fMRI of Working Memory Abnormalities in Schizophrenic Patients

Hypothesis

Hypothesis

Hypothesis:
1. Impaired working memory in schizophrenia is associated with a deficit in prefrontal cortical and medial temporal neurotransmission.
2. The atypical antipsychotic medication, risperidone, improves working memory by correcting the deficit in prefrontal cortical and medial temporal neurotransmission.

Goals:
To use functional magnetic resonance imaging (fMRI) to localize the impaired distributed neuronal network that underlies working memory deficits in schizophrenia, and to determine the neuronal mechanisms that cause improvement in working memory. The specific aims are:
1. To compare the pattern and extent of the working-memory evoked fMRI signal acquired from unmedicated schizophrenic patients and healthy control subjects in an event-related experimental design.
2. To determine the change in working memory performance and the corresponding change in working memory evoked fMRI signal in schizophrenic patients following 30 days of double blind treatment with the atypical antipsychotic drug risperidone, vs. the conventional antipsychotic drug haloperidol.

Methods:
The fMRI images are acquired with a 1.5 T GE scanner using an echo-planar gradient echo pulse sequence while patients with schizophrenia and healthy controls perform working memory tasks (IMT/DMT) to retain a visual stimulus in memory and to recognize it after a 3.5 s delay for DMT and 1.5 s for IMT. The event-related design enables the fMRI signal that is evoked during the working memory delay period to be analyzed separately from the other behavioral events in the experiment. The relationship between performance and fMRI response is determined parametrically by presenting several levels of task difficulty in each fMRI session.

Follow-on Funding:
"Neural Correlates of Cognition in Schizophrenia;" (principal investigator) NIH/NIMH - RO1-MH61927
"Serotonin, Drug Use and MDMA Induced Deficits" (co-investigator) NIH/NIDA - R01-DA15345

Findings:
During the 3-digit working memory maintenance period, the schizophrenic subjects showed significantly less activation compared to the normal subjects in several brain regions: left dorsolateral prefrontal cortex, right precuneus, hippocampus, paracentral lobule, and putamen. These findings are consistent with theories in schizophrenia research that have postulated that deficits in the prefrontal cortex and hippocampus are associated with this disorder. In addition, the memory performance on these trials was not significantly different between the schizophrenic and control groups during the fMRI scans. Thus, the difference in neuronal activation between groups was unlikely to be due to difference in task performance.