Schizophrenia is a devastating and common disorder, affecting 1% of the population worldwide, and causing tremendous suffering at great societal cost. Psychosis, consisting of the symptoms of delusions and- hallucinations, represents the most striking and severe part of the psychiatric symptom spectrum, and causes significant morbidity. Nevertheless, less is known about the pathophysiology of such positive symptoms, compared with the widely studied deficit or negative symptoms. Functional neuroimaging is uniquely suited to an in vivo, systems-level investigation of psychiatric disorders, and can be adapted for the study of psychosis. Functional magnetic resonance imaging (fMRI) methods are now mature enough to reliably take advantage of the increased spatial and temporal resolution offered by this technology. The investigators have optimized methods of fMRI study design, image acquisition and analysis for the study of psychotic symptoms.. They have also developed behavioral activation paradigms to target the specific neural circuits and neuropsychological functions implicated in these symptoms, based upon their previous work, in the context of current knowledge in the field. In this project these methods will be used with well-characterized, actively paranoid schizophrenic patients as well as non-psychotic patient and normal control subjects, to identify and characterize patterns of neural activity associated with the prominent psychotic symptom of paranoid delusions, and to test a neurobiologically specific model of psychosis in schizophrenia. This model is closely integrated with basic neuroscientific models and experiments, and focuses upon increased activity in mesotemporal and subcortical mesolimbic structures, in the setting of decreased activity in medial prefrontal regions. Such a neurobiological characterization of the major psychotic symptoms can increase our understanding of the pathophysiology of schizophrenia, and thereby provide a necessary foundation for the development of more targeted, biologically based diagnostic and therapeutic strategies.
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