Effect of Simultaneous Combined Treadmill Training and Magnetic Stimulation on Spasticity and Gait Impairments after Cervical Spinal Cord Injury.

Cervical spinal cord injury (CSCI) can induce lifelong disabilities, including spasticity and gait impairments. The objective of this pre-clinical study was to evaluate the therapeutic effects of simultaneous and combined early locomotor treadmill training (Tm) and injury site magnetic stimulation (TMSsc) on spasticity and gait impairments in a rat model of C6/7 moderate contusion SCI. The Tm training was initiated at post-injury (PI) day 8, whereas TMS treatment was added to Tm 14 days PI, and then the combined therapy (TMSTm) was continued for six weeks. Untreated CSCI animals revealed significant and enduring hindlimb spasticity (measured as velocity-dependent ankle torques and time-locked triceps surae electromyography), significant alterations in limb coordination, and significant reductions in forelimb grip strength. The TMSTm showed significantly lower spasticity, significantly more normal limb coordination (quantitated using three-dimensional (3D) kinematics and Catwalk gait analyses), and significantly greater forelimb grip strength compared with the CSCI untreated controls. In addition, three-dimensional gradient echo and diffusion tensor magnetic resonance imaging showed that TMSTm treated animals had smaller cavity volumes and better preservation of the white matter. In addition, compared with the CSCI untreated animals, the lumbar spinal cord (SC) of the treatment group revealed significant up-regulation of dopamine beta-hydroxylase, glutamic acid decarboxylase, gamma-aminobutyric acid receptor B, and brain-derived neurotrophic factor. The treatment-induced up-regulation of these molecules may have enhanced the activity-induced adaptive plasticity in the SC and contributed to normalization of pre- and post-synaptic reflex regulatory processes. In addition, the TMSTm therapy may have decreased injury-induced progressive maladaptive segmental and descending plasticity. Our data are the first to suggest that an early simultaneous combination of Tm and injury-site TMSsc application can be an effective therapy for CSCI-induced spasticity and gait impairments. These pre-clinical data demonstrated the feasibility and efficacy of a novel therapeutic strategy for SCI-induced spasticity and gait impairments.

Testosterone dose dependently prevents bone and muscle loss in rodents after spinal cord injury.

Androgen administration protects against musculoskeletal deficits in models of sex-steroid deficiency and injury/disuse. It remains unknown, however, whether testosterone prevents bone loss accompanying spinal cord injury (SCI), a condition that results in a near universal occurrence of osteoporosis. Our primary purpose was to determine whether testosterone-enanthate (TE) attenuates hindlimb bone loss in a rodent moderate/severe contusion SCI model. Forty (n=10/group), 14 week old male Sprague-Dawley rats were randomized to receive: (1) Sham surgery (T9 laminectomy), (2) moderate/severe (250 kdyne) SCI, (3) SCI+Low-dose TE (2.0 mg/week), or (4) SCI+High-dose TE (7.0 mg/week). Twenty-one days post-injury, SCI animals exhibited a 77-85% reduction in hindlimb cancellous bone volume at the distal femur (measured via µCT) and proximal tibia (measured via histomorphometry), characterized by a >70% reduction in trabecular number, 13-27% reduction in trabecular thickness, and increased trabecular separation. A 57% reduction in cancellous volumetric bone mineral density (vBMD) at the distal femur and a 20% reduction in vBMD at the femoral neck were also observed. TE dose dependently prevented hindlimb bone loss after SCI, with high-dose TE fully preserving cancellous bone structural characteristics and vBMD at all skeletal sites examined. Animals receiving SCI also exhibited a 35% reduction in hindlimb weight bearing (triceps surae) muscle mass and a 22% reduction in sublesional non-weight bearing (levator ani/bulbocavernosus [LABC]) muscle mass, and reduced prostate mass. Both TE doses fully preserved LABC mass, while only high-dose TE ameliorated hindlimb muscle losses. TE also dose dependently increased prostate mass. Our findings provide the first evidence indicating that high-dose TE fully prevents hindlimb cancellous bone loss and concomitantly ameliorates muscle loss after SCI, while low-dose TE produces much less profound musculoskeletal benefit. Testosterone-induced prostate enlargement, however, represents a potential barrier to the clinical implementation of high-dose TE as a means of preserving musculoskeletal tissue after SCI.