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， 增强记忆力的治疗方法直接操纵神经活动的策略很有前途， 目前有严重的局限性。脑深部电刺激（DBS）的内嗅皮层（ERc），大脑的一部分 DBS对记忆力很重要，在一小部分患者中已被证明可以改善记忆力，但DBS对记忆力的影响很大。 侵入性的并且需要神经外科手术。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层结构。在MCI和AD中，包括ERc在内的脑深部结构 和受影响最大的海马体（HC）。低强度聚焦超声脉冲（LIFUP）使用 具有比人类可以听到的频率更高的声波能量波穿透头骨， 针对大脑深部区域因此，LIFUP可以靶向脑深部结构，这些结构对发作性脑损伤至关重要。 记忆形成，与MCI和AD中受影响的区域相同。我们是第一个这样做的，我们的 初步数据显示，LIFUP：增加ERc的灌注;增加ERc的功能连接; ERc/HC记忆网络，并可能改善行为记忆性能。我们的LIFUP设置可以安全使用 在磁共振成像（MRI）机器内，该机器允许同时进行大脑调制和真实的- 使用MRI的调制的时间测量。我们将使用每个参与者的结构脑MRI来瞄准LIFUP 在ERC。这将使我们能够直接测试LIFUP对ERc活动的影响，在其他大脑区域 与ERc（例如HC）相连，以及HC和其他对记忆重要的大脑区域的血流。 将其应用于MCI患者，我们将尝试确定LIFUP效应的剂量、增强效应和持续时间 对大脑和血液流动，结构和功能的影响，确定这些LIFUP相关的变化是否改善 在这个人群中的记忆，并评估LIFUP对AD相关的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影响 LIFUP对大脑、生物标志物和记忆表现的影响和持续时间将是朝着 构建一个全面的临床试验。通过改变大脑区域的活动和血液流动的能力， 用LIFUP瞄准他们将是开发非侵入性记忆假体的重要一步 这将对AD治疗做出非常重要的贡献。

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.