Sex-differences in brain multimodal estimates of white matter microstructure during early adolescence: Sex-specific associations with biological factors

Adolescence is marked by significant maturation of brain white matter microstructure, with evidence for sex-specific maturational trajectory. Most studies have examined conventional diffusion tensor imaging (DTI) metrics, which lack specificity to the underlying tissue modifications. In this study, we characterized sex-differences in white matter microstructure cross-sectionally using DTI, advanced diffusion spectrum imaging (DSI) and diffusion kurtosis imaging (DKI), as well as the white matter tract integrity-Watson (WMTI-W) biophysical model. We also aimed to explore the effect of age and biological systems undergoing sex-specific changes during adolescence, namely pubertal hormones, hypothalamic-pituitary-adrenal (HPA)-axis function, and glutathione-redox cycle homeostasis. The results indicate widespread sex-differences in all the white matter derived metrics, suggesting more advanced maturation in females compared to males as well as distinct tissue modifications underlying white matter maturation between males and females during this narrow developmental period. Additionally, the three biological factors explored appeared to be associated with indices of white matter maturation in females specifically, emphasizing this period as critical in female white matter development and sensitivity to environmental factors.