Hierarchical Pathways from Sensory Processing to Cognitive, Clinical, and Functional Impairments in Schizophrenia

Abstract

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.

Keywords: cognitive function; functional outcomes; gamma-band auditory steady-state response (ASSR); mismatch negativity (MMN); schizophrenia.

Fig. 1.

Path models for the associations among Sensory Discrimination, Gamma-band ASSR, Cognition, Negative Symptoms and Functional Outcomes constructs. In these models, we used negative symptoms as one latent variable because we intended to simply focus on the hierarchical organization from neurophysiological indices to functional outcomes via neurocognition and negative symptoms, but not on complex clinical symptoms in schizophrenia patients. Thus, these models are different from our previous work as the addition of Gamma-band ASSR into the neurophysiologic model of Sensory Discrimination allows a clearer resolution of the spectrum of neurophysiologic impairments as their causal “up stream” effects on Cognition, Negative Symptoms, and Functional Outcomes. ASSR, auditory steady-state response (Colored figure is available online).

Fig. 2.

Event-related potentials (A), inter-trial phase coherence, and event-related spectral perturbation (B) at Fz. The inter-trial phase coherence indicates phase consistency across trials and ranges between 0 (random phase across trials) and 1 (identical phase across trials). The time-course figures on the right side (B) show mean of inter-trial phase coherence and event-related spectral perturbation between 35 and 45 Hz, respectively (Colored figure is available online).

Fig. 3.

Correlations among observed indices of Sensory Discrimination indices, Gamma-band ASSR indices, Cognition, Negative Symptoms, and Functional Outcomes. Asterisks and bold values indicate statistical significance P < .00042 (0.05/120; 120 indices) adjusted with Bonferroni correction. CVLT-II, California Verbal Learning Test-Second Edition; ERSP, Event-Related Spectral Perturbation; ITC, Inter-Trial Coherence; MMN, Mismatch Negativity; SANS, Scale for the Assessment of Negative Symptoms; SOF, Scale of Functioning (Colored figure is available online).

Fig. 4.

Measurement model (M0) and final path model (M5). Associations between nodes (observed variables [rectangles] and latent variables [ovals]) are represented by edges (lines) that can be either directed (single-headed arrow) or undirected (double-headed arrow). Coefficients for the completely standardized solution are reported in the figure. Information in italics indicates constrained loadings (supplementary method S4). *P < .05. CVLT-II, California Verbal Learning Test-Second Edition; SANS, Scale for the Assessment of Negative Symptoms; ASSR, Auditory Steady-State Response; SOF, Scale of Functioning (Colored figure is available online).