Effect of Genotype on Brain Function and Structure in Schizophrenia

Jason R. Tregellas, Ph.D.

University of Colorado at Denver Health Sciences Center

Funded in June, 2006: $100000 for 3 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Are Functional and Structural Brain Deficits in People with Schizophrenia Related to a Specific Gene?

Colorado researchers will combine MRI imaging with genetic studies to explore the possibility that structural and functional brain deficits in people with schizophrenia are associated with a specific gene.  If so, the research could identify new a new genetic target for drug therapy.

One of the most common problems for people with schizophrenia is the inability to filter out unimportant sounds (called “sensory gating deficit”).  Studying schizophrenic patients with MRI imaging, the researchers found increased brain activity in the thalamus and hippocampus, suggesting that these regions may fail to block sensory overload. Additionally, they found that patients’ cells in these two brain regions had far fewer “α7 nicotinic receptors” than expected. These receptors, located on cells, are activated by the neurotransmitter acetylcholine for cell to cell communication and are also activated by nicotine (which has been found in some studies to temporarily alleviate the sensory overload). The gene that produces this receptor has been identified, and small variations in the gene result in production of fewer α7 nicotinic receptors.

The researchers hypothesize that people with schizophrenia have variations in this gene, resulting in poor sensory inhibition by brain cells in the thalamus and hippocampus and in structural differences in the brain’s gray and white matter in these two regions. They will test this hypothesis by comparing imaging results in patients and healthy “control” participants.  The investigators will use fMRI to see whether patients have increased sensory input in the thalamus and hippocampus, compared to controls; and, “voxel-based morphometry” will be used to compare white and gray matter volumes in these brain areas in patients and controls. If gene variations are implicated, drugs that are under development to act on this receptor could be tested for their ability to restore function in the hippocampus and thalamus to normal levels.

Significance:  The findings may lead to development of new treatments that improve the ability of people with schizophrenia to block out unimportant sounds and to focus attention.  This improvement, in turn, could increase their capacity to interact in their environment and improve their cognitive skills.   

ABSTRACT

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Effect of Genotype on Brain Function and Structure in Schizophrenia

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.

Aim #1 will 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. Inhibitory deficits in sensory gating are one of the most reproducible physiological deficits associated with schizophrenia, and have recently been successfully imaged in our laboratory with fMRI. We will test the hypothesis that increased hemodynamic response (consistent with diminished inhibition) will be observed in subjects with polymorphisms in the α7 nicotinic receptor gene, regardless of diagnosis.

Aim #2 will use voxel-based morphometry to determine the effects of the polymorphisms on brain structure, including gray and white matter volume. This aim will 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). This would be one of the first studies to examine genetic effects on both functional and structural measures as assessed by MRI.

 

HYPOTHESIS

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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.

SELECTED PUBLICATIONS

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Tregellas J.R., Davalos D.B., and Rojas D.C. Effect of task difficulty on the functional anatomy of temporal processing. Neuroimage. 2006 Aug 1;32(1):307-15.

Tregellas J.R., Tanabe J.L., Martin L.F., and Freedman R. FMRI of response to nicotine during a smooth pursuit eye movement task in schizophrenia.  Am J Psychiatry. 2005 Feb;162(2):391-3.

Tregellas J.R., Tanabe J.L., Miller D.S., Ross R.G., Olincy A., and Freedman R.  Neurobiology of smooth pursuit eye movement deficits in schizophrenia: an fMRI study.  Am J Psychiatry. 2004 Feb;161(2):315-21.

Tregellas, J.R., Tanabe J.L., Miller D.S., and Freedman R.  Monitoring eye movements during fMRI tasks with echo planar images.  Hum Brain Mapp. 2002 Dec;17(4):237-43.