This application uses functional imaging to examine cerebellar dysfunction in schizophrenia. It builds on our previous work, which has consistently shown that patients with schizophrenia have functional abnormalities in regional cerebral blood flow (rCBF) in distributed circuits (including cortical regions, thalamus, and cerebellum) in many types of cognitive tasks. We have described the resulting behavioral/cognitive abnormality as """"""""cognitive dysmetria."""""""" In this application we propose to focus primarily on the cerebellum, based on our work during the past four years. During this time we examined a variety of tasks, which ranged from """"""""classic cerebellar"""""""" (eyeblink conditioning) to """"""""higher"""""""" cognitive and emotional tasks. All types of tasks showed cerebellar activations in normals and decreased flow in schizophrenia. Therefore, in the present application we plan to extend this work by examining three different models of cerebellar function in the normal brain: associative learning, timing and psychomotor integration, and multipurpose microcomplexes. We will examine these three models by using eight different PET protocols in healthy normal volunteers. These models are hierarchical, in that models 1 and 2 are encompassed in model 3. We hypothesize that we will confirm all three models, and that model 3 provides the best characterization of the role of the cerebellum in cognition. The eight protocols include studies of """"""""classic cerebellar"""""""" functions (e.g., associative learning and psychomotor integration) and """"""""higher cortical"""""""" functions (e.g., working memory, emotion, and social cognition). We will use these protocols to study these functions in eight different groups of patients suffering from schizophrenia. We hypothesize that the patients will show decreased cerebellar blood flow in all eight groups of tasks (as compared to the healthy volunteers), thereby confirming that the cerebellum is dysfunctional in schizophrenia in a broad range of tasks and suggesting that the importance of the cerebellum in both normal mental function and in schizophrenia has been underestimated.
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