The Brain Imaging Research Core, BIRC, a new core in this Center, has assembled a group of highly skilled investigators with expertise in various aspects of brain imaging such as study design, image analysis, radiochemistry and kinetic modeling. The general missions of the BIRC will include: 1) providing expert logistical support to """"""""project specific"""""""" studies, 2) training young investigators, 3) providing """"""""center wide"""""""" measurements (MRI volumetric analyses and electrophysiological studies), and 4) development new imaging modalities pertinent to schizophrenia.. """"""""Project specific"""""""" studies are generally performed on a predefined set of patients, and are mainly funded by RO1s while """"""""center- wide"""""""" measurements are performed on all patients admitted to the Center and are available to all investigators of the MHCRC. Over the next five years, the development effort of this core will target the dopamine (DA) system with PET, and the gamma-amino-butyric (GABA) system with MRS. The choice of these objectives is guided by a general model of neurochemical imbalances and dysregulations in specific cortico-subcortical neuronal networks in schizophrenia. The overall hypothesis, based on preliminary results and data from animal models, proposes that schizophrenia is related to a failure of normal brain development associated with disruption of hippocampal formation connectivity, and reduction of DA and/or GABA function in the prefrontal cortex (PFC), leading to a dysregulation of subcortical DA systems. We will develop and validate measures of DA activity in the PFC in schizophrenia, using a D1 receptor radiotracer, [11C]NNC 112, and a DA depletion paradigm, and in the mesial temporal structures using a high affinity D2 receptor radiotracer, [18F]fallypride, combined with DA challenge tests. We will develop a D2 receptor agonist, [11C] pramipexole, to study potential alterations in the affinity of D2 receptors for agonists in schizophrenia; and a radiotracer for the D4 receptor, [18F]fluoropropyl-L745,870. For the GABAergic system, our goal is to develop and validate an MRS method to measure GABA concentration in the PFC in schizophrenia. Combined together, these developments will provide the tools to test different components of the cortico-subcortical network in schizophrenia, and to integrate them into a heuristic model of the illness.
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