developmental patterns of chimpanzee cerebral tissues ......sex and age of the subjects,...

, 20122398280 2013 Proc. R. Soc. B and Tetsuro MatsuzawaJuri Suzuki, Masayuki Tanaka, Takako Miyabe-Nishiwaki, Haruyuki Makishima, Masato Nakatsukasa Tomoko Sakai, Mie Matsui, Akichika Mikami, Ludise Malkova, Yuzuru Hamada, Masaki Tomonaga, enlargement of the human brainprovide important clues for understanding the remarkable Developmental patterns of chimpanzee cerebral tissues

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ResearchCite this article: Sakai T, Matsui M, MikamiA, Malkova L, Hamada Y, Tomonaga M, Suzuki

J, Tanaka M, Miyabe-Nishiwaki T, Makishima H,

Nakatsukasa M, Matsuzawa T. 2013 Develop-

mental patterns of chimpanzee cerebral tissues

provide important clues for understanding the

remarkable enlargement of the human brain.

Proc R Soc B 280: 20122398.

http://dx.doi.org/10.1098/rspb.2012.2398

Received: 10 October 2012

Accepted: 28 November 2012

Subject Areas:evolution, neuroscience

Keywords:brain evolution, brain development,

chimpanzees, encephalization, infancy,

magnetic resonance imaging

Author for correspondence:Tomoko Sakai

e-mail: [email protected]

Electronic supplementary material is available

at http://dx.doi.org/10.1098/rspb.2012.2398 or

via http://rspb.royalsocietypublishing.org.

& 2012 The Author(s) Published by the Royal Society. All rights reserved.

Developmental patterns of chimpanzeecerebral tissues provide important cluesfor understanding the remarkableenlargement of the human brain

Tomoko Sakai1, Mie Matsui2, Akichika Mikami3, Ludise Malkova4,Yuzuru Hamada1, Masaki Tomonaga1, Juri Suzuki1, Masayuki Tanaka5,Takako Miyabe-Nishiwaki1, Haruyuki Makishima6, Masato Nakatsukasa6

and Tetsuro Matsuzawa1

1Primate Research Institute, Kyoto University, Inuyama, Aichi 484-8506, Japan2Department of Psychology, Graduate School of Medicine, University of Toyama, Toyama 930-0190, Japan3Faculty of Human Welfare, Chubu Gakuin University, Seki, Gifu 504-0837, Japan4Department of Pharmacology, Georgetown University, Washington DC 20007, USA5Wildlife Research Centre, Kyoto University, Sakyo, Kyoto 606-8203, Japan6Department of Zoology, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan

Developmental prolongation is thought to contribute to the remarkablebrain enlargement observed in modern humans (Homo sapiens). However,the developmental trajectories of cerebral tissues have not been exploredin chimpanzees (Pan troglodytes), even though they are our closest living rela-tives. To address this lack of information, the development of cerebral tissueswas tracked in growing chimpanzees during infancy and the juvenile stage,using three-dimensional magnetic resonance imaging and compared withthat of humans and rhesus macaques (Macaca mulatta). Overall, cerebraldevelopment in chimpanzees demonstrated less maturity and a more pro-tracted course during prepuberty, as observed in humans but not inmacaques. However, the rapid increase in cerebral total volume and pro-portional dynamic change in the cerebral tissue in humans during earlyinfancy, when white matter volume increases dramatically, did not occurin chimpanzees. A dynamic reorganization of cerebral tissues of the brainduring early infancy, driven mainly by enhancement of neuronal connec-tivity, is likely to have emerged in the human lineage after the splitbetween humans and chimpanzees and to have promoted the increase inbrain volume in humans. Our findings may lead to powerful insights intothe ontogenetic mechanism underlying human brain enlargement.

1. IntroductionThe brain size of humans has increased dramatically during the evolution ofHomo [1–5]. As a result, although brain size in primates is primarily relatedto body size, the human brain is approximately three times larger than expectedfor a primate of the same body weight, a process called encephalization [6].Neuroanatomical studies show that the number of neurons and glia : neuronratio of the human brain do not deviate from what would be expected froma primate brain of similar body weight, implying that the human brain con-forms to a scaled-up primate brain [7,8]. However, studies comparinghumans with non-human primates reveal that human brain evolution has con-sisted of not merely an enlargement, but rather has involved changes at alllevels of brain structure. These include the cellular and laminar organizationof cortical areas [9–12]. Therefore, elucidating the differences in the ontogeneticmechanism underlying brain structure between humans and non-human

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primates will provide important clues to clarify theremarkable brain enlargement observed in modern humans.

