Modulation of Hippocampal Circuitry and Memory Function with Focused Ultrasound in Amnestic MCI

摘要 对于轻度认知障碍（MCI）和阿尔茨海默病（AD）患者来说，有效的治疗方法很少 增强记忆力的治疗。直接操纵神经活动的策略很有希望，但 目前存在严重的局限性。内嗅皮层 (ERc)（大脑的一部分）的深部脑刺激 (DBS) 对记忆力很重要，在一小部分患者样本中已被证明可以改善记忆力，但 DBS 的效果非常显着 侵入性的，需要神经外科手术。其他不需要手术的神经调节技术是有限的 因为它们只针对大脑表面结构。在 MCI 和 AD 中，是大脑深层结构，包括 ERc 以及受影响最严重的海马体（HC）。低强度聚焦超声脉动（LIFUP）用途 频率高于人类听觉范围的声能波可穿透颅骨，产生特定效果 针对深部大脑区域。因此，LIFUP 可以针对对情景性发作至关重要的深部大脑结构。 记忆形成，MCI 和 AD 中受影响的区域相同。我们是第一个这样做的人，我们的 初步数据表明 LIFUP：增加 ERc 的灌注；增加的功能连接 ERc/HC 记忆网络并可能改善行为记忆表现。我们的 LIFUP 设置可以安全使用 在磁共振成像 (MRI) 机器内，允许同时进行大脑调制和实时 使用 MRI 测量调制的时间。我们将使用每个参与者的结构性脑部 MRI 来瞄准 LIFUP 在急诊室。这将使我们能够直接测试 LIFUP 对 ERc 和其他大脑区域活动的影响 与 ERc（例如 HC）以及 HC 和其他对记忆很重要的大脑区域的血流有关。 将其应用于 MCI 患者，我们将尝试确定 LIFUP 效果的剂量、增强效果和持续时间 大脑和血流、结构和功能，确定这些与 LIFUP 相关的变化是否有所改善 该人群的记忆力并评估 LIFUP 对 AD 相关血液生物标志物的影响 神经变性。了解 LIFUP 剂量和加强疗程的参数如何影响效果 LIFUP 对大脑、生物标志物和记忆力表现的持续时间将是朝着这一目标迈出的重要一步 构建全面的临床试验。通过改变大脑区域的活动和血流的能力 用 LIFUP 瞄准它们将是开发非侵入性记忆假体的重要一步 这将为 AD 治疗做出非常重大的贡献。

ABSTRACT For patients with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD) there are few effective treatments for memory enhancement. Strategies that directly manipulate neural activity are promising but currently have serious limitations. Deep brain stimulation (DBS) of the entorhinal cortex (ERc), a part of the brain important for memory, in a small sample of patients has been shown to improve memory, but DBS is highly invasive and requires neurosurgery. Other neuromodulation techniques that do not require surgery are limited in that they target only surface brain structures. In MCI and AD, it is the deep brain structures, including the ERc and the hippocampus (HC) that are most affected. Low intensity focused ultrasound pulsation (LIFUP) uses acoustic energy waves with frequencies higher than humans can hear to penetrate the skull to effect specifically targeted deep brain regions. Therefore, LIFUP could be targeted at the deep brain structures critical for episodic memory formation, the same regions that are affected in MCI and AD. We are the first to do just this and our preliminary data shows that LIFUP: increases perfusion of the ERc; increased functional connectivity of the ERc/HC memory network and may improve behavioral memory performance. Our LIFUP set-up is safe to use inside a magnetic resonance imaging (MRI) machine which allows for simultaneous brain modulation and real- time measurement of the modulation using MRI. We will use each participant’s structural brain MRI to aim LIFUP at the ERc. This will allow us to directly test the effects of LIFUP on activity in the ERc, in other brain regions connected to the ERc (e.g. HC), as well as on blood flow in the HC and other brain areas important for memory. Applying this to patients with MCI, we will try to determine the dose, booster effect and duration of LIFUP effects on brain and blood flow, structure and function, determine whether these LIFUP-related changes improve memory in this population and evaluate the effect of LIFUP on blood-based biomarkers of AD-related neurodegeneration. Understanding how the parameters of LIFUP dose and booster session effect the impact and duration of LIFUP on brain, biomarker and memory performance will be a significant step towards constructing a comprehensive clinical trial. The ability to change the activity and blood flow of brain regions by targeting them with LIFUP would be an important step towards developing a non-invasive memory prosthetic that would make a very significant contribution to AD treatment.