Fragmented early-life experiences, aberrant circuit maturation, emotional vulnerabilities

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Mood and anxiety disorders afflict >20% of adolescents and young adults, with tremendous social and fiscal costs. Late adolescent/young adult service members facing combat are at significant risk for trauma- related disorders, constituting an ideal population to test predictions of the overarching hypothesis driving this Center renewal: that early-life fragmentation/unpredictability (FRAG) is associated with early manifestations of anhedonia and related mental health symptoms via alterations in pleasure-reward circuits which presage increased risk for psychopathology in adulthood. The studies of Project 4, guided by constructive Reviewer suggestions, aim to provide evidence for the role of FRAG-related anhedonia as a novel, unsuspected risk factor for psychopathology in a vulnerable population. We will leverage a large prospective and longitudinal cohort of late-adolescents/young adults recruited in the Marine Resiliency Study (MRS). MRS assessed emotional and cognitive health including anhedonia (within a broad battery of laboratory, self-report and clinical assessments) in young service members before a combat deployment and 3-6 month after it. We will recruit 800-1000 subjects to determine if self-report of early life FRAG is associated with altered mental health trajectories in adulthood. While capitalizing on rich and broad-based assessments of the MRS, we will test three hypotheses: 1) That FRAG, in addition to other established early-life factors, predicts anhedonia during late adolescence / early adulthood. (2) That early-life FRAG and subsequent anhedonia in late adolescence/early adulthood increases risk for adult trauma-related psychopathology. This prediction is supported by preliminary data that pre-deployment anhedonia predicts increased PTS symptoms and increased prevalence for PTSD after deployment (N=1972). This hypothesis will probe the clinical significance and impact of the Center-proposed FRAG and anhedonia risk factors. (3) That FRAG and anhedonia promote trauma-related psychopathology via aberrant pleasure-reward circuitry. A subset of MRS participants identified in Aims 1 & 2 will be recruited into 4 groups with either high or low levels of risk (i.e. combined early-life FRAG and adolescent /early adult anhedonia) and with either high or low levels of PTS symptoms. All will undergo structural MRI, DTI and fMRI and behavioral and cognitive assessments similar to those in Projects 2 and 3 to extend the developmental trajectories of FRAG- associated circuit changes and psychopathology to adulthood. In addition to testing specific Center hypotheses, the broad, longitudinal emotional and cognitive measures within MRS, coupled with data-driven MRI analyses (Imaging core), will enable examination of the role of FRAG in the trajectory of a broad spectrum of adult psychopathology.