Comparative primate neuroimaging:insights into human brain evolutionJames K. Rilling1,2,3,4

1 Department of Anthropology, Emory University, Atlanta, GA 30322, USA2 Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA3 Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA4 Center for Translational Social Neuroscience, Emory University, Atlanta, GA 30322, USA

Review

Glossary

Allometry: study of how one part of an organism grows either in relation to the

whole organism or to some other part. Many allometric relationships are well

Comparative neuroimaging can identify unique featuresof the human brain and teach us about human brainevolution. Comparisons with chimpanzees, our closestliving primate relative, are critical in this endeavor.Structural magnetic resonance imaging (MRI) has beenused to compare brain size development, brain structureproportions and brain aging. Positron emission tomog-raphy (PET) imaging has been used to compare restingbrain glucose metabolism. Functional MRI (fMRI) hasbeen used to compare auditory and visual system path-ways, as well as resting-state networks of connectivity.Finally, diffusion-weighted imaging (DWI) has been usedto compare structural connectivity. Collectively, thesemethods have revealed human brain specializationswith respect to development, cortical organization, con-nectivity, and aging. These findings inform our knowl-edge of the evolutionary changes responsible for thespecial features of the modern human mind.

The importance of comparative primate neuroimagingIn the quest for a scientific understanding of human na-ture, no topic is more important than the evolution of thespecial features of the human brain [1,2]. The fossil recordshows that brain size approximately tripled over the last2.5 million years of human evolution [3]; however, the fossilrecord cannot identify potential evolutionary changes tothe internal organization of the brain [4]. To investigatethis question, we must turn to the comparative study of thebrains of living primate species. If we can identify acharacteristic of the human brain that is not found inthe brain of any closely related primate species, then wecan infer that the trait evolved in the hominin lineage (seeGlossary) after we diverged from our common ancestorwith chimpanzees some 5–7 million years ago (mya). Thisapproach renders the study of chimpanzees crucial forlearning about human brain evolution: we cannot inferthat a trait uniquely evolved in the human lineage unless itis absent in modern chimpanzees (Box 1) [5].

1364-6613/$ – see front matter

� 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tics.2013.09.013

Corresponding author: Rilling, J.K. (jrillin@emory.edu).Keywords: neuroimaging; evolution; comparative; human; chimpanzee.

46 Trends in Cognitive Sciences, January 2014, Vol. 18, No. 1

We have extensive knowledge of rhesus macaque brainanatomy and physiology obtained through lesion studies,single-cell electrophysiology, and tracer studies. Similardetailed knowledge from humans and great apes is highlydesirable, but these invasive methods cannot be ethicallyapplied in humans and great apes. Fortunately, the recentadvent of non-invasive neuroimaging techniques hasopened new possibilities for comparative studies (Box 2)[2].

Structural MRIThe earliest comparative neuroimaging studies utilizedstructural MRI to compare the absolute and relative sizeof brain structures across anthropoid primate species.Similar studies had been conducted earlier using post-mortem brain specimens [6–8], but MRI offered the advan-tage that data could be rapidly collected from living,healthy, nonelderly adult subjects without sacrificing ani-mals or waiting for them to die. This facilitated collection oflarger within-species sample sizes that permitted formalstatistical tests of between-species differences. Anotherimportant advantage of MRI is that brain structurevolumes do not need to be corrected for shrinkage thatoccurs during the post-mortem fixation process [9].

Against the backdrop of evidence that brain structuresize could be accurately predicted from overall brain sizeacross a broad sample of mammals [10], early MRI findingsshowed that human brains in fact deviated from predic-tions derived from non-human anthropoid primates insome important respects, and could not simply be consid-ered scaled-up versions of typical non-human primatebrains [11]. In particular, relative to a hypothetical ‘typical’anthropoid primate of our brain size, humans have larger

described by the equation Y = bXa, where a is the allometry exponent. When

a = 1, the relationship is linear. When a > 1, increases in Y outpace increases in

X and the relationship is positively allometric. When a < 1, increases in Y do

not keep pace with increases in X and the relationship is negatively allometric.

Hominin: living and extinct members of the human lineage after the split from

chimpanzees.

Homology: correspondence between species due to a common evolutionary

origin.

Voxel: the smallest volumetric element of a brain image, analogous to a pixel,

but with the added dimension of depth.

Box 1. Primate phylogeny

In taxonomic terms, primates are one of several orders in the

mammalian class. The earliest primates appear in the fossil record

around 60 million years ago (mya), shortly after the dinosaurs

became extinct. The two primate suborders, anthropoids and

prosimians, diverged from each other early in primate evolution.

