Alterations in resting state electrocortical network oscillations, schizophrenia-like symptoms and their relationships induced with the administration of the NMDA receptor antagonist ketamine in human volunteers

Objective: Growing evidence indicates that some of the core psychopathological phenomena observed in schizophrenia, including positive, negative and cognitive symptoms reflect abnormalities in glutamatergic neurotransmission. Combined with the observations that acute administration of sub-anesthetic doses of the N-methyl-D-aspartate receptor (NMDA-R) antagonist, ketamine, induces schizophrenia-like psychopathological effects in healthy volunteers, in vitro and in vivo electrophysiological studies suggest that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) interneurons and alter oscillatory activity and connectivity in several brain regions to produce psychotic, cognitive and emotional manifestations in schizophrenia. In this study, we use resting state electroencephalographic (EEG) oscillations to examine the hypothesis that the NMDA-R antagonist ketamine alters cortical activity and functional connectivity that are associated with changes in behavioral symptoms.

Methods: Intravenous ketamine was administered to a sample of 21 healthy volunteers in a randomized, placebo-controlled, doubleblind crossover design. Clinical symptoms were assessed with the “Clinician Administered Dissociative States Scale” (CADSS) and the 3-min eyes-closed EEG recordings were subjected to: a) spectral analysis for computation of power in delta, theta, alpha, beta, and gamma frequency bands; b) eLORETA analysis for source localization of activity and connectivity in cortical regions of interest (ROIs).

Results: In addition to significant increases in symptom ratings, elevations in posterior delta and diffuse gamma power were evidenced with acute ketamine (vs. placebo) along with power reductions in alpha and beta, with power decreases in the latter two bands being associated with symptom increases. While delta, alpha and beta indexed activity of representative hubs of a cognitive central network (CCN), a default mode network (DMN) or an affective network (AN) were diminished with ketamine, gamma activity of both DMN and CCN were increased. Alpha DMN-CCN connectivity was also reduced with ketamine compared to placebo.

Conclusion: This study supports the hypothesis that NMDA-R-mediated alterations in resting state electrocortical network oscillations contribute to the production of psychotic symptoms associated with schizophrenia.