size includes
60 humans, 29 chimpanzees, and 19 macaques, thereby enabling
estimates of variability in each population. We found the proportion of PFC cortical gray matter volume in humans to be up
to 1.9-fold greater than in macaques and up to 1.2-fold greater
than in chimpanzees. The differences in the proportion of PFC
subcortical white matter volume are even more pronounced, with
humans exhibiting a 2.4-fold greater proportion than in macaques and a 1.7-fold greater proportion than in chimpanzees.
Thus, consistent with several previous studies (2, 5, 6, 12, 23, 26,
27), our results strongly support the hypothesis that the proportion of cortical gray and white matter volumes attributed to
frontal association cortex is larger in humans than in nonhuman
primates. Furthermore, the absolute size of the conservatively
delineated human PFC is 4.5-fold larger than in the chimpanzee,
which is especially striking considering the more modest difference in the size of the primary visual cortex (1.9-fold larger in
humans). Coupled with the evidence that humans have substantially more PFC white matter volume (23, 27), this points to
an impressively greater amount of neural machinery associated
with the PFC in humans compared with nonhuman primates.
Scaling relative to total cortical volume, however, is impacted
by the similarity in scaling between the PFC and other cortical
association areas. Therefore, scaling of PFC volume based on
that of primary sensory and motor areas can shed light on allometric differentiation of different cortical regions (12, 23). Our
results indicate a hypometric scaling of V1 with respect to cortical volume relative to the hypermetric scaling of PFC (Fig. 4A)
and a prominently hypermetric scaling of PFC with respect to V1
(Fig. 4B). The hypometric scaling of V1 is likely related to the
high visual acuity and importance of vision in all three species,
resulting in only modest species differences in the size of V1. For
area 4, the lack of an allometric scaling relationship prevented an
Donahue et al.
Donahue et al.
PNAS PLUS
White Matter Underlying Human PFC Is Particularly Large Compared
with Nonhuman Primates. We found that human PFC white matter
volume (as a percentage of total white matter) is 2.4-fold greater
than in the macaque and 1.7-fold greater than in the chimpanzee
(Fig. 4C and Table 2), corroborating earlier reports (23, 27). It is
intriguing to speculate on the neuroanatomical basis of these
striking species differences. Given the aforementioned evidence
(17) that PFC neuronal density is relatively low in humans vs.
nonhuman primates, the density of output axons from human
PFC projection neurons (i.e., pyramidal cells) is presumably
lower as well. A disproportionately large white matter volume
underlying human PFC might instead reflect (i) an increased
density of afferent projections from distant (non-PFC) regions
contributing to an increased axonal density within human PFC
gray matter; (ii) a disproportionately high percentage of human
PFC output axons that traverse the underlying white matter but
nonetheless terminate within other PFC targets; (iii) a disproportionately large average axonal diameter in human PFC white
matter; and/or (iv) a disproportionately high degree of axonal
branching within human PFC white matter. Disentangling these
and other possibilities is unlikely to be easy but might become
feasible with further advances in neuroanatomical methods.
Improving the Granularity of Interspecies Comparisons. Our analysis
has focused on measurements of the PFC in its entirety, even
though it is very heterogeneous in its internal organization,
connectivity, and function. Previous comparisons between macaque and human that used interspecies surface-based registration (4, 5) provided evidence that relative expansion in the
human lineage is highly nonuniform within the PFC as well as in
other higher-cognitive regions (e.g., lateral parietal and temporal
cortex) relative to early sensory and motor regions. However,
such “evolutionary expansion” maps should be interpreted with
caution, given that (i) some of the candidate homologs are
plausible but not firmly established and (ii) the surface-based
registration algorithm used to constrain the interspecies mapping tolerated local nonuniformities that are not well-grounded
neurobiologically. Recent algorithmic improvements in surfacebased registration such as the Multimodal Surface Matching
(MSM) method (58, 59) should help address the latter problem
when adapted to interspecies registration constraints. The former
problem (identifying candidate homologs) should benefit from recent advances in parcellating human cortex (34) and in characterizing its network organization (especially resting-state networks),
combined with recent and prospective advances in parcellating
macaque cortex and characterizing its network organization.
