Neural Excitability and Entrainment as Predictive Biomarkers for Personalized Closed-Loop Neurostimulation in Depression

Major depressive disorder (MDD) remains a leading cause of disability worldwide, with substantial variability in treatment response. We developed a closed-loop, EEG-synchronized rTMS framework that aligns stimulation with each individual’s intrinsic alpha oscillations to enhance network-level synchrony and treatment predictability. In a randomized, double-blind, active comparator-controlled clinical trial, personalized phase-synchronized rTMS produced more predictable clinical outcomes in treatment-resistant depression compared to unsynchronized stimulation. We identified two EEG-derived neurophysiological biomarkers—progressive decreases in cortical excitability and increases in entrainment—that predicted clinical improvement following synchronized treatment. In an accelerated protocol combining EEG-synchronized rTMS with cognitive behavioral therapy in patients with recent suicide attempts, all participants achieved clinical response and remission sustained at one month. Biomarker trajectories replicated the entrainment-excitability pattern, with the optimal stimulation phase aligning across emotion regulation and cognitive flexibility networks, reinforcing synchrony as a robust and predictive mechanism for therapeutic modulation.