Modern day prosimians are generally believed to have retained

more similarities with the earliest ancestral primates than anthro-

poid primates have. Anthropoid primates include New World

monkeys (from central and south America), Old World monkeys

(from Africa and Asia), and the hominoids, which include lesser

apes (from Asia), great apes (from Africa and Asia), and humans.

Among the hominoids, humans are most distantly related to the

lesser apes, and most closely related to the African great apes. Our

two closest living primate relatives are the chimpanzees and the

bonobos, both members of the genus Pan, with whom we shared a

common ancestor some 5–7 mya. Chimpanzees and bonobos are

believed to have shared their last common ancestor approximately

1–2 mya. To conclude that a neurobiological trait is uniquely human,

we would ideally show that it is not present in any other living

species. However, given the practical difficulty of doing so, the

minimum criterion for suggesting that a trait uniquely evolved in

humans is to establish its absence in our closest living relative,

either chimpanzees or bonobos, as well as in some more distantly

related primate species that serves as an outgroup, to determine

whether a difference between chimpanzees and humans represents

a chimpanzee or a human specialization. However, this more limited

approach leaves open the possibility of parallel evolution of the

human trait in a particular primate or even non-primate species.

Box 2. Neuroimaging techniques

MRI can be used to image either brain structure or brain function

using the same instrument. In MRI, the subject is positioned within

the bore of a large magnet that exposes them to a strong magnetic

field, which causes a small fraction of the protons in their body to

orient in the direction of that magnetic field. If radiofrequency pulses

are then applied at the precession frequency of these protons, they

are tipped out of alignment with the main magnetic field. The signal

intensity of voxels in MRI images is related to the behavior of the

protons following this perturbation. This can be affected by (i) the

water and fat content of tissues, (ii) the direction of water diffusion,

and (iii) the ratio of deoxygenated to oxygenated hemoglobin.

These variables can be used, respectively, to create images that

show (i) contrast between gray matter, white matter, and cere-

brospinal fluid (structural images for morphometrics), (ii) images of

water diffusion (DWI images for measuring white matter integrity

and tractography), and (iii) increases in blood flow in response to

stimuli (fMRI).

PET involves the injection or consumption of radioactive com-

pounds, followed by detection of the distribution and concentration

of radioactivity in the brain with an instrument known as a PET

scanner. PET can be used to measure cerebral glucose metabolism

and cerebral blood flow, both known correlates of synaptic activity

in the brain. PET can also be used to image the density and

distribution of neurotransmitter receptors and transporters in the

brain. This involves injection of a radioactively labeled molecule that

binds to a specific receptor (i.e., a ligand), followed by detection of

the location and intensity of the radioactivity. A great deal of

research is devoted to synthesizing radiolabeled ligands that have

the appropriate binding characteristics in terms of their specificity

and affinity for their receptors. Ligands are currently available for

several subtypes of dopamine and serotonin receptors, as well as

their transporters. The number of available ligands will continue to

grow in the future.

All of these techniques are available for comparative neuroima-

ging studies that teach us about human brain evolution.

Review Trends in Cognitive Sciences January 2014, Vol. 18, No. 1

neocortices [9], temporal lobe volume [12,13], and estimat-ed prefrontal white matter volume [14], as well as greatergyrification (cortical folding) in prefrontal cortex [9] andmore gyral white matter in the frontal and temporal lobes[15] (Box 3). When combined with older post-mortem datashowing that primary sensory and motor areas are smallerthan expected in human brains [16–18], these MRI data ledto the summary prediction that one special feature of thehuman brain is that it has relatively more associationcortex compared with other primate brains [19].

As more sophisticated brain imaging software becameavailable, it became possible to warp non-human primatecortical surfaces into the shape of the human cortex using aset of suspected anatomical and functional homologies aslandmarks to constrain the registration. As predicted,macaque-to-human brain warping showed the largest rel-ative expansion in human prefrontal, parietal, and tempo-ral association cortex, and the least expansion in primarysensory and motor areas [20]. A chimpanzee-to-humanbrain warping study based on a more limited set of homol-ogies also showed selective expansion of human prefrontaland lateral temporal association cortices [21]. Associationcortex is known to be less well-myelinated than primarysensory and motor cortices [22]. A recent MRI study gen-erated maps of cortical myelin content in humans andchimpanzees. These maps show qualitatively that lesswell-myelinated association cortex occupies a larger pro-portion of the cortical surface in humans compared witheither chimpanzees or rhesus macaques (Figure 1) [23].Collectively, these findings suggest that compared withother living primate species, relatively more of the humancerebral cortex is dedicated to conceptual and other formsof higher-order cognitive processing as opposed to percep-tual processing.

