Phase-targeted Poisson closed-loop peripheral nerve stimulation modulates sensorimotor oscillations in human MEG

Abstract

Closed-loop brain stimulation offers a promising approach for modulating neural oscillations, but the mechanisms of phase-dependent neuromodulation remain poorly understood. We developed a real-time MEG-based closed-loop system delivering median nerve stimulation using a phase-modulated Poisson process. Sixteen healthy participants (11 female, 5 male) underwent open-loop characterization followed by closed-loop testing of eight phase-offset conditions (0°-315°), each paired with a statistically matched replay control. Closed-loop stimulation induced robust phase-dependent modulation (14.21 ± 8.24%) versus replay (7.03 ± 2.95%; p = 0.0003), with consistent phase specificity across participants (circular mean: 70.2°, referenced to each individual’s dominant frequency). At the group level, alpha oscillations (8-12 Hz) showed bidirectional modulation (mean boost: +21.0 ± 19.9% at 0°-135°; mean suppression: −13.3 ± 10.8% at 180°-315°), while beta oscillations (13-30 Hz) showed predominantly unidirectional suppression (−9.3 ± 9.6%). Successful fixed-frequency targeting required alignment with each individual’s natural peak. Misalignment led to different phase shifts producing power at different frequencies—a phenomenon we term phase-frequency coupling. Dynamic frequency tracking (8-30 Hz) automatically identified and targeted each individual’s natural peak, achieving robust bidirectional modulation without prior knowledge of peak location. These findings demonstrate that real-time phase-locked peripheral nerve stimulation selectively modulates sensorimotor oscillations beyond statistically matched open-loop stimulation. The distinct phase-excitability relationships of alpha and beta oscillations, together with the importance of aligning stimulation with individual natural peaks, establish principled guidelines for personalized closed-loop neuromodulation. Significance Statement Closed-loop brain stimulation offers a promising approach for modulating neural activity, but it remains unclear whether stimulation must be precisely timed to ongoing brain rhythms to be effective. Here, we show that real-time phase-locked peripheral nerve stimulation selectively modulates human sensorimotor oscillations, and that this effect is lost when stimulation timing is independent of brain state. By combining a novel phase-modulated Poisson stimulation paradigm with a rigorous replay control, we establish that phase alignment to the brain’s endogenous rhythm is critical for effective neuromodulation. These findings provide principled guidelines for designing personalized closed-loop neurostimulation strategies, with implications for both understanding brain state-dependent excitability and developing adaptive interventions for neurological disorders.