改变神经通路治疗卒中内囊损伤后难治性运动障碍的应用基础研究

Patients with stroke confined to the posterior limb of the internal capsule (PLIC) often have diminished response to rehabilitation efforts. The poor motor outcome could be due to the condensed organization of corticofugal projections and the density of pyramidal fibres from the primary motor cortex in this subsector, which makes it impossible to restore upper-extremity function and hand coordination. Our previous study has found that after the procedure of peripheral nerve rewiring (PNR, here refers to contralateral C7 nerve transfer, which means 20% fibres transfers to the contralateral side), the contralesional hemispheric compensation was markedly strengthened and significantly related to behavioral improvements. The findings also revealed a feasible and effective way to maximize the potential of one hemisphere in controlling both limbs. An original study was carried out. Hemiplegic patients with cortex injury received the PNR surgery of contralateral C7 to C7 of the affected side and the motor control of the affected upper extremity improved significantly. This PNR approach constructed a new bridge between the affected limb and the exempt cortex for the first time. In the present study, we will make use of this PNR surgery to improve the upper-limb function which is extremely hard to restore. Combined use of functional assessment, optogenetics (in vivo laser-electrophysiology), and nerve functional imaging (micro-fMRI) mechanism, retrograde tracing and anterograde tracing will be applied to outline the dynamic change process of upper-limb functional restore and motor cortical reorganization. This could be a new method and theoretical basis for the intervention of hand function recovery after the internal capsule lesion.

累及内囊的脑卒中常遗留严重肢体功能障碍，康复治疗极难恢复。其发病机理是传导通路损伤导致患肢与皮层失去联系，现有的治疗策略难以突破。对于一侧半球皮层损伤的中枢性偏瘫，本课题组前期原创提出通过周围神经通路交叉移位可以诱发一侧半球运动皮层同时司管双侧上肢。具体操作是将双侧的第7颈神经根切段，通过神经移植交叉连接，将20%的神经纤维由对侧支配改变为同侧支配，建立了健存大脑和同侧瘫痪肢体的新连接，实验和临床效果满意。本研究拟在上述基础上，探讨是否可以将该方法应用于皮层完好、但神经通路被破坏的累及内囊的脑卒中，促进难治性运动障碍的功能恢复。本研究拟在小鼠模型联合运用行为学评估、光遗传学、功能影像学、神经示踪等方法连续动态观察上肢功能变化和中枢重塑过程，以证实这一方法的可行性并探索其机制。这将是恢复内囊损伤后运动功能的全新方法，具有广阔的应用前景。

脑卒中后瘫痪肢体的治疗尤其是恢复上肢随意控制运动的治疗缺乏突破性进展，而累及内囊的脑卒中恢复更有限。课题组前期通过改变周围神经通路（健侧C7神经移位）重建皮层损伤后的肢体运动功能，效果满意。本课题在上述基础上，进一步将该方法应用于累及内囊神经通路损伤的脑卒中模型，研究术式的有效性和中枢重塑变化。本课题使用啮齿类小鼠建立皮层损伤和内囊通路损伤的精准脑损伤模型，并进一步构建健侧颈神经移位手术模型，通过行为学测试、光遗传学-电生理相结合技术、小动物功能磁共振研究以及逆行和顺行神经示踪技术等研究瘫痪肢体运动功能恢复的中枢重塑机制。首先我们分别通过光栓法和药物注射建立了啮齿类动物一侧控制性皮层梗死和内囊区通路梗死模型及健侧颈神经移位模型，术后通过行为学观察探索上肢运动功能的损伤及恢复曲线，运用在体光遗传学-电生理技术绘制伸肌群肌肉代表区的动态图谱变化，并记录刺激双侧上肢各靶肌肉代表区位置及运动诱发电位潜伏期和波幅的变化。研究发现光栓法造成的皮层损伤模型，运用健侧颈神经移位术后，患肢功能可恢复至接近正常对照组水平；而内囊损伤组术后步态测试中的双侧平均压力强度、前爪面积和步长较神经移位术前均明显好转，具有统计学差异，抓取实验和水平梯踏空实验较术前也有统计学差异的恢复(P<0.05)，患侧肢体运动恢复与皮层损伤组间有统计学差异(P<0.05)。在动态皮层代表区图谱的描绘过程中发现，健侧皮层刺激可诱发出弥散的患侧前臂伸肌群代表区，并随时间进程呈汇聚趋势。随后我们使用功能磁共振的方法进一步研究脑重塑过程中的脑网络变化，最后我们通过神经示踪研究发现健侧颈神经移位后，支配健肢的C7 节段脊髓前角运动神经元改为支配瘫痪上肢，其机制值得进一步深入探究。本研究证实了健侧颈神经移位术可提高内囊区神经通路损伤后模型的患肢运动功能。临床上脑损伤患者多合并有通路损伤，本研究结果将为恢复内囊损伤后运动功能提供新的思路，具有广阔的应用前景。