Comparative structural neuroimaging studies have alsodemonstrated that certain brain asymmetries originallypresumed to support uniquely human characteristics suchas language and (supposedly) handedness are in fact alsopresent in great apes. For example, the surface area of theplanum temporale, a portion of Wernicke’s area knownsince 1968 to be leftwardly asymmetric in humans [24],was more recently shown by MRI to be leftwardly asym-metric in great apes as well [25,26]. The same is true of theknob area of the motor cortex responsible for motor skill ofthe hand. Population-level leftward asymmetries are foundin both humans and chimpanzees [27]. Subsequent MRIstudies have linked various brain asymmetries in chim-panzees with handedness behavior [28–31]. Thus, neuro-anatomical asymmetry and functional laterality are likelyto have preceded the evolutionary divergence of humansand chimpanzees, although these have subsequently be-come more pronounced in humans [32–34].

Comparative structural neuroimaging has also in-formed our knowledge of the evolution of human braindevelopment. The most obvious difference between humanand non-human primate brains is absolute size. The aver-age human brain is 1330 cm3, compared with 405 cm3 inchimpanzees [3] and 88 cm3 in macaque monkeys [35].How do these pronounced differences in brain size develop?The traditional answer based on analyses of post-mortemspecimens has been that human and non-human primatebrains grow at similar rates in utero, but that whereas thegrowth rate of non-human primate brains slow at birth,

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Box 3. Comparative morphometrics

Brain structure sizes can be compared across species in a variety of

ways, each of which provides different information. Most obviously,

we can compare the absolute size of brain structures across species.

For example, because the human brain is approximately three times

larger than the largest non-human primate brain, we expect that

most if not all brain structures are absolutely larger in humans

compared with non-human primates. This is generally true, but

there are rare exceptions, such as the olfactory bulbs which are

smaller in humans than in great apes [92]. So do humans have a

larger prefrontal cortex than other primate species? Yes, absolutely,

obviously, and tremendously. A second method of comparing brain

structure sizes across species is to compare the ratio of the size of

the brain structure to the size of the entire brain. This tells us the

relative importance of that structure in that brain. For example,

humans have a larger ratio of prefrontal cortex surface area to total

neocortical surface area compared with other primates [93],

suggesting that the prefrontal cortex has more influence or

importance in the human brain [94]. The third type of comparison

involves a concept known as allometry, in which we ask whether

species differences in relative structure sizes (i.e., ratios) are

predictable consequences of differences in brain size. That is,

primate brains may predictably change proportions as they vary in

size owing to developmental constraints on brain growth. Thus, for

example, humans may have a large ratio of prefrontal to total

neocortical surface area because they are following an allometric

rule of brain growth in which increases in prefrontal cortex area

outpace increases in the size of the rest of the neocortex as primate

brains become larger. In this case, the large human ratio would not

be surprising. Indeed, prefrontal cortex area does scale with positive

allometry on total neocortex area [93]. However, the human

prefrontal cortex is even larger than predicted by the non-human

primate allometry [94]. This important fact suggests that human

brains violate a rule of brain growth. Departures from allometry are

generally interpreted as evidence of adaptations due to natural

selection. Thus, the available data suggest that the large size of the

human prefrontal cortex is a unique, species-specific adaptation of

the human brain. One limitation of allometry is that the slope of the

regression line relating brain structure size to brain size can vary

depending on the taxa through which the line is fitted. Thus,

predictions based on data from apes might differ from those based

only on anthropoid primates or the entire order [95]. Therefore,

allometric data must be interpreted with caution.

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human brain growth continues at the prenatal rate foranother year postnatally [36,37]. A remarkable prenatalbrain imaging study provides further insight into thisquestion. Sakai et al. used three-dimensional ultrasonicimaging of two living chimpanzee fetuses to describe thetrajectory of brain growth in utero in comparison with anexisting human sample [38]. Beginning at 16 weeks ofgestation, human brains are already twice as large aschimpanzee brains. Afterwards, brain growth velocity sim-ilarly increases in both species until 22 weeks of gestation,after which time chimpanzee brain growth velocity slowswhereas human brain growth velocity continues to in-crease. As a result, newborn human brains (�400 cm3)are already approximately 2.7 times larger than newbornchimpanzee brains (�150 cm3) at birth. However, thisdifference falls short of the greater than threefold differ-ence in adult brain size, implying that additional develop-mental differences occur postnatally. Despite their muchlarger size, newborn human brains are at an earlier stageof development at birth than other primate brains are. Forexample, newborn human brains are approximately 25–30% of the adult size, whereas newborn chimpanzee andmacaque brains are closer to 40% and 50%, respectively

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[39]. Recent structural MRI scans from a small sample ofchimpanzees echo earlier post-mortem findings [40] inshowing that human brain growth rates are twice thoseof chimpanzee brain during early infancy, with the furtherinsight that these species differences in postnatal braingrowth are driven by white matter rather than gray matterdevelopment [41]. Thus, maturation of white matter con-nections during infancy may be fundamental to the devel-opment of unique features of human cognition.

