Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, “bottom-up” effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions.
Background: Schizophrenia patients exhibit cognitive deficits across multiple domains, including verbal memory, working memory, and executive function, which substantially contribute to psychosocial disability. Gamma oscillations are associated with a wide range of cognitive operations, and are important for cortico-cortical transmission and the integration of information across neural networks. While previous reports have shown that schizophrenia patients have selective impairments in the ability to support gamma oscillations in response to 40-Hz auditory stimulation, it is unclear if patients show abnormalities in gamma power at rest, or whether resting-state activity in other frequency bands is associated with cognitive functioning in schizophrenia patients. Methods: Resting-state electroencephalogram (EEG) was assessed over 3 min in 145 healthy comparison subjects and 157 schizophrenia patients. Single-word reading ability was measured via the reading subtest of the Wide Range Achievement Test-3 (WRAT). Auditory attention and working memory were evaluated using Letter-Number Span and Letter-Number Sequencing. Executive function was assessed via perseverative responses on the Wisconsin Card Sorting Test (WCST). Verbal learning performance was measured using the California Verbal Learning Test second edition (CVLT-II). Results: Schizophrenia patients showed normal levels of delta-band power but abnormally elevated EEG power in theta, alpha, beta, and gamma bands. An exploratory correlation analysis showed a significant negative correlation of gammaband power and verbal learning performance in schizophrenia patients. Conclusions: Patients with schizophrenia have abnormal resting-state EEG power across multiple frequency bands; gamma-band abnormalities were selectively and
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