This application requests five years of funding in order to conduct a series of interrelated imaging studies of the major psychoses, principally schizophrenia, using three imaging modalities: MRl, SPECT, and PET. These studies build sequentially on one another. The MRl studies emphasize the development of automated volumetric techniques that will provide a foundation for identifying structural locations on functional images of the brain through PET and SPECT. In addition, lesions will be localized using MRl in order to study a series of patients who have received prefrontal leukotomy in order to increase our knowledge of frontal lobe anatomy and function. The SPECT studies provide a relatively inexpensive functional imaging technique that will be used to develop new and relatively specific frontal lobe activation tasks. These studies of normals will be followed by studies of patients suffering from schizophrenia in order to determine whether they show specific deficits in prefrontal cortical function and whether these are related to a particular type of clinical syndrome such as prominent negative symptoms. In addition, we will begin to search for new 1-123 labelled ligands in order to measure dopamine receptor function with SPECT. A series of PET studies is proposed that will map the dopamine system in psychosis. These studies will compare two models developed for measuring D2 receptor density, the equilibrium model and the dynamic model. Twenty drug-naive patients will be evaluated for increased D2 receptor density; their response to treatment will also be examined in a dose response study that simultaneously monitors clinical status, receptor occupancy as measured by PET, and serum blood levels; this study will be followed by a withdrawal study in these drug-naive patients in order to determine whether neuroleptic treatment has induced increased D2 receptor numbers. PET studies of patients with tardive dyskinesia are also proposed in order to explore whether they show increased D2 receptor density. A study of treatment- refractory patients will examine relationships between receptor numbers, receptor occupancy, and clinical status. A sample of drug-naive manics will also be studied in order to determine whether dopamine system abnormalities are specific to psychosis. PET studies of cognitive activation (frontal and language systems) will also be conducted with both normals and schizophrenics, probably using oxygen-15 labelled water to measure changes-- in cerebral perfusion.
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