Basic Aims: To achieve an increasingly fine resolution of the components of the cognitive processes that are disordered in schizophrenia (e.g., attention, memory, language); to relate them to the symptomatic manifestations of the disorder; to identify their neural substrates; to further refine a unifying concept of schizophrenia that will facilitate more basic research targeted toward identification of its cellular, molecular, and developmental mechanisms. Basic Hypothesis: Schizophrenia is characterized by a fundamental cognitive deficit, referred to as """"""""cognitive dysmetria."""""""" This deficit is due to an underlying dysfunction of the neural circuits that provide interconnections and ongoing feedback between prefrontal cortex and the cerebellum, linked through the thalamus. In the healthy brain, these circuits facilitate the fluid coordination of mental functions--planning, initiation, timing, and monitoring of behavior. Patients with schizophrenia display impairments in both cognitive and motor behavior that reflect a dysfunction in this circuitry. The presence of this fundamental cognitive deficit leads to the very frequently observed phenomenon that patients with schizophrenia display a 'generalized deficit' on most cognitive tasks. It also explains the fact that schizophrenia is a polythetic disorder, that patients present with a diversity of symptoms, and that these symptoms cover the broad range of human cognitive, perceptual, emotional, and motor functions. Basic Methods: This hypothesis will be tested through convergent measures, using the techniques of MR imaging, PET imaging, experimental cognitive psychology, clinical psychopathology, and assessments of motor function. Interrelated experiments are proposed that permit the use of PET to dissect the components of cognitive operations and define their functional circuitry, complemented by the use of MR to localize these components anatomically and to determine whether they have gross anatomical substrates. During the five-year period of the grant, a total of 200 patients and controls will be studied. We have developed innovative MR sequences to measure the cerebellum and thalamic nuclei. We will also apply innovative image analysis techniques, either locally developed or obtained from experienced consultants, including neural nets, flat maps, and high dimensional transformations. These will be used to measure cortical surface anatomy and the volume of substructures such as caudate or hippocampus. Ten different groups of PET experiments will be completed, which are grouped into three general categories: motor rhythms and perception of time intervals, memory and temporal computation, and attention and executive function and temporal computation.
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