Structural MRI has also been used to compare brainaging between humans and other primates. As in humans[42–46], gray matter volume decreases with age in chim-panzees and rhesus monkeys [47,48]. Also like humans,chimpanzees show a trend for decreased white mattervolume with age, but this decrease occurs proportionallylater in the chimpanzee lifespan than in humans, implyingthat there is more time for white matter atrophy beforedeath in humans compared with chimpanzees. This may bepart of the explanation for increased human vulnerabilityto neurodegenerative diseases.

continues at the prenatal for anotherStructural MRI studies of non-human primates were fol-lowed in time by PET studies that enabled measurement ofbrain function by injection of radioactive tracers that couldmeasure regional cerebral blood flow or glucose metabo-lism. An early application relevant to human brain evolu-tion was to ask whether listening to species-specificvocalizations activated homologs of human language areasin macaque monkeys [49]. Indeed, in a small sample ofmacaque monkeys, blood flow responses were more pro-nounced for species-specific calls compared with non-bio-logical sounds within cortical area Tpt and the dorsalfrontal operculum, presumed homologs of Wernicke’sand Broca’s areas, respectively. Notably, however, theseactivations were not leftwardly asymmetric as is typicallyfound in humans. Furthermore, some evidence suggeststhat area Tpt, rather than being exclusively involved inlanguage-specific processes, is involved in early auditoryprocessing more generally [50].

PET imaging has also been used to suggest that, likehumans [51], macaque monkeys have a default mode ofbrain function that is active at rest and suppressed duringattention-demanding cognitive tasks [52]. Similar tohumans, blood flow is higher at rest within medial prefron-tal and medial parietal areas than during working memorytasks.

In humans, default-mode network areas also have highlevels of resting glucose metabolism. A study of resting-state brain glucose metabolism in chimpanzees showed thehighest level of activity within areas that overlapped ex-tensively with the human default-mode network, includingmedial prefrontal and medial and lateral parietal cortices(Figure 2) [53]. A subsequent study has established thatthese areas are also deactivated by focused cognitive activ-ity [54], as is true of the human and macaque default-modenetworks. Given evidence that the default mode network isinvolved in internal thought processes and mental self-projection [55], these findings raise the prospect that simi-lar thought processes may be ongoing in chimpanzees andmacaque monkeys at rest. However, this conclusion is

(A)

1x 32x

(C)

(B)

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Figure 1. Human brains have relatively more association cortex compared to non-human primate brains. (A) The degree of macaque cortical expansion required to warp

macaque to human cerebral cortex (adapted from [20]). (B) Colored regions of chimpanzee cortex must be expanded when warping chimpanzee to human cerebral cortex

(adapted from [21]). (C) Cortical myelin maps in humans (top), chimpanzees (middle), and rhesus macaques (bottom), illustrating the relative amount of lightly myelinated

association cortex across species. More heavily myelinated primary cortices are in color, whereas lightly myelinated association cortex is in gray. Adapted, with permission

from Glasser, M. et al. (2011) Comparative mapping of cortical myelin content in humans, chimpanzees, and macaques using T1-weighted and T2-weighted MRI. Poster

presented at the Society for Neuroscience Annual Meeting, Washington, DC, November 12–16, 2011.

Review Trends in Cognitive Sciences January 2014, Vol. 18, No. 1

contingent on the functional similarity of these regionsacross species, a proposition that has yet to be fully inves-tigated.

Finally, PET imaging has recently been used to explorethe neural bases of object-directed grasping and its obser-vation in chimpanzees [56] as a window onto the neuralsystems involved in social learning and imitation. Relativeto rest, both grasping an object and observing object grasp-ing activated components of a putative mirror systembelieved to be involved in action understanding, includinginferior frontal and lateral temporal cortices. However,another mirror system component, the inferior parietalcortex, was only active for execution of object grasping.It has been suggested that imitation is supported by anindirect pathway from superior temporal sulcus (STS) toinferior frontal cortex via inferior parietal cortex, withinferior parietal cortex supporting the spatial mappingof observed actions. Thus, the lack of inferior parietal lobeactivation during observation of object-directed graspingmovements might relate to the chimpanzee penchant foremulation, which involves reproducing only the goals ofactions, over imitation, which also involves reproducingthe specific movements used to achieve the goal [57].

