Selective Prefrontal Disinhibition in a Roving Auditory Oddball Paradigm Under N-Methyl-D-Aspartate Receptor Blockade

Abstract

Background: Disturbances in N-methyl-D-aspartate receptors (NMDARs)—as implicated in patients with schizophrenia—can cause regionally specific electrophysiological effects. Both animal models of NMDAR blockade and clinical studies in patients with schizophrenia have suggested that behavioral phenotypes are associated with reduction in inhibition within the frontal cortex. Methods: Here we investigate event-related potentials to a roving auditory oddball paradigm under ketamine in healthy human volunteers (N = 18; double-blind, placebo-controlled, crossover design). Using recent advances in Bayesian modeling of group effects in dynamic causal modeling, we fit biophysically plausible network models of the auditory processing hierarchy to whole-scalp event-related potential recordings. This allowed us to identify regionally specific effects of ketamine in a distributed network of interacting cortical sources. Results: We show that the effect of ketamine is best explained as a selective change in intrinsic inhibition, with a pronounced ketamine-induced reduction of inhibitory interneuron connectivity in frontal sources, compared with temporal sources. Simulations of these changes in an integrated microcircuit model shows that they are associated with a reduction in superficial pyramidal cell activity that can explain drug effects observed in the event-related potential. Conclusions: These results are consistent with findings from invasive recordings in animal models exposed to NMDAR blockers, and provide evidence that inhibitory interneuron–specific NMDAR dysfunction may be sufficient to explain electrophysiological abnormalities induced by NMDAR blockade in human subjects.