Isometric Exercise Combined With Transcranial Electrical Stimulation Improves Conditioned Pain Modulation.

Exercise and primary motor cortex (M1) stimulation may alleviate pain by enhancing the endogenous pain-inhibitory system, with its efficacy assessed through conditioned pain modulation (CPM). This study examined whether combining exercise with M1-targeted transcranial electrical stimulation enhances CPM more effectively than either intervention alone. Two randomized, sham-controlled experiments were conducted. In Experiment 1 (N = 70), participants completed a 3-min isometric handgrip exercise or quiet rest. In Experiment 2 (N = 140), participants received 20 min of M1-targeted transcranial random noise stimulation with direct current offset (tRNS + DC-offset) or sham stimulation, followed by either exercise or rest. CPM was assessed at baseline, immediately after, and 30 min post-intervention. Results showed that exercise alone did not significantly enhance CPM efficacy. In contrast, M1-targeted tRNS + DC-offset significantly enhanced CPM efficacy at both post-intervention time points. Critically, individuals with low baseline CPM showed greater benefits from the combination of tRNS + DC-offset and exercise compared to either exercise alone or tRNS + DC-offset alone, particularly at 30 min post-intervention. These results highlight the potential of combining motor cortex stimulation with exercise to optimize endogenous pain inhibition, particularly as a personalized, nonpharmacological intervention for individuals with impaired pain modulation.