Sex differences in the developing brain: insights from multimodal neuroimaging

Abstract

Youth (including both childhood and adolescence) is a period when the brain undergoes dramatic remodeling and is also a time when neuropsychiatric conditions often emerge. Many of these illnesses have substantial sex differences in prevalence, suggesting that sex differences in brain development may underlie differential risk for psychiatric symptoms between males and females. Substantial evidence documents sex differences in brain structure and function in adults, and accumulating data suggests that these sex differences may be present or emerge during development. Here we review the evidence for sex differences in brain structure, white matter organization, and perfusion during development. We then use these normative differences as a framework to understand sex differences in brain development associated with psychopathology. In particular, we focus on sex differences in the brain as they relate to anxiety, depression, psychosis, and attention-deficit/hyperactivity symptoms. Finally, we highlight existing limitations, gaps in knowledge, and fertile avenues for future research.

Fig. 1

Female youth generally show smaller volumes than male youth (uncorrected for total brain size) while males show greater variability in brain volumes than females. a Sex differences in cortical volumes depend on the complex interaction between cortical thickness, convex hull area, and gyrification (adapted with permission from ref. [27]). b Male youth show greater gray matter volume (GMV) and gray matter mass (GMM) than female youth, where GMM = GMV × GMD. Brain maps indicate the percentage net change explained by sex (adapted with permission from ref. [21]). c Males show greater brain volume variance than females across multiple structures (adapted with permission from ref. [48])

Fig. 2

Developmental sex differences in gray matter density. a Although gray matter density is similar at age 8 in males and females, gray matter density increases more rapidly in females than males throughout adolescence. This differential rate of development results in females having higher gray matter density across the entire brain. b Sex differences vary with age, with males and females showing no differences at 8 years of age. Females then began to show greater gray matter density across many regions soon thereafter. All data adapted with permission from ref. [21]

Fig. 3

Sex differences in cortical thickness in youth vary depending on brain region. a Global cortical thickness decreases over the developmental age range in both male and female youth (adapted with permission from ref. [21]). b Age-related changes in cortical thickness within structural covariance networks vary substantially between males and females. For example, males display thicker parietal cortex at younger ages, but nearly equivalent cortex by adulthood (adapted with permission from ref. [60]). c In a study spanning the lifespan from 7 to 87 years, cortical thickness evolved differently with age in males and females (adapted with permission from ref. [15])

Fig. 4

Males show higher fractional anisotropy and lower mean diffusivity than females. a Best fit curves for fractional anisotropy (FA) and mean diffusivity (MD) by age reveal that FA increases with age until adulthood and then declines thereafter, while MD decreases during development and then begins to increase later in life (adapted with permission from ref. [73]). b Male youth show higher fractional anisotropy and lower mean diffusivity than females in key regions (adapted with permission from ref. [80])

Fig. 5

Cerebral blood flow (CBF) shows marked developmental sex differences. a CBF declines in males (blue) until late adolescence, while CBF in females (pink) declines until mid-adolescence and then increases thereafter. b Age-related differences in CBF diverge in males (blue) and females (pink) with advancing pubertal development (a and b adapted with permission from ref. [92]). c Higher anxious-misery symptoms in post-pubertal females are  mediated in part by higher perfusion in the left amygdala (adapted with permission from ref. [120])