Alterations in temporal-spatial brain entropy in treatment-resistant depression treated with nitrous oxide: Evidence from resting-state EEG

Objective: Entropy analysis can quantify the dynamic states of the brain and reflect its information processing capacity. Nitrous oxide has shown rapid antidepressant effects in treatment-resistant depression (TRD) patients, but its biomarkers are not yet established. Methods: We recruited 44 TRD patients and randomly assigned them to two groups: one received a 1-hour nitrous oxide inhalation treatment, while the other received a placebo. Resting-state EEG (rs-EEG) scans were conducted at baseline and 24 h post-treatment. A novel approach based multivariate multiscale entropy (MMSE) was employed to analyze temporal-spatial brain entropy (ts-BEN) across four hierarchical brain regions. Results: TRD patients exhibited significant time-dependent increases in BEN in the frontal lobe region (sensor space: time scales 5–10; source space: time scales 1–5), changes not previously observed. Temporal-spatial BEN correlated with the severity of TRD symptoms and treatment efficacy, indicating adaptive adjustments in brain resting states. Conclusion: MMSE offers a novel supplementary method for rs-EEG BEN analysis, quantifying the sensitivity of ts-BEN in monitoring nitrous oxide treatment effects. Changes in frontal region ts-BEN may serve as potential biomarkers for TRD and its treatment outcomes. Significance: Our findings enhance the understanding of the physiological mechanisms underlying nitrous oxide treatment for TRD, aiding in clinical diagnosis.