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Sex differences in brain structure significantly influence traumatic brain injury (TBI) onset and progression, yet this area is understudied. Herein, we developed sex-specific brain anatomical (macroscale) and axonal tract (mesoscale) templates and explored the sex variations at subject level using a set of T1-MRI (609 males, 721 females) and DTI images (506 males, 594 females). The FreeSurfer, ANTs, and DSI-Studio packages were used. We investigated overall/regional volumes, DTI metrics (including fractional anisotropy (FA), mean diffusivity, and radial diffusivity), and connectivity matrix across 23 brain regions. The brain connectome was derived by multiplying the fiber tract counts and the FA values within the connecting tracts, quantifying the connection strength within each pair of regions. Our subject-wise analysis revealed significant sex based differences (Mann-Whitney p-values < 0.05) across most studied regions for all parameters. The largest sex differences in brain connections were observed in five regions: corpus callosum and right/left cortex and cerebral white matter, all stronger in females. Brain regions were typically larger in males, yet females had higher fractional volumes in the majority of regions except for CSF and ventricles, known for their cushioning effect during head impacts. Additionally, the sex-specific templates better represented their targeted sex compared to opposite or mixed-sex populations as evaluated by root-mean-square-errors when comparing the DTI metrics and connectivity from the DTI templates against the median of subjects and deformation field in registering the subjects to the T1-MRI templates. Our findings highlight the necessity of sex-specific templates in accurate brain modeling and TBI research. 

In this study, we aim to investigate the anatomical features and volumetric measurements of brain (macroscale), along with diffusion tensor imaging (DTI) metrics and the connections between brain regions (mesoscale), to explore sex-specific variations in the brain structure from biomechanics perspective. Such information is crucial for future studies involving FEMs in the field of brain biomechanics particularly when examining the impact of sex-specific differences on the onset and outcomes of TBI. 

The human brain is sexually dimorphic and these sex differences have shown to affect brain response to trauma. We investigated the sex differences in the tract structures by studying diffusion weighted (DW) images of 594 females and 506 males from the Human-Connectome-Project dataset. All the female and male DW images were reconstructed in the ICBM152 space using Q-Space diffeomorphic reconstruction technique and their mapped orientation distribution function images were averaged to generate the female- and male-DW-templates. The tract streamlines were generated through tractography for female and male templates and normalized to the total brain volume . The distributions of normalized tract lengths were significantly different between female- and male-templates and the female-template showed to have more longer normalized tracts compared to the male template. For the regional analysis, the templates were parcellated into sixteen regions of interests (ROI) including brain-stem, five subregions of corpus-callosum, and right and left hippocampus, thalamus, cerebellum white-matter (WM), cerebral WM, and cerebellum cortex using a FreeSurfer-based segmentation atlas. For all the ROIs, the average fractional anisotropy (0.5-5.7%) and normalized tract lengths (1.1-2.7%) were larger in female template while the average mean diffusion was larger (1.3-5.6%) in male-template. Quantifying brain connectivity by counting number of tracts passing through pairs of ROIs, showed more pairs with a higher connectivity in female-template, and one of the highest percentages of sex differences in right/left cerebellum WM/cortex connections. Our results reinforce the need to continue investigating the sex variations in axonal structure and their effects to brain trauma. 

he sex-based human brain structural variations alongside the necessity and development process for sex-specific brain templates were investigated in this study. Comparing magnetic resonance images of 500 female and 500 male subjects, no significant sex-based difference was observed for average cortical thickness, however, all the volumetric values, including the total brain volume (TBV) and major 19 brain regions, were found to be significantly different between females and males. Moreover, analyzing the fractional volume of the regions showed that these sex variations were not proportional to TBV for all regions. These findings underscore the importance of distinguishing the sex-based differences in human brain studies. While brain templates have been developed for general population and cohorts with the same characteristics such as race or age, there is a lack of sex-specific brain templates. To fill this gap and find a representative reference brain image for each sex, nonlinear templates were developed for female, male, and mixed population subjects. Next, a separate set of 109 female and 109 male brain images were used to evaluate the sex-specificity of the brain templates. It was observed that the female and male test subjects were registered to their sex-specific templates with the lowest amount of deformation/warping confirming better representativeness of the sex-specific templates for their target population. The findings of this study including the templates and the reported variations can be used in research involving sex dimorphic brain disorders, diseases, and/or injuries such as traumatic brain injury that is affected by the sex-based brain anatomical differences. Statement of significance: Human brain exhibits sex-based variation both in size and volumetric composition of different regions. Despite these differences, there is a paucity of sex-specific brain templates. Addressing this gap marks the significance of our study as briefly explained here. We have shown that differences in male and female brain go beyond simple scaling and the observation of regional differences that are not proportional to the sex-based total brain volume variations has motivated us to develop sex-specific templates. The representativeness and difference of these sex-specific templates were assessed by measuring the amount of required warping in nonlinear registration of test subjects to them. It was shown that registration of female and male subjects to their corresponding sex-specific template involved lower level of warping compared to their registration to their opposite sex or mixed population brain template.