Childhood trauma, hippocampal function, and anhedonia among those at heightened risk for psychosis

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PROJECT SUMMARY/ABSTRACT Individuals with schizophrenia spectrum disorders experience a range of symptoms which cause high levels of functional impairment, thus representing a large personal and public health burden. Similarly, individuals at clinical high risk (CHR) for the development of psychosis experience general work and academic impairments, social impairment, and reductions in quality of life that are evident even prior to the onset of full-threshold psychosis. Therefore, studies evaluating CHR populations can help to uncover how symptoms of schizophrenia first arise and indicate more effective avenues for early intervention. Of particular importance is the examination of negative symptoms, such as anhedonia, as they tend to present prior to the onset of positive symptoms, are more resistant to treatment, and are more strongly predictive of functional outcomes. Further, although anhedonia commonly occurs in those with psychosis, it also is a hallmark feature of depression, a disorder with high comorbidity in CHR individuals. Mounting evidence suggests that childhood trauma not only increases risk of developing psychosis, but is associated with anhedonia, specifically, across diagnoses, including for individuals with depression, as well as non-psychiatric controls. Further, childhood trauma has deleterious effects on the mesolimbic system, particularly the hippocampus, a region which animal models have recently implicated in the development of reward deficits underlying anhedonia. Despite these converging lines of research, no one, to date, has examine the mediating role of mesolimbic functioning in the relationship between childhood trauma and anhedonia. Therefore, the proposed study will examine the association between childhood trauma and anhedonia via the indirect effect of hippocampal function during novelty processing, which has been shown to engage dopaminergic reward systems. The proposed study, in the context of my sponsor's NIMH-funded R01, will recruit non-help-seeking 16-30 year olds who represent the full spectrum of psychosis-risk to complete self- report questionnaire and clinical interviews, with a subset completing both resting-state and task-based functional magnetic resonance imaging (fMRI) scans. Findings from the proposed study have the capacity to provide additional insight into previously established reward-related alterations associated with anhedonia, thus providing a novel framework to understand the relationship between childhood trauma and anhedonia. Further, we will explore potential differences in the association between childhood trauma, mesolimbic engagement, and anhedonia across CHR and non-CHR individuals to assess specificity. To complete this study, a training plan has been developed that consists of formal coursework, workshops, experiential learning, and mentorship. This fellowship would allow me to obtain additional training opportunities that would not otherwise be available to me, in order to develop the expertise in the pathophysiology of reward dysfunction, neuroimaging, and data analysis necessary to become an independent clinical scientist.