Over the past century, studies of comparative primate mor-phology led to the proposal that prolongation of the high foetaldevelopmental rate after birth [13–16] and extension of thejuvenile period [17–21] were essential to promote the remark-able brain enlargement of modern humans and the emergenceof human-specific cognitive and behavioural traits. Recently,a highly cited study obtained the brain size growth profile ofprimates from a number of preserved brain samples andconcluded that rapid growth velocity of the brain in the earlypostnatal stage rather than prolongation of the developmentalperiod contributes to the brain enlargement observed inhumans [22]. However, confounding factors inherent tousing preserved brain samples to capture the true ontogeneticbrain pattern (e.g. individual variation and abnormality/pathology resulting in early death) raise concerns about therobustness of this conclusion [22]. More importantly, com-prehensively and quantitatively elucidating the ontogeneticchanges in brain tissues is important to verifying the ontogen-etic modulation hypothesis of human encephalization from theperspective of brain structural reorganization processes.

Recently, an increasing number of studies have usedthree-dimensional magnetic resonance imaging (MRI) todetermine ontogenetic changes to grey matter (GM) andwhite matter (WM) volumes in humans [23–27] and mon-keys [28–30]. However, the underlying ontogenetic processgoverning the remarkable brain enlargement observed inmodern humans remains unclear, because the developmentaltrajectory of the WM and GM volumes has not been exploredin our closest living primate relatives, the chimpanzees.

To address this lack of information and uncover empiricalevidence for the remarkable enlargement of the human brainduring the postnatal period, we tracked the development ofthe cerebral tissues in growing chimpanzees from infancyto the juvenile period using three-dimensional MRI andcompared these results with previously recorded datafrom humans and rhesus macaques. Our findings revealcommon features of the developmental trajectory of braintissues between the hominoids (humans and chimpanzees),as well as unique features of humans.

2. Material and methods(a) Measurement of age-related volumetric changes

in chimpanzees(i) ParticipantsThree growing chimpanzees, named Ayumu (male), Cleo(female) and Pal (female) and two adult chimpanzees, namedReo (male) and Ai (female) participated in this study. All sub-jects lived within a social group of 14 individuals in anenriched environment at the Primate Research Institute, KyotoUniversity (KUPRI) [31,32]. Our three young chimpanzees wereborn on 24 April 2000, 19 June 2000 and 9 August 2000, respect-ively. The treatment of the chimpanzees was in accordance withthe 2002 version of the Guidelines for the Care and Use ofLaboratory Primates issued by KUPRI.

(ii) Image acquisitionThree-dimensional T1-weighted whole brain images were acquiredfrom the three growing chimpanzees, when ages ranged from sixmonths to 6 years, with a 0.2-Tesla MR imager (Signa Profile,

General Electric) using the same three-dimensional spoiled-gradient recalled echo (three-dimensional spoiled gradient recalledacquisition in steady state (SPGR)) imaging sequence. For compari-son, adult data were obtained from two chimpanzees. Prior toscanning, the three growing and two adult chimpanzees wereanaesthetized with ketamine (3.5 mg kg21) and medetomidine(0.035 mg kg21), and then transported to the MRI scanner. The sub-jects remained anaesthetized for the duration of the scans andduring transportation between their home cage and the scanner(total time anaesthetized, approx. 2 h). They were placed in thescanner chamber in a supine position with their heads fittedinside either the extremity (for the growing chimpanzees;figure 1a) or the head coil (for the adult chimpanzees). The three-dimensional SPGR acquisition sequence was obtained with the fol-lowing acquisition parameters: repetition time, 46 ms; echo time,10 ms; flip angle, 608; slice thickness, 1.0 mm; field of view, 14–16 cm (for the growing chimpanzees) or 24 cm (for the adultchimpanzees); matrix size, 256 � 256; number of excitations, two.

