Sex differences in the neural substrates of spatial working memory during adolescence are not mediated by endogenous testosterone

Abstract

Adolescence is a developmental period characterized by notable changes in behavior, physical attributes, and an increase in endogenous sex steroid hormones, which may impact cognitive functioning. Moreover, sex differences in brain structure are present, leading to differences in neural function and cognition. Here, we examine sex differences in performance and blood oxygen level-dependent (BOLD) activation in a sample of adolescents during a spatial working memory (SWM) task. We also examine whether endogenous testosterone levels mediate differential brain activity between the sexes. Adolescents between ages 10 and 16 years completed a SWM functional magnetic resonance imaging (fMRI) task, and serum hormone levels were assessed within seven days of scanning. While there were no sex differences in task performance (accuracy and reaction time), differences in BOLD response between girls and boys emerged, with girls deactivating brain regions in the default mode network and boys showing increased response in SWM-related brain regions of the frontal cortex. These results suggest that adolescent boys and girls adopted distinct neural strategies, while maintaining spatial cognitive strategies that facilitated comparable cognitive performance of a SWM task. A nonparametric bootstrapping procedure revealed that testosterone did not mediate sex-specific brain activity, suggesting that sex differences in BOLD activation during SWM may be better explained by other factors, such as early organizational effects of sex steroids or environmental influences. Elucidating sex differences in neural function and the influence of gonadal hormones can serve as a basis of comparison for understanding sexually dimorphic neurodevelopment and inform sex-specific psychopathology that emerges in adolescence.

Keywords: Adolescence; Sex differences; Spatial working memory; Testosterone; fMRI.

Fig. 1

Statistical maps of female (left) and male (right) percent BOLD activation in spatial working memory - vigilance (SWM-Vig) contrast overlaid on a standard Talairach template. For visualization, both maps were voxel thresholded at p < .001.

Fig. 2

Statistical map of sex differences in percent BOLD activation in spatial working memory - vigilance (SWM-Vig) contrast (controlling for age and pubertal developmental status) overlaid on a standard Talairach template. In all significant clusters (p < .01 voxel and α < .05 cluster correction) including bilateral inferior frontal gyrus/anterior insula, rostral anterior cingulate cortex, precuneus, right middle frontal gyrus, left dorsolateral prefrontal cortex, and right middle temporal gyrus, boys show increased activation (blue) relative to girls.

Fig. 3

Default mode network-related brain activity patterns during spatial working memory and vigilance trials. Percent BOLD signal plotted against trial type: vigilance (Vig), spatial working memory (SWM), and SWM-Vig, including standard error of the mean. Boys are represented in light grey and girls in dark grey. BOLD percent signal change in right rostral anterior cingulate cortex, right middle temporal gyrus, right precuneus, and right middle frontal gyrus is depicted. Percent BOLD signal change refers to BOLD activity changes from baseline activation. Asterisks denote significant at p < .05.

Fig. 4

Cognitive control-related brain activity patterns during spatial working memory and vigilance trials. Percent BOLD signal plotted against trial type: vigilance (Vig), spatial working memory (SWM), and SWM-Vig, including standard error of the mean. Boys are represented in light grey and girls in dark grey. BOLD percent signal change in left dorsolateral prefrontal cortex, right inferior frontal gyrus/anterior insula, and left inferior frontal gyrus/anterior insula is depicted. Right and left inferior frontal gyrus/anterior insula clusters were further divided into inferior frontal gyrus and anterior insula components, and the corresponding percent BOLD signal is represented as right anterior insula, right inferior frontal gyrus, left anterior insula, and left inferior frontal gyrus. Percent BOLD signal change refers to BOLD activity changes from baseline activation. Asterisks denote significant at p < .05.

Fig. 5

Spatial working memory (SWM) and vigilance conditions were included in the fMRI analysis. In SWM trials, participants were instructed to press a button each time a letter appeared in the same location two letters prior, regardless of the letter. During vigilance trials, participants were asked to press a button any time a gray dot appeared on the screen.