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 older children), although it did not impact anxious-depressed symptoms. There were no significant sex effects on any of the above relationships. These findings confirm the importance of developmental timing on oestradiol-related effects and hint at the non-sexually dimorphic role of oestradiol-related cortico-amygdalar structural networks in aspects of cognition distinct from emotional processes.

Keywords: adolescence; cognition; oestrogen; puberty; structural covariance.

FIGURE 1.. Variation of estradiol levels by pubertal stage, sex and age.

Because of concerns concerning the unreliability of the ELISA assay at the lower limit of detection (LOD; 1*10^−5 ug/d), none of the LOD samples was included in our analyses. The minimum estradiol level in our restricted sample was 2.13 ug/dL, with the bulk of estradiol values between 5–20 ug/dL, for both boys and girls. Mean age per pubertal stage are indicated on the scale at the bottom of the figure. Most children matured from pubertal stages 1–3 between ages 10–15 years old and from pubertal stages 3–4 between 15–20 years old. For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.

FIGURE 2.. Age-related associations between estradiol, amygdala-frontal structural covariance and word identification.

Brain figures A (the amygdala is displayed in the dark shaded region) and B (cortical regions are displayed in dark shaded regions) show the brain regions involved in the significant ‘Estradiol*Amygdala*Age’ interaction, with a focus in this figure on the left pre-supplementary motor area and frontal eye field (Pre-SMA and FEF). In order to visualize the interactions between estradiol, age, cortico-amygdalar structural covariance and cognition, graphs display estradiol and cognitive scores as dichotomous groups and each child’s longitudinal structural covariance trajectory is not included. Y axis represents residuals for cortical thickness (averaged over the significant region of the left SMA/FEF). The bars represent the range of expected cortical thickness residuals for each age bracket (e.g. 7–9 years) based on the parameters obtained from the mixed effect model. Age brackets were restricted to the ages for which there were the greatest number of data points (approximately 95% of the data were collected between 7–17 years of age, though the full age range of the sample is 6–22 years old). Note: The data are presented categorically for visualization purposes, i.e. continuous measures of estradiol, age, cortical thickness, amygdalar volumes, and cognitive scores were used in all analyses. (Full statistics are provided in the Results, sections Estradiol-Related Cortico-Amygdalar Structural Covariance and Cortico-Amygdalar Structural Covariance and Cognition). Data from the left amygdala are shown; similar results were present for the right amygdala. The lower left panel shows the age-specific relationship between estradiol and amygdala-frontal structural covariance. Amygdala-frontal covariance switched from positive to negative with increasing age. Higher estradiol levels tended to diminish this age effect such that there was a decrease in positive covariance in younger children and a decrease in negative covariance in older children. The lower right panel shows the age-specific relationship between estradiol-related amygdala-frontal covariance and word identification. The amygdala-frontal covariance related to higher estradiol levels was associated with higher word identification scores across the age range examined.

FIGURE 3.. Age-related associations between estradiol, amygdala-posterior cingulate structural covariance and reading comprehension.

Brain figures A (the amygdala is displayed in the dark shaded region) and B (cortical regions of interest are displayed in dark shaded regions) show the brain regions involved in the significant ‘Estradiol*Amygdala*Age’ interaction, with a focus in this figure on the left posterior cingulate cortex. Similar to Figure 2, modifications were made to the data in order to visualize the interactions between estradiol, age, cortico-amygdalar covariance and cognition (see Figure 2 caption for more details). The graph shown in the lower left panel shows the age-specific relationship between estradiol and amygdala-posterior cingulate structural covariance. Amygdala-cingulate covariance switched from a positive to a negative relationship with age (from younger to older children). Higher estradiol levels enhanced this age effect in younger children, such that there was an increase in positive covariance, and diminished this effect in older children, with a decrease in negative covariance. The graph shown in the lower right panel shows the age-specific relationship between estradiol-related amygdala-posterior cingulate covariance and reading comprehension. The amygdala-cingulate covariance related to higher estradiol levels was associated with higher reading comprehension scores in older children, but this effect was reversed in younger children.

FIGURE 4.. Age-related associations between estradiol, amygdala-retrosplenial structural covariance and spatial working memory.

Brain figures A (the amygdala is displayed in the dark shaded region) and B (cortical regions of interest are displayed in dark shaded regions) show the brain regions involved in the significant ‘Estradiol*Amygdala*Age’ interaction, with a focus in this figure on the left retrosplenial cortex. Similar to Figure 2, modifications were made to the data in order to visualize the interactions between estradiol, age, cortico-amygdalar covariance and cognition (see Figure 2 legend for more details). The graph in the lower left panel shows the age-specific relationship between estradiol and amygdala-retrosplenial structural covariance. Amygdala-retrosplenial covariance switched from a positive to a negative relationship with age (from younger to older children). Higher estradiol levels diminished this age effect (such that there was a decrease in positive covariance in younger children, and a decrease in negative covariance in older children). The graph in the lower right panel shows the age-specific relationship between estradiol-related amygdala-retrosplenial covariance and spatial working memory. The amygdala-retrosplenial covariance related to higher estradiol levels was associated with higher spatial working memory scores across the age range examined.

FIGURE 5.. Age-related differences in cortico-amygdalar structural covariance mediate the developmental relationship between estradiol and cognition.

The beta coefficients and standard errors are displayed on the left, for the age-specific relationships between estradiol and cortico-amygdalar covariance, and on the right, for the age-specific relationship between cortico-amygdalar covariance and cognition. Test statistics and p-values for the formal Sobel-Goodman mediation tests are displayed in the bottom right table. Data from the left amygdala are shown; similar results were present for the right amygdala. AG: Amygdala