Voluntary engagement predicts recovery across rehabilitation time points after experimental spinal cord injury

Abstract

Rehabilitation is the cornerstone of clinical care following spinal cord injury (SCI) and is frequently incorporated into preclinical studies to evaluate emerging therapies. However, the variables that influence the effectiveness of rehabilitation interventions in rodent models remain poorly characterized, limiting the translational value of preclinical research. Here, we performed a meta-analysis of 150 preclinical studies comprising more than 3000 rodents and 292 effect sizes to identify such factors associated with successful rehabilitation after SCI. Rehabilitation improved functional outcomes across multiple behavioral domains, with larger effects observed in thoracic than cervical injury models. Meta-regression identified environmental enrichment as the most effective strategy, particularly when combined with task-specific training. Longer rehabilitation duration was associated with improved recovery, whereas greater daily exposure to forced rehabilitation was associated with smaller gains. In contrast, prolonged access to voluntary rehabilitation did not show this relationship. Rehabilitation improved outcomes when initiated at all time points after injury, with greater benefits when initiated during the late subacute and intermediate phases. Rehabilitation approaches associated with higher stress burden produced reduced benefits, suggesting that stress may limit rehabilitation-induced recovery. Collectively, these findings identify rehabilitation type, duration, and delivery context as important determinants of recovery after SCI and support a broad therapeutic window for intervention. Our results favor low-stress, voluntary rehabilitation strategies that promote sustained engagement and provide principles for designing effective and biologically appropriate rehabilitation strategies, potentially improving translational success for emerging SCI therapies. One Sentence Summary Sustained voluntary rehabilitation promotes functional recovery across stages of experimental spinal cord injury, whereas prolonged forced training may reduce its benefits.