Clinical Outcomes and Corticomotor Excitability After Accelerated High-Frequency rTMS in Refractory Trigeminal Neuralgia: A Prospective Comparative Cohort Study

Objective: The objective of this study is to evaluate three-month changes in corticomotor excitability, assessed by motor-evoked potential (MEP) amplitudes, following accelerated high-frequency repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) in patients with refractory trigeminal neuralgia (TN), and to determine whether chronological age modifies neurophysiological and clinical outcomes. Methods: This prospective, non-randomized, parallel-group comparative cohort study enrolled 192 patients with refractory classical TN, diagnosed according to the International Classification of Headache Disorders, third edition (ICHD-3). The active rTMS group (n = 108) received 10 intensive sessions over five consecutive days (two sessions per day, 40 min interval) using combined 10 Hz and 20 Hz sub-protocols targeting the M1 facial motor representation contralateral to the symptomatic side, guided by international 10/20 electroencephalography (EEG) landmarks and functional MEP optimization. The control group (n = 84) received optimized standard pharmacological care (carbamazepine and/or gabapentin). We assessed Brief Pain Inventory (BPI) and Quality-of-Life Pain (QoLp) scores at baseline (T0), one month (T1), and three months (T3) in both cohorts to evaluate the sustainability of the analgesic effect without maintenance therapies. Longitudinal MEP monitoring was performed exclusively in the active rTMS cohort to trace trajectories; no direct between-group MEP comparisons were performed, and follow-up was fixed at three months. Results: At 3 months, mean facial MEP amplitudes decreased within the active rTMS group (58.11 ± 12.77 μV to 49.77 ± 12.49 μV; p < 0.001), indicating a temporal association with reduced local cortical excitability. This neurophysiological shift paralleled robust clinical improvements: cumulative BPI scores dropped from 96.60 ± 24.88 to 32.88 ± 24.75 (p < 0.001), representing a 65.96% pain reduction, and QoLp scores rose from 4.32 ± 1.85 to 8.57 ± 1.36 (p < 0.001), indicating substantial elevation in functional independence. The control group showed statistically significant but clinically modest changes (p < 0.001, consistent with tabulated estimates), substantially lower than those in the active cohort (group-by-time interaction, p < 0.001). Mixed-design ANCOVA indicated that therapeutic benefits were not modified by chronological age (age-by-time interaction, p > 0.05), despite the active rTMS group having an older baseline age profile (54.69 ± 16.27 vs. 43.17 ± 17.27 years; p < 0.001) due to protracted clinical pharmacoresistance. Conclusions: Accelerated dual-frequency rTMS over the contralateral M1 facial representation may produce measurable reductions in corticomotor excitability that strongly co-occur temporally with clinical remission at 3 months among patients with refractory TN. Significance: These findings may indicate preserved cortical neuroplastic capacity in older, highly treatment-resistant populations, potentially supporting accelerated M1 rTMS as an age-resilient therapeutic strategy for chronic neuropathic pain, although a direct causal relationship remains to be established and extensive randomized trials are required.