Mapping the functional organization of the cortex across development: The principal hierarchy and transdiagnostic psychopathology risk

PROJECT SUMMARY Mental illness is increasingly understood through the lens of brain development, as these disorders are highly heritable and often emerge during the transition from childhood to adulthood. Thus, it is essential to investigate functional brain development and its genetic underpinnings. The adult human cortex is organized along a principal hierarchy indexed by functional MRI connectivity, anchored on one end by regions involved in perception and action and on the other by regions responsible for abstract cognition. The extent to which the cortex functionally aligns with this hierarchy has been associated with both development and diverse psychopathology, suggesting that abnormal hierarchical development may be mechanistically related to broad psychiatric vulnerability. Using a normative modeling framework, this proposal will test the overarching hypothesis that deviations in the development of the principal hierarchy are associated with transdiagnostic psychopathology burden and genetic risk. To do so, I will use four large-scale developmental datasets that include fMRI and clinical data: the Philadelphia Neurodevelopmental Cohort (PNC, N=1,559), the Lifespan Human Connectome Project in Development (HCP-D, N=1,350), the Nathan Kline Institute-Rockland Sample (NKI-RS, N=426) and the Adolescent Brain Cognitive Development study (ABCD, N=11,878). This proposal aims to 1) investigate how deviations in principal hierarchy development relate to transdiagnostic clinical psychopathology., and 2) investigate the role of the principal hierarchy as an intermediate phenotype of genetic risk for transdiagnostic psychopathology. This work will advance our understanding of functional cortical development, its genetic basis, and its relationship to the emergence of psychiatric risk. Findings from this study will lay a foundation for future endeavors to identify diagnostic markers, therapeutic targets, and interventional windows of opportunity for neuropsychiatric disorders. Study feasibility will be ensured by expert guidance from an integrated mentorship team comprised of Drs. Aaron Alexander-Bloch, Theodore Satterthwaite, Dylan Tisdall, Monica Calkins, and Laura Almasy. Mentorship from these experts, along with a coordinated program of coursework, seminars, workshops, conferences, and clinical training, will provide the applicant with rigorous training in functional MRI, developmental psychopathology, and psychiatric genetics, enabling him to pursue a future career as an independently-funded physician-scientist.