White matter microstructure shows sex differences in late childhood: Evidence from 6797 children

Abstract

Sex differences in white matter microstructure have been robustly demonstrated in the adult brain using both conventional and advanced diffusion-weighted magnetic resonance imaging approaches. However, sex differences in white matter microstructure prior to adulthood remain poorly understood; previous developmental work focused on conventional microstructure metrics and yielded mixed results. Here, we rigorously characterized sex differences in white matter microstructure among over 6000 children from the Adolescent Brain Cognitive Development study who were between 9 and 10 years old. Microstructure was quantified using both the conventional model-diffusion tensor imaging (DTI)-and an advanced model, restriction spectrum imaging (RSI). DTI metrics included fractional anisotropy (FA) and mean, axial, and radial diffusivity (MD, AD, RD). RSI metrics included normalized isotropic, directional, and total intracellular diffusion (N0, ND, NT). We found significant and replicable sex differences in DTI or RSI microstructure metrics in every white matter region examined across the brain. Sex differences in FA were regionally specific. Across white matter regions, boys exhibited greater MD, AD, and RD than girls, on average. Girls displayed increased N0, ND, and NT compared to boys, on average, suggesting greater cell and neurite density in girls. Together, these robust and replicable findings provide an important foundation for understanding sex differences in health and disease.

Keywords: development; diffusion tensor imaging; diffusion-weighted MRI; microstructure; restriction spectrum imaging; sex differences; white matter.

FIGURE 1

Sex differences in white matter microstructure. The effect size, significance, and replicability of sex differences in DTI and RSI metrics are depicted separately for the discovery cohort (left) and replication cohort (right) for (a) bilateral white matter tract ROIs, (b) left hemisphere white matter tract ROIs, and (c) right hemisphere white matter tract ROIs; commissural tracts are included in the left and right hemisphere graphs for completeness only. Positive standardized betas indicate girls > boys, and negative standardized betas indicate boys > girls. DTI metrics are depicted in warm colors, and RSI metrics in cool colors. Filled circles indicate the association was both significant in the discovery cohort after FDR correction across the number of ROIs (q < 0.05) and demonstrated p < .05 in the replication cohort. Diffusion‐weighted MRI abbreviations: AD, axial diffusivity; dMRI, diffusion‐weighted MRI; DTI, diffusion tensor imaging; FA, fractional anisotropy; MD, mean diffusivity; N0, normalized isotropic diff; ND, normalized directional diffusion; NT, normalized total diffusion; RD, radial diffusivity; ROI, region of interest; RSI, restriction spectrum imaging. White matter tract ROI abbreviations: ATR, anterior thalamic radiation; CC, corpus callosum; CGC, cingulum (cingulate); CGH, cingulum (parahippocampal); CST, corticospinal/pyramidal tract; Fmaj, forceps major; Fmin, forceps minor; fSCS, superior corticostriate (frontal cortex); FX, fornix; FXcut, fornix (excluding fimbria); IFO, inferior fronto‐occipital fasciculus; IFSFC, inferior frontal superior frontal cortex; ILF, inferior longitudinal fasciculus; pSCS, superior corticostriate (parietal cortex); pSLF, superior longitudinal fasciculus (parietal); SCS, superior corticostriate; SIFC, striatal inferior frontal cortex; SLF, superior longitudinal fasciculus; tSLF, superior longitudinal fasciculus (temporal); UNC, uncinate fasciculus

FIGURE 2

Sex differences in white matter microstructure, controlling for pubertal development. The effect size, significance, and replicability of sex differences in DTI and RSI metrics are depicted separately for the discovery cohort (left) and replication cohort (right) for bilateral white matter tract ROIs. Positive standardized betas indicate girls > boys, and negative standardized betas indicate boys > girls. DTI metrics are depicted in warm colors, and RSI metrics in cool colors. Filled circles indicate the association was both significant in the discovery cohort after FDR correction across the number of ROIs (q < 0.05) and demonstrated p < .05 in the replication cohort. Diffusion‐weighted MRI abbreviations: AD, axial diffusivity; dMRI, diffusion‐weighted MRI; DTI, diffusion tensor imaging; FA, fractional anisotropy; MD, mean diffusivity; N0, normalized isotropic diffusion; ND, normalized directional diffusion; NT, normalized total diffusion; RD, radial diffusivity; ROI, region of interest; RSI, restriction spectrum imaging. White matter tract ROI abbreviations: ATR, anterior thalamic radiation; CC, corpus callosum; CGC, cingulum (cingulate); CGH, cingulum (parahippocampal); CST, corticospinal/pyramidal tract; Fmaj, forceps major; Fmin, forceps minor; fSCS, superior corticostriate (frontal cortex); FX, fornix; FXcut, fornix (excluding fimbria); IFO, inferior fronto‐occipital fasciculus; IFSFC, inferior frontal superior frontal cortex; ILF, inferior longitudinal fasciculus; pSCS, superior corticostriate (parietal cortex); pSLF, superior longitudinal fasciculus (parietal); SCS, superior corticostriate; SIFC, striatal inferior frontal cortex; SLF, superior longitudinal fasciculus; tSLF, superior longitudinal fasciculus (temporal); UNC, uncinate fasciculus

FIGURE 3

Sex differences in white matter microstructure, controlling for dimensional externalizing and internalizing problems. The effect size, significance, and replicability of sex differences in DTI and RSI metrics are depicted separately for the discovery cohort (left) and replication cohort (right) for bilateral white matter tract ROIs when controlling for (a) dimensional externalizing problems and (b) dimensional internalizing problems. Positive standardized betas indicate girls > boys, and negative standardized betas indicate boys > girls. DTI metrics are depicted in warm colors, and RSI metrics in cool colors. Filled circles indicate the association was both significant in the discovery cohort after FDR correction across the number of ROIs (q < 0.05) and demonstrated p < .05 in the replication cohort. Diffusion‐weighted MRI abbreviations: AD, axial diffusivity; dMRI, diffusion‐weighted MRI; DTI, diffusion tensor imaging; FA, fractional anisotropy; MD, mean diffusivity; N0, normalized isotropic diffusion; ND, normalized directional diffusion; NT, normalized total diffusion; RD, radial diffusivity; ROI, region of interest; RSI, restriction spectrum imaging. White matter tract ROI abbreviations: ATR, anterior thalamic radiation; CC, corpus callosum; CGC, cingulum (cingulate); CGH, cingulum (parahippocampal); CST, corticospinal/pyramidal tract; Fmaj, forceps major; Fmin, forceps minor; fSCS, superior corticostriate (frontal cortex); FX, fornix; FXcut, fornix (excluding fimbria); IFO, inferior fronto‐occipital fasciculus; IFSFC, inferior frontal superior frontal cortex; ILF, inferior longitudinal fasciculus; pSCS, superior corticostriate (parietal cortex); pSLF, superior longitudinal fasciculus (parietal); SCS, superior corticostriate; SIFC, striatal inferior frontal cortex; SLF, superior longitudinal fasciculus; tSLF, superior longitudinal fasciculus (temporal); UNC, uncinate fasciculus