(iii) Image processingThe MRIs for each individual were analysed using the followingseries of manual and automated procedures. (i) All imageswere analysed using ANALYZE v. 9.0 software (Mayo Clinic,Mayo Foundation, Rochester, MN, USA) and converted intocubic voxel dimensions of 0.55 mm using a cubic spline interp-olation algorithm. (ii) Brain image volumes were realigned to astandard anatomical orientation with the transaxial plane paral-lel to the anterior commissure-posterior commissure line andperpendicular to the interhemispheric fissure. (iii) The cerebralportion of the brain was semi-manually extracted using brainextraction tool (BET) [33] in the FSL package (v. 4.1; www.fmrib.ox.ac.uk/fsl) [34]. Non-brain tissues (scalp, orbits) wereremoved, followed by cerebellar and brain stem tissues (mid-brain, pons, medulla). Non-cerebral tissues were removed inthe coronal plane, starting at the most posterior point and pro-ceeding anteriorly until no obvious break was evident betweenthe midbrain and thalamus [35,36]. Next, non-cerebral tissueswere removed in the axial plane according to the methods of pre-vious studies [35,36], starting at the most inferior slice andproceeding superiorly until no obvious break was evidentbetween the midbrain and the posterior limb of the internal cap-sule (the transition between the cerebral peduncle and theposterior limb of the internal capsule). Thus, the cerebral portionincluded most of the deep central GM (caudate nuclei, putamen,globus pallidus, lentiform nuclei, thalamus and intervening WM),the hippocampus and the amygdala in all subjects. (iv) MRI datawere spatially smoothed using smallest univalue segment assimilat-ing nucleus [37] in FSL, which reduces noise, without blurring theunderlying images. (v) Each brain volume was segmented intoGM, WM and cerebrospinal fluid (CSF) based on signal intensity,and magnetic field inhomogeneity was corrected using FMRIB’sautomated segmentation tool (FAST) [38] in FSL (figure 1b).This method was based on a hidden Markov random field modeland an associated expectation–maximization algorithm. A sampleof the results of tissue segmentation at each developmental stage,particularly in infancy, were reviewed by a neuroradiologist (H.T.)to determine whether the GM/WM borders determined by FASTwere accurate. Next, all the results of the GM and WM segmentationwere reviewed and corrected semi-automatically when necessary.(vi) The absolute volumes of GM and WM in the cerebrum weremeasured. The volumes of the cerebrum were calculated from anautomatic count of the number of voxels per mm3 using FSLUTILSin FSL (see the electronic supplementary material, table S1). Thetotal volume of the cerebrum corresponded to the sum of GM andWM volumes of the cerebrum.

Two image analysts (T.S. and H.M.), who were blinded to thesex and age of the subjects, semi-manually traced and measuredthe entire cerebrum. T.S. identified the landmarks of the cerebrum

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Figure 1. An ontogenetic series of MRI images of the whole cerebrum in a chimpanzee brain during early infancy and the juvenile stage. (a) MRI scanning of thebrain of a chimpanzee infant (Ayumu) at age of six months. (b) MRI brain images aligned by age are shown for a representative young chimpanzee (Pal) and anadult chimpanzee (Reo) for comparison. (i) T1-weighted anatomical brain images. (ii) Segmentation of the cerebrum: grey matter (GM), white matter (WM) andcerebrospinal fluid (CSF). (iii) Three-dimensional renderings of the cerebrum from superior and right and left lateral views. The coloured bar to the left of the imagesindicates the developmental stage based on dental eruption and sexual maturation. The indicated developmental stages in chimpanzees are early infancy (magenta),late infancy (yellow), juvenile (green) and adult stage ( purple).


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in all brain images in consultation with a neuroradiologist (H.T.)and anatomical experts (A.M. and M.M.). An inter-rater reliabilityanalysis was conducted to compare the cerebral measurementsobtained by T.S. with a sample of brain scans measured by H.M.Ten brain scans were randomly selected for analysis. The Pearson’scorrelation coefficient for the comparison of the results obtained byT.S. and H.M. was r ¼ 0.91, p , 0.01.

(b) Comparison of the developmental trajectories ofchimpanzee, human and rhesus macaque braintissue volumes

Direct comparison of the developmental trajectories of the chim-panzees with those in humans and rhesus macaques allowed theidentification of features shared across humans, chimpanzeesand macaques; hominoid (human and chimpanzee)-shared fea-tures; and human-specific features. In statistical analyses, thesame procedures were used to analyse data from chimpanzees,humans and macaques.

(i) HumansHuman cross-sectional data of age-related brain volume from28 healthy Japanese children (14 males and 14 females), whose

ages ranged from one month to 10.5 years (see details inMatsuzawa et al. [24]) were analysed. The comparison withhuman adult volumes was based on the data from 16 healthyadults who served as controls (M. Matsui, C. Tanaka, L. Niu,J. Matsuzawa, K. Noguchi, T. Miyawaki, W. B. Bilker,M. Wierzbicki and R. C. Gur 2010, unpublished data; thesedata were presented as an abstract entitled ‘age-related volu-metric changes of prefrontal grey and white matter fromhealthy infants to adults’ at the twentieth annual RotmanResearch Institute Conference, ‘Frontal Lobes’). Adult subjectcharacteristics were as follows: mean (s.d.) age, 21.3 (1.8) years;female : male ratio, 50 per cent male. All parents and adult par-ticipants gave written informed consent for participation afterthe nature and possible consequences of the study wereexplained. All protocols of the study were approved by the Com-mittee on Medical Ethics of Toyama University.

