Abstract
Repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (MI) is expected to provide a therapeutic impact on spinal cord injury (SCI). On the other hand, treatment with antibody against repulsive guidance molecule-a (RGMa) has been shown to ameliorate motor deficits after SCI in rodents and primates. Facilitating activity of the corticospinal tract (CST) by rTMS following rewiring of CST fibers by anti-RGMa antibody treatment may exert an enhanced effect on motor recovery in a primate model of SCI. To address this issue, we examined whether such a combined therapeutic strategy could contribute to accelerating functional restoration from SCI. In our SCI model, unilateral lesions were made between the C6 and the C7 level. Two macaque monkeys were used for each of the combined therapy and antibody treatment alone, while one monkey was for rTMS alone. The antibody treatment was continuously carried out for four weeks immediately after SCI, and rTMS trials applying a thermoplastic mask and a laser distance meter lasted ten weeks. Behavioral assessment was performed over 14 weeks after SCI to investigate the extent to which motor functions were restored with the antibody treatment and/or rTMS. While rTMS without the preceding antibody treatment produced no discernible sign for functional recovery, a combination of the antibody and rTMS exhibited a greater effect, especially at an early stage of rTMS trials, on restoration of dexterous hand movements. The present results indicate that rTMS combined with anti-RGMa antibody treatment may exert a synergistic effect on motor recovery from SCI.
Highlights
Meta-analysis of the therapeutic effects of Repetitive transcranial magnetic stimulation (rTMS) was generally performed in three key aspects of motor/sensory functions, spasticity, and neuropathic pain [23], the outcome especially concerning the motor/sensory functions was not always consistent in human patients
Our rTMS trials targeting the MI, on the other hand, failed to improve dexterous motor deficits in the present monkey model of spinal cord injury (SCI). These contradictory results might depend on varying trial conditions, such as SCI severity and stage, treatment timing, and rTMS parameters
In our prior study [17], the impact of anti-repulsive guidance molecule-a (RGMa) antibody treatment on functional recovery was investigated in macaque monkeys whose manual dexterity was impaired after SCI at the cervical enlargement level
Summary
During the process of functional recovery from central nervous system disorders, effective approaches that strengthen appropriate neural circuits by facilitating their activity is critical. The funders had no further role in study design, data collection and analysis, decision to publish, or preparation of the manuscript This event can be promoted by physical exercise, and by brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) (for review, see Fitzgerald et al, 2006 [1]). We hypothesized that rewiring of corticospinal tract (CST) fibers through anti-RGMa antibody treatment, followed by facilitation of CST activity through rTMS targeting the MI, might contribute to accelerating motor recovery from SCI. To test this hypothesis, we analyzed a possible enhanced effect of such a combined therapeutic strategy on functional restoration in the SCI model using macaque monkeys. To archive constant and effective magnetic stimulation over the MI of awake animals, we have developed a novel system in which a thermoplastic mask and a laser distance meter were applied (for the usefulness of thermoplastic mask in rTMS, see Drucker et al, 2015 [18])
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