Combining therapeutic strategies with rehabilitation improves motor recovery in animal models of spinal cord injury: A systematic review and meta-analysis

Background: Despite the lack of clinically validated strategies for treating spinal cord injury (SCI), combining therapeutic strategies with rehabilitation is believed to promote recovery of motor function; however, current research findings are inconsistent. Objectives: To explore whether combination therapy involving therapy and rehabilitative training (CIRT) has a synergistic effect on motor function recovery in animal models of SCI. Methods: We conducted a systematic review and meta-analysis of studies identified in a keyword search of 6 databases and extracted open-field motor scores from the Basso Mouse Scale (BMS) and the Basso, Beattie, and Bresnahan Locomotor Rating Scale (BBB) for meta-analysis using a weighted mean difference (WMD) and 95 % CI. We also performed qualitative synthesis and analysis of secondary outcome measures related to histological improvements and adverse effects. Results: Eighty-seven preclinical studies were included. Combination treatment with treadmill training resulted in a significant improvement in motor function (1.40, 95 % CI 0.82 to 1.98, P < 0.01, I² = 49 %), especially when initiated 1–2 weeks post-injury (1.77, 95 % CI 1.10 to 2.45, P < 0.01, I² = 33 %) in rats. In mice, CIRT lasting <6 weeks may enhance recovery (0.95, 95 % CI 0.49 to 1.40, P < 0.01, I² = 33 %). Although there is a trend toward better outcomes in the chronic phase, insufficient sample sizes prevent definitive conclusions from being drawn. Combined therapy also enhances the reorganization of inhibitory synaptic structures and functions, without aggravating allodynia or spasticity. Conclusions: This systematic review and meta-analysis suggest that CIRT can lead to superior motor function recovery compared to single-modality therapy (SMT) in animal models of SCI, with no significant adverse effects on allodynia or spasticity. However, the efficacy of CIRT depends on various factors, and further research is needed to establish optimal treatment strategies and understand the underlying mechanisms of recovery.