Functional MRIfMRI is able to measure changes in blood flow without useof the radioactive tracers required for PET imaging. fMRIimages can also be acquired in less time than it takes toacquire PET images (fMRI has higher temporal resolu-tion). The lack of fMRI data from awake chimpanzeesconstitutes a crucial gap in our knowledge of comparativehigher primate brain function. The sensitivity of fMRI tohead movement would require either restraint of these

very strong animals, or training them to lie still whileinside a confined, noisy space. This is indeed a formidablechallenge.

Several research groups have succeeded in collectingfMRI data from awake monkeys. Comparative fMRI stud-ies have begun mapping the visual systems of humans andmacaque monkeys in detail [58–61]. These studies involvepresenting awake monkeys and humans with identicalvisual stimuli and comparing patterns of activation. Thisbody of research has shown that human early and mid-level visual areas are located more posteriorly and medi-ally than their macaque counterparts [59]. For example,visual motion area MT lies within the STS in macaques,but typically within either the anterior or inferior occipitalsulcus in humans [62]. Thus, the distance between MT andprimary auditory cortex is much greater in humans than inmacaques, suggesting expansion of the intervening cortexin humans. These comparative fMRI studies have providedadditional information that can be used as landmarks toconstrain the inter-species registrations mentioned earli-er. The new information has reinforced conclusions thatparietal and ventral temporal cortices have disproportion-ately expanded in humans relative to macaque monkeys.The intraparietal sulcus (IPS) has been a particular regionof focus. It has expanded markedly in humans relative tomacaques, and possesses four regions that are involved inthe perception of three-dimensional structure from motion(3D-SFM), whereas macaque IPS has only one region withlimited sensitivity to 3D-SFM [58]. Humans also possess aregion in the anterior supramarginal gyrus that is respon-sive to observation of tool-use actions, a region that is notactivated in tool-experienced monkeys viewing the samestimulus [61]. The authors proposed that this region

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(A) (B)

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Figure 2. Similar brain regions show the highest resting glucose metabolism in

humans and chimpanzees. Medial (left) and lateral (right) views of the 5% most

active voxels in (A) humans and (B) chimpanzees. Adapted, with permission, from

[53].

Review Trends in Cognitive Sciences January 2014, Vol. 18, No. 1

underlies a specific way of understanding tool actionsbased on appreciation of the causal relationship betweenthe intended use of the tool and the result obtained byusing it. Without parallel data from other primates includ-ing chimpanzees, it is premature to conclude that thesefeatures are truly human specializations that uniquelyevolved in human evolution.

Comparative fMRI has also been applied to investi-gate brain activity related to visual processing of faces.Given that primates are highly social mammals and thatfaces are a highly salient social stimulus for primates,researchers have compared regions of face-selective cor-tex in monkeys and humans. One comparative fMRIstudy that presented monkeys and humans with identi-cal face and non-face stimuli revealed multiple patches offace-selective cortex along the rostral–caudal axis of thetemporal lobes in both humans and monkeys. However,whereas the monkey face patches were in lateral tempo-ral cortex, most of the human patches were in ventraltemporal cortex [63]. This finding is consistent withsuggestions that an evolutionary expansion of lan-guage-related cortex displaced these areas in the humanbrain (see below) [64].

Cortical auditory systems have also been comparedbetween humans and macaques using fMRI. A recentstudy showed that whereas both humans and macaquesactivate the lateral sulcus and superior temporal gyrus(STG) when listening to monkey and human vocalizations,only in humans did the STS also respond to intelligiblehuman utterances. Macaque STS did not respond to mon-key calls. Notably, the human STS activations spannednearly the entire length of the sulcus, and the authorsconcluded that the evolution of language appears to haverecruited most of STS in humans [65].

Whereas the above studies are focused on task-relatedactivation, task-independent deactivation has also beenexplored in monkeys and humans to identify and comparethe default-mode network in the two species. Following theabove PET study suggesting the existence of a default-mode network in monkeys that is similar to that ofhumans, Mantini et al. conducted a meta-analysis of fMRIimaging data collected in ten awake monkeys [66] to showconsistent task-related deactivation within a similar net-work as the PET study that included medial prefrontal andmedial and lateral parietal cortices.

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As the neuroimaging community has expanded its focuson identifying networks of brain activity rather thanisolated activation foci, Mantini et al. used fMRI andindependent components analysis (ICA) to identify a largeset of resting-state networks in both humans and macaquemonkeys, including the default-mode network [67]. Al-though 11 spatially corresponding networks were identi-fied in the two species, three networks were identified inhumans that are absent in macaques. Notably, all threehuman-specific networks include cortical regions with larg-er than average expansion relative to macaque monkeys[20]. Two are fronto–parietal networks that have previous-ly been identified as being related to tool use, among otherfunctions, and the third network involves the dorsal ante-rior cingulate cortex (ACC) and anterior insula, both criti-cally involved in empathy [68].

