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Neuropsychological and Electrophysiological Biomarkers of the Schizophrenia Spectrum

Koychev, Ivan

[Thesis]. Manchester, UK: The University of Manchester; 2011.

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Abstract

Schizophrenia is a neuropsychiatric disorder lying at the extreme of a spectrum of disorders that possibly share a common abnormality in neural connectivity. Efforts to reverse the core cognitive manifestations of schizophrenia using drug treatments have so far been unsuccessful. This thesis investigates the cognitive abnormalities and their electrophysiological correlates across the schizophrenia spectrum in order to identify and validate biomarkers for proof of concept studies of cognitive enhancers. Such studies in milder disorders of the schizophrenia spectrum such as schizotypal personality trait may be a crucial method in identifying new effective compounds, as reviewed in Chapter 3, and tested in Chapter 4. The latter features the results of a large three-centre study which probed the sensitivity of several neuropsychological measures to the schizotypy phenotype, as well as to the effects of amisulpride, risperidone and nicotine. Schizotypal volunteers showed impaired performance only on the more difficult tasks. The most consistent pharmacological finding was that amisulpride tended to improve performance in the high schizotypy group but to impair it in the average schizotypy controls. One interpretation is that the ability of low dose amisulpride to enhance dopamine function in frontal cortex reversed an impairment of dopamine function present in the high schizotypes which is thought to occur in schizophrenia. Chapter 5 explored the methodological question of whether low or average schizotypy individuals should be used as controls in cognitive comparisons versus high schizotypy. The results suggest that low schizotypes have the most intact cognitive performance and are therefore the control group of choice. Chapters 6, 7 and 8 tested the hypothesis that cognitive deficits are part of a larger information processing abnormality in the schizophrenia spectrum. In accordance, both high schizotypy and schizophrenia patients exhibited reduced amplitude of an early visual evoked potential P1 (Chapters 6 and 8, respectively) and disruptions of the underlying evoked neural oscillations (Chapters 7 and 8). The pattern of abnormalities suggested an inefficient top-down modulation of perception in the schizophrenia spectrum. These data argue that cognitive abnormalities and their electrophysiological correlate may be sensitive biomarkers of the core dysconnectivity deficit in schizophrenia. This thesis supports their use in proof of concept studies to foster the development of cognitive enhancers.