(ii) Rhesus macaquesMacaque longitudinal data of age-related brain volume from sixnormal rhesus macaques (four males, six females), whose agesranged from three months and 4 years, were analysed (see detailsin Malkova et al. [28]). The macaque subjects were raised byexperienced veterinary nursery staff and were also placed for

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several hours daily in a social group with several other animalsof the same age. These rearing conditions have proved optimalfor the development of social relationships in infant macaquesseparated from their mothers near birth, when compared withrearing without conspecifics or pair-rearing with several rotatingpartners. The treatment of the macaques was in accordance withthe NRC Guide for Care and Use of Laboratory Animals, and theanimal protocol was approved by the Institutional Animal Careand Use Committee of the National Institute of Mental Health.

Unlike in the chimpanzee and human studies, the ventricularsystem was included in the cerebrum in the macaque study [28].Moreover, the estimation of GM volume in the macaque study (notpreviously published) differed somewhat from the GM volume esti-mation in the chimpanzee and human studies. GM volume inmacaques was calculated by subtracting the WM volume fromthe total volume, including the ventricular volume, whereas thosein chimpanzees and humans were calculated by subtracting theWM volume from the total volume, not including the ventricu-lar volume [28]. No significant age-related changes in the totalamount of CSF in the ventricles and external space surroundingthe brain were found in a previous study in rhesus macaques [29].Therefore, developmental changes in the estimated GM of the maca-que cerebrum in this study were considered to parallel those of thereal GM of the macaque cerebrum. A more detailed description ofthe demarcation of the cerebal tissues and the different types of data-sets in humans and rhesus macaques is included in the electronicsupplementary material.

(c) Definitions of developmental stages in chimpanzees,humans and rhesus macaques

In this study, developmental indicators were chosen based on acombination of dental eruption and sexual maturation forinter-species comparisons. In the developmental stages, basedon dental eruption, three developmental stages were defined:‘early infancy’, ‘late infancy’ and ‘juvenile’ (see the electronicsupplementary material, figure S1) [39–41]. These stages weredemarcated by the eruption of the first deciduous tooth andthe eruption of the first permanent tooth. The juvenile stageends at sexual maturation (menarche, first ejaculation) [42–45].The developmental stages analysed were, in chimpanzees,approximately 1 year of age, approximately 3 years of ageand approximately 8 years of age; in humans, approximately 2years of age, approximately 6 years of age and approximately 12years of age; and in macaques, approximately 0.4 years of age,approximately 1.3 years of age and approximately 3.2 years of age.

(d) Statistical analysisAll statistical analyses were performed using SPSS v. 19 (SPSS,Chicago, IL, USA) and R v. 2.11.1 (http://www.r-project.org/)software. Hypothesis tests for model building were based on F-statistics. All statistical hypothesis tests were conducted at asignificance level of 0.05.

(i) Total and tissue volumes of the cerebrumF-tests were used to determine whether the order of a develop-mental model was cubic, quadratic or linear. First, linear,quadratic or cubic polynomial regression models were fitted byage using SPSS 19 to identify the brain volume development pat-terns in the cerebrum. If a cubic model did not yield significantresults, a quadratic model was tested; if a quadratic model didnot yield significant results, a linear model was tested. Thus, agrowth model was polynomial/nonlinear if either the cubic orquadratic term significantly contributed to the regressionequation. The Akaike information criterion (a log-likelihoodfunction) [46] was used to ensure effective model selection.

Second, using R v. 2.11.1 software, the data that showed non-linear trajectories were fitted by locally weighted polynomial

regression [47]. In this way, even with relatively few datapoints, gestational age-related volume changes could be deli-neated by applying the curve fitting suggested by previoushuman studies [48,49] and a previous chimpanzee study [36],without enforcing a common parametric function on the dataset,as is the case with linear polynomial models. The fit at a givenage was made using values in a neighbourhood that includeda proportion, alpha, and for alpha less than 1, the neighbourhoodincluded a proportion, alpha, of the values. Data were fitted infour interactions with a ¼ 0.70. The observed and fitted valuesof the total, WM and GM volumes in the cerebrum were plottedas a function of age to display the age-related change.