Another resting-state fMRI study compared connectivi-ty patterns of dorsal prefrontal cortex in humans andmacaque monkeys [69]. Diffusion-weighted MRI tractogra-phy (see below) was applied in humans to define ten dorsalfrontal regions with distinct patterns of connectivity. Foreach of these regions, it was possible to identify regions ofthe macaque dorsal prefrontal cortex with similar patternsof resting-state functional connectivity. Thus, there did notappear to be any uniquely human areas in human dorsalprefrontal cortex. However, despite the overall impressionof similarity, differences in the specific details of connec-tivity patterns were observed that could potentially relateto human cognitive specializations. For example, consis-tent with the above study, specific regions within dorsolat-eral prefrontal cortex (areas 9/46) were connected withsuperior and medial parietal cortex in humans but notin macaque monkeys. Furthermore, an earlier study by thesame group demonstrated resting-state connections be-tween anterior prefrontal cortex and central inferior pari-etal lobule (IPL) in humans that are absent in macaques[70].

Diffusion-weighted imagingDWI is another structural neuroimaging method and themost recent to be applied in a comparative framework.DWI is able to measure the diffusion of water molecules inthe brain [71]. Because water preferentially diffuses par-allel to the direction in which axons are oriented, tracto-graphy software can use this information to attempt toreconstruct the trajectory of major white-matter fibertracts in the brain [72,73].

DWI has been used to describe differences betweenhumans and non-human primates in the white-matterpathways involved in human language [74,75]. Gesch-wind’s classic model of the functional neuroanatomy oflanguage [76] postulates that a region in the posteriorportion of the left STG, Wernicke’s area, is responsiblefor speech comprehension, whereas a region in the leftinferior frontal cortex, Broca’s area, is involved in speechproduction. These two regions are connected by a largewhite-matter bundle known as the arcuate fasciculus.Homologs of Broca’s and Wernicke’s areas apparently existin non-human primate brains [19]. Diffusion tractographyhas revealed connections between Broca’s and Wernicke’sareas (or their homologs) via the arcuate fasciculus in

(A) (B)

(E)

Human

Chimpanzee

Dorsal

Ventral

Ventral

y = 0 mm y = –3 mm

y = –2.4 mm

Dorsal

(D)(C)

(F) (G)

(J)

(I)(H)

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Figure 3. Relative strength of dorsal (arcuate fasciculus) and ventral (extreme capsule) language pathways in humans and chimpanzees. (A–D) Group average left dorsal,

right dorsal, left ventral, and right ventral pathways, respectively, for 26 humans. (E) Left (y = –3 mm) and right (y = 0 mm) dorsal and ventral pathways in coronal slices; the

dorsal pathway is yellow–red and the ventral pathway is light blue–blue. (F–I) Group average left dorsal, right dorsal, left ventral, and right ventral pathways, respectively,

for 26 chimpanzees. (J) Left and right (both y = –2.4 mm) dorsal and ventral pathways in coronal slices. Surface regions of interest (ROIs) are displayed as white outlines.

Fascicle selection ROIs are displayed as a translucent white layer over the pathways. For surface results (coronal sections), the scale is 0 (clear) to 30 (red) streamlines; for

the volume results (surface views), the scale is 5 (clear) to 300 (yellow or light blue) streamlines. Reproduced, with permission, from [74].

Review Trends in Cognitive Sciences January 2014, Vol. 18, No. 1

humans, chimpanzees, and rhesus macaques. There is,however, one striking difference between humans andthe other two species. In both rhesus macaques and chim-panzees, the posterior terminations of the arcuate arefocused on the homolog of Wernicke’s area in the posteriorSTG. Humans, however, also possess a massive projectionof the arcuate into the middle and inferior temporal gyri,ventral to the classic Wernicke’s area [75]. These projec-tions lie within a region of temporal association cortex thatseems to have expanded in human evolution, displacingnearby extrastriate visual cortex in the process. The regionof expanded cortex that receives arcuate projections hasbeen dubbed an epicenter for lexical–semantic processingbased on lesion, fMRI, and structural and functional con-nectivity data [77,78]. Thus, this portion of the arcuatefasciculus may carry lexical–semantic information to Bro-ca’s area. Although some have postulated that evolutionrecruited the extreme capsule pathway into the humanlanguage system, and that it plays a key role in languageevolution, comparative DWI data suggest that the evolu-tionary expansion of the arcuate fasciculus far exceeded thatof the extreme capsule, implicating the arcuate fasciculus as

the key substrate for human language evolution. Further-more, although language is typically left-lateralized, thehuman arcuate fasciculus is leftwardly asymmetric, where-as the extreme capsule is not (Figure 3) [74].

