三叉神经慢性电刺激的神经调控方法在癫痫治疗中的作用

It is found that trigeminal nerve stimulation (TNS) has significant antiepileptic effect. Our research further demonstrated that chronic TNS could significantly suppress the spontaneous recurrent seizure (SRS) attack with the expression of inhibitory neurotransmitter upregulated in interneuron. And simultaneously, this chronic TNS could protect the hippocampal neurons from damage induced by status epilepticus (SE). Basing on the well accepted epileptic network in the brain, i.e. the network of brainstem-thalamus-cerebral cortex and hippocampus, we raised such hypothesis: chronic trigeminal nerve electrostimulation will mildly activate cerebral cortex or hippocampus via the signal transduction through thalamus. The long-lasting mild activation of the cerebral cortex and hippocampus will lead to chronic upregulation of neurotransmitters of the inhibitory system. On the other hand, the long-lasting mild activation of the cerebral cortex and hippocampus will result in an excitatory habituation alteration of the cerebral cortex and hippocampus, thus protecting neurons from damage induced by SE. Thus, suppression of the spontaneous recurrent seizures can be achieved through the upregulated inhibitory system as well as through the excitatory habituation alterations in the brain. Stereotaxic destroy of thalamus nucleus,electroencephalography and behavior recording, immunohistochemistry, Western blot, and fMRI techniques will be employed to investigate the effect of chronic trigeminal nerve stimulation on SRS in different animal models of chronic epilepsy and in patients with refractory epilepsy and to preliminarily make clear the antiepileptic mechanisms of chronic TNS involving the network of thalamus-cerebral cortex and hippocampus in the brain. This will lay a theoretical basis for a new therapeutic method for patients with intractable epilepsy, and will also expand our understanding of the mechanism of epilepsy.

新近发现三叉神经电刺激有显著的抗癫痫作用，我们的研究进一步发现三叉神经慢性电刺激具有减少癫痫自发性反复发作的作用，并且能够上调皮层和海马中间神经元的抑制性作用物质基础，同时对癫痫持续状态所致海马神经元损伤具有显著的保护作用。基于被普遍认可的脑干- - 丘脑- - 皮层、海马这一癫痫网络，我们形成如下假说：三叉神经慢性电刺激-间断性激活丘脑- - 慢性上调皮层和海马的中间神经元抑制系统/或皮层、海马神经元兴奋性预适应- - 对癫痫脑神经元产生保护作用和抑制癫痫的慢性反复发作。本研究通过立体定向核团毁损、脑电和行为记录、免疫组织化学、Western blot和fMRI等方法进一步观察三叉神经慢性电刺激在不同慢性癫痫动物模型和顽固性癫痫病人中的治疗作用，初步明确丘脑- - 皮层及海马这一癫痫网络在三叉神经慢性电刺激治疗慢性癫痫中的作用，为临床治疗顽固性癫痫提供一新的技术方法和理论基础。

项目的背景：国外有研究初步证明了三叉神经电刺激治疗癫痫的有效性和安全性，但关于慢性三叉神经电刺激对癫痫反复发作和认知功能的长期影响等尚未见有研究报导，关于三叉神经刺激抗癫痫作用的基本机制并不清楚。. 主要研究内容：观察经皮三叉神经慢性电刺激对不同化学点燃癫痫大鼠自发性癫痫发作及神经细胞损伤和炎性反应的影响，及其对癫痫患者癫痫发作的影响，同时观察经皮三叉神经慢性电刺激对癫痫大鼠和癫痫患者的学习记忆能力的影响；观察丘脑前核毁损后经皮三叉神经慢性电刺激对化学点燃癫痫大鼠自发性癫痫发作和皮层、海马神经细胞损伤的影响，及其对反映神经兴奋性和抑制性传导的vGlut1和VGAT表达的影响。最后，通过fMRI-BOLD值的检测三叉神经慢性电刺对癫痫患者皮层、海马兴奋性的影响。. 重要结果、关键数据及其科学意：①经皮三叉神经慢性电刺激降低癫痫大鼠癫痫发作的严重程度、持续时间和死亡率，减少了皮层、海马神经细胞凋亡和脱失，降低了各时间点海马炎性因子含量和活性小胶质细胞数，提高了癫痫大鼠学习记忆能力。说明在实验性癫痫中，经皮三叉神经电刺激有显著的抗癫痫作用，提高了癫痫发作的阈值，其机制可能与其对脑神经细胞受损的保护作用和炎性反应的下调作用有关。②癫痫大鼠三叉神经慢性电刺激结束后24h内VGLUT1表达显著增高，但在随后的3d至28dVGLUT1表达则显著降低，而VGAT则迅速增高并维持至28d以上。癫痫大鼠在三叉神经电刺激前予以丘脑前核毁损预处理则降低了三叉神经慢性电刺激的抗癫痫、神经保护、和VGLUT1下调及VGAT上调作用，说明三叉神经慢性电刺激可能通过丘脑前核传导产生脑兴奋性适应性改变而发挥抗癫痫作用和神经保护这作用。③三叉神经慢性电刺激减轻了癫痫患者的癫痫发作，提高了癫痫患者已受损的学习记忆能力，同时降低了额、颞叶fMRI-BOLD值，提示三叉神经慢性电刺激可能通过脑兴奋性适应性改变而发挥对癫痫患者的抗癫痫作用和神经保护这作用。