To assess the differences in the developmental patterns of thetotal, GM and WM volumes in the cerebrum among chimpanzees,humans and macaques, the relative total, GM and WM volumeswere calculated as a percentage of the adult volumes in the cere-brum. To adequately describe the variability in the data amongadult chimpanzees compared with that among young chimpan-zees, data on the GM and WM volumes of the cerebrum from sixadult chimpanzees used in a previous study [35] were added tothe present data from the two adult chimpanzees.

(ii) The increase of grey matter relative to white matterThe differences in the postnatal developmental patterns of thetotal volume of the cerebrum between chimpanzees, humans andmacaques appears probably to be owing to differences in the devel-opmental patterns of brain tissues during the postnatal period, andthese differences greatly influence the ultimate difference inthe adult brain volume size among the three species. Therefore, toelucidate species-specific variations in chimpanzees, humans andmacaques, the relative growth of the GM versus the WM of thedeveloping cerebrum was evaluated and compared with the adultvalue. The relative growth of the GM versus the WM was calculatedand compared with the adult value by dividing the ratio of GMvolume to WM volume in the cerebrum by the adult ratio.

3. Results(a) Total and tissue volumesThe results of brain tissue segmentation revealed noteworthydevelopmental changes in chimpanzees over the course of thestudy period (figure 1b and the electronic supplementarymaterial, figure S1). The increase in total cerebral volumeduring early infancy and the juvenile stage in chimpanzeesand humans was approximately three times greater than thatin macaques. The total volume of the chimpanzee cerebrumincreased 32.4 per cent over the developmental period fromthe middle of early infancy to the second half of the juvenilestage (six months to 6 years; figure 2a). The correspondingvalue in the human cerebrum during approximately the samedevelopmental period (1 year to 10.5 years) was 27.7 per cent(figure 2b). By contrast, the total volume of the macaque cere-brum increased only 10.9 per cent during approximately thesame developmental period (three months to 2.7 years; figure2c). A more detailed description of the total and tissue volumesin chimpanzees, humans and macaques is available in the elec-tronic supplementary material, table S1–S4.

Chimpanzees and humans demonstrated a nonlineardevelopmental course of the GM and WM volumes and acommon rate of increase in these tissue volumes from earlyinfancy through the juvenile stage. The GM and WMvolumes of the chimpanzee cerebrum increased by 10.0 percent and 92.5 per cent, respectively, from the middle ofearly infancy to the second half of the juvenile stage (six

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Figure 2. Evaluation of total, GM and WM volumes in the cerebrum during early infancy and the juvenile stage. Age-related changes in the total, GM and WMvolumes in the cerebrum are shown for (a) chimpanzees (Ayumu, Cleo and Pal), (b) humans (n ¼ 28) and (c) rhesus macaques (n ¼ 6). To compare thedevelopmental trajectory of GM volume in rhesus monkeys with that of chimpanzees and humans, the estimation of GM volume in rhesus macaques was calculatedby subtracting the WM volume from the total volume, including the ventricular volume. The coloured bar below the graphs indicates the developmental stage basedon dental eruption and sexual maturation. The indicated developmental stages are early infancy (magenta), late infancy (yellow), juvenile (green) and puberty(blue). When no evidence of a significant effect of age on the estimation of brain volume was detected, no regression line was fitted. See also [24] and [28] formore details of the human and rhesus macaque data, respectively.


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months to 6 years; figure 2a). The respective values in thehuman cerebrum during the corresponding developmentalperiod were 6.7 per cent and 96.7 per cent (figure 2b). Bymarked contrast, in rhesus macaques, no significant increasein GM volume occurred during approximately the samedevelopmental period (three months to 2.7 years; figure 2c).Moreover, the increase in WM volume in the macaque cere-brum during this developmental period was 74.7 per cent,which was smaller than that the increase in WM volume inchimpanzees and humans (figure 2c).

(b) Higher rate of total cerebrum volume accumulationin human infants

Chimpanzees and humans differed from macaques in show-ing less maturity of brain volume after birth and prolongeddevelopment of the total and WM volumes of the cerebrum.The total and WM volumes in chimpanzees at the middle ofearly infancy (six months) were 73.8 per cent and 36.5 percent of the adult volume, respectively (figure 3a). The corre-sponding values in humans at approximately the same

developmental period (1 year) were 74.2 per cent and 40.5per cent, respectively (figure 3b). By contrast, the total cer-ebral volume of macaques had already reached a plateau atthe middle of early infancy (three months; figure 3c). The cer-ebral WM volume of macaques reached 51.2 per cent of theadult volume at the middle of early infancy (figure 3c).

