Mapping Person-Specific and Spatially Precise White Matter Development to Transdiagnostic Psychopathology and Polygenic Risk

Psychiatric disorders are increasingly conceptualized as disorders of brain development. White matter (WM) structure develops rapidly in adolescence and has been linked to many psychiatric illnesses. However, the neurobiological mechanisms linking WM development, transdiagnostic psychiatric symptoms, and genetic risk for psychopathology remain poorly understood. This proposal tests the central hypothesis that transdiagnostic psychiatric symptoms and genetic risk will be associated with WM that undergoes the most protracted development: superficial regions of WM tracts connected to higher-order association cortices. We will leverage the large, longitudinal Adolescent Brain Cognitive Development (ABCD) study (n=11,875; ages 9-16), which includes multi-shell diffusion MRI, clinical, and genotype data. In Aim 1, we will characterize within-individual, along-tract WM development and we will evaluate whether associations with transdiagnostic symptoms are strongest in superficial WM regions adjacent to higher-order association cortices. In Aim 2, we will assess how polygenic risk scores (PRS) for transdiagnostic psychiatric illness relate to spatially precise WM microstructure metrics. We will assess whether PRS effects are strongest in superficial WM regions adjacent to higher-order association cortices. Together, this work will identify brain regions where protracted WM maturation is linked to transdiagnostic symptoms and genetic risk, advancing our understanding of how WM development is related to symptomatology and genetic liability for trans-diagnostic psychiatric illness. Project Number: 1F30MH144778-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Briana Macedo | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $55,114 | Activity Code: F30 | Study Section: Special Emphasis Panel[ZRG1 F01A-S (21)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11385179