Abnormal Effective Connectivity Underlying Auditory Mismatch Negativity Impairments in Schizophrenia

Abstract

BackgroundAuditory mismatch negativity (MMN) is a translatable event-related potential biomarker, and its reduction in schizophrenia is associated with the severity of clinical symptoms. While MMN recorded at the scalp is generated by a distributed network of temporofrontal neural sources, the primary contributing sources and the dynamic interactions among sources underlying MMN impairments in schizophrenia have not been previously characterized. MethodsA novel data-driven analytic framework was applied to large cohorts of healthy comparison subjects (n = 449) and patients with schizophrenia (n = 589) to identify the independent contributing sources of MMN, characterize the patterns of effective connectivity underlying reduced MMN in patients, and explore the clinical significance of these abnormal source dynamics in schizophrenia. ResultsA network of 11 independent contributing sources underlying MMN distributed across temporofrontal cortices was identified. Orderly shifts in peak source activity were detected in a steplike manner, starting at temporal structures and progressing across frontal brain regions. MMN reduction in patients was predominantly associated with reduced contributions from 3 frontal midline sources: orbitofrontal, anterior cingulate, and middle cingulate cortices. Patients showed increased connectivity from temporal to prefrontal regions in conjunction with decreased cross-hemispheric connectivity to prefrontal regions. The decreased connectivity strength of precentral to prefrontal regions in patients with schizophrenia was associated with greater severity of negative symptoms. ConclusionsAlterations in the dynamic interactions among temporofrontal sources underlie MMN abnormalities in schizophrenia. These results advance our understanding of the neural substrates and temporal dynamics of normal and impaired information processing with novel applications for translatable biomarkers of neuropsychiatric disorders.