Esketamine disinhibits brain networks in depression: Evidence from oscillatory and aperiodic activity

Nasal Esketamine is a rapid-acting intervention for depression, hypothesized to exert its effects through cortical disinhibition. However, the spatio-temporal dynamics of brain network activity and their relationship to the subjective drug experience following Esketamine administration remain elusive. This observational study aims to delineate brain network-level effects of Esketamine by analyzing changes in oscillatory and aperiodic EEG activity within 90 min following nasal Esketamine treatment in depression.

Eight individuals with major depressive disorder undergoing regular Esketamine treatment participated in the study. High-density, eyes-open resting state EEG was recorded before and subsequently five times up to 90 min post-administration. Before each recording, individuals completed ratings of individual drug experience. EEG spectral features were separated into canonical frequency bands and aperiodic exponent. Primary outcomes were changes in neural activity and their association with individual drug experience.

Following Esketamine administration, we observed a marked decrease of frontoparietal alpha power and central beta and a significant increase of frontal midline delta and low gamma power, indicative of cortical disinhibition and reduction of top-down control. Correspondingly, the aperiodic exponent decreased, suggestive of a shift of the excitation/inhibition balance towards excitation. These electrophysiological changes were accompanied by an increase in subjective ratings of highness and happiness, and a decrease in tension. Further analyses revealed significant relationships between changes in neural activity and subjective drug experience.

Our findings suggest that Esketamine induces brain network disinhibition and reduces top-down control. These neurophysiological changes closely correlate with individual drug experience, providing valuable insights into the neural mechanisms underlying Esketamine's immediate behavioral effects.