Summary: Analysis of more than 2,000 human brain scans identified reproducible sex differences in regional cortical volume. On average, females showed relatively greater volume in medial and lateral prefrontal, orbitofrontal, superior temporal, and lateral parietal cortices, while males showed greater volume in ventral temporal and occipital regions. Cross-referencing with gene-expression maps points to a potential contribution of sex-chromosome genes.
Source: NIH/NIMH
Researchers at the National Institute of Mental Health (NIMH) analyzed neuroimaging and gene-expression data to identify consistent sex differences in human brain anatomy. The study, published in Proceedings of the National Academy of Sciences (PNAS), combines high-resolution imaging from large cohorts with postmortem cortical gene-expression maps to explore whether sex chromosomes may help explain anatomical differences between males and females.
Understanding how male and female brains differ in structure is important for interpreting established differences in cognition, behavior, and risk for psychiatric disorders. To close the gap between recent animal-model discoveries and human brain studies, the research team led by Armin Raznahan, M.D., Ph.D., and lead author Siyuan Liu, Ph.D., examined imaging datasets and gene-expression atlases to test the reproducibility and biological correlates of sex-based anatomical patterns.
Previous animal studies have long reported sex differences in subcortical regions and have often favored hormone-based explanations for those differences. More recent work in mice, however, has revealed reproducible sex differences across cortical areas and has pointed to a possible role for genes on the X and Y chromosomes. Because the human brain shares many organizational features with the mouse brain, the NIMH team set out to determine whether similar cortical sex differences and genetic associations appear in people.
The investigators first used neuroimaging data from the Human Connectome Project (HCP), analyzing scans from 976 healthy adults aged 22 to 35. These analyses revealed a reliable spatial pattern of sex differences in cortical volume. On average, females exhibited relatively greater cortical volume in medial and lateral prefrontal cortex, orbitofrontal cortex, superior temporal cortex, and lateral parietal cortex. In contrast, males on average showed relatively larger volume in ventral temporal and occipital regions, including the temporal pole, fusiform gyrus, and primary visual cortex.
To test the stability of these findings, the researchers applied two complementary reproducibility checks. First, they performed 1,000 split-half tests by randomly dividing the HCP dataset and comparing results across halves. Those split-half comparisons showed the pattern of sex differences was highly stable across samples. Second, they assessed whether the same anatomical pattern appeared in an independent dataset from the UK Biobank. Despite demographic and methodological differences between the datasets, the overall map of sex-based cortical volume differences replicated robustly in the UK Biobank data.
Next, the team compared the anatomical maps with publicly available gene-expression maps derived from 1,317 postmortem cortical tissue samples collected from six donors. This cross-reference revealed a notable spatial correspondence: cortical regions with relatively high expression of sex-chromosome genes tended to show greater volume in males. In other words, the regional pattern of sex differences in cortical volume aligned with the cortical distribution of genes located on the X and Y chromosomes.
This correspondence supports the idea that sex-chromosome gene expression may contribute to anatomical sex differences in the cortex, complementing evidence from animal models and suggesting some genetic mechanisms have been conserved across mammals. While environmental and hormonal factors also influence brain development, the reproducible anatomical patterns and their link to sex-chromosome expression indicate that genetics likely play a meaningful role.
The researchers also compared their anatomical results with meta-analytic data from more than 11,000 functional neuroimaging studies. That comparison showed spatial overlap between cortical areas with sex-based volume differences and regions implicated in face processing in functional imaging literature, suggesting potential functional relevance for the observed anatomical variation.
Taken together, the study offers a reproducible map of sex differences in human cortical anatomy and a correlational bridge to sex-chromosome gene expression. These findings provide a roadmap for future work aimed at unpacking the biological mechanisms and behavioral consequences of sex-based brain differences, and they highlight genetic factors as promising targets for follow-up investigations.
About this brain anatomy research article
Source:
NIH/NIMH
Media Contacts:
Anna Mikulak – NIH/NIMH
Image Source:
The image is in the public domain.
Original Research: The study will appear in PNAS.