耳针治疗小儿癫痫及其与迷走神经效应关系

Based on long-term clinical and animal studies, Prof Bing Zhu in our resaerch group firstly put forward the "Auriculo-vagal relation" theory: auricular acupuncture may increase the vagal tone via activating the projections from the auricular branch of vagus neve(ABVN) to the nucleus tractorus solitorius (NTS). The "auriculo-vagal relation" is proposed to be the possible mechanism of auricuar acupuncture for the treatment of pediatric epilepsy. .In the present randomized controlled clinical trial, pediatric patients with refractory seizures (aged less than 12 years) from the Beijing Children's Hospital of Capital Medical University, were randomly assigned to the following groups: acupuncture at auricular chonca group , acupuncture at non-auricular chonca group, and control group. The frequencies of epileptic seizures and the score of life quality in pediatric patients is observed to analyze the antiseizure effect of auricular acupuncture in pediatric epilepsy. In animal studies,by using behaviorial, electrophyiological, morphological technologies, we observed the effect of auricular acupuncture on epileptic behavior scores, firing rates of the neucleus tractus solitorius (NTS), epileptic discharges in electroencephalogram (EEG), GABA immune responsepositive neunons in the NTS in immature genetical absence epilepsy rats(GAERS), in oder to explore the antiseizure effect of auricular acupuncture in rats. The role of the NTS in the antiseizure effect is analyzed By microinjection of excitatory amino acids (glutamate), the inhibitory amino acid (GABA) receptor antagonist or agonist into the NTS. .In the present study, clinical and animal results provide scientific evidence to the mechanism of auricular acupuncture for pediatric epilepsy, and also provide evidence to the "Auriculo-vagal relation" theory. Auricular acupuncture is a convenient, effective method to treat pediatric epilepsy.

申请者所在课题组经过长期临床和实验研究，建立了"耳－迷走神经联系"理论，为耳针治疗癫痫奠定了科学基础。本课题拟通过随机对照临床试验，观察耳针对12岁以下难治性小儿癫痫患者的癫痫发作频率、生活质量评分等影响，分析耳针治疗小儿癫痫临床疗效。通过动物实验从行为学、电生理学、形态学等不同角度探讨耳针对遗传性癫痫模型幼鼠行为学评分，孤束核（NTS）神经元放电频率，脑电图癫痫波，孤束核GABA免疫反应阳性神经元的影响，以及NTS微量注射兴奋性氨基酸（Glutamate）、抑制性氨基酸（GABA）受体拮抗剂或激动剂对耳针抗癫痫效应的影响，探讨耳针抗癫痫及其与迷走神经效应关系,为丰富"耳-迷走神经联系"理论提供科学依据，也为临床小儿癫痫病的治疗提供简、便、廉、验的方法。

迷走神经传入支除了内脏传入支，在体表还有一分支分布于耳甲部，即迷走神经耳支（Auricular branch of vagus nerve, ABVN）。本课题组第1次用HRP神经示踪法观察到大鼠ABVN有纤维向上投射到孤束核（NTS）。根据以上基础，朱兵研究员首次提出“耳-迷走神经联系”理论：耳针可能通过激活ABVN-NTS通路，增强迷走紧张效应，通过纠正自主神经功能失衡，从而治疗癫痫[7]，抑郁症[8]等。本课题以此作为理论基础，研究了耳针治疗小儿癫痫与迷走神经的效应关系。课题主要从临床试验和动物实验两方面进行了研究。临床多中心随机对照研究观察到：耳针治疗小儿癫痫安全。而且耳针可以抑制小儿癫痫的发作频率，10%的患儿接受耳针补充治疗后，癫痫发作基本得到控制（癫痫频率减少90%以上）。以癫痫发作频率减少50%作为耳针治疗的responder，在治疗16周，24周后，耳甲治疗组responder rate较外耳非迷走神经刺激对照组增加，差异有统计学意义（P<0.05）。提示，治疗组在治疗16，24周后，疗效较对照组显著，且疗效可持续到24周治疗完毕。动物实验观察到，耳针可以通过激活孤束核神经元的放电频率，抑制癫痫脑电波的发放；而且可以通过纠正癫痫模型大鼠心率变异性的异常变化，抑制皮层癫痫脑电发作；外耳耳甲部神经存在辣椒素受体1（VR1）阳性, 酪氨酸羟化酶（TH）阳性， 降钙素基因相关肽（CGRP）阳性神经纤维，耳针是可能通过刺激外耳部的耳迷走神经耳支VR1,TH， CGRP阳性神经纤维抑制癫痫。本研究为耳针治疗小儿癫痫提供了临床证据和实验支持。