周围神经交叉移位治疗中枢性上肢瘫的运动中枢动态重塑模式研究

As one of the most serious sequelae of central nervous system injury, the results of treating upper extremity spastic paralysis are far from satisfactory. Original studies from our research group showed that changing the peripheral nerve pathway to increase the ipsilateral fibers in controlling the hemiplegia limb could achieve healthy cerebral hemisphere controlling bilateral upper extremities, and pretty good clinical results have also been achieved. However, the dynamic central plastic mechanism involved in limb functional recovery in the clinical patients’ consecutive recovery follow-ups is still not clear. Compared with other central intervening methods, the technique of optogenetics boasts of precise cortical localization and stimulation, repeatability as well as unreplaceable advantage of high efficiancy. Based on previous achievements, the project intends to innovatively apply in vivo optogenetic-electrophysiology coulped techniques to dynamically assess the plastic changes on the healthy hemisphere of Thy1-ChR2-YFP transgenic mice undergoing cross nerve transfer after traumatic brain injury, which can help dynamically follow up bilateral extremity representations and the motor cortex excitability parameter changes at different time intervals after surgery. Combined with behavioral assessment, the results will illustrate the central reorganizational changes during improved extremity function and helps to reveal the central cortical mechanism of unilateral hemisphere controlling bilateral extremities, providing basis for ensuing actively intervening cortical reorganization for a better recovery.

痉挛性偏瘫是中枢神经损伤后常见的严重后遗症，其中以上肢功能恢复最为困难。课题组原创性提出了通过周围神经交叉转位诱发脑功能重塑让健存半球控制瘫痪肢体的治疗策略，并获得了良好的临床效果。临床现象显示术后病人的运动功能从粗大动作到精细功能逐步改善，提示运动中枢的功能重塑是一个动态过程。但是，这种动态重塑规律尚不清楚。光遗传学技术具有皮层定位及刺激精确可控、可动态观察的优势。本课题拟在前期工作基础上，建立一侧脑外伤后经健侧颈七神经根移位的Thy1-ChR2-YFP转基因小鼠模型，应用在体光遗传学-电生理结合技术动态观察双侧上肢运动代表区兴奋参数的变化，结合行为学评估结果，阐明患肢运动功能恢复过程中运动中枢的脑功能重塑规律。研究成果对于今后采用皮层刺激等干预措施促进和加速有效的功能重塑有重要的理论价值。

背景：作为中枢神经损伤后较为严重的后遗症之一，上肢痉挛性瘫痪的治疗方法及效果均有限。通过改变周围神经通路增强同侧神经纤维对肢体的支配可以实现偏瘫患者的健存大脑半球同时司管双侧上肢。但具体涉及到的神经通路以及患肢运动功能恢复的动态中枢机制尚不明确。.方法：我们建立了小鼠左侧控制性皮层撞击脑外伤（CCI）及健侧颈七-患侧颈七神经根切断及移位模型，术后通过滚轴实验和阶梯步行实验检测上肢运动功能的损伤及恢复情况，在体光遗传学-电生理技术相结合用于绘制正常小鼠初级运动皮层 M1、前肢各肌肉代表区图谱以及动态记录术后不同时间点健侧皮层刺激后双侧上肢各靶肌肉代表区位置及运动诱发电位（MEP）参数的变化。.结果：CCI+健侧颈七-患侧颈七移位组的患肢在术后5月时滚轴实验评分开始好于对照组，至术后6个月时更为显著且一直持续至术后10月。术后7月时患肢在滚轴实验的提携项目评分以及阶梯步行实验评分开始好于对照组，至术后8个月时更为显著且一直持续至术后10月。通过光遗传学方法绘制了转基因小鼠M1图谱，并发现前肢代表区由位于偏前方较小面积的代表区RFA以及偏后方较大面积的代表区CFA构成。术后4月以内，右（健）侧皮层刺激仅能记录到左（健）侧肢体靶肌肉的MEP；术后5月时，右（健）侧皮层刺激可以同时记录到双侧肱三头肌的MEP，且术后右（患）侧肱三头肌代表区逐渐缩小并向左（健）侧肱三头肌代表区汇聚；术后7月时，右（健）侧皮层刺激可以同时记录到双侧前臂伸肌群的MEP，且术后右（患）侧前臂伸肌群代表区呈现出逐渐缩小并向左（健）侧前臂伸肌群代表区汇聚的趋势，而右（健）侧皮层内刺激始终无法诱发出右（患）侧肱二头肌的MEP。右（健）侧皮层刺激诱发出左（健）侧肢体靶肌肉的代表区及波幅未见明显变化。 .结论：对于重度CCI小鼠，健侧颈七神经根移位术可以促进患肢粗大（伸肘）及部分精细（伸腕指及协调）功能的恢复，前者恢复更为显著。术后健侧皮层参与了对双侧上肢运动的支配。