In recent years, human researchers have launched amassive effort to map the human brain connectome usingstructural (DWI) and functional (resting-state fMRI) con-nectivity [79]. Similar efforts have just begun for non-human primates. For chimpanzees and macaque monkeys,diffusion tractography has been combined with graph the-ory to compare the distribution of cortical hubs, regionsthat are particularly well connected with other regions,among humans, chimpanzees, and macaque monkeys [80].Although the accuracy of DWI-based area-to-area connec-tivity patterns is still being evaluated [81], preliminaryresults reveal both cross-species similarities and speciesdifferences in hub distribution. For example, across allthree species, a hub was consistently identified in themedial parietal cortex. This finding is consistent withgraph theory analysis of monkey tracer data [82,83]. Giventhe large amount of information being integrated in medialparietal cortex, we might expect it to be among the most

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10% 100%

Figure 4. Map of putative hubs of white matter connectivity in humans (top),

chimpanzees (middle), and macaque monkeys (bottom). A medial parietal hub

(blue circle) is found in all three species, but a medial frontal pole hub (green circle)

is present only in macaques and chimpanzees. The color scale reflects the

frequency with which a region is identified as a hub across a range of five assumed

network densities and two nodal spatial resolutions. Adapted, with permission,

from [80].

Review Trends in Cognitive Sciences January 2014, Vol. 18, No. 1

metabolically active areas of the brain, and this is indeedthe case in both humans and chimpanzees [51,53]. Thereare also potentially important species differences in thelocation of cortical hubs. Preliminary findings suggest thatmacaques and chimpanzees have hubs in polar and medialprefrontal cortex, whereas humans do not (Figure 4) [80].These differences complement the morphometric evidencepresented above implying important changes in prefrontalcortex during human evolution, a region involved in myri-ad higher cognitive functions, including memory, lan-guage, planning, attention, cognitive control, decision-making, and emotion regulation.

In addition to estimating structural connectivity, DWIcan be used to estimate white matter integrity, which isbelieved to reflect fiber density and diameter and myelina-tion status [84,85]. In healthy humans, white matter in-tegrity increases during development, peaks in middle age,and decreases in old age [86]. Chimpanzees show a similarlifespan trajectory; however, white matter integrity peaksand begins its decline relatively earlier in the humancompared to the chimpanzee lifespan [47]. Thus, as withwhite matter volume, humans apparently have more time

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for white matter integrity to deteriorate before deathcompared with chimpanzees, and this may be part of theexplanation for higher rates of neurodegenerative diseasesamong humans. According to one anthropological theory,the human lifespan has been uniquely extended beyondthe female reproductive period because it enables grand-parental provisioning for weaned offspring [87]. Our datasuggest that there has not been an accompanying delay inthe onset of white matter senescence in humans.

Concluding remarksThis review has highlighted neuroimaging studies thatcompare humans and chimpanzees because these compar-isons are the most informative with respect to understand-ing the evolution of the unique features of the humanbrain. What have these comparative neuroimaging studiestaught us about the evolution of the neural substrates ofhuman uniqueness? The most obvious specialization of thehuman brain is its size. Comparative neuroimaging hasclarified how these dramatic differences in brain size de-velop. First, human brains are already twice as large aschimpanzee brains from an early point in gestation (16weeks). Although both show an increase in growth velocityat this time, they diverge sharply at 22 weeks of gestation,when human brain growth continues to accelerate, where-as chimpanzee brain growth decelerates [38]. Finally,during early infancy, humans experience a very rapidincrease in white matter volume that significantly eclipsesthat found in chimpanzees [41].

In adulthood, human brains are distinguished not onlyby their size but also by a greater proportion of theircortical surface allocated to higher-order association cortexrather than primary sensory and motor areas [19–21,23].This observation suggests that relatively more of the hu-man cerebral cortex is dedicated to conceptual as opposedto perceptual and motor processing. Within parietal asso-ciation cortex, human–macaque comparisons suggestchanges concentrated in the intraparietal sulcus that couldrelate to human tool-use abilities (e.g., extracting 3Dshapes from motion) [58]. Within ventral temporal associ-ation cortex, comparative data suggest expansion of cortexinvolved in language processing in humans, as well as thewhite matter fascicle that innervates that cortex (thearcuate fasciculus pathway) [21,23,59,63,74,75].

