Mapping Neurodevelopment Abnormality in Schizophrenia

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Abnormalities of brain structure have been shown to be a key biologic characteristic of schizophrenia. Losses of tissue volume and changes in neuronal density have been found in subjects with schizophrenia, involving a group of functionally-related cortical structures in the temporal and frontal lobes. Substantial reductions in neuronal number and volume have also been described in the thalamus of schizophrenia subjects, underscoring the importance of assessing cortical-subcortical circuitry in the disease. The central goal of the proposed Center is to define in greater detail the anatomical pattern of these brain structure abnormalities, the cause of these abnormalities (i.e., genetic versus non-genetic), their potential cellular basis in an animal model, and to establish the linkages between these abnormalities and cognitive manifestations of the disease. The proposed Conte Feasibility Center for Neuroscience Research will have four objectives: 1) to establish a multi-institutional collaboration between scientists with special expertise is psychiatry; neurobiology; neuroimaging and biomedical engineering; 2) to further develop a group of computer software tools that will be of unique value in defining the neurobiology of neuropsychiatric disorders, including but not limited to schizophrenia; 3) to test specific hypotheses and to generate new hypotheses related to the causes and consequences of neuroanatomical abnormalities in subjects with schizophrenia; and 4) to further define the pathogenesis of schizophrenia. In the context of three related Projects supported by two Cores, we propose to test the overarching hypothesis that genetic factors lead to a cascade of neurodevelopment irregularities that are later manifested by abnormalities of brain structure, cognition, and psychopathology in subjects with schizophrenia. Several themes are carried across the individual Projects proposed for the Center. Taken together with shared technologies and resources, these themes represent a strong rationale for the funding of this research as a Center, rather that a series of R01 projects. The first theme stressed in all our projects is the embedding of concepts of brain function within a precise neuroanatomical framework. Our new tools for high dimensional brain mapping provide this framework in a concrete sense for each of the projects. A second theme shared by all projects is the focus on the same distributed network of brain structures. Thirdly, we have used common cognitive concepts and paradigms across studies of human and non- human primate subjects.