Sex Differences in the Adult Human Brain: Evidence from 5216 UK Biobank Participants

Abstract

Sex differences in the human brain are of interest for many reasons: for example, there are sex differences in the observed prevalence of psychiatric disorders and in some psychological traits that brain differences might help to explain. We report the largest single-sample study of structural and functional sex differences in the human brain (2750 female, 2466 male participants; mean age 61.7 years, range 44-77 years). Males had higher raw volumes, raw surface areas, and white matter fractional anisotropy; females had higher raw cortical thickness and higher white matter tract complexity. There was considerable distributional overlap between the sexes. Subregional differences were not fully attributable to differences in total volume, total surface area, mean cortical thickness, or height. There was generally greater male variance across the raw structural measures. Functional connectome organization showed stronger connectivity for males in unimodal sensorimotor cortices, and stronger connectivity for females in the default mode network. This large-scale study provides a foundation for attempts to understand the causes and consequences of sex differences in adult brain structure and function.

Figure 1.

Density plots of sex differences in overall brain volumes (left section) and subcortical structures (right section). d = Cohen’s d (mean difference); VR = Variance Ratio (variance difference). All mean differences were statistically significant at P < 3.0 × 10⁻²⁵, all variance differences were significant at P < .003, after correction for multiple comparisons (see Table 1).

Figure 2.

Sex differences across the subregions in volume, surface area, and cortical thickness. Shown are (A) mean differences, (B) mean differences adjusted for total brain volume, total surface area, and mean cortical thickness (respectively by column); and (C) variance differences. Adjusted variance differences were near-identical to those shown in (C); see Figure S5. See Figure S3 for subregional atlas.

Figure 3.

Mean sex differences in white matter microstructural measures (A) fractional anisotropy and (B) orientation dispersion across 22 white matter tracts. For both measures, numerically the largest effect was found in the right cortico-spinal tract. See Figure S4 for tract atlas.

Figure 4.

Percentage of the sex-cognitive relation mediated by each of the brain regions selected in a LASSO model to be linked to either verbal-numerical reasoning (left column) or reaction time (right column). Results for volume, surface area, and cortical thickness are shown in each row. Regions were averaged across the hemispheres; thus only a medial and lateral view for each measure and each cognitive test is shown.

Figure 5.

Results for resting-state fMRI connectivity and weighted degree of nodes. (A) Spatial maps for individual connections. Colors and line thickness represent the effect sizes of sex on the strength of connections (red = stronger in females; blue = stronger in males; darker/thicker = larger effect size). Only effect sizes (Cohen’s d) larger than ±0.2 are shown. Nodes were clustered into 5 categories using FSLnets based on their group-mean full-correlation matrix (yellow/orange: sensorimotor network; red: default mode network; purple: salience network and executive control network; green: dorsal attention network; blue: visual network). (B) and (C) Weighted degrees of nodes with higher values in males and females, respectively. The spatial maps of significant group-ICA nodes were multiplied by the effect size of the sex correlation. In order to show the regions with the largest associations with sex, only regions that had intensity over 50% of the whole-brain peak value are presented. See Table S14 for values for each connection and for each node’s weighed degree.