Computational Modeling of Oddball Sequence Processing Exposes Common and Differential Auditory Network Changes in First-Episode Schizophrenia-Spectrum Disorders and Schizophrenia

Abstract

Background and Hypothesis: Differences in sound relevance filtering in schizophrenia are proposed to represent a key index of biological changes in brain function in the illness. This study featured a computational modeling approach to test the hypothesis that processing differences might already be evident in first-episode, becoming more pronounced in the established illness. Study Design: Auditory event-related potentials to a typical oddball sequence (rare pitch deviations amongst regular sounds) were recorded from 90 persons with schizophrenia-spectrum disorders (40 first-episode schizophrenia-spectrum, 50 established illness) and age-matched healthy controls. The data were analyzed using dynamic causal modeling to identify the changes in effective connectivity that best explained group differences. Study Results: Group differences were linked to intrinsic (within brain region) connectivity changes. In activity-dependent measures these were restricted to the left auditory cortex in first-episode schizophrenia-spectrum but were more widespread in the established illness. Modeling suggested that both established illness and first-episode schizophrenia-spectrum groups expressed significantly lower inhibition of inhibitory interneuron activity and altered gain on superficial pyramidal cells with the data indicative of differences in both putative N-methyl-d-aspartate glutamate receptor activity-dependent plasticity and classic neuromodulation. Conclusions: The study provides further support for the notion that examining the ability to alter responsiveness to structured sound sequences in schizophrenia and first-episode schizophrenia-spectrum could be informative to uncovering the nature and progression of changes in brain function during the illness. Furthermore, modeling suggested that limited differences present at first-episode schizophrenia-spectrum may become more expansive with illness progression.