Editorial: Rehabilitation to guide functional plasticity and regeneration with novel cellular, pharmacological and neuromodulation therapies

Abstract

Editorial on the research topic: Rehabilitation to Guide Functional Plasticity and Regeneration with Novel Cellular, Pharmacological and Neuromodulation Therapies While we, as a research field, strive to improve outcomes for people with neurological conditions, we understand that no single therapy or intervention can work in isolation.Combining methods represents the future of optimizing outcomes in rehabilitation.Research on combinatorial treatments remains limited. While some studies have explored the combination of exercise-or activity-based therapies with neuromodulation, little has been done to investigate the integration of neuromodulation with cellular or pharmacologic treatments. Given the stablished safety of a broad range of neuromodulton techniques, there is an interesting opportunity to further investigate the potential benefits of combining pharmacologic approaches with neuromodulation.The quest to restore function following neurological injuries continues to drive innovation in the field of rehabilitation. Despite the complexity of central nervous system injuries and the limited capacity for regeneration, promising avenues are emerging. By integrating rehabilitation with cutting-edge cellular therapies, pharmacological interventions, and neuromodulation strategies, researchers aim to harness the body's inherent plasticity to facilitate recovery and functional regeneration.Spinal cord injury (SCI) rehabilitation offers a compelling example of these advancements. Cervical SCI disrupts critical neural circuits controlling upper limb function. While endogenous repair mechanisms promote reorganization and adaptive plasticity in sparred circuits, maladaptive rewiring can hinder functional recovery (Bareyre et al., 2004;Cohen et al., 1991;Green et al., 1999Green et al., , 1998;;von Euler et al., 2002;Zai and Wrathall, 2005). Therefore, strategies targeting the functional rewiring of motor pathways are essential to enhance meaningful recovery. Multiple preclinical (de Leon et al., 1998;Leon et al., 1998) and clinical (Behrman andHarkema, 2007, 2000) studies have demonstrated that rehabilitation improves functional recovery after SCI by training the spared motor networks and providing activity-dependent feedback to locomotor pathways. For instance, Gregoire Courtine's research on neuromodulation for SCI recovery in humans highlights the integration of rehabilitation strategies with epidural (Wagner et al., 2018) or transcutaneous spinal cord stimulation (Moritz et al., 2024), brain-spine interfaces (Hachem et al., 2023;Lorach et al., 2023), and hypothalamic deep brain stimulation (Cho et al., 2024). Importantly, the neuroplastic changes induced by rehabilitation training are dependent on the type of adopted training paradigm (Adkins et al., 2006). Strength training primarily modulates motor network excitability and increases number of synapses, whereas skilled motor training elicits broader mechanisms, including synapse formation, enhanced synaptic strength, and network reorganization (Adkins et al., 2006). In stroke, studies on anti-NOGO therapy demonstrate that its efficacy is optimized when combined sequentially with appropriate rehabilitation regimen (Wahl et al., 2014). These examples underscore the critical need for combined and targeted rehabilitation paradigms.Building on these concepts, this research topic examines perspectives on combining rehabilitation with advanced therapies, including stem cell applications for SCI (Balbinot, 2024), the safety of Hebbian-type stimulation (Haakana et al., 2023), personalized strategies for pediatric cerebral palsy (Behboodi et al., 2023;Raess et al., 2022), and the sex-specific effects of acrobatic training on cognitive decline induced by cerebral hypoperfusion (Martini et al., 2024).Balbinot, 2024 emphasizes the synergy between targeted rehabilitation and stem cellbased therapies, particularly for improving upper extremity function in cervical SCI.Preclinical studies