A disorder of thought and language has long been considered a core feature of schizophrenia. The broad objective of this proposal is to identify abnormalities in the neural dynamics of language processing in schizophrenia using multimodal imaging techniques. It is hypothesized that abnormally increased neural/synaptic activity within a temporal-prefrontal network (left superior and middle temporal, bilateral inferior temporal and left inferior prefrontal cortices) to semantic relationships between individual words leads to abnormal modulation of temporal-prefrontal activity as context is built up, word by word, within and across sentences. This cognitive neurobiological theory of language dysfunction in schizophrenia will be tested in a series of experiments studying (a) semantic relationships between word pairs, (b) the build up of context within sentences and (c) contextual integration across sentences (discourse). In order to investigate """"""""when"""""""" and """"""""where"""""""", a multimodal approach will be taken, integrating the advantages of two complementary neuroimaging techniques. First, electrophysiological experiments will determine the time course of neurocognitive abnormalities during language processing in schizophrenia by examining the N400 and late positive components - event related potentials that are known to be sensitive to contextual integration. Second, event-related functional (magnetic resonance imaging studies will characterize the functional neuroanatomy of language abnormalities in schizophrenia by examining the extent, magnitude and temporal dynamics of the hemodynamic response within the temporal-prefrontal semantic network. Third, data obtained using these complementary techniques will be directly compared, allowing inferences to be made about underlying neural/synaptic activity, and quantitatively combined, allowing the delineation of spatiotemporal patterns of activation across temporal and prefrontal cortices during language processing in schizophrenia.
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