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.

- INCLUSION CRITERIA::

Individuals will be eligible for participation in one of the proposed experimental groups
on the condition that they are:

1. Aged between 18 55 years.

2. In good health, based on history and physical examination

3. Right-handed (i.e. as assessed using the Edinburgh Handedness Inventory)

In addition, patient participants:

1. Must meet DSM-IV criteria for schizophrenia or schizoaffective disorder at the time of
assessment, and

2. Must have had 4 weeks of stable pharmacological treatment (same medications at same
doses).

Behavioral Subject Only:

1. Aged between 18 55 years.

2. In good health, based on history and physical examination

3. Right-handed (i.e. as assessed using the Edinburgh Handedness Inventory)

In addition, patient participants:

1. Must meet DSM-IV criteria for schizophrenia or schizoaffective disorder at the time of
assessment, and

2. Must have had 4 weeks of stable pharmacological treatment (same medications at same
doses).

Individuals will be eligible for participation in one of the proposed experimental groups
on the condition that they are:

EXCLUSION CRIERIA:

Participants in MRI scanning experiements

All participants in the MRI scanning experiements will undergo standard screening as in the
clinical policies of the IRP:

All Participants in the MRI scanning experiments

Participants in both experimental groups will be excluded from participation if they:

1. Are unable to undergo MRI scanning due to pregnancy (via pregnancy test), implanted or
attached metallic devices (e.g. cardiac pacemaker or neurostimulator; some artificial
joints metal pins; surgical clips; braces; or other implanted metal parts),
claustrophobia, or syncope, by self-report;

2. Show current evidence of severe hypertension, as indicated by a blood pressure
measurement at or above 190 systolic or 110 diastolic on two separate occasions.
Potential participants with evidence of chronic and/or poorly controlled hypertension
may be excluded by the MRP even with measurements below those values;

3. Show current evidence of diabetes, as indicated by a blood sugar measurement of over
300 mg/dl. Potential participants with evidence of chronic and/or poorly controlled
diabetes may be excluded by the MRP even with measurements below those values;

4. Suffer from HIV infection, coagulopathies, or other major medical illness which, in
the judgment of the MRP, would seriously compromise the quality of the data gathered;

5. Have any neurological illnesses that would interfere with the quality of the
neuroimaging data gathered, i.e. to include (but not limited to): seizure disorders;
migraine; multiple sclerosis; movement disorders; or history of head trauma, CVA, or
CNS tumor;

6. Are notably cognitively impaired by history or observation;

7. Have a DSM-IV diagnosis of past alcohol or substance dependence (with the exception of
nicotine);

8. Test positively for any of 7 common banned substances at the time of screening;

9. Are lactating, as hormonal fluctuations associated with lactation may interact with
dopamine system function.

Normal, Healthy Control Participants

In addition to those exclusion criteria already outlined above, control participants will
also be excluded if they:

1. Have any current, or previous, diagnosis of any major psychiatric disorder, i.e. to
include (but not limited to) mood, anxiety, and psychiatric disorders, or any
substance-induced psychiatric disorders.

2. Have any first-degree relatives with history of psychosis likely related to
schizophrenia, bipolar affective disorder, or schizoaffective disorder.

3. Have previously been diagnosed with a DSM-IV Axis II spectrum disorder.

Patient Participants

Patient patients will be excluded if they meet any of the criteria already outlined, and
also if they:

1. Have experienced any changes in pharmacological treatment and dose in the 4 weeks
preceding study enrollment.

2. We will exclude patients whose paranoid ideation might prevent them from feeling
comfortable in the task- or scanning-environment.