Anhedonia is at the center of multiple devastating psychiatric conditions. Anhedonia is one of the cardinal negative symptoms in schizophrenia, which substantially worsen long-term outcome in affected patients. In bipolar disorder, anhedonia is also a core feature of the cyclic depressive episodes that produce the majority of the morbidity of that illness. In both schizophrenia and bipolar disorder, symptoms of anhedonia often begin in adolescence. Regardless of the underlying clinical diagnosis, anhedonia is associated with poor treatment response. Several studies and our preliminary data have linked anhedonia to dysfunction of the brain's reward system. However, very little is yet known regarding how reward dysfunction develops in adolescence to produce anhedonia. Early identification of the biological substrates of anhedonia is needed for advances in treatment. Here, I propose to capitalize upon our ongoing large-scale RC2 Grand Opportunity ("GO") study of neurodevelopment. I plan to comprehensively assess anhedonia and reward system function in a follow-up sample of GO participants with symptoms of psychosis or bipolar disorder, compared to typically developing youths. Specialized clinical measures, dedicated imaging of reward system responses, and follow-up longitudinal neuroimaging of brain structure and functional connectivity will be applied. Multivariate pattern analysis techniques will be used to integrate high-dimensional imaging data and produce a brain-based, dimensional measure of anhedonia. We expect to demonstrate that the presence of anhedonia is related to diminished responsiveness and disrupted connectivity of the ventral striatum, a key node of the reward system. Relating anhedonia to reward system dysfunction on a dimensional basis across diagnostic categories coheres closely with the recently released NIMH Research Domain Criteria. The proposed effort will produce novel scientific results and additionally provide criticl training to the candidate, who is a psychiatrist finishing his post-doctoral neuropsychiatry fellowship. The application builds upon the candidate's established interest in reward system function and substantial neuroimaging experience, most recently with the GO study. The candidate will be mentored by an experienced mentorship committee, lead by primary mentor Dr. Raquel Gur, who is a renowned expert in schizophrenia and investigations of the biological basis of psychopathology. Dr. Gur and the other application mentors will assure that the experience resulting from the proposed training plan will enable the candidate to establish an independent research program in the neuroscience of reward system dysfunction in adolescence.
Anhedonia is a debilitating symptom that is present in multiple psychiatric disorders, including schizophrenia and bipolar disorder. Greater understanding of how dysfunction of the brain's reward system develops during adolescence to give rise to symptoms of anhedonia may be critical for the development of earlier and more effective treatments. This would benefit public health by reducing the great costs of anhedonia to individuals and society at large.
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