Deep brain stimulation for seizure suppression in experimental epilepsy

中内侧颞叶癫痫（MTLE）是成人中最常见的耐药癫痫形式，其癫痫发作通常起源于颞叶结构，如海马或内嗅皮层。手术切除癫痫病灶目前是治疗耐药患者的唯一方法。然而，对于多发发作灶或切除相关并发症高风险的病例，手术是不可能的，这表明迫切需要新的治疗途径。一种缓解难治性癫痫发作的有希望的方法是高频率（100-200赫兹）的深部脑刺激（DBS）。通常，高频刺激（HFS）可以连续、间断或按需进行。然而，HFS对伴有海马硬化（HS）的MTLE患者的癫痫抑制效果较低，可能是由于广泛的神经元丢失和神经胶质瘢痕。低频刺激（LFS）是另一种方法，已应用于包括HS耐药患者在内的小队列研究。在这个项目中，我们建立在我们之前的临床前研究结果的基础上，确定了1 Hz的内嗅事件LFS是抑制癫痫发作的一种有希望的方法。因此，我们的目标是优化DBS的靶结构和刺激参数，并评估潜在的认知副作用。为此，我们将使用已建立的与人类病理密切相关的MTLE伴HS小鼠模型。首先，我们将应用光遗传学工具来确定内嗅-海马回路中最适合用于癫痫抑制LFS的神经元群。第二步，我们将把我们的发现转化为电刺激。我们将比较三种常用的HFS配置（连续、不连续和按需）和LFS，最终目的是建立持久的癫痫发作控制。最后，我们将通过标准化的行为测试来确定LFS对认知表现以及学习和记忆的影响。综上所述，我们的项目将在很大程度上扩展目前关于DBS治疗难治性癫痫的知识，因此，可以将LFS作为一种有希望的MTLE癫痫控制方法引入。

Mesial temporal lobe epilepsy (MTLE) is the most frequent form of drug-resistant epilepsy in adults, in which seizures typically originate from temporal lobe structures such as the hippocampus or entorhinal cortex. Surgical resection of the epileptic focus currently represents the only curative approach for pharmacoresistant patients. However, in cases with multiple seizure foci or high risk for resection-related complications, surgery is impossible, demonstrating an urgent need for new therapeutic avenues. One promising approach to alleviate intractable seizures is deep brain stimulation (DBS) at high frequencies (100-200 Hz). Commonly, high-frequency stimulation (HFS) is applied either continuously, discontinuously, or on-demand. However, HFS has low seizure-suppressive efficacy in MTLE patients with hippocampal sclerosis (HS), presumably due to extensive neuronal loss and glial scarring. Low-frequency stimulation (LFS) represents an alternative approach, which was applied in small cohort studies including pharmacoresistant patients with HS.In the proposed project, we build on our previous preclinical findings that identified 1 Hz LFS of entorhinal afferents as a promising approach for seizure suppression. Therefore, our aim is to optimize target structures and stimulation parameters for DBS and assess potential cognitive side effects. To this end, we will use an established mouse model for MTLE with HS, which closely reflects the human pathology. Firstly, we will apply optogenetic tools to identify the most suitable neuronal population for seizure-suppressive LFS in the entorhinal-hippocampal circuit. In a second step, we will translate our findings to electrical stimulation. We will compare the three commonly used HFS configurations (continuous, discontinuous, and on-demand) to LFS with the final aim to establish long-lasting seizure control. Finally, we will determine the influence of LFS on cognitive performance with standardized behavioral tests for mobility and anxiety, as well as learning and memory. Taken together, our project will largely extend the current knowledge regarding DBS for the treatment of intractable epilepsy and therefore, could introduce LFS as a promising approach for seizure control in MTLE.