Functional gradient analysis reveals potential therapeutic mechanisms of nrTMS for postoperative motor deficits in glioma patients: A randomized controlled trial

• High-frequency nrTMS targeting the ipsilateral hand knob significantly accelerates motor recovery in glioma patients with postoperative motor deficits, with therapeutic benefits sustained for at least three months. • Functional gradient analysis reveals that nrTMS induces a specific increase in the principal gradient score of the sensorimotor network (SMN), reflecting a shift in its functional connectivity profile. • Parcel-level analysis identifies healthy side upper limb motor area (HHSomMot₂2) as a key region whose gradient changes are most strongly correlated with motor function improvement, highlighting bilateral network modulation by unilateral nrTMS. This study aimed to investigate the therapeutic effects and neural mechanisms of high-frequency neuro-navigated repetitive transcranial magnetic stimulation (nrTMS) targeting the hand knob in glioma patients with postoperative motor deficits, using functional gradient analysis to characterize cortical reorganization. Thirty patients with postoperative motor deficits were randomized to receive nrTMS or sham stimulation targeting the ipsilateral hand knob. Motor function was assessed using Fugl-Meyer Assessment (FMA) and muscle strength. Resting-state fMRI was acquired to compute principal functional gradients. Control/tumor, nrTMS/sham, and Pre-TMS/Post-TMS gradient changes were analyzed. Correlation and regression analyses related to motor recovery were performed. The nrTMS group showed significantly greater improvement in muscle strength (Post-treatment: nrTMS: 3. 533 ± 0. 720, Sham: 2. 067 ± 0. 572, p = 0. 019, d = 1. 082; 3-month follow-up: nrTMS: 4. 600 ± 0. 408, Sham: 3. 733 ± 0. 609, p = 0. 035, d = 1. 012). Gradient analysis revealed increased sensorimotor network (SMN) gradient scores following nrTMS (Pre-TMS: −0. 707 ± 0. 108; Post-TMS: −0. 636 ± 0. 077; p = 0. 016), and HHSomMot₂2 within upper limb motor cortex is most strongly correlated with motor recovery. High-frequency nrTMS targeting the hand knob accelerated the motor recovery. Gradient analysis findings provide novel insights into therapeutic mechanisms of nrTMS and underscore the value of the hand knob as a stimulation target.