Computational Dissection of Neural Circuit Mechanisms Underlying Anticipatory Anhedonia in Schizophrenia

Columbia University Health Sciences, New York NY

Investigators

Abstract

Abstract: Anhedonia, characterized by the inability to experience pleasure, poses a significant challenge in schizophrenia. This is due to the lack of effective treatments and its association with severe cognitive deficits. However, the neural circuitry underlying anhedonia remains poorly understood, hindering the identification of treatment targets. Anhedonia in schizophrenia is often expressed as a deficit in reward anticipation (anticipatory anhedonia). Here we propose an innovative computational psychiatry approach to dissect the neural circuitry underlying altered reward anticipation. This will give insights into how anhedonia links to cognitive deficits in schizophrenia. Furthermore, our study will also advance our understanding of the underexplored transdiagnostic NIMH RDoC construct: reward anticipation. We will utilize the behavioral economics notion of anticipatory value computation, a concept that has not yet been applied to understand psychiatric conditions. Unlike existing approaches, our framework offers (1) a computational model that quantitatively predicts the behavioral and neural correlates of dynamic reward anticipation processes and (2) a new experimental paradigm for measuring anticipatory value signals in the brain and the behavioral manifestations. We recently validated this framework in task-based fMRI experiments with healthy volunteers, successfully identifying the neural circuitry associated with reward anticipation. Building upon our recent findings, we hypothesize that an altered functional coupling between the hippocampus and the dopaminergic midbrain underlies anticipatory anhedonia, a novel, untested hypothesis. We will test our hypothesis with two sets of studies: (1) large-scale online experiments, and (2) fMRI experiments with individuals with schizophrenia and matched healthy volunteers. First, we will establish the relationship between anticipatory value computation and anhedonia traits within a large diverse online sample, by examining task behavior and self-reported questionnaires. Second, we will identify the neural circuitry involved in altered anticipatory value computation using model-based fMRI analysis. We will explore alternative hypotheses including the altered hippocampus-prefrontal cortex coupling. Third, we will examine whether the neural alterations responsible for anhedonia could also account for cognitive deficits. Our studies will uncover neural circuit alterations underlying reward anticipation deficits, which may serve as novel targets for treating anhedonia and cognitive deficits in schizophrenia. Furthermore, our study will contribute to developing a new task-based computational framework, which can identify potentially distinct reasons for altered reward anticipation and anhedonia. Thus, our computational and experimental framework has the potential to develop novel personalized treatment interventions for individual patients, e.g., with connectivity-based neurostimulation approaches.