Effects of non-invasive brain stimulation combined with exercise training on pain and physical function in knee osteoarthritis: a systematic review and meta-analysis

Background Non-invasive brain stimulation (NIBS) combined with exercise training (ET) is a promising treatment for knee osteoarthritis (KOA), but its effects on pain and physical function lack systematic evaluation. Purpose To evaluate the effects of NIBS combined with ET on pain and physical function in KOA patients. Methods PubMed, Embase, the Cochrane Library, and Web of Science were systematically searched from inception to December 9, 2025, for randomized controlled trials (RCTs) investigating the efficacy of NIBS + ET for KOA. Primary outcomes were pain and physical function. Secondary outcomes included gait speed and quality of life (QoL). Results This review included 8 studies with 340 participants. Our findings revealed that compared with the control, NIBS + ET showed a favorable but non-significant effect on pain measured by the numerical rating scale (NRS) or visual analog scale (VAS) (standardized mean difference [SMD] = −0.41, 95% confidence interval [CI] [−0.83, 0.01], p = 0.0566; I2 = 67.3%). Subgroup analyses by assessment time point, stimulation site, and NIBS modality showed no statistically significant effects. Additionally, the combined intervention significantly reduced the WOMAC total score (MD = −6.76, 95% CI [−11.85, −1.68], p = 0.0091; I 2 = 51.3%). Subgroup analyses showed beneficial effects at ≥ 12 weeks (MD = −11.44, 95% CI [−15.32, −7.55], I 2 = 0%) and for rTMS + ET (MD = −10.70, 95% CI [−16.46, −4.93], I 2 = 19.5%). However, after accounting for within-study correlations across WOMAC outcomes, three-level meta-analyses and robust variance estimation (RVE) analyses provided weaker statistical support, with statistical significance less consistently observed across analyses. Available evidence suggested a beneficial effect on gait speed. No clear QoL improvement was observed. Conclusion NIBS + ET may not significantly reduce NRS/VAS pain scores but was associated with reduced WOMAC total scores, although analyses accounting for within-study correlations provided weaker statistical support for WOMAC outcomes. Limited evidence suggested benefits for gait speed, whereas effects on QoL remained unclear. The certainty of evidence was moderate for physical function and low for pain, gait speed, and QoL. Further high-quality RCTs are needed to clarify these effects and optimize NIBS and ET protocols. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251186212 , identifier PROSPERO (CRD420251186212).