NEUROPHYSIOLOGICAL STUDIES OF SCHIZOPHRENIA

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The broad goal of this work is to define neurophysiological abnormalities in schizophrenia, and thus to lay a foundation for a more rational approach to treatment. A first group of studies will examine the characteristics of our thrice-replicated findings of a topographic asymmetry of the auditory P300 event-related potential (ERP) in schizophrenics, referred to as the "left temporal feature" (LTF) and consisting of an amplitude reduction at T3 that maximally differentiates schizophrenics from normals. Its presence in a larger unmedicated schizophrenic group will be determined. A longitudinal study will investigate the state-trait nature of the LTF in schizophrenics and its covariation with changes in clinical status, including positive symptoms. Its diagnostic specificity will be examined in contrast groups of patients with major mood disorders with psychotic features (bipolar and unipolar). This application also proposes new ERP and attentional measures bearing on left hemisphere and attentional pathology in schizophrenia that will both complement and contrast with the P300 LTF. The visual N400, and ERP associated with semantic incongruity, will be used as a possible convergent measure, since both N400 and P300 may have temporal lobe sources and both may be associated with positive symptoms. The N400 will be studied in schizophrenics and contrast groups of normal controls and of bipolar and unipolar mood disorders with psychotic features. It is further proposed to develop "manic-specific" and "schizophrenic-specific" anomalous sentence completions that will have N400 effects specific to each diagnostic group, and to determine the relationship of thought disorder in individual patients (cloze probabilities of speech) to the N400 ERP abnormalities. As a contrasting measure, the application proposes to investigate whether the P200 abnormalities and their correlations with negative symptoms reported by us will replicate in unmedicated schizophrenic subjects. A computerized visual continuous performance task using degraded stimuli to match initial performance of patients and normals will determine if the P300 LTF is related to a schizophrenic deficit in sustained attention. Visual P300 ERPs to the target stimuli of the CPT will be examined to determine if amplitude and topographic abnormalities covary with a decline in performance. Finally, to contrast with our auditory tasks, and as a complementary and contrasting measure of hemispheric pathology, the "Posner paradigm" of visual attention testing will be utilized in unmedicated schizophrenics and normals to determine if there is a right hemisphere visual attention deficit, as preliminary data suggest. Methodological features of the studies proposed include 28-electrode scalp recordings, age-matched normal control groups, unmedicated patients (except for the longitudinal study), and the use of multivariate statistics for hypothesis testing.