Abnormal effective connectivity underlying auditory mismatch negativity impairments in schizophrenia

Abstract Background Auditory 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 Methods A novel data-driven analytic framework was applied to large cohorts of healthy comparison subjects (n=449) and schizophrenia patients (n=589) in order 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 Results A network of 11 independent contributing sources underlying MMN distributed across temporofrontal cortices was identified. Orderly shifts in peak source activity were detected in a step-like manner starting at temporal structures and progressing across frontal brain regions. MMN reduction in patients was predominantly associated with reduced contributions from three frontal midline sources: orbitofrontal and anterior and middle cingulate. Patients showed increased connectivity from temporal to prefrontal regions in conjunction with decreased cross-hemispheric connectivity to prefrontal regions. The decreased precentral to prefrontal regions connectivity strength in patients was associated with greater severity of negative symptoms Conclusions Alterations 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.