Acute Effects of Esketamine on the EEG Power Spectrum and Signal Complexity in Prolonged Disorders of Consciousness: A Prospective Exploratory Cohort Study.

BACKGROUND

Effective treatments for prolonged disorders of consciousness (pDoC) remain limited. Grounded in the entropic brain hypothesis-that psychedelic agents facilitate consciousness recovery by increasing brain complexity-this study investigated esketamine, a nonclassical psychedelic drug, and its effects on electroencephalographic (EEG) neurophysiological metrics in pDoC patients.

METHODS

In this prospective exploratory cohort study, 27 patients with pDoC were enrolled, and 22 with sufficient EEG signal quality were included in the final analysis. Patients were diagnosed with vegetative state/unresponsive wakefulness syndrome (VS/UWS) or a minimally conscious state (MCS). Patients received a 1-hour intravenous infusion of esketamine (0.3 mg/kg/h). EEG data were collected at baseline, 1 hour after infusion, and 30 minutes post-discontinuation. The power spectral density and Lempel-Ziv complexity (LZC) were analyzed. The study was registered at ClinicalTrials.gov (NCT06473285) on June 23, 2024.

RESULTS

Esketamine reshaped the EEG power spectrum, suppressing global delta relative power (p_FDR=0.040) while increasing beta (p_FDR=0.040) and gamma (p_FDR=0.009) relative power. The alpha relative power increased selectively in the VS/UWS (p_FDR=0.012). The LZC increased in the parietal (P=0.030) and occipital (P=0.007) regions. In MCS patients, the increase in LZC persisted for 30 minutes post-discontinuation, most prominently in the occipital region, whereas changes in VS/UWS were transient. No behavioral improvements were observed on the Coma Recovery Scale-Revised assessments.

CONCLUSIONS

Esketamine-induced neurophysiological alterations in patients with pDoC are characterized by reorganization of the EEG power spectral density and region-specific increases in signal complexity. However, these changes were not accompanied by improvements in behavioral responsiveness.