Hypothesis:
Schizophrenia is a complex neurobiological disorder, resulting from the interaction of multiple genes and environmental factors. One gene that may be involved in the pathology of schizophrenia is the α7 nicotinic receptor gene, which has been linked both to schizophrenia itself, and to an elementary deficit in sensory processing observed in schizophrenia patients and their relatives. A key missing link in understanding how genotype relates to disease pathology is knowing how alterations in the gene lead to changes in brain function and structure. To address this question, the proposed study will evaluate brain function and structure in the context of genetic information in subjects with schizophrenia and healthy controls.We will test the hypothesis that increased hemodynamic response during a sensory gating task (consistent with diminished inhibition) will be observed in subjects with polymorphisms in the α7 nicotinic receptor gene, regardless of diagnosis. We will also test the hypothesis that subjects with polymorphisms in the α7 nicotinic receptor gene will have decreased volume (consistent with neuronal and glial developmental abnormalities) in brain regions where the gene is maximally expressed (e.g., hippocampus and thalamus).
Goals:
1. To determine the effects of polymorphisms in the α7 nicotinic receptor gene on brain hemodynamic response during auditory sensory gating in individuals with schizophrenia and healthy comparison subjects.
2. To use voxel-based morphometry (VBM) to determine the effects of α7 nicotinic receptor gene polymorphisms on brain structure, including gray and white matter volume.
Methods:
Four groups of individuals, comprising a two by two design, will undergo structural and functional MRI: controls drawn from the population without known CHRNA7 polymorphisms, controls drawn from the general population with known CHRNA7 polymorphisms, schizophrenics with known CHRNA7 polymorphisms, and other schizophrenics, who have no known CHRNA7 polymorphism. Following a structural scan for VBM analysis, functional scans will be acquired while subjects perform an MR-compatible sensory gating task. The paradigm will use clustered volume acquisition to 1) allow a 6s silent period following scanner noise for neuronal inhibitory circuitry to reset, and to 2) allow auditory stimuli to be presented during silence. A novel technique, voxel-shift interpolation, will be used to improve 1) the sensitivity of detecting activation and 2) the spatial accuracy of the detected activation.