Methods
Data Collection. We used publicly available healthy young adult human
structural T1w and T2w scans acquired at 0.7-mm isotropic resolution as part
of the HCP, using the HCP’s standard protocol (60). Although we were able
to balance by sex in choice of human subjects, this was not feasible for
nonhuman primates due to data availability. From a larger HCP subject set,
60 unrelated subjects (30 male and 30 female) were selected for analysis
from the S500 HCP data release. Human data were acquired, processed, and
publicly released by the Human Connectome Project (HCP). The HCP
obtained informed consent from all participants and was approved to conduct human studies by the Washington University in St. Louis Institutional Review Board (#201105040 date: June 2, 2011). For the macaque and
chimpanzee structural T1w and T2w scans we used data previously acquired
at the Yerkes National Primate Research Center at Emory University. A group
of 19 adult macaques (1 male and 18 female) was scanned at 0.5-mm isotropic
resolution. A group of 29 adult chimpanzees (all female) was scanned at
0.8-mm isotropic resolution. For the macaque and chimpanzee datasets,
localized signal dropout was observed in anterior insular and orbitofrontal
cortex. Nonhuman primate data were acquired through separate studies
covered by animal research protocols approved by the relevant institutional
committees.
PNAS | vol. 115 | no. 22 | E5189
NEUROSCIENCE
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analogous comparison of slopes. However, it is visually apparent
that chimpanzee and human area 4 scale similarly to area V1.
The relatively small size of macaque motor cortex is potentially
related to its small body size and muscle mass.
Although other studies have argued for a more general scaling
up of the human brain compared with nonhuman primates (17,
19), we do not view the idea of a predictive positive allometric
scaling as mutually exclusive with a preferential expansion of
PFC or association cortex in general. For example, Semendeferi
et al. (19) reported that the proportion of the cortical mantle
occupied by cortex anterior to the precentral gyrus does not
differ significantly between humans and great apes. However,
Passingham and Smaers (12), analyzing the size of various cortical regions relative to primary sensory and motor areas, found
that the human PFC deviates from the allometric relationship
between the PFC and area V1 determined from nonhuman
primate species and thus showed disproportionate enlargement
(figure 1 and table 1 in ref. 12). Our analyses corroborate those
from Passingham and Smaers by revealing a larger ratio of PFC
gray matter volume to primary visual cortex in humans compared
with nonhuman primates (Fig. 4B). However, the slopes reported
for the regressions in our study are limited by the inclusion of
only three species. Therefore, we emphasize how the regression
slopes differ when comparing different regions of cortex: When
using total cortical gray matter as a reference, conservative PFC
exhibits positive allometry compared with non-PFC and particularly with area V1. Furthermore, the non-PFC delineation still
contains highly expanded regions of association cortex in the
parietal and temporal lobes, thus biasing its scaling toward
isometry and making the findings related to non-PFC cortical
volume reported here likely to be conservative.
Defining PFC as anterior to the genu of corpus callosum, Gabi
et al. (17) used an isotropic fractionator approach (52) to count
neurons and nonneuronal cells as well as gray matter and white
matter volumes as measured in 2-mm coronal tissue slabs through
one hemisphere in a single brain from each of eight primate
species. For humans vs. the average of two macaque species, they
reported 10% vs. 7.6% of cortical gray matter, 5.5% vs. 4.5% of
white matter, and 8% vs. 7.35% of total cortical neurons belonging
to genu-based PFC (table S1 in ref. 17). Thus, for these two
species, their results suggest a slightly positive allometric relationship for PFC cortical gray matter and a nearly isometric
relationship for neuronal numbers. In the present study, we found
a greater species disparity for both genu-based (15% vs. 10%) and
parcellation-based (21% vs. 13%) delineations. Our finding that
the genu-based approximation underestimates PFC volume (to
somewhat different degrees in humans, chimpanzees, and macaques) (Fig. 4) is consistent with the prediction of Schoenemann
et al. (26), as noted by others (12, 23, 53).
Along with their allometric analyses, Gabi et al. reported that
human neuronal density increases anteriorly to posteriorly, with
lowest density at the frontal pole, whereas macaques exhibit a
double gradient of high neuronal densities near both the frontal
and occipital poles. A complementary perspective comes from
cellular neuroanatomical analyses by Elston et al. (54–57), revealing that pyramidal neurons in nonhuman primate granular
PFC (and in other regions of association cortex such as lateral
temporal cortex) exhibit more complex dendritic structure (size
of basal dendritic arbors, branching structure, and spine density)
compared with the less elaborate dendritic structure found in
evolutionarily conserved regions such as sensorimotor and early
visual cortex (56). In this context, neuron number or density is
not a simple surrogate for the information-processing complexity
handled by any given brain region. Thus, the differential increase
in PFC volume documented in the present study likely in part
reflects increased synaptic machinery and not simply an increased number of PFC neurons in the human lineage.
Fig. 5. Mapping of surface-based ROI to cortical gray matter ribbon volume. (A) Illustration of human cortical surface ROI mapped to underlying
gray matter ribbon volume. (B) Illustration of human genu-based ROI volume anterior to a coronal slice at the genu of the corpus callosum when the
image is AC–PC aligned.