Networks of resting-state functional connectivity, in-cluding the default-mode network, exist not only inhumans but also in macaque monkeys [52,66,67] andchimpanzees [53,54]. The presence of the default-modenetwork in other primate species raises the possibility thatother primates may also engage in internal thought pro-cesses that are not immediately related to their externalenvironment when resting. However, humans also possessresting-state networks that have not been identified inmacaque monkeys and that may be involved in functionssuch as empathy, attention, and even tool use [67]. Struc-tural connectivity networks, as defined by DTI, have iden-tified a common hub in the medial parietal cortex ofhumans, chimpanzees, and macaque monkeys. However,the apparent lack of medial prefrontal hubs in humansthat are present in chimpanzees and macaque monkeys,coupled with evidence of increased gyrification in human

Box 4. Outstanding questions

� How does chimpanzee functional neuroanatomy compare with

that of humans and macaque monkeys? Although comparative

PET studies have provided some important insights, fMRI studies

of awake chimpanzees would provide a wealth of additional

information, but present formidable challenges that have yet to be

overcome.

� Chimpanzees (Pan troglodytes) and bonobos (Pan paniscus) are

equally close phylogenetic relatives of humans. How do human

brains differ from those of our other closest living primate

relative, the bonobo (Pan paniscus)? Answering this question will

provide important new insights into human brain evolution, but

the effort is hampered by the limited number of bonobos available

for study.

� How do the density and distribution of neurochemical receptors

compare between humans and non-human primates? This can be

assessed with PET imaging.

� MRS has not yet been applied comparatively. How do regional

concentrations of neurochemicals such as glutamate and GABA

compare between humans and other primates?

� How do brain structure sizes, white matter status, regional

glucose metabolism, and brain receptor and metabolite levels

change across development and aging, and how does this differ

between humans and other primates?

� What genetic differences are responsible for the neurobiological

differences between humans and other primates and what are the

neurodevelopmental pathways by which these materialize?

Review Trends in Cognitive Sciences January 2014, Vol. 18, No. 1

prefrontal cortex, suggests important evolutionarychanges in the connectivity of human prefrontal cortex[80].

Finally, comparative neuroimaging studies of brainaging show that human white-matter ages relatively morerapidly than that of chimpanzees [47], perhaps renderingus more vulnerable to age-related cognitive decline.

There remain unexplored frontiers in comparative pri-mate neuroimaging (Box 4). For example, in addition tomeasuring blood flow and glucose metabolism, PET imag-ing can be used to map the density and distribution ofneurochemical receptors for the subset of receptors forwhich suitable PET ligands are available. Comparativestudies of neurochemical receptor distribution using post-mortem brains have already begun [88]. With these meth-ods, it should be possible, for example, to compare wholebrain maps of different serotonin and dopamine receptorsand transporters across species. In the future, we cananticipate the exciting possibility of mapping receptorsfor modulators of social behavior such as oxytocin, vaso-pressin, and sex steroid hormones, should such ligandsbecome available. Another neuroimaging method that hasyet to be applied in a comparative framework is magneticresonance spectroscopy (MRS), which can quantify theconcentration of neurochemicals such as glutamate andGABA, as well as a variety of other metabolites [89].

In the USA, the National Institutes of Health (NIH) isphasing out almost all invasive biomedical studies onchimpanzees. It appears that non-invasive behavioral,genetic, and neuroimaging studies of chimpanzees shouldbe able to continue if they meet strict new criteria foranimal living conditions. Nevertheless, most of the NIHresearch chimpanzees are scheduled to be retired to thenational sanctuary, with plans to sustain a single colony ofonly 50 animals for future research. As the NIH begins to

withdraw support for chimpanzee research, and the exist-ing captive populations of chimpanzees continue to agewithout replacement through breeding, the future of chim-panzee research in the USA is in question [90]. Privatelyfunded chimpanzee research is still possible in the USA,and non-invasive chimpanzee research is allowed in coun-tries such as Japan, where such research is generatingimportant insights into human neural and cognitive spe-cializations [38,41,91]. In the USA, however, where large-scale chimpanzee research facilities still exist, now is theopportune time to collect a complete set of neuroimagingdata from chimpanzees of various ages using the bestpossible imaging sequences with every known neuroimag-ing modality. If done with the care and foresight of thehuman connectome project [79], in which years were allo-cated to carefully optimize protocols, the data could be ofsufficient quality to serve humanity for generations as avaluable resource to define the unique features of thehuman brain, and teach us about the evolution of the mostremarkable organ of our species.

AcknowledgmentsI thank Matthew Glasser, Longchuan Li, Todd Preuss, and Hanne VanDer Iest for their many helpful comments and suggestions on thismanuscript.

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