健侧脑区在强制性运动促进脑缺血后患肢功能恢复中的作用机制

Clinical studies have shown that constraint-induced movement therapy (CIMT) overcame “learned non-use” and promoted functional recovery by limiting the unaffected limb, emphasizing intensive use of the affected limb. Corticospinal tract (CST) is the main neural pathway for voluntary movement, which is very important for movement recovery. CIMT may significantly improve the affected upper limb function by promoting formation of new neurons, inducing the contralateral CST fibers integration into the neural network of the affected limb. In our preliminary studies, through the micro-PET imaging, some regions of contralateral hemisphere relating to motor function were significantly activated. Therefore, CIMT may improve functional recovery through the contralateral compensation mechanism. Preliminary experiment also found that the number of contralateral CST fibers and FA value increased through DTI imaging. However, the degree of contralateral compensation, if new neurons presented in the contralateral cortex, if there are nerve fibers integrating into the neural network that control the affected limbs and the molecular mechanisms are unclear. Therefore, in order to explore the mechanism of CIMT in neural functional recovery and axon remodeling, this research will focus on three aspects: CST plasticity (DTI), new neurons proliferation and the integrated control of neural network (using PRV retrograde nerve tracer) and the expression of Notch1 pathway related proteins and factors.

研究表明脑缺血后强制性运动疗法（CIMT）通过限制健侧肢体、强化使用患肢，矫正患肢的“习得性废用”，进而促进功能的恢复。皮质脊髓束（CST）是支配肢体随意运动的主要神经通路，对脑卒中运动功能的恢复具有重要意义。有证据表明CIMT可明显改善大鼠患肢功能，促进患侧新生神经元形成，并可能诱导健侧CST纤维整合、支配患肢。我们前期研究通过micro-PET成像发现健侧相关脑区明显激活，提示CIMT的作用机制可能是通过健侧相关脑区的代偿。预实验通过DTI成像亦发现CIMT后健侧CST纤维数量增多。但脑缺血后CIMT发挥健侧代偿的程度、健侧有无新的神经元和神经纤维整合支配患肢及其分子机制尚不明确。因此，本课题拟在CST可塑性（DTI）、支配患肢神经网络整合（PRV逆行神经示踪）和Notch1通路相关蛋白和因子的表达三个方面进行研究，以期探讨健侧脑区在强制性运动促进脑缺血后患肢功能恢复中的作用机制。

强制性运动疗法（CIMT）是指通过限制健侧肢体、强化使用患肢，矫正患肢的“习得性废用”，进而促进脑卒中后患侧肢体功能的恢复。大量临床和基础研究证明了CIMT能够改善脑卒中后上肢功能的恢复，但其机制尚不明确。皮质脊髓束（CST）是支配肢体随意运动的主要神经通路，对脑卒中运动功能的恢复具有重要意义。研究表明CIMT可明显改善大鼠患肢功能，促进皮质脊髓束的生长和新生神经元形成。本研究通过PRV逆行神经示踪观察脑缺血大鼠患侧前肢的神经元支配网络，发现CIMT增强了健侧运动皮层和红核部位的神经元对患侧前肢的支配。但是，通过DTI影像技术，我们发现缺血性脑卒中导致患侧皮质脊髓束受损，而CIMT通过促进患侧CST重塑改善脑缺血大鼠患侧肢体的运动功能。此外，通过免疫荧光标记Lectin以及BrdU与NeuN双标发现CIMT促进缺血灶周围皮质的血管新生和神经元新生，并增加缺血灶周围皮质内HIF-1α 和VEGF的表达水平。以上结果表明，脑卒中后患侧半球和健侧半球的结构和功能都会发生可塑性变化，可能在不同层面上，这与患侧半球的损伤程度是密切相关的。因此，脑卒中后两侧半球间的关联与平衡值得进一步探究。