ROUGH DRAFT authorea.com/43038

# Jeffrey Young$${}^{\textbf{1}}$$, Yundi Shi$${}^{\textbf{1}}$$, Marc Niethammer$${}^{\textbf{1}}$$, Michael Grauer$${}^{\textbf{2}}$$, Christopher Coe$${}^{\textbf{3}}$$, Gabriele Lubach$${}^{\textbf{3}}$$, Bradley Davis$${}^{\textbf{2}}$$, Francois Budin$${}^{\textbf{1}}$$, Rebecca Knickmeyer$${}^{\textbf{1}}$$, Andrew Alexander$${}^{\textbf{3}}$$, Martin Styner$${}^{\textbf{1}}$$ 1 University of North Carolina at Chapel Hill, NC 2 Kitware, Inc., Carrboro, NC 3 University of Wisonsin-Madison, WI

## Introduction

Brain maturation is a complex process driven by myelination, growth of neurons and of their connections during the first years of life. The increase in brain connections is followed by a process of dendritic pruning and loss of synaptic contacts, presumably shaping and sculpting a more efficient network of connections that are continuously remodeled throughout life (Engert 1999, Stepanyants 2002, Lebel 2008). Although brain maturation has been studied extensively, both at a functional level (behavior) and at a structural and mediating level (cellular physiology), information at the level of neuroanatomical connectivity and about maturational changes during the peripubertal years is not as comprehensive. However, this information is of special interest because it provides insight into a different perspective of the anatomical substrates and captures a second period of major changes in brain development. Furthermore, understanding developmental brain changes will ultimately help us to better diagnose psychiatric conditions that first present clearly in adolescence, such as depression, and devise targeted therapies for neurodegenerative brain disorders with later adult onset.

### Primate Models and Brain Development

Nonhuman primate models are widely used to provide comparative information associated with human neuropathology (Lubach 2006, Segerstrom 2006, Bennett 2008, Grant 2003, Lebherz 2005, Williams 2008, Barr 2006, Glatzel 2002, Machado 2003, Sullivan 2005). Advantages include the biological similarity of monkeys and humans, such as the gestation of a single offspring, a prolonged in utero development, and the maturational stage of the neonatal brain at birth. Among nonhuman primate models, the rhesus macaque (Macaca mulatta) has been the most widely used monkey to investigate the neural substrates of human behavior, due to its phylogenetic closeness to humans (Lacreuse 2009) and the potential to examine more complex cognitive functions and social behavior associated with encephalization (Price 2000). Furthermore, primate models allow for brain imaging at the very early, critical stages of neurodevelopment when it is challenging to recruit and image young human participants. The use of monkeys in a laboratory setting also facilitates genetically and environmentally controlled studies. Additionally, rhesus macaques show hemispheric asymmetry and sex differences in their brains during adolescence similar to humans. For more than forty years, this species has also been used to evaluate how disturbances of the early rearing environment can induce behavioral abnormalities and influence brain development (Harlow 1971).

MRI studies have significantly expanded our knowledge of human brain development during childhood and adolescence through several large-scale cross-sectional (Pfefferbaum 1994, Caviness 1996, Reiss 1996, Courchesne 2000, de Bellis 2001) and longitudinal studies (Giedd 1999, Sowell 2004, Lenroot 2006). Critical periods in human brain development have been identified. In contrast, there are still some lacunae in our knowledge of nonhuman primate development, especially the maturational changes during the peripubertal years. While there are detailed neuroanatomical descriptions of early brain maturation in the monkey (Rakic 1982), less information on the normal postnatal maturation of the monkey brain is available, with the exception of certain brain regions, such as the visual cortex. The prevailing view from studies in humans is that the total brain volume undergoes a rapid non-linear increase during childhood and reaches a maximum around puberty. Gray matter and white matter follow distinct structure-specific developmental trajectories (Gilmore 2007, Knickmeyer 2008, Giedd 1999, Jernigan 1990, Schaefer 1990, Reiss 1996). The only MRI study of juvenile and adolescent brain development in the rhesus macaque reported that, as in humans, they attain a maximum total brain volume around sexual maturity and then and have an extended period of white matter growth into adulthood (Malkova 2006). While human studies suggest that postnatal cortical development is very heterochronous, postmortem studies suggest that cortical development in monkeys is more synchronous (Rakic 1986, Bourgeois 1993).

Studies in humans indicate that there is marked sexual dimorphism in the central nervous system during childhood and adulthood. The most consistent findings include: greater volume of the cerebrum in males, higher proportion of gray matter to white matter in females, relatively greater volume of the amygdala in males, and relatively greater volume of the caudate and hippocampus in females (Dekaban 1978, Filipek 1994, Caviness 1996, Giedd 1996, Reiss 1996, Giedd 1997, Nopoulos 1997, Filipek 1999, Gur 1999, de Bellis 2001, Good 2001, Goldstein 2001, Allen 2003, Gilmore 2007a, Knickmeyer 2008). Males and females also differ in specific developmental growth trajectories. Total cerebral volume, caudate volume, and gray matter volume in the frontal and parietal lobes peak earlier in girls than in boys (ages vary depending on region), a pattern which may relate to sex differences in timing of puberty. In adolescence, white matter increases more rapidly in males than females (Lenroot 2007). These sex differences in neurobiology may be highly relevant to neurodevelopmental pathologies, which frequently show marked sex differences in risk, phenotypic expression, and treatment response (Szatmari 1989, Moffitt 1990, Gur 1996, Häfner 1998, Chakrabarti 2001, Moffitt 2001, Baird 2006, Kulkarni 2008). Research on monkeys can be particularly informative about the role of pubertal onset in determining these brain changes because females reach puberty one to three years before males. In addition, adult rhesus monkeys also display large sex differences in brain size (Falk 1999). This dimorphism occurs in part because the male brain continues to grow significantly after puberty (Franklin 2000). However, some areas, such as the amygdala, continue to be of similar size in male and female monkeys.

As portrayed in Figure \ref{fig:DTI_changes_comparison} below, white matter changes are observed throughout the first two decades of life and beyond in humans (Lebel 2008) and can be measured by DTI. Few developmental studies using DTI have been published for non-human primates. Makris et al. (Makris 2007) investigated changes in white matter fiber bundles with aging, but this study was done in elderly macaques. They reported reductions in fractional anisotropy (FA) in cortico-cortical association fibers with age and general agreement with observations in humans. Styner et al. (Styner 2008) explored changes in the developing macaque brain using an atlas-driven brain parcellation and showed increases in FA, particularly in the corpus callosum, as well as a decrease in mean diffusivity. Combining structural MRI and DTI is particularly useful to investigate brain development over the full range of neurodevelopment. While DTI provides sufficient white matter contrast at the earliest stages of brain development, it is more difficult to analyze the fetal and young infant brain with structural MRI due to weak intensity contrast and contrast inversion.

This report marks the major release of data to our publicly available MRI database characterizing macaque brain development. It is hoped that this freely available resource will be of great utility to others in the neuroimaging field and enable more effective use of nonhuman primates as translational models in both basic neuroscience and clinical research. Nonhuman primates, such as the rhesus macaque, provide a unique opportunity to study normal brain maturation and development in a comparative manner, especially in early infancy, where crucial information about formative developmental trajectories is still missing in young children.