This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.1/22/2008Alterations in connectivity among brain regions such as the frontal lobe, basal forebrain and limbic system have been proposed as network deficits in schizophrenia. The multiregional aspects of the hypothesized problems in connectivity implicate a possible deficit in white matter that could lead to the rerouting or interruption of a number of specific brain circuits. A global deficit in myelin in schizophrenia may also produce a pattern of distributed multiregional deficits compatible with the complex, not clearly localizing, behavioral and cognitive disorganization in schizophrenia. Alteration in numbers, distribution, and ultrastructural integrity of oligodendrocytes, key white matter components, has recently been reported in the prefrontal cortex in schizophrenia, consistent with our original diffusion tensor findings of diminished anisotropy in frontal white matter and our replication of this in the first funding period of this project. To extend our findings of white matter abnormalities in schizophrenia we plan four projects: 1) we will complete a longitudinal sample study with follow-up scans 3 yrs in a cohort of patients with schizophrenia and controls where we have already acquired diffusion tensor and structural images from the already acquired sample of 3T longitudinal sample (240 subjects - 125 patients with schizophrenia and 115 matched controls); 2) We will also acquire FDG-PET with absolute glucose quantification on a cohort of 32 unmedicated patients with schizophrenia and 32 age- and sex-matched controls to further develop our initial finding of increased white matter relative metabolic rate in schizophrenia, we will develop exploratory voxel-by-voxel correlations between anisotropy and glucose metabolic rate; 3) We will exploit our recently developed tract tracing programs to assess the specific tract directions and termination points for cingulate, thalamic, striatal, and callosal fibers in the prefrontal cortex; 4) We will share white matter anisotropy and volumetric measures with Projects 1, 2, 3 and 5 and Core B in order to facilitate and inform their potential choice of brain areas to be examined. Taken together, these aims will allow us to obtain the most reliable, valid, functionally different, and informative white matter assessments to confirm specific thalamo-frontal, fronto-striatal and cingulate pathway abnormalities in schizophrenia. Hypothesis: This project is an extension of work completed during the first five years of the Conte Center grant (August 2003-July 2007) (GCO #: 01-1186). During the next funding period we will perform follow-up behavioral and imaging assessments on the cohort of subjects recruited under the previous funding period of our Conte Center recruited through July 31, 2007. In addition we will perform FDG-PET on a newly recruited cohort of subjects in order to further evaluate the white matter hyperactivity findings presented above. We will use pilot data previously collected on an independent cohort to help guide the selection of specific white matter tracts and tract-tracing parameters.
The specific Aims of this project are as follows:
Aim 1 : We will acquire follow-up DTI scans on the chronic and first episode schizophrenic and matched control cohorts scanned with DTI on the 3T machine during the previous funding cycle of our Conte Center (August 2003 - July 2003). In addition, measures of symptom severity, cognitive performance, functional competence and assessments of medical health will be collecteed for exploratory correlational analyses with white matter tract measures. Pilot data on both diffusion tensor and structural images from the previous scans collected under the Conte Center, in addition to other independent DTI data will be used to select the most promising white matter tract regions of interest and cortical areas of volumetric loss. In addition we will collect blood samples on all subjects recruited for follow-up DTI scans for DNA analyses to be conducted by the investigators of Project 2 (O'Donovan).
Aim 2 : We will acquire FDG-PET (Fluoro-deoxy-glucose Positron Emission Tomography) with absolute glucose quantification and DTI scans on a newly identified cohort of 32 un-medicated subjects with schizophrenia and 32 age- and sex-matched controls to test the hypothesis that individuals with low anisotropy in cingulate, frontal white matter, corpus callosum and the superior longitudinal fasciculus will have high metabolic rates in these structures, consistent with disorganized and therefore inefficient white matter. We will develop exploratory voxel-by-voxel correlations between anisotropy and glucose metabolic rate. In addition we will collect blood samples on all 64 subjects recruited for FDG-PET scans for DNA analyses to be conducted by the investigators of Project 2 (O'Donovan).
Aim 3 : We will analyze all DTI images and clinical measures collected during the previous funding cycle of the Conte Center grant (August 2003-July 2007 in detail using new tractography methods. The first of these methods is currently operational (explained in detail in the project text). We will test the hypothesis that Prefrontal cortex organization of thalamocortical fibers will be abnormal in schizophrenia with the 12 Brodmann areas receiving a different proportion and direction of traced tracts.
Aim 4 : We will share diffusion tensor FA data obtained from traced regions and tract number and length measurements with Projects 1, 2, 3 and the Brain Bank Core of the Conte Center in order to facilitate and inform on the selection of interesting brain regions for neuroanatomical studies and to explore the relationships between these imaging findings and important white matter genes identified by Project 2..
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