Alterations in connectivity among brain regions such as the frontal lobe, basal forebrain and limbicsystem have been proposed as network deficits in schizophrenia. The multiregional aspects of thehypothesized problems in connectivity implicate a possible deficit in white matter that could lead to thererouting or interruption of a number of specific brain circuits. A global deficit in myelin in schizophrenia mayalso produce a pattern of distributed multiregional deficits compatible with the complex, not clearly localizing,behavioral and cognitive disorganization in schizophrenia. Alteration in numbers, distribution, andultrastructural integrity of oligodendrocytes, key white matter components, has recently been reported in theprefrontal cortex in schizophrenia, consistent with our original diffusion tensor findings of diminishedanisotropy 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 willcomplete a longitudinal sample study with follow-up scans 3 yrs in a cohort of patients with schizophreniaand controls where we have already acquired diffusion tensor and structural images from the alreadyacquired sample of 3T longitudinal sample (240 subjects - 125 patients with schizophrenia and 115 matchedcontrols); 2) We will also acquire FDG-PET with absolute glucose quantification on a cohort of 32unmedicated patients with schizophrenia and 32 age- and sex-matched controls to further develop our initialfinding of increased white matter relative metabolic rate in schizophrenia, we will develop exploratory voxelby-voxel correlations between anisotropy and glucose metabolic rate; 3) We will exploit our recentlydeveloped 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 andvolumetric measures with Projects 1, 2, 3 and 5 and Core B in order to facilitate and inform their potentialchoice 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-frental,fronto-striatal and cingulate pathway abnormalities in schizophrenia.
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