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Image Preprocessing. For each human subject, T1w and T2w scans were initially processed using the minimal preprocessing pipelines developed for the
HCP (60) to maximize alignment across imaging modalities and minimize
distortions and blurring of the data. Field maps were available, and readout
distortion was corrected in humans. Intersubject registration to a groupaverage atlas surface was performed using a two-stage process based on
the MSM algorithm (58), where an initial gentle stage is driven by cortical
folding patterns and a more aggressive second stage utilizes cortical areal
features of myelin, resting-state network maps, and visuotopic maps (34).
A version of the HCP pipelines adapted for nonhuman primates (HCP-NHP
pipelines) (39) was used to process macaque and chimpanzee T1w and T2w
structural scans. Initially, the PreFreeSurfer pipeline aligns T1w and T2w
volumes to native anterior commissure–posterior commissure (AC–PC) space
and performs brain extraction, cross-modal registration, bias field correction, and nonlinear volume registration to atlas space using the FMRIB
Software Library (FSL; University of Oxford) (61).
A nonhuman primate-specific pipeline, FreeSurferNHP, differs from the
HCP FreeSurfer pipeline in the following ways: (i) using nonhuman primate
volume templates and adjusting the brain size parameter to 80 mm for the
macaque and 120 mm for the chimpanzee and (ii) converting the data into a
“fake” 1-mm × 1-mm × 1-mm space to conform to FreeSurfer requirements
without interpolation (62). This last modification allows the full resolution of
the nonhuman primate data to be used for surface generation. Speciesspecific volume and surface templates were used for registration before
transformation back into the 0.5-mm input space. Cortical thickness is then
computed, modifying the maximum cortical thickness parameter (from a
default value of 5 mm) in the FreeSurfer mris_make_surfaces command to
conform to scan resolution as 5=resolution mm to ensure that the fake 1-mm
space does not set too low a cap on the cortical thickness (0.5 mm data faked
to 1 mm would make a 5-mm cortical thickness limit into a 2.5-mm cortical
thickness limit if not adjusted).
The PostFreeSurfer pipeline uses MSM-Sulc surface registration, a version
of MSM where alignment is driven by cortical shape [FreeSurfer’s “sulc”
(sulcal) measure]. The pipeline produces a high-resolution 164-k surface
mesh (∼164,000 vertices per hemisphere), as well as two lower-resolution
meshes (32 k/10 k for macaque and 32 k/20 k for chimpanzee). In addition to
surface reconstruction, myelin maps (average maps of myelin content across
the cortical layers) are created based on the T1w/T2w ratio (6, 45, 60).
However, the cortical thickness and myelin maps are likely biased in regions
of localized signal dropout (anterior insular and orbitofrontal cortex) because of an imperfect cortical segmentation.
Group-Average Atlases and Cortical Parcellations. Individual subject registration to a group-average atlas enables accurate comparisons across subjects.
The HCP Multimodal Parcellation [HCP_MMP1.0 (34)] provided both an atlas
space for registration of individual human subjects and a cortical areal
classifier for creating individual-subject parcellations. This classifier identi-
E5190 | www.pnas.org/cgi/doi/10.1073/pnas.1721653115
fied the 180 cortical areas per hemisphere if the fingerprint of each area was
detected but allowed the identification of fewer areas. These areas vary in
size and shape relative to the original areas defined using group-average
data. Additionally, a more accurate medial wall was created to restrict
analyses to neocortex and transitional cortex (but excluding the hippocampal formation medial to the presubiculum).
The Yerkes19 macaque surface-based atlas (39) was created using the
19 previously described adult macaque subjects. The HCP-NHP pipelines
were used to extract cortical surfaces and subcortical volumes from structural MRI scans. Interhemispheric alignment was driven by 45 geographically
corresponding landmark contours per hemisphere, analogous to the
landmark-based alignment performed for the F99 macaque surface-based
atlas (2). The Ferry et al. (36), Lewis and Van Essen (37), and Paxinos et al. (38)
histological parcellations were mapped to the Yerkes19 atlas from the
F99 atlas (36, 38, 63) using the MSM algorithm driven by a combination of
cortical folding (mean curvature) and revised medial walls (excluding hippocampal cortex medial to the presubiculum) for both atlases. Mean
curvature was used as a registration constraint because an accurate
FreeSurfer-based sulc map was not available for the F99 atlas surface, which
had been generated using the SureFit segmentation method (3) that does
not produce the white matter surface required to create a sulc map.
The Yerkes29 chimpanzee surface-based atlas was created in a similar fashion,
using the 29 previously described adult chimpanzee subjects. The Bailey et al.
cytoarchitectural atlas (42) was used to systematically map cortical areas from
published coronal volume slices to the Yerkes29 atlas. Images of histological slice
drawings (intermediate between coronal and axial planes) taken from the Bailey
et al. atlas were visually matched to corresponding slices in an individual chimpanzee MRI structural scan, using an individual chimpanzee (Edwina) whose
frontal convolutions were like those in the atlas, based on visual inspection.
