海马癫痫样放电传播的内生电场传导机理研究

Clinical seizure focus moves with a slow dynamics and the key of identifying seizure focus is to understand the mechanism of epileptiform discharge propagation. It has been shown recently that there coexist two types of dendritic oscillation-dependent travelling waves associated with propagating epileptiform activities in hippocampus, a slow and a fast one with the propagating speed depending on the endogenous electric field intensity, and further the initial position of fast wave is not fixed but moves following slow wave propagation. However, the underlying biophysical mechanism is not clear. Spontaneous neural electrical activities can induce the potential differences in extracellular space and then produce the endogenous electric field which can influence the electrical activities of neighbor cells. In our opinion, cellular dendritic oscillations are the important sources of endogenous electric field and field effect interactions between neurons contribute to the structured spatial propagation of neural dendritic oscillations. Thus, this project proposes the theory about endogenous electric field conducting dendritic oscillations in order to reveal the propagation mechanism of hippocampal epileptiform discharge. In this project, the temporal-spatial dynamics mechanism of endogenous electric field conducting dendritic oscillations will be achieved based on the field effect model for hippocampus from the following two aspects: studying the interaction between dendritic slow oscillation and fast oscillation to reveal that dendritic slow oscillation is the source of fast oscillation; exploring endogenous electric field induced spatial propagating properties of both dendritic slow oscillation and fast oscillation to reveal that the slow wave is the source of fast wave. Moreover, combined with experimental data analysis and theoretical study, the field effect mechanism about coexisting epileptiform slow wave and fast wave in hippocampus will be elucidated. This research will provide the theoretical guidance for both understanding the movement of clinical seizure focus and identifying the focus.

临床癫痫发作灶点呈现慢速移动特性，理解癫痫样放电传播机制是识别灶点的关键。研究表明海马癫痫样传播活动共存着不同树突振荡引起的慢波和快波，其传播速度依赖于内生电场强度，且快波起始位置表现为与慢波相关的移动特性，但其潜在的机制尚不清楚。内生电场是神经元自发电活动在细胞外空间产生的电场，能够影响周围神经元的电活动，我们认为神经元树突振荡是内生电场产生的源泉，而场效应交互能够实现树突振荡在空间上的有序传播。项目提出内生电场传导树突振荡的理论以揭示海马癫痫样放电传播机理。基于海马场效应模型研究树突慢振荡和快振荡之间的交互特性，揭示树突慢振荡是快振荡产生的“源”，刻画内生电场传导树突慢振荡和快振荡的空间传播特性，揭示慢波是快波产生的移动“源”，得到内生电场传导树突振荡的时空动力学机制；结合实验数据分析，阐释海马癫痫样慢波和快波共存的场效应机理。成果可为理解临床癫痫发作灶点移动以及识别灶点提供理论指导。

临床癫痫发作灶点呈现慢速移动特性，理解癫痫样放电传播机制是识别灶点的关键。海马癫痫样传播活动共存着不同树突振荡引起的慢波和快波，但其潜在的机制尚不清楚。项目研究树突快慢振荡之间的交互特性，揭示慢振荡是快振荡产生的“源”；刻画内生电场传导树突快慢振荡的空间传播特性，揭示慢波是快波产生的移动“源”；阐释海马癫痫样慢波和快波共存的场效应机理。主要成果包括：.1）记录了海马制备中癫痫样放电活动的高分辨率时空信号，分析了NMDA依赖的快波和Ca流依赖的慢波的传播特性，结果表明：癫痫样放电传播与突触传递无关，而取决于内生电场强度；.2）结合树突固有特性建立了真实形态以及简化的锥体神经元场效应模型；结合内生电场耦合原理建立了神经集群场效应模型；.3）得到内生电场传导树突振荡的动力学机制：海马癫痫样放电活动依赖于树突NMDA振荡，并通过电场耦合形成了稳定的快波；电场强度决定了快波传播速度；阻断场耦合通路可封锁快波；.4）建立了电场极化、树突Ca振荡以及胞体-树突耦合之间的生物物理联系，得到电场调节树突Ca放电的动力学机制；.5）得到慢波是快波产生的移动“源”的动力学机制：树突Ca放电通过电场耦合方式形成慢波，且其传播通路中可诱发间歇性快波；.6）得到电场调节树突NMDA超线性整合的动力学机制：远端树突超极化增加NMDA放电的阈值；而去极化则降低NMDA放电的阈值；.7）得到电场调节树突Ca振荡同步特性的动力学机制：同步依赖于网络放电频率；相比高钙模式，低钙模式下对网络放电率的变化更加敏感；.8）建立闭环电磁刺激硬件在环实时仿真平台，重构了个性化癫痫样放电的输入-输出模型，为临床前电磁刺激的优化提供了重要的验证平台；.9）基于子空间辨识方法重构了丘脑-基底核网络的线性状态空间模型，设计了二次型最优控制策略优化了DBS参数，为抑制癫痫发作的神经调控术提供了可行的闭环控制策略；.10）得到线圈结构以及磁刺激的时序对脑组织内感应电场分布特性的影响规律，线圈结构优化可实现多靶点刺激；采用时间干涉策略可达到对深部脑组织进行定位刺激；