Dopamine Function and Reward Processing In Schizophrenia

Objective:

Schizophrenia (SC) is associated with cognitive impairment in a variety of domains, including learning and memory. The neural underpinnings of these cognitive deficits, however, are poorly understood. Based on evidence that abnormal functioning of brain dopamine (DA) systems is implicated in both schizophrenia and mechanisms of reinforcement processing, we proposed to test theories of the functional role of dopamine in schizophrenia. Specifically, the studies described here test two main ideas about DA function and its possible contribution to SC: 1) its role in facilitating learning of cue-reward associations; and 2) its role in signaling mismatches between expected and experienced outcomes (called prediction errors).

Study Population:

In order to assess brain responses to outcomes, and cues predictive of outcomes, we will enroll 135 total participants (SC patients and controls), aged 18 - 55. For a first set of experiments, we enrolled 54 total subjects (37 SCs and 17 controls) to achieve 34 total completers (24 SCs and 10 controls). In a second set of experiments, our goal is to examine two types of SC patients (those taking clozapine and those taking a different second-generation antipsychotic). For these experiments, we will enroll 81 total subjects (27 controls, 27 SCs taking clozapine, and 27 SCs taking a different second-generation antipsychotic) to achieve approximately 47 total completers (15 controls, 16 SCs taking clozapine, and 16 SCs taking a different second-generation antipsychotic).

Design:

We will measure brain activity using functional magnetic resonance imaging (fMRI), in conjunction with the performance of reinforcement processing tasks from the literature. These paradigms involve either the passive observation of reinforcement contingencies, or the requirement to make an appropriate response within a time window in order to earn positive feedback. The ongoing study uses two specific paradigms: one examining the impact of brain responses to feedback on subsequent learning, and one investigating how brain responses to a monetary reinforcer are modulated by the unexpectedness of the event.

Outcome Measures:

In the current study, we will investigate differences in MRI responses to outcomes between SC patients and controls, and between subgroups of patients. In particular, we are interested in determining whether MRI responses in components of reward circuits, such as the midbrain, basal ganglia, and orbitofrontal cortex, are attenuated in SC patients, in the context of paradigms that require individuals to detect mismatches between expected and experienced outcomes, and to modify responses based on those mismatches. We hypothesize that learning deficits in SC stem primarily from impairments in the signaling of errors in reward prediction, and that abnormalities in the signaling of errors in reward prediction will be reflected in abnormal stimulus-evoked activation in the primarily in two brain areas in SC patients (both DA target areas): prefrontal cortex and the neostriatum. We predict that these signals will relate systematically to performance on a reinforcement-learning task.