Interestingly, the rate of increase in total volume of thechimpanzee cerebrum during early infancy was only halfthat of humans, although both chimpanzees and humansexhibited immaturity of the total volume at early infancy anda relatively protracted development of the total volume com-pared with macaques during early infancy and the juvenilestage. The total volume of the chimpanzee cerebrum increasedby 8.4 per cent from the middle of early infancy until the endof early infancy (six months to 1 year; figure 2a), whereas thetotal volume of the human cerebrum increased by 16.4per cent during approximately the same developmentalperiod (1–2 years; figure 2b). By contrast, the total volume ofthe macaque cerebrum increased by only 1.6 per cent duringapproximately the same developmental stage (three to 4.8months; figure 2c).


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Figure 3. Evaluation of total, GM and WM volumes relative to the adult volumes in the cerebrum during early infancy and the juvenile stage. Age-related changesin total, GM and WM volumes relative to the adult volumes in the cerebrum are shown for (a) chimpanzees (Ayumu, Cleo and Pal), (b) humans (n ¼ 28) and(c) rhesus macaques (n ¼ 6). The coloured bar below the graphs indicates the developmental stage based on dental eruption and sexual maturation. The indicateddevelopmental stages are early infancy (magenta), late infancy (yellow), juvenile (green) and puberty (blue). When no evidence of a significant effect of age on theestimation of brain volume was detected, no regression line was fitted.


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This great difference in the developmental patterns of thetotal volume of the cerebrum at early infancy between chim-panzees and humans appears to be caused by differences inthe developmental patterns of brain tissues during thisstage and to greatly influence the ultimate difference in theadult brain volume between the two species. To verify thispossibility, we attempted to evaluate the relative growth ofthe GM versus the WM of the developing chimpanzee cere-brum. We then compared the results with the adult valueand with those of humans and macaques. The proportionof GM relative to WM was calculated by dividing theratio of GM volume to WM volume in the cerebrum at agiven developmental stage by the adult ratio.

Like humans, chimpanzees substantially differed frommacaques in the proportions of brain tissues of the cerebrumat an early developmental stage. At the middle of earlyinfancy (six months), the proportion of GM relative to WMof the cerebrum in chimpanzees was 3.51 (figure 4a). Thecorresponding value in humans at approximately the samedevelopmental stage (1 year) was 3.29 (figure 4b). By contrast,the proportion of GM relative to WM of the macaque cere-brum at approximately the same developmental stage(three months) was only 1.93 (figure 4c).

However, the proportion of GM relative to WM of thecerebrum in chimpanzee infants developed along a slower

trajectory during early infancy compared with that ofhuman infants. The proportion of GM relative to WM ofthe chimpanzee cerebrum changed from 3.51 to 3.18 fromthe middle of early infancy to the end of early infancy (sixmonths to 1 year; figure 4a). By marked contrast, inhumans, the proportion changed from 3.29 to 2.05 duringapproximately the same developmental stage (1–2 years;figure 4b). In macaques, the proportion of GM relative toWM of the cerebrum changed only from 1.93 to 1.82 duringapproximately the same developmental stage (three to 4.8months; figure 4c). These results suggest that human infantsexhibit a more dynamic proportional change in brain tissuesduring early infancy. A more detailed description of the timecourse of changes in the proportion of GM relative to WM ofthe cerebrum in chimpanzees, humans and macaques isincluded as electronic supplementary material, table S5.

Although we observed that GM and WM volumes ofthe cerebrum increased during early infancy both in chim-panzees and humans, we demonstrated that this differenceis attributable to differences between the species in the rateof WM volume increase during this developmental stage.The rate of WM volume increase in the chimpanzee cerebrumduring early infancy was lower than that in the humancerebrum, whereas the rate of GM volume increase inthe chimpanzee cerebrum at this developmental stage was


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Figure 4. Evaluation of the proportion of GM volume to WM volume in thecerebrum during early infancy and the juvenile stage with that in adults.Age-related changes in the growth velocity of tissue volumes in the cerebrumare shown in (a) chimpanzees (Ayumu, Cleo and Pal), (b) humans (n ¼ 28)and (c) rhesus macaques (n ¼ 6). The coloured bar below the graphsindicates the developmental stage based on dental eruption and sexualmaturation. The indicated developmental stages are early infancy (magenta),late infancy (yellow), juvenile stage (green) and puberty (blue). When noevidence of a significant effect of age on estimation of brain volume wasdetected, no regression line was fitted.


