Age‐specific associations between oestradiol, cortico‐amygdalar structural covariance, and verbal and spatial skills

Abstract

Oestradiol is known to play an important role in the developing human brain, although little is known about the entire network of potential regions that might be affected and how these effects may vary from childhood to early adulthood, which in turn can explain sexually differentiated behaviours. In the present study, we examined the relationships between oestradiol, cortico-amygdalar structural covariance, and cognitive or behavioural measures typically showing sex differences (verbal/spatial skills, anxious-depressed symptomatology) in 152 children and adolescents (aged 6-22 years). Cortico-amygdalar structural covariance shifted from positive to negative across the age range. Oestradiol was found to diminish the impact of age on cortico-amygdalar covariance for the pre-supplementary motor area/frontal eye field and retrosplenial cortex (across the age range), as well as for the posterior cingulate cortex (in older children). Moreover, the influence of oestradiol on age-related cortico-amygdalar networks was associated with higher word identification and spatial working memory (across the age range), as well as higher reading comprehension (in 2 of 18 | NGUYEN Et al. | INTRODUC TI ONThe amygdala and cortex undergo significant structural changes during critical developmental periods when there is a rise in steroid hormones, such as the prenatal and pubertal periods. In particular, endocrine disruption related to prenatal stress may influence amygdalar volumetric properties, 1,2 as well as alter behavioural outcomes such as aggression levels. 3 Many steroid hormones may play an important role in brain development during these developmental periods, including but not limited to oestrogens, androgens and corticosteroids. 4 In the present study, we focus on the effects associated with the most potent oestrogenic hormone, 17β-oestradiol, during the transition from childhood to young adulthood. 5 The amygdala appears to exhibit significant oestradiol-related growth and sex differentiation during the pubertal and postpubertal periods in animal models, 6,7 and structural brain studies in human amygdalar volumes are related to oestradiol levels during puberty. 8 In addition to this role in modulating the structure of the amygdala, oestradiol is considered to play a key role in sex-specific corticogenesis. 9 For example, cortical decreases in gray matter volume have been associated with increasing oestradiol levels across adolescence. 8 These effects of oestradiol on brain structure appear to play an important functional role, particularly during puberty. 5,10 Structural covariance is one way of examining how different brain regions may follow similar developmental trajectories. The extent to which morphology in one brain region correlates with the morphology in other brain regions (ie, covariance patterns) is considered to reflect underlying anatomical connectivity, 31,32 as well as functional changes in brain networks. 2,3 Cortical thickness (CTh) is a component of cortical volume and, compared to the latter, is assume...

Role of testosterone: cortisol ratio in age- and sex-specific cortico-hippocampal development and cognitive performance

“…We previously observed similar age-related variation in the effects of estradiol on brain structure and cognitive performance, linking estradiol, PCC-amygdalar covariance, and visual attention (letter-word identification). 54 These results provide further evidence that the polymorphic effects of testosterone on cognition are composed of both direct (activation of androgen receptors and effects on cortico-hippocampal development) and indirect effects (conversion to estradiol, activation of estradiol receptors, and effects on cortico-amydalar development). 12,15,43,54 We also document sex-specific contributions of TC ratio to prefrontal-hippocampal development.…”

“…54 These results provide further evidence that the polymorphic effects of testosterone on cognition are composed of both direct (activation of androgen receptors and effects on cortico-hippocampal development) and indirect effects (conversion to estradiol, activation of estradiol receptors, and effects on cortico-amydalar development). 12,15,43,54 We also document sex-specific contributions of TC ratio to prefrontal-hippocampal development. However, sex differences in brain structure as a function of TC ratio did not result in sex differences in cognition in our study.…”