Inactivation of the hippocampus by electrical stimulation to preview post-surgical verbal recognition memory deficits

项目摘要 接受海马切除术治疗内侧颞叶癫痫（MTLE）的患者经常 经历记忆缺陷。临床医生在计划手术时几乎没有工具来预览这些缺陷; Wada测试，麻醉每个半球以测试对侧可用的记忆功能 这是目前的医学标准。它是在颞叶切除术是主要的 MTLE手术治疗。相比之下，现代外科技术，如开放选择性 杏仁核切除术（AH）和激光间质热治疗（LITT）可以精确，选择性损伤 同时最大限度地减少对周围组织的损伤。预览和切除之间的比例差异 是一个变量，有助于不一致的效用和田测试，以准确地预览记忆缺陷。 临床医生需要一种更精确地靶向待切除组织的测试，从而更准确地预测 失去组织的功能性后果。我们建议使用电刺激（ES）通过 立体脑电图（SEEG）深度电极，放置在海马中用于临床癫痫发作 监测，以在预期的手术切除的空间尺度上产生暂时的记忆缺陷。虽然 海马ES常被用来研究海马在记忆过程中的作用， 临床实用性预览记忆缺陷后，小脑切除术的研究较少。因为和田测试 仍然是临床标准，我们已经设计了我们的研究，以匹配其测试范式。在这一框架内， 我们的计划将研究在哪里（目标1），何时（目标2），以及如何（目标3）刺激海马产生 记忆受损虽然海马体参与记忆功能是无可争议的， 海马体的哪个（哪些）子区域应该被刺激以损害记忆功能。我们相信刺激 海马体的头部和身体都会导致损伤，但在目标1中，我们还将测试海马体的刺激。 头部和身体单独地，看看更多的局部刺激是否可以产生期望的效果。 同样，海马体也参与了编码和提取记忆的过程，但事实并非如此。 已知哪些过程应该被ES破坏以损害记忆功能。在目标2中，我们将测试 在这些阶段中单独地和在两个阶段中进行刺激，以确定哪一个导致最佳损伤。 最后，在目标3中，我们将研究刺激频率如何影响记忆功能的损害。的 文献报道了使用从5到200 Hz的宽频率范围的研究。因为更高的频率 更有可能产生癫痫活动，我们将测试限制在较低的频率范围内。我们将评估ES 在5 Hz，这与海马内的内源性神经生理学调制相匹配， 长期以来一直是用于破坏整个神经组织功能的临床标准。这项提议是一项新研究 方向，将建立将海马ES转化为临床可行的 工具，以预览记忆缺陷所造成的切除海马在治疗MTLE。

PROJECT SUMMARY Patients who have undergone hippocampal resection to treat mesial temporal lobe epilepsy (MTLE) frequently experience memory deficits. Clinicians have few tools to preview these deficits when planning surgeries; the Wada test, which anesthetizes each hemisphere to test memory function available in the contralateral hemisphere, is the current medical standard. It was developed when temporal lobectomy was the primary surgical treatment for MTLE. In contrast, modern surgical techniques such as open selective amygdalohippocampectomy (AH) and laser interstitial thermal therapy (LITT) enable precise, selective lesions while minimizing damage to surrounding tissue. The difference in scale between the preview and the resection is one variable contributing to inconsistency in the utility of the Wada test to accurately preview memory deficits. Clinicians need a test which more precisely targets the tissue to be removed, and thus more accurately predicts functional consequences of losing the tissue. We propose using electrical stimulation (ES) through stereoelectroencephalography (SEEG) depth electrodes, placed in the hippocampus for clinical seizure monitoring, to generate temporary memory deficits at the spatial scale of intended surgical resection. Although ES of the hippocampus has been frequently employed to study the hippocampus' role in memory processes, its clinical utility to preview the memory deficits after hippocampectomy is less studied. Because the Wada test remains the clinical standard, we have designed our study to match its testing paradigm. Within this framework, our proposal will study where (Aim 1), when (Aim 2), and how (Aim 3) to stimulate the hippocampus to produce memory impairment. While the involvement of the hippocampus in memory function is undisputed, it is not clear which subregion(s) of the hippocampus should be stimulated to impair memory function. We believe stimulating both the head and body of the hippocampus will lead to impairment, but in Aim 1 we will also test stimulation of the head and body individually to see whether more localized stimulation can produce the desired effect. Similarly, the hippocampus has been implicated in both encoding and retrieval memory processes, but it is not known which of these processes should be disrupted by ES to impair memory function. In Aim 2 we will test stimulation in these phases individually and in both phases to determine which leads to the best impairment. Finally, in Aim 3 we will examine how the frequency of stimulation affects impairment of memory function. The literature reports studies using a wide range of frequencies, from 5 to 200 Hz. Because higher frequencies are more likely to generate epileptic activity, we limit our testing to a lower range of frequencies. We will evaluate ES at 5 Hz, which matches endogenous neurophysiological modulation within the hippocampus, and 50 Hz, which has long been a clinical standard used to disrupt function throughout neural tissue. This proposal, a new research direction, will establish the baseline results needed to translate ES of the hippocampus into a clinically viable tool to preview memory deficits resulting from resection of the hippocampus in the treatment of MTLE.