Replicability, Mechanisms, and Trajectory of Neural Alterations Related to General Psychopathology

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Project Summary/Abstract High rates of psychiatric comorbidity (~50% of adults) pose significant challenges to mental health research and practice. Accumulating mental health research encourages a shift in focus towards transdiagnostic dimensional features that are shared across categorical disorders due to difficulties identifying causes, biomarkers, and treatments with specificity to individual disorders. In support of this shift, transdiagnostic research has identified a general psychopathology factor – often called the ‘p’ factor – that accounts for shared variation across internalizing, externalizing, and thought disorders in diverse samples. Identifying neural correlates of this general psychopathology factor would substantiate its importance in characterizing the shared origins of mental disorders and help us begin to understand the mechanisms through which the p factor may contribute to risk. Previous research by the applicant has identified relations between the p factor and structural alterations within a cerebello-thalamo-cortical circuit (CTCC), involved in higher-order cognitive and emotional processing. An F32 postdoctoral fellowship would allow the applicant to critically expand this research by examining replicability, mechanisms, and trajectory of associations between CTCC neural alterations and p factor scores in two large, openly available existing datasets: the Consortium for Neuropsychiatric Phenomics (CNP) and the Adolescent Brain and Cognitive Development (ABCD) studies. The CNP includes healthy adults and patients (aged 21-50) with attention deficit/hyperactivity disorder, bipolar disorder, and schizophrenia. ABCD includes a nationally representative sample of youth (aged 9-10) who are being followed longitudinally for 10 years. Using data from these two studies will allow the applicant to (1) examine whether the association between p factor scores and CTCC alterations are identifiable in youth, prior to the onset of most major mental illnesses (ABCD), and in patients with serious mental illness (CNP), (2) test neurocognitive mechanisms underlying this association, and (3) trace unfolding of symptoms over time related to these neural alterations. In addition, the applicant will conduct a feasibility study in healthy young adults to learn how to reliably activate the CTCC during a cognitive control task and provide pilot data for future grants. With substantial research and training opportunities available at McLean Hospital/Harvard Medical School, the mentorship of Dr. Diego Pizzagalli (primary mentor), a leader in the field of clinical neuroscience of depression, and the consultation of Dr. Roman Kotov (expert in statistical modeling of psychiatric symptoms) and Dr. Blaise Frederick (expert in magnetic resonance imaging physics), the applicant will receive training in all aspects of MRI experimental design and analysis, statistical modeling of the structure and trajectory of symptoms over time, professional development skills, and in designing and implementing her first independent functional MRI (fMRI) study. Together, the proposed training plan will support the applicant in contributing to transdiagnostic neuroscience research, honing skills in statistical modeling and advanced neuroimaging research, and building a program of independent research.