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almost the same as that in human infants. The GM and WMvolumes of the chimpanzee cerebrum increased by 5.2 percent and 17.2 per cent, respectively, over the developmentalperiod from the middle of early infancy to the end of earlyinfancy (six months to 1 year; figure 2a). By contrast, the cor-responding values increased to 8.4 per cent and 42.8 per cent,respectively, during approximately the same developmentalperiod (1–2 years) in humans (figure 2b). In macaques, nosignificant age-related change in the GM volume of the cere-brum occurred during the study period (three months to 4years; figure 2c). The WM volume of the macaque cerebrumincreased only by 9.4 per cent from the middle of earlyinfancy to the end of early infancy (three months to 4.8months; figure 2c).

4. DiscussionWe succeeded in empirically verifying the previously pro-posed hypothesis concerning the ontogenetic mechanismunderlying the remarkable brain enlargement in modernhumans. Despite the relatively small sample size, our resultsrevealed that overall cerebral development in chimpanzeesfollowed a less mature and more protracted course duringprepuberty, as observed in humans but not in macaques.However, a rapid increase in the cerebral total volumeduring early infancy did not occur in chimpanzees. There-fore, our findings support the hypothesis of a previousstudy based on preserved brain samples; that the rapidbrain development rate in the early postnatal stage ratherthan the extension of the developmental period contributesto the enlargement of the human brain [22]. Moreover,these findings suggest that dynamic changes in the pro-portions of human brain tissues, driven mainly by anincrease in WM during early infancy, may promote theenlargement of the human brain.

From the results of this brain imaging study alone, it isdifficult to draw firm conclusions regarding the cellularchanges involved in the dynamic maturational processesinvolved. However, the increase in GM volume during thepostnatal period is presumed to reflect the increase in den-drites and axons as well as glial cells, which are crucial tothe formation, operation and maintenance of neural circuits[25,50]. The data used in the present study included subcor-tical GM such as the basal ganglia in the three species. TheGM of the basal ganglia typically decreases in volume overthe course of development in humans [51]. In this context,the decrease in subcortical GM volume after birth seemedto influence the developmental changes in total GM volumeof the cerebrum in humans and chimpanzees in this study.

The increase in WM volume is consistent with the results ofpost-mortem studies showing that maturational changes areaccompanied by myelination, which improves the conductionspeed of fibres between different brain regions [52,53]. Interest-ingly, the process of WM development after birth is expected toprovide powerful insights into the evolutionary history ofhuman brain structure and function. Recent imaging studiesof human brain development confirmed a positive correlationbetween structural and functional connectivity in WM matu-ration and demonstrated that this relationship strengthenedwith age [54–56]. Furthermore, the refinement of neural net-works mediated by WM maturation promotes increasedconnection efficiency throughout the brain by continuouslyincreasing integration and decreasing segregation of structuralconnectivity with age [55]. Thus, our results suggest that theenhancement of the neural connectivity between brain regionsand the construction of the neural circuits observed during thepostnatal period was established in the ancestral lineage ofchimpanzees and modern humans after its divergence fromthat of macaques. However, the lineage leading solely tomodern humans must have undergone dramatic changes inconnectivity to explain the dynamic reorganization of humanbrain tissues that occurs during infancy.

Moreover, a recent comparative neuroanatomical studyshows that the developmental trajectory of neocortical myeli-nation in humans is distinct from that in chimpanzees [57]. Inchimpanzees, the density of myelinated axons increased untiladult-like levels were achieved at approximately the time ofsexual maturity [57]. By contrast, humans show a prolonged



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increase in myelination beyond late adolescence [57]. Thus,as the next step of our ongoing longitudinal MRI study, wewill trace the developmental trajectory of the WM volumeof the chimpanzee cerebrum after puberty and compare itwith that of the human cerebrum in order to determinewhether the enhancement of the neural connectivity of thecerebrum continues beyond puberty and adolescence atthe neuroimaging level.

Importantly, several recent studies have suggested thatthe period from birth to 2 years, corresponding to earlyinfancy, is a critical period of postnatal brain developmentin humans from the perspectives of brain structures resultingfrom increased brain volume [24,58]; elaboration of newsynapses, myelination [59] and dendrites [60]; and thebrain’s default network [54]. Moreover, children placed infoster care before the age of two appear to make far betterimprovements in cognitive development than those placedin foster care after the age of two [61]. Our finding of arapid increase in the volume of the human cerebrumduring the first 2 years after birth, a process that results inthe dynamic reorganization of brain tissue, complements pre-vious findings on human neurodevelopment and humancognitive development from the standpoint of human brainontogenetic patterns.

