丘脑前部电刺激治疗癫痫的电生理机制及高选择性靶点调控研究

Global research as well as our pilot studies demonstrate that deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is of significant clinical value in the treatment of refractory epilepsy, whose outcomes vary significantly, as the underlying mechanisms remain unclear. There is general agreement that neuronal excessive excitation is the fundamental mechanism of epileptic discharges, whereas the synchronization of neuronal excitation plays a key role in the development of epileptic discharges. Based on our preliminary observations supporting the novel “desynchronization” hypothesis of ANT-DBS for epilepsy, we will further clarify the mechanism of neuromodulation for epilepsy by studying the effects of ANT-DBS on hypersynchronization in the epileptogenic zone (EZ) and characteristic changes in the EZ-cortex connection network. One of the stereoelectroencephalography (SEEG) electrodes that toward the thalamus is to be implanted into the anterior thalamus with the subtle angle adjusted appropriately, which provides an opportunity to record the electrical activities of the anterior thalamus and cortex simultaneously. Furthermore, by utilizing the technology of cortex-cortex evoked potential (CCEP), combined with multiple methods of signal processing, the effect of the stimulation, as illustrated above, of the EZ and cortical network was assessed, and the specific correlation between the sub-nuclei of the anterior thalamus and the epileptic seizure types was investigated. This was done in order to facilitate the discovery and further understanding of the electrophysiological mechanism underlying the treatment of epilepsy with anterior thalamus-DBS, making an optimal choice about the most suitable seizure types and producing precise individualized neuromodulation at the level of sub-nuclei.

近年国际研究和本课题组前期观察显示，丘脑前核脑深部电刺激治疗药物难治性癫痫具有重要的临床价值，但治疗效果存在差异，调控机制并不明确。本课题组考虑到神经元异常兴奋是癫痫性放电的基础，而异常兴奋的神经元能否同步化放电则是产生癫痫性放电的核心，在前期工作支持丘脑前部电刺激治疗癫痫的“去同步化”新颖假设基础上，进一步针对调控机制这一关键问题，在难治性癫痫患者需要植入立体定向电极的临床程序中，将适宜角度的植入电极延伸至丘脑前部核团，实现丘脑前部核团和皮质脑电活动的同步记录，重点研究丘脑核团电刺激对于致痫区局部的病理性过度同步化放电的影响以及致痫区－脑皮质之间网络连接特征的改变，并结合丘脑亚核团的精准定位和丘脑－皮质诱发电位技术，力图构建丘脑核团－发作类型的特异相关性。本项目有助于完善丘脑电刺激治疗癫痫的电生理机制，确定基于癫痫发作类型的高选择性丘脑前部核团的调控靶点，提高目前丘脑前核调控治疗的疗效。

癫痫是神经系统最常见的疾病之一，约30%的患者对多种药物耐药。临床医生面对的情况是，尽管有些患者可以通过切除性手术获得癫痫控制，但仍有一部分药物难治性癫痫患者，基于现有技术条件无法准确找到癫痫灶，或存在多灶性起源以及癫痫灶位于重要功能区等情况，并不适合目前的切除性手术。近年来，国际多中心临床实验显示，丘脑前核电刺激是治疗药物难治性癫痫的临床新方法。但是，这一方法的作用机制仍不十分明确，限制了其临床应用。.本课题通过对接受脑深部电极植入进行致痫灶定位评估的耐药性癫痫患者的研究，进一步揭示了丘脑前核电刺激控制癫痫发作的机制，主要包括以下3方面：（1）丘脑前核的高频刺激导致癫痫源区海马的神经元活动及癫痫性电活动立即减弱并去同步化，并且这种效应具有丘脑前核和大脑皮质间的位置特异性，即丘脑前核与颞叶海马的电生理连接最为紧密；（2）对丘脑前核进行电刺激时，海马显示出频率依赖性的刺激效果，即低频刺激导致海马神经元活动的同步性增加，而高于45 Hz的频率刺激则导致海马神经元活动显著的去同步化现象，这种去同步化也是抑制癫痫发作的重要机制，同时也为临床患者的刺激频率选择提供了参考依据；（3）高频刺激丘脑前核也导致了大尺度的皮质网络联结程度降低，这可能也与抑制癫痫发作有一定关系。.本课题通过对丘脑前部电刺激调控癫痫网络的电生理机制的揭示，明确了ANT与相应皮层之间的功能联系，明确了精准靶点选择与癫痫类型选择之间的相关关系，有助于改进现有的手术方案和适应症选择，实现癫痫精准调控治疗，并对神经调控术后刺激频率的选择具有指导意义。通过本课题研究，研究团队建立了成熟的丘脑-皮层癫痫网络的研究分析方法，并进一步开始研究丘脑底核、丘脑枕对癫痫网络调控作用，进一步拓展研究领域。