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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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Testosterone is thought to play a crucial role in mediating sexual differentiation of brain structures. Examinations of the cognitive effects of testosterone have also shown beneficial and potentially sex-specific effects on executive function and mnemonic processes. Yet these findings remain limited by an incomplete understanding of the critical timing and brain regions most affected by testosterone, the lack of documented links between testosterone-related structural brain changes and cognition, and the difficulty in distinguishing the effects of testosterone from those of related sex steroids such as of estradiol and dehydroepiandrosterone (DHEA). Here we examined associations between testosterone, cortico-hippocampal structural covariance, executive function (Behavior Rating Inventory of Executive Function) and verbal memory (California Verbal Learning Test-Children's Version), in a longitudinal sample of typically developing children and adolescents 6-22 yo, controlling for the effects of estradiol, DHEA, pubertal stage, collection time, age, handedness, and total brain volume. We found prefrontal-hippocampal covariance to vary as a function of testosterone levels, but only in boys. Boys also showed a specific association between positive prefrontal-hippocampal covariance (as seen at higher testosterone levels) and lower performance on specific components of executive function (monitoring the action process and flexibly shifting between actions). We also found the association between testosterone and a specific aspect of executive function (monitoring) to be significantly mediated by prefrontal-hippocampal structural covariance. There were no significant associations between testosterone-related cortico-hippocampal covariance and verbal memory. Taken together, these findings highlight the developmental importance of testosterone in supporting sexual differentiation of the brain and sex-specific executive function., Competing Interests: The authors declare no conflict of interest., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Humans and the great apes are the only species demonstrated to exhibit adrenarche, a key developmental event leading to increased production of dehydroepiandrosterone (DHEA), suggesting that this hormone may play an important evolutionary role. Similarly, visual attention networks have been shown to evolve in a human-specific manner, with some anatomical connections and elements of cortical organization exclusive to our species. Existing studies of human brain development support the notion that DHEA shows significant uptake in cortical structures and the amygdala, and as such, could be involved in the bottom-up regulation of visual attention. Here we examined associations between DHEA, structural covariance of the amygdala with whole-brain cortical thickness, and tests of visual attention, in a longitudinal sample of typically developing children and adolescents 6-22 years of age. We found that DHEA predicted covariance between amygdalar volume and the left occipital pole, right somatosensory parietal cortex and right anterior cingulate cortex. Amygdala-occipital covariance predicted visual awareness; amygdala-parietal covariance predicted visuo-motor dexterity and processing speed; amygdala-prefrontal covariance predicted global attentional impairment. Further, effects of DHEA were above and beyond those of age and sex, as well as distinct from those of pubertal stage, estradiol and testosterone. These findings support the notion that DHEA may play a unique role in shaping amygdala-dependent cortical plasticity and in regulating 'bottom-up' visual attention processes from childhood to young adulthood., (Copyright © 2016 Elsevier Ltd. All rights reserved.)