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ItemThe role of adrenarche in shaping the mind: how adrenarcheal hormones contribute to the development of brain connectivity and internalising symptomsBarendse, Marjolein Eva Andrea ( 2018)The transition from childhood to adolescence is a particularly vulnerable period for the development of internalising symptoms and disorders. Hormonal changes as well as changes in brain structure and function may play a role in this increased vulnerability. Most of the research to date has focused on the hormonal and brain changes during gonadarche, whereas the literature is much more limited for adrenarche, an earlier pubertal phase that takes place prior to gonadarche. Therefore, this thesis aimed to examine how (changes in) adrenarcheal hormones relate to the development of brain structural and functional connectivity, and how that in turn affects internalising symptoms in late childhood to early adolescence. Data were used from two longitudinal community-based samples with two time points each (sample 1 M ages 9.5 and 12.2 years; sample 2 M ages 8.5 and 10 years). At each time point in each study, levels of dehydroepiandrosterone (DHEA), its sulfate (DHEAS) and testosterone were measured and averaged from morning saliva samples collected across several days. Participants also underwent Magnetic Resonance Imaging (MRI) scans, and completed self-report questionnaires, at both time points. Diffusion-weighted imaging scans were analysed to examine white matter structural connectivity. Functional Magnetic Resonance Imaging (fMRI) scans during an affective face processing paradigm were analysed to examine functional connectivity. Levels of internalising symptoms were based on self-report questionnaires: the Spence Children’s Anxiety Scale, the Children’s Depression Inventory, and the Positive And Negative Affect scale. Analyses were conducted to investigate associations between hormone levels (initial levels and changes in levels over time) and brain structural and functional connectivity (baseline and change over time). Analyses were also conducted to investigate whether hormone-related changes in structural/functional connectivity were associated with symptoms. The results showed that children with high DHEA levels at age 9 had higher mean diffusivity (cross-sectionally) in a wide range of white matter tracts, suggesting that relatively early exposure to DHEA might be negatively associated with white matter microstructure. Changes in testosterone from age 8.5 to 10 years were negatively associated with the development of white matter structure as quantified by fibre cross-section in posterior white matter tracts. Higher levels of testosterone at age 8.5 years, however, were related to stronger development of fibre cross-section from age 8.5 to age 10 years. These hormone-related changes in white matter structure were not significantly associated with levels of internalising symptoms. Analyses of functional connectivity during affective face processing focused on connectivity of the amygdala to the rest of the brain, because of the crucial role of the amygdala in emotion processing and consistent findings of its involvement in internalising disorders. Indirect effects were found of adrenarcheal hormone levels (controlled for age, potentially indicating a timing effect, i.e. maturation relative to same-age peers) on anxiety symptoms at age 9 years, mediated by amygdala connectivity to visual and limbic areas. Timing of adrenarcheal hormone exposure was also found to have indirect effects on anxiety symptoms longitudinally. Specifically, higher DHEA at age 9 years was indirectly related to more anxiety symptoms at age 12 years, controlling for symptoms at age 9 years, via more positive amygdala to inferior frontal gyrus connectivity. Thus, the findings in this thesis have demonstrated that elevated adrenarceal hormone levels (potentially reflecting early timing of adrenarche) are both cross-sectionally and longitudinally associated with anxiety symptoms through an effect on amygdala functional connectivity. We also showed that the hormonal processes of adrenarche have an impact on white matter microstructure development. These findings have implications for the understanding of how individual variation in adrenarcheal processes can impact children’s brain development and mental health. Future studies should examine whether effects of variation in adrenarcheal processes on brain development and mental health are persistent, as well as establish whether predictors found in the current thesis are also relevant in clinical samples.