Experience-dependent white matter plasticity offers new potential for rehabilitation-induced recovery after neurotrauma. This first-in-human translational experiment combined myelin water imaging in humans and genetic fate-mapping of oligodendrocyte lineage cells in mice to investigate whether downhill locomotor rehabilitation that emphasizes eccentric muscle actions promotes white matter plasticity and recovery in chronic, incomplete spinal cord injury (SCI). In humans, of 20 individuals with SCI that enrolled, four passed the imaging screen and had myelin water imaging before and after a 12-week (3 times/week) downhill locomotor treadmill training program (SCI + DH). One individual was excluded for imaging artifacts. Uninjured control participants (n = 7) had two myelin water imaging sessions within the same day. Changes in myelin water fraction (MWF), a histopathologically-validated myelin biomarker, were analyzed in a priori motor learning and non-motor learning brain regions and the cervical spinal cord using statistical approaches appropriate for small sample sizes. PDGFRα-CreER^T2:mT/mG mice, that express green fluorescent protein on oligodendrocyte precursor cells and subsequent newly-differentiated oligodendrocytes upon tamoxifen-induced recombination, were either naive (n = 6) or received a moderate (75 kilodyne), contusive SCI at T9 and were randomized to downhill training (n = 6) or unexercised groups (n = 6). We initiated recombination 29 days post-injury, seven days prior to downhill training. Mice underwent two weeks of daily downhill training on the same 10% decline grade used in humans. Between-group comparison of functional (motor and sensory) and histological (oligodendrogenesis, oligodendroglial/axon interaction, paranodal structure) outcomes occurred post-training. In humans with SCI, downhill training increased MWF in brain motor learning regions (postcentral, precuneus) and mixed motor and sensory tracts of the ventral cervical spinal cord compared to control participants (P < 0.05). In mice with thoracic SCI, downhill training induced oligodendrogenesis in cervical dorsal and lateral white matter, increased axon-oligodendroglial interactions, and normalized paranodal structure in dorsal column sensory tracts (P < 0.05). Downhill training improved sensorimotor recovery in mice by normalizing hip and knee motor control and reducing hyperalgesia, both of which were associated with new oligodendrocytes in the cervical dorsal columns (P < 0.05). Our findings indicate that eccentric-focused, downhill rehabilitation promotes white matter plasticity and improved function in chronic SCI, likely via oligodendrogenesis in nervous system regions activated by the training paradigm. Together, these data reveal an exciting role for eccentric training in white matter plasticity and sensorimotor recovery after SCI.

依赖于经验的白质可塑性为神经创伤后的康复诱导恢复提供了新的潜力。这项首次人体转化实验结合了人体髓鞘水成像和小鼠少突胶质细胞谱系基因命运图谱，以研究强调离心肌肉动作的下坡运动康复是否促进慢性、不完全性脊髓损伤的白质可塑性和恢复（科学论文集）。在人类中，在 20 名 SCI 患者中，有四名通过了成像屏幕，并在为期 12 周（3 次/周）的下坡运动跑步机训练计划（SCI + DH）前后进行了髓鞘水成像。一个人因成像伪影而被排除在外。未受伤的控制参与者 ( n = 7) 在同一天进行了两次髓鞘水成像。髓鞘水分数 (MWF) 的变化是一种经组织病理学验证的髓鞘生物标志物，使用适用于小样本量的统计方法在先验运动学习和非运动学习大脑区域以及颈脊髓中进行了分析。PDGFRα-CreER ^T2：mT/mG小鼠，在他莫昔芬诱导的重组后，在少突胶质细胞前体细胞和随后新分化的少突胶质细胞上表达绿色荧光蛋白，要么是幼稚的（n  = 6），要么是接受中度（75 kilodyne）、挫伤性 SCI在 T9 时随机分配到下坡训练组（n  = 6）或未运动组（n = 6). 我们在受伤后 29 天，即下坡训练前 7 天开始重组。小鼠接受了为期两周的每日下坡训练，训练强度与人类使用的 10% 下坡度相同。功能（运动和感觉）和组织学（少突胶质细胞发生、少突胶质细胞/轴突相互作用、旁节结构）结果的组间比较发生在训练后。在患有 SCI 的人中，与对照组参与者相比，下坡训练增加了大脑运动学习区域（中央后、楔前叶）和腹侧颈脊髓混合运动和感觉束的 MWF（P < 0.05)。在胸部 SCI 小鼠中，下坡训练诱导颈背侧白质少突突发生，增加轴突-少突胶质细胞相互作用，并使背柱感觉束中的节旁结构正常化（P  < 0.05）。下坡训练通过使髋关节和膝关节运动控制正常化并减少痛觉过敏来改善小鼠的感觉运动恢复，这两者都与颈背柱中的新少突胶质细胞相关（P  < 0.05）。我们的研究结果表明，偏心、下坡康复促进慢性 SCI 的白质可塑性和功能改善，可能通过由训练范式激活的神经系统区域的少突。总之，这些数据揭示了偏心训练在脊髓损伤后白质可塑性和感觉运动恢复中的令人兴奋的作用。