Delayed maturation in the prefrontal cortex, a brain region associated with complex cognitive processing, has been proposed to be specific to humans. However, we found, using a longitudinal design, that prefrontal white matter volume in chimpanzees increased gradually with age, and the increase appears to continue beyond the onset of puberty, as in humans. This provides the first evidence for a prolonged period of prefrontal connection elaboration in great apes

Akichika Mikami

Daichi Hirai

Haruyuki Makishima

Juri  Suzuki

Masaki Tomonaga

Masato Nakatsukasa

Masayuki Tanaka

Takako Miyabe-Nishiwaki

Tetsuro Matsuzawa

Tomoko  Sakai

Yuzuru  Hamada

English

Nature Precedings

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Prolonged maturation of prefrontal white matter in 
chimpanzees 
Tomoko Sakai1, Daichi Hirai2, Akichika Mikami3, Juri Suzuki4, Yuzuru Hamada4, Masaki 
Tomonaga4, Masayuki Tanaka5, Takako Miyabe-Nishiwaki4, Haruyuki Makishima1, 
Masato Nakatsukasa1, Tetsuro Matsuzawa4 
1 Department of Zoology, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-
8502, Japan; 2 Department of Morphological Brain Science, Graduate School of Medicine, 
Kyoto University, Sakyo, Kyoto 606-8501; 3Faculty of Human Welfare, Chubu Gakuin 
University, Seki, Gifu 504-0837, Japan;  4Primate Research Institute, Kyoto University, 
Inuyama, Aichi 484-8506, Japan; 5Wildlife Research Center, Kyoto University, Sakyo, 
Kyoto 606-8203, Japan 
Correspondence and requests for materials should be addressed to TMa (matsuzaw@pri.kyoto-u.ac.jp). 
Delayed maturation in the prefrontal cortex, a brain region associated with complex 
cognitive processing, has been proposed to be specific to humans. However, we found, 
using a longitudinal design, that prefrontal white matter volume in chimpanzees 
increased gradually with age, and the increase appears to continue beyond the onset 
of puberty, as in humans. This provides the first evidence for a prolonged period of 
prefrontal connection elaboration in great apes.  
One of the most marked evolutionary changes underlying human-specific cognitive 
traits is a greatly enlarged prefrontal cortex1-2. This area has been found to mediate 
evolutionarily unique functions such as working memory, temporal integration, motivation, 
decision-making, self-awareness, creativity, language, and social interaction1. Intriguingly, 
the executive role played by the prefrontal cortex depends critically on its reciprocal 
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connections to the posterior processing area1. Thus, focusing on the augmentation of white 
matter (WM) volume underlying the prefrontal cortex, which is thought to be attributable to 
the myelination of the cortico-cortical axons, is a key to understanding human brain 
evolution3-4.  
Comparative imaging studies suggested that prefrontal WM volume is 
disproportionately larger in humans than in other primates4. The prefrontal region is a 
relatively recently evolved brain region and exhibits relatively late maturation1, 3.  The 
prefrontal WM volume of humans continues to increase gradually beyond  puberty until 
young adulthood3, 5-6,  whereas that of macaques first increases and then decreases soon 
after the onset of puberty7. 
These findings suggested that a large disparity of central neural development has 
arisen between humans and monkeys since the last common ancestor 25-30 million years 
ago8-9. Given this deep branching history, comparisons of brain development between 
humans and chimpanzees, the closest living nonhuman primate, whose lineage diverged 
from humans 6-7 million years ago, are essential for understanding human brain evolution. 
To this end, we obtained longitudinal T1-weighted magnetic resonance imaging 
(MRI) scans from three growing chimpanzees at scheduled intervals from six months to six 
years of age (= infant and the age of juvenile stages based on dental development10) 
(Supplementary Methods). For comparison, adult data were obtained from three 
chimpanzees. All subjects lived within a social group of 14 individuals in an enriched 
environment at the Primate Research Institute, Kyoto University (KUPRI) 11-12. Our three 
study chimpanzees were born in 2000, and were raised by their biological mothers. They 
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had not yet reached puberty by seven years of age. All protocols were approved by the 
Committee for the Care and Use of Laboratory Primates of KUPRI.  
We defined the prefrontal portion as all coronal slices anterior to the corpus callosum 
of the cerebrum in accord with previous studies4, 11. The non-prefrontal portion is the 
remainder of the cerebrum. Through comparison with the findings of previous studies in 
humans, we sought to determine whether the human prefrontal white matter develops 
significantly more slowly than that of chimpanzees during infancy and the juvenile period. 
The results of tissue segmentation revealed noteworthy developmental changes from 
six months to six years of age, and differences between juveniles and adults (Fig.1 and 
Supplementary Fig. 1-3). Gray matter (GM) and WM volumes in the cerebrum, the 
prefrontal and non-prefrontal portions were calculated, based on a segmentation map 
generated with FSL software13 (Supplementary Methods and Supplementary Table 1). 
The total volumes of each portion were the sum of GM and WM volume of that portion. 
We used linear polynomial regression analysis to assess the growth patterns of total and 
WM volume changes in each portion during this age period (Supplementary Methods). 
The total volume of each of the cerebrum, prefrontal and non-prefrontal portions 
increased significantly during the period from six months to six years of age  (F = 3.72; 
cubic effect, P < 0.05; Fig. 2a). The WM volume of the cerebrum, prefrontal and non-
prefrontal portions increased non-linearly across this age period (F = 74.49; cubic effect, P 
< 0.0001, F = 13.44; cubic effect, P < 0.0001, F = 83.57; cubic effect, P < 0.0001; Fig. 2a).  
The relative WM volume of the prefrontal plus non-prefrontal portions (the 
percentage of the total volume normalized by the adult percentage) increased non-linearly 
4 
 
