Lower pre-treatment TMS-evoked cortical reactivity and alpha-band oscillatory dynamics predict efficacy of primary motor cortex neuromodulation for chronic pain

Repetitive transcranial magnetic stimulation (rTMS) to the primary motor cortex (M1) provides significant pain relief in ∼45% of chronic pain patients. Identifying biomarkers that predict treatment response before starting rTMS is essential for guiding clinical decision-making. Here, we used TMS combined with electroencephalography (TMS-EEG) to assess pre-treatment cortical function in 43 patients with chronic pain before receiving 12 sessions of therapeutic 10 Hz rTMS to M1 over eight weeks as a secondary analysis from a trial comparing effects of rTMS in different cortical targets. Responders were defined as individuals reporting a ≥ 30% reduction in pain intensity on a visual analogue scale at week 8. Pre-therapy TMS-evoked cortical reactivity was quantified using global mean field power (GMFP) and local mean field power (LMFP) within an early post-stimulus window (20-120 ms). Oscillatory dynamics were measured by event-related spectral perturbation (ERSP) and intertrial coherence (ITC) in alpha (8-12 Hz), low-beta (13-20 Hz), and high-beta (21-30 Hz) bands. Compared with non-responders, responders (n = 20; 47%) showed lower GMFP, LMFP, alpha-band ERSP, and ITC at the stimulation site (p < 0.05). These low measures correlated with greater reductions in pain intensity (p < 0.05). Exploratory supervised machine-learning analysis using three TMS-EEG features (GMFP, alpha-band ERSP, alpha-band ITC) predicted responder status with acceptable performance (ROC-AUC=0.70, PR-AUC=0.76). These findings suggest that lower pre-treatment TMS-evoked cortical reactivity and alpha-band oscillatory dynamics may identify patients more likely to benefit from rTMS. Prospective clinical trials should test pre-therapy reactivity and connectivity metrics to select patients more likely to benefit from therapy.