Deep brain stimulation for seizure suppression in experimental epilepsy

内侧颞叶癫痫（MTLE）是成人中最常见的耐药性癫痫，其中癫痫发作通常起源于颞叶结构，如海马或内嗅皮层。手术切除癫痫病灶是目前治疗耐药性患者的唯一方法。然而，在具有多个癫痫灶或切除相关并发症的高风险的情况下，手术是不可能的，这表明迫切需要新的治疗途径。缓解顽固性癫痫发作的一种有前途的方法是高频（100-200 Hz）的脑深部电刺激（DBS）。通常，高频刺激（HFS）被连续地、不连续地或按需地应用。然而，HFS在伴有海马硬化（HS）的MTLE患者中具有较低的神经抑制功效，这可能是由于广泛的神经元损失和胶质瘢痕形成。低频刺激（LFS）是一种替代方法，它被应用于小队列研究，包括耐药性患者HS。在拟议的项目中，我们建立在我们以前的临床前研究结果，确定1 Hz LFS的内嗅传入作为一个有前途的方法抑制癫痫发作。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MTLE伴HS小鼠模型，该模型密切反映了人类病理学。首先，我们将应用光遗传学工具来鉴定在内鼻-海马回路中最适合用于抑制LFS的神经元群体。在第二步中，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）与LFS，最终目的是建立持久的癫痫控制。最后，我们将通过标准化的行为测试来确定LFS对认知表现的影响，这些测试包括移动性和焦虑，以及学习和记忆。综上所述，我们的项目将在很大程度上扩展目前的知识，DBS治疗难治性癫痫，因此，可以引入LFS作为一种有前途的方法，在MTLE癫痫发作控制。

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.