Combination of repetitive transcranial magnetic stimulation and treadmill training reduces hyperreflexia by rebalancing motoneuron excitability in rats after spinal cord contusion

Spasticity commonly emerges during the process of recovery after spinal cord injury (SCI) and critically exacerbates motor dysfunction. Given insufficient effects of individual therapies, we combined repetitive transcranial magnetic stimulation (rTMS) with treadmill training (Tr) in rats with SCI to investigate potential synergistic effects on alleviating spasticity and motor dysfunction. Animals were randomized into four groups: SCI only, rTMS, Tr, and rTMS plus Tr. At the study endpoint eight weeks after the start of interventions, the rTMS plus Tr group exhibited the largest decrease in maximal H-reflex amplitude/maximal M-wave amplitude ratio (effect size (ES): −0.082, 95% confidence interval (CI): −0.118 to −0.046, p < 0.001) as well as the greatest improvement in motor function measured with the Basso, Beattie, and Bresnahan locomotor scale (ES: 1.811, 95% CI: 1.018 to 2.603, p < 0.001; significantly different from all other groups at p < 0.01) and grid-walking test (ES: −5.1, 95% CI: −7.784 to −2.416, p < 0.001, significantly different from rTMS alone at p < 0.01). Pathological analyses demonstrated that the combined treatment facilitated the growth of serotonergic axons around the lesion site, and the upregulation of 5-hydroxytryptamine, potassium-chloride cotransporter-2, and glutamic acid decarboxylases 67 in the lumbar spinal cord distal to the injury site. All effects of combined treatment of rTMS and treadmill training were enhanced compared to treadmill training or rTMS alone. Treadmill training and rTMS intervention appear to have synergistic effects on hyperreflexia and locomotion likely related to a restored balance between facilitatory and inhibitory inputs to motoneurons.