Dopamine Function and Reward Processing In Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Observational

Summary: 
      Background:

      - Schizophrenia is associated with cognitive impairment in different parts of the brain,
      including those associated with learning and memory. The brain activity associated with these
      impairments, however, is poorly understood. Researchers are interested in studying how the
      brain chemical dopamine, which is involved in responding to incentives and rewards like money
      or food, works differently in the brains of people who have schizophrenia.

      Objectives:

      - To study reward processing in individuals with schizophrenia who are taking different types
      of medication, compared with healthy volunteers.

      Eligibility:

      - Individuals between 18 and 55 years of age who (a) have been diagnosed with
      schizophrenia/schizoaffective disorder and are taking the antipsychotic medication clozapine,
      (b), have been diagnosed with schizophrenia/schizoaffective disorder and are taking a
      different second-generation antipsychotic, or (c) are healthy volunteers.

      Design:

        -  This study will involve one screening visit and one or more visits for testing and
           functional magnetic resonance imaging (fMRI) scans. During the screening visit,
           participants will complete questionnaires and provide information about their physical
           and psychological health.

        -  Participants will receive training in the tasks to be performed at the scanning sessions
           during the screening visit.

        -  During the fMRI scans, participants will complete one or two of four possible
           reward-based tasks:

        -  A task that enables participants to win money based on their response to a target item.

        -  A task that provides small amounts of juice over specific time intervals, followed by a
           procedure to be completed outside the scanner.

        -  A task that involves choosing figures or shapes and winning money based on responses.

        -  A game of chance involving predictions based on shapes shown on a screen.

        -  Participants will also provide blood samples for research and testing.
    

Detailed description: 
      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.
    

Keywords: Classical Conditioning; fMRI; Schizophrenia; TD Model; Incentive Salience