Collectively, our results suggest that prolonged develop-ment of the cerebrum at postnatal developmental stagesexisted in the last common ancestor of chimpanzees andhumans. However, the dynamic developmental changes inthe human brain tissues, mainly driven by the elaborationof neural connections, may have emerged in the human

lineage after the split between humans and chimpanzeesand may have promoted the evolutionary enlargement ofthe modern human brain. These findings point to the exist-ence of an ontogenetic mechanism for the remarkable brainenlargement observed in modern humans. Furthermore, theinformation obtained in this study via a direct comparisonof the developmental trajectories of brain tissues of three pri-mate species highlights the importance of focusing on earlyinfant development for understanding the patterns of braindevelopment and changes in cognition in human children.

All protocols were approved by the Committee for the Care and Useof Laboratory Primates of KUPRI, and the part of the study involvinghumans was approved by the Committee on Medical Ethics ofToyama University. The study involving macaques was in accord-ance with the NRC Guide for Care and Use of Laboratory animals,and the animal protocol was approved by the Institutional AnimalCare and Use Committee of the National Institute of Mental Health.

This work was financially supported by grants (nos 16002001,20002001 and 2400001 to T.M.) from the Ministry of Education, Cul-ture, Sports, Science and Technology (MEXT), Japan, by the GlobalCentre of Excellence Programme of MEXT (A06 to Kyoto University),by a Japan Society for the Promotion of Science grant-in-aid forYoung Scientists (no. 21-3916 to T.S.), the Kyoto University ResearchFunds for Young Scientists (start-up; to T.S.) and by WISH grant toKUPRI. We thank T. Nishimura, A. Watanabe, A. Kaneko, S. Goto,S. Watanabe, K. Kumazaki, N. Maeda, M. Hayashi, T. Imura andK. Matsubayashi for assisting with the care of chimpanzees duringscanning; we also thank H. Toyoda for technical advice, andM. Saruwatari and W. Yano for helpful comments. We also thank thepersonnel at the Centre for Human Evolution Modelling Research atKUPRI for daily care of the chimpanzees and E. Nakajima for criticalreading of the manuscript. This paper is a part of the PhD thesis of T.S.

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Developmental patterns of chimpanzee cerebral tissues provide important clues for understanding the remarkable enlargement of the human brainIntroductionMaterial and methodsMeasurement of age-related volumetric changes in chimpanzeesParticipantsImage acquisitionImage processing

Comparison of the developmental trajectories of chimpanzee, human and rhesus macaque brain tissue volumesHumansRhesus macaques

Definitions of developmental stages in chimpanzees, humans and rhesus macaquesStatistical analysisTotal and tissue volumes of the cerebrumThe increase of grey matter relative to white matter

ResultsTotal and tissue volumesHigher rate of total cerebrum volume accumulation in human infants

DiscussionAll protocols were approved by the Committee for the Care and Use of Laboratory Primates of KUPRI, and the part of the study involving humans was approved by the Committee on Medical Ethics of Toyama University. The study involving macaques was in accordance with the NRC Guide for Care and Use of Laboratory animals, and the animal protocol was approved by the Institutional Animal Care and Use Committee of the National Institute of Mental Health.This work was financially supported by grants (nos 16002001, 20002001 and 2400001 to T.M.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, by the Global Centre of Excellence Programme of MEXT (A06 to Kyoto University), by a Japan Society for the Promotion of Science grant-in-aid for Young Scientists (no. 21-3916 to T.S.), the Kyoto University Research Funds for Young Scientists (start-up; to T.S.) and by WISH grant to KUPRI. We thank T. Nishimura, A. Watanabe, A. Kaneko, S. Goto, S. Watanabe, K. Kumazaki, N. Maeda, M. Hayashi, T. Imura and K. Matsubayashi for assisting with the care of chimpanzees during scanning; we also thank H. Toyoda for technical advice, and M. Saruwatari and W. Yano for helpful comments. We also thank the personnel at the Centre for Human Evolution Modelling Research at KUPRI for daily care of the chimpanzees and E. Nakajima for critical reading of the manuscript. This paper is a part of the PhD thesis of T.S.References

developmental patterns of chimpanzee cerebral tissues ......sex and age of the subjects,...

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