Wednesday, April 2, 2025
4/2/2025
Reward, Salience and Value Processing in Youths at Risk for Psychosis: The RSVP Study - PROJECT SUMMARY Schizophrenia and its clinical risk states are characterized by both positive and negative symptoms. Positive symptoms in schizophrenia comprise hallucinations and delusions; among teens and young adults at clinical high-risk (CHR) for psychosis, these are subthreshold in nature (e.g., perceptual disturbances and unusual thoughts). Negative symptoms in schizophrenia and CHR include anhedonia (the reduced experience or expectation of pleasure) and avolition (a severe reduction in motivated, goal-directed behavior). Prior work in schizophrenia suggests that both types of symptoms may result from impairment in salience processing, which is the appropriate evaluation of the importance and relevance of diverse experiences for normative learning and decision-making. Adaptive salience is the appropriate response to good or positive experiences; its blunting has been linked to both anhedonia and avolition. Positive symptoms in schizophrenia have been associated with aberrant salience, which is the inappropriate assignment of importance to neutral events. In this proposal, we will study salience processing and symptoms in CHR individuals, who have evolving pathophysiology and minimal antipsychotic exposure. We will, for the first time, study both adaptive and aberrant salience together in a CHR cohort sufficiently large (N = 96) to allow simultaneous examination of both negative and positive symptoms, who will be followed prospectively for clinical and functional outcome. We will use fMRI and computational modeling of reinforcement learning and decision-making to capture quantitative behavioral and neural correlates of: (Aim 1) blunted adaptive salience (and associations with negative symptoms); and (Aim 2) heightened aberrant salience (and associations with positive symptoms). In longitudinal study (Aim 3), we will determine the extent to which these two types of salience processing predict future and/or track change in symptom severity and functional outcome. Exploratory analyses will use all behavioral, imaging, and clinical data to determine if some salience subconstructs may contribute to both positive and negative symptoms. This proposal is significant for several reasons. There are, as yet, no robustly effective treatments for the CHR syndrome, which has significant current morbidity related to its positive and negative symptoms (in addition to cognitive deficits). Also, the CHR syndrome offers an opportune window for preventive intervention related to worsening symptoms and function and has the added advantage of minimal confounding by illness chronicity and antipsychotic medication use. Finally, if we find that the neural and behavioral mechanisms involved in salience processing are associated with negative and positive symptoms, this offers a promising novel target for treatment of both types of symptoms across the schizophrenia spectrum.
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