This project is a longitudinal prospective study of the phenomenology and neurobiology of subjects at high risk for schizophrenia by virtue of their family history, age and manifestation of prodromal symptoms.
The aims are to identify behavioral, neurocognitive and neurobiological abnormalities that precede the onset of, or are associated with the transition to, psychosis. The vast majority of studies of this disorder have examined its clinical phenomenology and neurobiology after patients had become demonstrably ill (in the first episode of psychosis) or after many years of illness and treatment exposure (in the chronic stages of schizophrenia). Consequently, we do not know which pathophysiological and phenomenological features are present prior to the onset of psychosis and which develop as psychosis emerges. Moreover, we do not know the critical brain events that trigger the development of psychotic symptoms, defining the onset of schizophrenia. We postulate that schizophrenia stems from a pathological neurodevelopmental process that occurs during a critical stage of forebrain development in gestation and affects the development of GABA interneurons and their ability to modulate the activity of assemblies of neurons in the hippocampus, prefrontal and anterior cingulate regions that comprise the thalamo-limbic-cortical circuit. These neurodevelopmental abnormalities are expressed premorbidly by subtle behavioral, cognitive, and structural 'vulnerability markers'. In most cases, these abnormalities require specific maturational processes (i.e. synaptic elimination, myelination) which occur postpubertally to unmask the vulnerability and trigger dysfunction, resulting in the onset of prodromal symptoms and ultimately psychosis. To test this hypothesis we will ascertain 120 subjects who meet operational criteria for the prodromal stage of schizophrenia and 30 matched healthy volunteers, and characterize the morphology and function of specific components of the TLC circuit and GABA neurons longitudinally to identify the neurobiological processes that underlie progression to schizophrenia spectrum psychotic disorders. Subjects will be assessed at study entry with clinical, neurocognitive, neurophysiologic, and neuroimaging measures, then followed prospectively through their period of risk for symptom onset or until they develop psychotic symptoms that meet DSM-IV criteria for an Axis I psychotic disorder, at which time they will again be assessed with all measures.
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