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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.
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This content will become publicly available on June 11, 2026
Sex and the Riddle of Variability
Scientific research associations, funders, and publishers have recently introduced sex inclusion mandates requiring the use of male and female specimens in preclinical research designs and the analysis and reporting of data disaggregated by sex. However, it is not necessarily a simple matter to incorporate males and females in the same study design with the aim of detecting differences between them while following best practices for rigorous inference in laboratory science using model organisms. For example, if there are ways in which male and female variability might differ for the trait or procedure of interest, principles of sound experimental design may require larger numbers of organisms and observations to make valid inferences about the presence of a sex difference. This paper analyzes a current scientific debate over differences in variability between male and female laboratory rodents, and specifically over whether potential sources of sex-specific variability such as the estrous cycle, group housing, and body size constitute components of sex that should be measured. The variability debate surfaces the trade-offs between constructs of sex difference and similarity that face scientific researchers attempting to meet mandates to include both males and females in research design and report sex-specific results. This riddle of variability illuminates how laboratory researchers using model organisms must make contextual choices (Richardson 2022) at multiple decision points in order to stabilize sex as a biological variable in a particular research design. These judgments are informed by social and epistemic values and carry consequences for the validity, precision, and generalizability of claims of biological sex differences derived from preclinical research models.
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- Award ID(s):
- 2341785
- PAR ID:
- 10642024
- Publisher / Repository:
- University of Michigan
- Date Published:
- Journal Name:
- Philosophy, Theory, and Practice in Biology
- Volume:
- 17
- Issue:
- 1
- ISSN:
- 2475-3025
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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