Mismatch negativity as a biomarker of theta band oscillatory dysfunction in schizophrenia

Mismatch negativity (MMN) is among the best established biomarkers of cortical dysfunction in schizophrenia. MMN generators are localized primarily to primary and secondary auditory regions, and are known to reflect activity mediated by cortical N-methyl-d-aspartate-type glutamate receptors (NMDAR). Nevertheless, mechanisms underlying MMN generation at the local circuit level remain incompletely understood. This review synthesizes recent advances in circuit-level conceptualization of MMN based upon neuro-oscillatory findings. In the neuro-oscillatory (aka event-related spectral perturbation, ERSP) approach, responses to sensory stimuli are decomposed into underlying frequency bands prior to analysis. MMN reflects activity primarily in theta (4-7Hz) frequency band, which is thought to depend primarily upon interplay between cortical pyramidal neurons and somatostatin (SST)-type local circuit GABAergic interneurons. Schizophrenia-related deficits in theta generation are also observed not only in MMN, but also in other auditory and visual contexts. At the local circuit level, SST interneurons are known to maintain tonic inhibition over cortical pyramidal interneurons. SST interneurons, in turn, are inhibited by a class of interneurons expressing vasoactive intestinal polypeptide (VIP). In rodents, SST interneurons have been shown to respond differentially to deviant vs. standard stimuli, and inhibition of SST interneurons has been found to selectively inhibit deviance-related activity in rodent visual cortex. Here we propose that deficits in theta frequency generation, as exemplified by MMN, may contribute significantly to cortical dysfunction in schizophrenia, and may be tied to impaired interplay between cortical pyramidal neurons and local circuit SST-type GABAergic interneurons.