Neurophysiology of mismatch negativity generation: a biophysical modeling study

The mismatch negativity, or MMN, is a ubiquitous evoked brain response elicited by any discriminable change of an otherwise regular stimulus sequence. Despite its potential clinical relevance - the MMN is known to be affected by brain state, lesions, and neurologic/psychiatric disorders - and a growing body of animal work, the underlying neurophysiology of the MMN is not well understood. This hinders translation of circuit-level animal findings and mitigates the utility of the MMN as a neurologic/psychiatric biomarker. Here, we used biophysical modeling to examine the neurophysiological basis of the MMN as measured in a canonical auditory oddball paradigm with frequency deviants (i.e., tones whose frequency was shifted slightly with respect to standard tones). The response to standards was successfully modeled by a typical feedforward-followed-by-feedback input sequence. The response to deviants required additional, prolonged input to supragranular layers, consistent with input from the non-lemniscal thalamus. This additional input resulted in downward-going pyramidal-neuron currents in both layer 2/3 (via indirect somatic inhibition) and, critically, layer 5 (via direct apical excitation), which together generated the MMN. The results suggest that current circuit-level models of MMN generation derived from animal models are incomplete, and that further work is required to characterize the underlying neurophysiology of the MMN.