Project Summary This application describes the research plan and program of study leading to a PhD as part of a combined MD- PhD Program at the University of Nebraska Medical Center and the Boys Town National Research Hospital. The central goal of this research plan is to identify how dehydroepiandrosterone (DHEA), testosterone, and estradiol modulate the development of cognitive systems serving selective attention and working memory processing. Briefly, the pubertal transition period is marked by significant increases in these hormones and substantial developmental advancements in higher-order cognitive functions, including working memory, selective attention, and others. However, on the other hand, the incidence of psychiatric disease also increases during puberty, and is accompanied by greater sex differences in disease prevalence. It has been suggested that this emergence of psychiatric illness during puberty might be associated with the drastic hormonal changes that mark this developmental stage, but the net impact of these hormonal changes on brain function and cognition is poorly understood. This F30 fellowship proposal will examine the sex and region-specific effects of DHEA, testosterone, and estradiol on working memory and selective attention processing using an advanced dynamic functional mapping approach based on magnetoencephalography (MEG), and includes a rigorous training and career development plan for a future physician-scientist in the areas of pediatric psychiatry and developmental cognitive neuro- science. The specific aims are (1) to examine the unique effects of pubertal hormones in predicting performance on selective attention and working memory tasks and (2) to identify the relationship between sex steroid hormone levels, neural oscillatory dynamics, and behavior during attention and working memory tasks. The trainee is a minority MD/PhD student in his 2nd year of PhD study who has already distinguished himself through two first- authored manuscripts in top journals, participation and presentation in scientific conferences, and a strong history of academic achievement. In sum, this application for an F30 fellowship will use MEG, advanced source reconstruction methods, neural oscillatory analyses, and hair-sampled hormone analysis to delineate the relationship between pubertal hormone levels, brain dynamics, and cognitive development. The program of study is designed to support this research plan through rigorous training by an internationally known expert in MEG and dynamic brain mapping who has a strong record of mentoring trainees, as well as an expert collaborator in pubertal hormone analysis and interpretation, with the primary goals of developing and expanding the research and clinical skills of the applicant to produce a physician-scientist who is well equipped and prepared for the next stage of his career.

Project Narrative Puberty is a period marked by the emergence of enhanced cognitive functioning, but also an increased incidence of psychopathology. Some research has suggested that the drastic changes in sex hormones that occurs during the pubertal transition, namely dehydroepiandrosterone (DHEA), testosterone, and estradiol exert sex and region-specific effects on neural structure that affects cognitive and affective development, but research to date has been largely restricted to animals, with only a handful of human neuroimaging studies in this area. The proposed work will train a promising physician-scientist to use an advanced dynamic functional brain mapping method to identify the impact of developmental changes in DHEA, testosterone, and estradiol on brain and higher-order cognitive function in typically-developing children and adolescents.