Posterior-superior insula repetitive transcranial magnetic stimulation reduces experimental tonic pain and pain-related cortical inhibition in humans

High frequency repetitive transcranial magnetic stimulation (rTMS) to the posterosuperior insula (PSI) may produce analgesic effects. However, the neuroplastic changes behind PSI-rTMS analgesia remain poorly understood. The present study aimed to determine whether tonic capsaicin-induced pain and cortical inhibition (indexed using TMS-electroencephalography) are modulated by PSI-rTMS. Twenty healthy volunteers (10 females) attended two sessions randomized to active or sham rTMS. Experimental pain was induced by capsaicin administered to the forearm for 90 minutes, with pain ratings collected every 5 minutes. Left PSI-rTMS was delivered (10Hz, 100 pulses per train, 15 trains) ∼50 minutes post-capsaicin administration. TMS-evoked potentials (TEPs) and thermal sensitivity were assessed at baseline, during capsaicin pain prior to rTMS and after rTMS. Bayesian evidence of reduced pain scores and increased heat pain thresholds were found following active rTMS, with no changes occurring after sham rTMS. Pain (prior to active rTMS) led to an increase in the frontal negative peak ∼45 ms (N45) TEP relative to baseline. Following active rTMS, there was a decrease in the N45 peak back to baseline levels. In contrast, following sham rTMS, the N45 peak was increased relative to baseline. We also found that the reduction in pain NRS scores following active vs. sham rTMS was partially mediated by decreases in the N45 peak. These findings provide evidence of the analgesic effects of PSI-rTMS and suggest that the TEP N45 peak is a potential marker and mediator of both pain and analgesia. ### Competing Interest Statement The authors have declared no competing interest.