These coronal areal designations were then projected to the cortical group average surface based on Bailey et al.’s cortical surface figures and our groupaverage maps of myelin and sulcal depth.
Delineations approximating PFC based on the genu of the corpus callosum
were created by identifying the coronal slice precisely anterior to the genu
when individuals were aligned so that the axial slice was parallel to the AC–PC
line. All gray and white matter anterior to this coronal slice was considered
part of this genu-defined region.
Assigning Prefrontal Cortical Areas. Individual cortical areas were identified as
belonging to PFC based on published criteria and delineations (28–30, 42, 64).
For each cortical area located in the frontal lobe, primary qualities tabulated
included previously published areal classification as PFC and the histological
description of areal cortical layer IV (granular, dysgranular, lightly granular, or
agranular). Cytoarchitectonically granular/dysgranular areas were included in
the delineation of conservative PFC, and agranular areas associated with
cognitive-related function were additionally included in the liberal PFC delineation. Additional information about the studies used to define PFC delineations is provided in Supporting Informationand Tables S2 and S3.
Delineating Areas V1 and 4. To identify area V1, we used the HCP_MMP1.0 (34)
for delineation of V1 in the human, myelin maps plus the Lewis and Van Essen
parcellation (37) for delineation in the macaque, and myelin maps plus the
Bailey et al. cytoarchitectural atlas (42) for delineation in the chimpanzee. Area
4 was identified in humans using the HCP_MMP1.0 parcellation; for chimpanzees and macaques, delineations were based mainly on group-average myelin
and cortical thickness maps and their gradients, while also striving for consistency with published atlases (38, 65) (see areal delineations in Fig. 2 and Fig. S4).
Calculation of Cortical Gray Matter and White Matter Volumes. Total cortical
volumes were determined by isolating the cortical gray matter ribbon (as
defined by the space between white and pial surfaces) and the underlying
white matter [as defined by FreeSurfer segmentation (62, 66)] in the native
subject space. Total cortical surface areas and mean cortical thicknesses were
computed for each subject using the native midthickness surface mesh and
excluding the medial wall, using a revised medial wall demarcation for the
macaque (i.e., excluding hippocampal cortex and other minor adjustments)
rather than a published version (39). For each conservative and liberal
parcellation-based PFC delineation, constituent areas were adjoined to create
contiguous PFC surface-based ROIs. In humans, these ROIs were created on each
subject’s 32-k mesh using each subject’s individual HCP_MMP1.0 parcellation
and then were mapped to each subject’s native space using an existing
mapping between the two mesh resolutions. In macaques, these ROIs were
created on a 164-k mesh using the composite parcellation defined on the
Yerkes19 group-average surface and subsequently were registered to each
subject’s native surface mesh. Similarly, the chimpanzee ROIs were created
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PNAS | vol. 115 | no. 22 | E5191
PNAS PLUS
Data Availability. All data related to this study are freely available via the BALSA
database (https://balsa.wustl.edu/) at https://balsa.wustl.edu/study/show/zlVX.
ACKNOWLEDGMENTS. We thank T. Coalson and E. Reid for technical
contributions and C. Sherwood for helpful suggestions and critiques during
the review and revision process. This work was supported by NIH Grants
T32EB014855 (to C.J.D.), F30MH097312 (to M.F.G.), and R01MH60974 (to
D.C.V.E.). Human datasets were provided by the Human Connectome
Project, Washington University-University of Minnesota Consortium
U54MH091657 (principal investigators: D.C.V.E. and Kamil Ugurbil),
funded by the 16 NIH Institutes and Centers that support the NIH Blueprint
for Neuroscience Research, and by the McDonnell Center for Systems
Neuroscience at Washington University. Macaque and chimpanzee datasets were provided through support from NIH Grant P01AG026423, National Center for Research Resources Grant P51RR165 (superseded by the
Office of Research Infrastructure Programs/OD P51OD11132), and National
Chimpanzee Brain Resource Grant R24NS092988.
NEUROSCIENCE
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on the Yerkes29 164-k surface mesh and were mapped to native subject meshes.
Genu-based ROIs were created by including all surface vertices rostral to a coronal slice of the AC–PC aligned volume at the genu of the corpus callosum, an
approximation of PFC used in previous studies (17, 26). Volume measurements
were determined by summing the volumes of individual polyhedral wedges
within each ROI, where each wedge is defined by a triangle in the white surface
and the corresponding triangle in the pial surface. This process was performed
on each individual subject (human, n = 60; macaque, n = 19; chimpanzee, n =
29), and the mean and SD of all subjects were reported for each case (Table 1).
This process is illustrated for an exemplar human in Fig. 5.
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