Contralesional Inhibitory TMS and Ipsilesional Facilitative TMS Combined With Constraint-Induced Movement Therapy for Post-Stroke Upper Limb Recovery: A 3-Arm RCT

This study investigates effect of contralesional inhibitory rTMS, ipsilesional facilitative rTMS, and sham TMS combined with constraint-induced movement therapy on upper limb motor recovery in subacute stroke within the context of neurological rehabilitation and non-invasive brain stimulation, an area of growing scientific importance given its implications for post-stroke TMS rehabilitation protocol selection, brain stimulation-CIMT combination therapy design, and neuroplasticity biomarker identification for treatment response prediction. Using 3-arm double-blind (patient and assessor) RCT, 10 daily TMS-CIMT sessions with 120 pulses TMS before 3h CIMT; Fugl-Meyer Upper Extremity (FM-UE) as primary outcome at 90 days; secondary: Wolf Motor Function Test, Motor FIM, cortical excitability by MEP amplitude, we examine contralesional inhibitory (1-Hz) rTMS reducing transcallosal inhibition of ipsilesional motor cortex; ipsilesional facilitative (10-Hz) rTMS increasing cortical excitability and long-term potentiation-like plasticity; both mechanisms facilitating motor learning during subsequent CIMT practice in 184 patients (60 contralesional inhibitory, 62 ipsilesional facilitative, 62 sham), mean age 64, mean FM-UE 32 at baseline, 90% retention at 90 days, 84% at 6 months drawn from Lakeside Medical Center Stroke Rehabilitation Unit with Magstim Rapid2 TMS system, blinded assessors, and 2-year follow-up schedule at weeks 1, 2, 4, 8, 12, 26. Results indicate that both active TMS conditions superior to sham: contralesional inhibitory +8.4 FM-UE points (p<0.001), ipsilesional facilitative +7.2 points (p<0.001), sham +3.2 points; no significant difference between the two active arms (p=0.38); gains maintained at 6 months with no group convergence (p < 0.001), with +8.4 FM-UE contralesional; +7.2 ipsilesional; vs. +3.2 sham; both active arms maintained at 6 months as the primary quantitative benchmark. Concordance between primary and confirmatory measurement approaches exceeded 93%, validating the analytical framework. These findings contribute empirically to neurological rehabilitation and non-invasive brain stimulation and carry actionable implications for the design of programs and policies targeting post-stroke TMS rehabilitation protocol selection, brain stimulation-CIMT combination therapy design, and neuroplasticity biomarker identification for treatment response prediction.