 
 
(F = 22.25; cubic effect, P < 0.05; F = 49.18; quadratic effect, P < 0.005; Fig. 2b) 
(Supplementary Methods). However, the relative increase of WM volume in the 
prefrontal portion was significantly smaller than that in the non-prefrontal portion 
(ANCOVA, F = 54.62; P < 0.001; Fig. 2b) (Supplementary Results). At six years of age 
(the prepubertal stage), the relative WM volume in the prefrontal portion was 56.5% of the 
adult value, whereas the relative WM volume in the non-prefrontal portion was 77.0%.  
The WM volume of the cerebrum, especially of the prefrontal portion, increased gradually 
with age, and appears to increase beyond the onset of puberty, which is analogous to the 
delayed growth pattern of the WM volume shown by humans, not macaques. 
In conclusion, we performed the first longitudinal analysis of the brain growth 
patterns in three chimpanzees for six consecutive years. Although an absolute difference in 
brain size between humans and chimpanzees is evident, a prolonged period of prefrontal 
connection elaboration is probably a shared feature that was present in the last common 
ancestor of humans and chimpanzees.  
 
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            159 (2006). 
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            (2005). 
5. Sowell, E.R., Thompson, P.M., Holmes, C.J., Jernigan, T.L. & Toga, A.W. Nat  
            Neurosci 2, 859-861 (1999). 
6. Sowell, E.R., Thompson, P.M., Tessner, K.D. & Toga, A.W. J Neurosci 21,  
            8819-8829 (2001). 
7. Knickmeyer, R.C., et al. Cereb Cortex  (2009). 
8. Kumar, S. & Hedges, S.B. Nature 392, 917-920 (1998). 
9. Steiper, M.E., Young, N.M. & Sukarna, T.Y. Proc Natl Acad Sci U S A 101,   
            17021-17026 (2004). 
10. Kuykendall, K.L., Mahoney C.J., and Conroy, G.C. Am. J. Phys 89, 379-399    
            (1992). 
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11. Matsuzawa, T., Tomonaga, M., Tanaka, M. ed.(Springer, Tokyo, 2006). 
12. Matsuzawa, T. Dev Sci 10, 97-103 (2007). 
13. Smith, S.M., et al. Neuroimage 23, S208-S219 (2004). 
 
 Note: Supplementary information is available on the Nature Neuroscience website. 
ACKNOWLEDGMENTS 
We thank T. Nishimura, A. Watanabe, A. Kaneko, S. Goto, S. Watanabe, K. Kumazaki, N. Maeda, M. 
Hayashi, and K. Matsubayashi for assisting in the care of chimpanzees during scanning, H. Toyoda for 
technical advice, and T. Kaneko for neuroanatomical advice. We also thank the personnel at the Centre for 
Human Evolution Modelling Research at PRI for daily care of the chimpanzees. This work was financially 
supported by grants (#16002001 and # 20002001 to TMa) from the Ministry of Education, Culture, Sports 
and Technology (MEXT), Japan, by the Global COE Program of MEXT (A08 and D10 to Kyoto University), 
and by a grant from the Japan Society for the Promotion of Science for Young Scientists (#21-3916 to TS). 
 
AUTHOR CONTRIBUTIONS 
TS designed the study, carried out the analysis and interpretation of the data, and wrote the first draft of the 
manuscript. AM and TS acquired the MRI data. YH oversaw the data-analysis strategy. TMa and MN 
supervised the study. DH assisted with data analysis and HM assisted with figure preparation. JS, MTa, MTo, 
and TMi, assisted with the MRI scans. This paper constitutes part of the first author’s PhD thesis. 
 
COMPETING INTERESTS STATEMENT 
The authors declare no competing financial interests. 
 
Published online at http://www.nature.com/natureneuroscience 
Reprints and permissions information is available online at http://npg.nature.com/ 
Reprintsandpermissions 
 
Correspondence and requests for materials should be addressed to MTa (matsuzaw@pri.kyoto-u.ac.jp). 
Figure 1 An ontogenetic series of the whole cerebrum and prefrontal portion of a 
chimpanzee during infancy and the juvenile period. MRI brain images aligned by age from 
a representative chimpanzee (Pal) and an adult (Reo) for comparison. (a) T1-weighted 
anatomical brain images. (b) Segmentation of the cerebrum: GM (green), WM (yellow), 
deep central gray matter (blue), and CSF (purple). (c) Three-dimensional renderings of the 
cerebrum from left and right lateral views, including the cortical portion designated as the 
prefrontal portion (red). The scale bar is 50 mm. 
Figure 2 Quantification of volume changes during infancy and the juvenile period in 
chimpanzees. (a) Total (blue) and WM (red) volumes in the cerebrum (left), prefrontal 
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portion (middle), and non-prefrontal portion (right). (b) Relative WM volume in the 
prefrontal portion (magenta) and non-prefrontal portion (cyan). Solid circles indicate the 
average volume of the three growing chimpanzees. Solid triangles, solid squares, solid 
diamonds, open triangles, open squares, and open diamonds indicate the volumes of 
Ayumu, Cleo, Pal, Reo, Puchi, and Popo, respectively. 
0.50
Infancy Juvenile period Adult
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Prolonged maturation of prefrontal white matter in chimpanzees

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Prolonged maturation of prefrontal white matter in chimpanzees

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