Transcranial temporal interference stimulation combined with soft robotic glove training improves upper-limb motor function after subacute stroke: a randomized controlled pilot trial

Background Upper-limb dysfunction, particularly impaired distal hand function, remains one of the most disabling sequelae following a stroke. Soft robotic glove (SRG) training can provide repetitive and task-specific hand practice; however, its therapeutic effects may be limited by insufficient modulation of the damaged motor network. Transcranial temporal interference stimulation (tTIS), a novel non-invasive neuromodulation approach capable of targeting deeper neural circuits, may enhance post-stroke motor recovery by engaging cerebellar-related motor pathways and promoting network-level plasticity. Objective This study investigated whether cerebellar tTIS combined with SRG training improves upper-limb motor function in patients with subacute stroke and explored the associated changes in cortical activation and resting-state functional connectivity (FC) using functional near-infrared spectroscopy (fNIRS). Method In this prospective, single-center, randomized, sham-controlled pilot trial, 46 patients with first-ever subacute stroke were randomized 1:1 to the tTIS-SRG group ( n = 22) or the SRG group ( n = 22). Both groups received conventional rehabilitation and SRG training. The tTIS-SRG group additionally received active cerebellar tTIS, whereas the SRG group received sham stimulation, delivered once daily, 5 days per week, for 2 weeks. The primary outcome was the upper-limb motor function assessed by the Action Research Arm Test (ARAT), and the secondary outcome was activities of daily living (ADL) assessed by the modified Barthel Index (MBI). fNIRS was used to evaluate task-related cortical activation and resting-state functional connectivity before and after the intervention. This trial has been registered with the Chinese Clinical Trial Registry (ChiCTR2500107031). Results Of the 46 randomized participants, 44 completed the trial and were included in the final analysis (22 per group). One participant in the tTIS-SRG group withdrew from the study due to hospital discharge, and one participant in the SRG group declined the final assessment for personal reasons. Participants in both groups showed improvements in ARAT and MBI scores following treatment. The tTIS-SRG group demonstrated a significantly greater improvement in ARAT scores than the SRG group ( Z = −2.955, p = 0.003), whereas the between-group difference in MBI change was not significant ( Z = −1.706, p = 0.088). fNIRS analysis revealed that false discovery rate (FDR)-corrected channel-level analysis identified greater oxyhemoglobin (HbO) changes in the tTIS-SRG group than in the SRG group in two channels located in the ipsilateral frontal pole area (FPA) and ipsilateral somatosensory cortex (SSC). No region of interest (ROI)-level comparison remained statistically significant after FDR correction. Although several channel-level comparisons reached nominal significance before correction, only two channels remained statistically significant after FDR correction. Conclusion In this pilot trial, cerebellar tTIS combined with SRG training provided a more significant improvement in upper-limb motor recovery compared with SRG training alone in patients with subacute stroke. The observed clinical improvement was accompanied by enhanced task-related cortical activation and changes in motor-related functional connectivity. Larger multicenter trials with longer follow-up are needed to confirm the efficacy, durability, and underlying mechanisms of this combined intervention. Clinical trial registration https://www.chictr.org.cn/searchprojEN.html , identifier ChiCTR2500107031.