PROJECT SUMMARY/ ABSTRACT Internalizing disorders such as major depressive disorder and generalized anxiety disorder show marked sex differences in prevalence, presentation, and trajectory. For example, depression and anxiety disorders are more prevalent in females than males. The neural mechanisms underlying such sex differences, however, are not well understood. Previous studies have suggested sex differences in internalizing symptoms may be due to abnormalities of the default mode network (DMN), a functional network that is critical for internally-directed cognition and emotional processes. The vast majority of studies on functional networks use methods that assume that the DMN is in the same anatomic location in every individual. However, evidence from multiple independent groups has recently shown that there is significant inter-individual variation in the spatial distribution of functional networks on the anatomic cortex and that person-specific networks predict aspects of cognition and psychopathology. We recently provided the first evidence of sex differences in such personalized functional networks and showed that sex differences in personalized networks are greatest in the DMN. Preliminary data demonstrate that DMN representation — a measure of normalized surface area — is greater in females. However, it is unknown if sex differences in personalized DMNs 1) evolve during development or 2) underly sex differences in internalizing symptoms. The over-arching hypothesis of this proposal is that DMN representation is greater in females, which confers a vulnerability to internalizing symptoms. Given that these symptoms typically emerge during childhood and adolescence, this hypothesis will be evaluated using three large developmental data resources: the Healthy Brain Network (HBN; n=5,000), the Human Connectome Project: Development (HCP-D; n=1,300), and the Adolescent Brain and Cognitive Development Study (ABCD, n=11,572). Aim 1 will characterize developmental sex differences in the spatial distribution of personalized functional networks, while Aim 2 will delineate how personalized networks relates to sex differences in internalizing symptoms. Finally, Aim 3 will use baseline variation in personalized functional networks to predict the longitudinal course of internalizing psychopathology. This innovative research project will establish that sex differences in personalized functional networks underly sex differences in internalizing psychopathology. Results will help inform targeted early interventions and trials of personalized neuromodulatory therapies. Successful completion of the proposed aims as an independent investigator will accelerate the candidate’s ability to exert a sustained impact on the field and advance our understanding of the contribution of sex as a biological variable to the development of internalizing psychopathology.

PROJECT NARRATIVE Findings from this study will lead to a more nuanced understanding of mechanisms underlying sex-specific trajectories of internalizing symptoms and help inform targeted early interventions. Specifically, results may identify sex-specific treatment targets and inform trials of personalized neuromodulatory therapies such as transcranial magnetic stimulation. Furthermore, predictors of longitudinal symptomatology could be used for treatment stratification in clinical trials using personalized biomarkers.