NIH study shows highly reproducible sex differences in aspects of human brain anatomy
Monday July 20, 2020
Gene expression data suggest a potential role for sex chromosomes.
Scientific analysis of more than 2,000 brain scans has shown highly reproducible sex differences in the volume of certain regions of the human brain. This pattern of sex-based brain volume differences matches patterns of sex chromosome gene expression seen in postmortem samples from the cerebral cortex, suggesting that sex chromosomes may play a role in the development or maintenance of the differences. sex in brain anatomy. The study, led by researchers at the National Institute of Mental Health (NIMH), part of the National Institutes of Health, is published in Proceedings of the National Academy of Sciences.
“Developing a clearer understanding of gender differences in the organization of the human brain is of great importance for how we think about established sex. differences in cognition, behavior and risk of psychiatric illness. We were inspired by new findings on sex differences in animal models and wanted to try to bridge the gap between this animal data and our models of sex differences in the human brain, ”said Armin Raznahan, MD, Ph.D. ., co-study. author and head of the NIMH Section on Developmental Neurogenomics.
Researchers have long observed consistent gender-based differences in subcortical brain structures in mice. Some studies have suggested that these anatomical differences are largely due to the effects of sex hormones, which lends weight to a “gonad-centered” explanation for sex differences in brain development. However, more recent studies in mice have also revealed consistent sex differences in cortical structures, and gene expression data suggests that sex chromosomes may play a role in forming these anatomical sex differences. Although the mouse brain shares many similarities with the human brain, it is not clear whether these key findings in mice apply to humans as well.
To explore the neurobiological basis of sex differences in the human brain, Raznahan, lead author Siyuan Liu, Ph.D., and colleagues first analyzed neuroimaging data collected as part of the Human Connectome Project (HCP). The data, obtained from 976 healthy adults aged 22 to 35, revealed consistent sex differences in the volume of certain cortical structures. On average, females had relatively larger cortical volume in the medial and lateral prefrontal cortex, orbitofrontal cortex, superior temporal cortex, and lateral parietal cortex. Males, on average, had relatively larger cortical volume in the ventral temporal regions and occipital regions, including the temporal pole, fusiform gyrus, and primary visual cortex.
Liu and his colleagues then used two complementary approaches to determine if these results were reproducible. First, the researchers performed 1,000 half comparisons by randomly dividing the HCP data set in half and comparing the results of the two halves. The results of these two-part comparisons indicated that the pattern of cortical volume differences by sex was very stable. Second, the researchers quantified the reproducibility of the HCP results in an unrelated neuroimaging dataset from UK Biobank. Although the data sets had notable demographic and methodological differences, the researchers found that the overall pattern of gender-based cortical volume differences was very consistent.
Liu and his co-authors then crossed their anatomical findings with publicly available brain gene expression maps, which are based on 1,317 postmortem tissue samples from six human donors. The results indicated that the spatial pattern of sex differences in cortical volume was similar to the spatial pattern of expression of sex chromosome genes in the cortex. Specifically, regions of the cortex with relatively high expression of sex chromosome genes tended to have greater cortical volume in males than in females.
This correspondence with cortical expression of sex chromosome genes is also consistent with results from previous studies in mice, suggesting that sex differences in brain anatomy may be due, at least in part, to genetic mechanisms. which have been preserved throughout mammalian evolution. These results suggest that sex differences in cortical volume may be influenced by genes located on the X and Y sex chromosomes.
“Men and women differ on many genetic and environmental factors, all of which could potentially influence brain development. Because it is difficult to experiment in humans, we often rely on observational data to infer potential genetic or environmental factors for brain sex. differences, ”said Raznahan. “The fact that we observed a very high level of reproducibility of the anatomical sex differences between different groups of men and women, and a link between these differences and gender expression of chromosomal genes, suggests that these differences are probably not primarily the result of environmental effects alone.
The researchers also compared the anatomical findings with data from more than 11,000 functional neuroimaging studies. The results indicated a spatial overlap between areas of the brain that exhibited gender differences in cortical volume in the HCP data set and areas of the brain associated with facial processing in functional neuroimaging studies.
Taken together, these findings shed light on mechanisms that may contribute to gender-based differences in brain anatomy and highlight genetic factors that may contribute to gender-based differences in brain disease and behavior. With these correlational findings as a roadmap, future research can more effectively study the causes and consequences of sex differences in the human brain.
Clinical test: NCT00001246
About the National Institute of Mental Health (NIMH): NIMH’s mission is to transform the understanding and treatment of mental illness through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.
About the National Institutes of Health (NIH):The NIH, the national agency for medical research, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the principal federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit www.nih.gov.
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Liu, S., Seidlitz, J., Blumenthal, JD, Clasen, LS and Raznahan, A. (2020). Structural, functional and integrative transcriptomic analyzes of the sexual brain organization in humans. Proceedings of the National Academy of Sciences. doi: 10.1073 / pnase.1919091117