The long-term objective of this proposal is to understand the nature of brain abnormalities in schizophrenia by applying in vivo neuroimaging tools from the rapidly developing field of neuroimaging. The short-term objective is to evaluate white matter abnormalities using Magnetic Resonance (MR) Diffusion Tensor Imaging (DTI), a relatively new neuroimaging tool that reveals the physical properties of white matter. Of particular note, this new imaging tool is the only in vivo tool available to evaluate white matter fiber bundle abnormalities in schizophrenia, and, while plagued by problems expected in a new field of inquiry, it is still the most promising and powerful tool available to evaluate white matter alterations in schizophrenia. This imaging technique will be used to investigate white matter abnormalities in fronto-temporal white matter connections, interhemispheric white matter connections, thalamo-frontal fiber tracts, and frontal-parietal white matter connections. The subject sample will be right-handed patients with schizophrenia (both chronic and first episode) and age, gender, handedness, and parental socioeconomic status group matched controls. The study sample will be comprised of 50 chronic patients,110 first episode patients, and 160 controls studied at baseline over the 5 year grant period, and 50 first episode and 50 controls studied again at follow up one year later. MR DTI region of interest and tractography measures will be used to quantify anisotropic diffusion (degree of directionality of water movement, measured as fractional anisotropy) and diffusivity (average diffusion in all directions) in the aforementioned fiber bundles. Longitudinal changes will also be evaluated one year later in first episode patients and controls in order to determine progressive changes in white matter over this time period in first episode patients compared with controls. Specific predictions are made with respect to cognitive and DTI abnormalities (e.g., correlations between semantic priming abnormalities and arcuate fasciculus abnormalities). In addition another measure of white matter health and integrity, the interhemispheric transfer time task (IHTT), will be included in a visual evoked potential study, where it is predicted that IHTT efficiency will be compromised in schizophrenia. It is also predicted that longer IHTT, and decreased asymmetry, will be correlated with DTI measures in posterior portions of the corpus callosum, the largest white matter tract in the brain, which, in turn, will be correlated with measures of speed of processing. A longitudinal design is also a part of the IHTT measures, i.e., first episode patients and controls will be evaluated one year later. The investigation of MR DTI in schizophrenia will lead to a further understanding of white matter fiber tract abnormalities in this disorder, which will add a key link to understanding the neuropathology of schizophrenia, and ultimately to better and more rational treatment.

Public Health Relevance

Schizophrenia is a devastating disorder that affects close to 1% of the general population and 40% of all VA mental healthcare costs ( Understanding this disorder is thus critical to the VA mission. Magnetic Resonance (MR) Diffusion Tensor Imaging (DTI) will be used to investigate white matter (WM) brain abnormalities in schizophrenia. Heretofore, conventional MR findings reported gray matter abnormalities, but few studies reported WM abnormalities. With the advent of DTI, WM tracts important to schizophrenia can now be investigated. DTI images will be acquired from chronic and first-episode patients, as well as controls. A measure of processing speed will also be included and relevant cognitive and symptom measures will be evaluated to determine associations among WM, cognitive abnormalities, clinical symptoms, and processing speed. This proposal will lead to new findings regarding WM abnormalities and cognitive and clinical correlates, which, in turn, will ultimately lead to better and more rationale treatment of this devastating disorder.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Mental Health and Behavioral Science B (MHBB)
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VA Boston Health Care System
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Ohtani, Toshiyuki; Del Re, Elisabetta; Levitt, James J et al. (2018) Progressive symptom-associated prefrontal volume loss occurs in first-episode schizophrenia but not in affective psychosis. Brain Struct Funct 223:2879-2892