Dehydroepiandrosterone impacts working memory by shaping cortico-hippocampal structural covariance during development

Abstract

Existing studies suggest that dehydroepiandrosterone (DHEA) may be important for human brain development and cognition. For example, molecular studies have hinted at the critical role of DHEA in enhancing brain plasticity. Studies of human brain development also support the notion that DHEA is involved in preserving cortical plasticity. Further, some, though not all, studies show that DHEA administration may lead to improvements in working memory in adults. Yet these findings remain limited by an incomplete understanding of the specific neuroanatomical mechanisms through which DHEA may impact the CNS during development. Here we examined associations between DHEA, cortico-hippocampal structural covariance, and working memory (216 participants [female=123], age range 6–22 years old, mean age: 13.6 +/−3.6 years, each followed for a maximum of 3 visits over the course of 4 years). In addition to administering performance-based, spatial working memory tests to these children, we also collected ecological, parent ratings of working memory in everyday situations. We found that increasingly higher DHEA levels were associated with a shift toward positive insular-hippocampal and occipito-hippocampal structural covariance. In turn, DHEA-related insular-hippocampal covariance was associated with lower spatial working memory but higher overall working memory as measured by the ecological parent ratings. Taken together with previous research, these results support the hypothesis that DHEA may optimize cortical functions related to general attentional and working memory processes, but impair the development of bottom-up, hippocampal-to-cortical connections, resulting in impaired encoding of spatial cues.

Sex‐specific contribution of DHEA‐cortisol ratio to prefrontal‐hippocampal structural development, cognitive abilities and personality traits

“…Specific decreases in verbal memory have already been reported in children exposed to high‐dose corticosteroids, and there is some evidence indicating that, at least in adults, these toxic effects may extend to other types of memories such as episodic autobiographical memories . By contrast, there is evidence from our group that endogenous DHEA levels in children and adolescents may be associated with better visual attention and working memory via cortico‐amygdalar and cortico‐hippocampal alterations and that higher DHEA or DHEA‐S levels may predict better working memory, attention and verbal fluency in women but not in men . In the present study, we find that DC ratio was associated with alterations in ACC‐hippocampal covariance that were in turn related to enhanced verbal immediate recall and calculation abilities.…”

“…Second, as previously postulated by our group, the effect of DHEA on the brain is complex and may both be beneficial and detrimental depending on the context as well as the specific genetic/environmental factors that may influence a child's development. For example, DHEA may improve both attention and overall working memory during development by decreasing the influence of amygdalar and hippocampal afferents on cortical functions, such that DHEA may inhibit amygdalar‐based functions (eg, the detection of emotional stimuli), and hippocampal‐based functions (eg, encoding and processing of spatial and social cues).…”

“…Finally, DHEA and cortisol were also found to alter performance on a difficult mathematical task, with DHEA playing a more important and beneficial role than cortisol in this regard . Despite these demonstrated associations between DC (or CD) ratios and sexually dimorphic cognitive/behavioural measures, prior studies from our group have not demonstrated sex differences in cortico‐hippocampal or cortico‐amygdalar structural variance related to DHEA in humans . Therefore, it remains unclear to what extent DC‐related alterations in structural covariance would lead to a sex‐specific difference in behaviour or cognition, and this has not been formally tested up to now.…”

“…Still, when taken together, these studies suggest that certain anatomical and functional brain circuits are regulated by DHEA and cortisol, in particular the cortico‐hippocampal and cortico‐amygdalar networks, and that these circuits may, at least in part, contribute to the development of sex differences in cognition and behaviour. For example, we found that DHEA may optimise cortical functions related to general attentional and working memory processes but impair the development of bottom‐up, hippocampal‐to‐cortical connections, resulting in impaired encoding of spatial, and possibly even social, cues …”

“…Although our group previously documented the relationship between DHEA levels and cortico‐hippocampal structural covariance, there are no prior studies, to our knowledge, examining the relationship between cortisol and cortico‐hippocampal covariance. As such, our hypotheses focus on DC ratio ‐as opposed to CD ratio‐.…”