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)的患者来说，几乎没有有效的方法 增强记忆力的治疗。直接操纵神经活动的策略很有前途，但 目前有严重的局限性。深部脑刺激(DBS)内嗅皮层(ERC)，大脑的一部分 对记忆很重要，在一小部分患者样本中已显示出改善记忆的作用，但DBS的作用很大 是侵入性的，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 因为它们只针对表面的大脑结构。在MCI和AD中，它是大脑的深层结构，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)的应用 频率高于人类所能听到的声波穿透头骨以产生特定的效果 瞄准深部大脑区域。因此，LIFUP可以针对对发作性疾病至关重要的大脑深层结构。 记忆形成，在MCI和AD中受影响的相同区域。我们是第一个这样做的人，我们的 初步数据显示，LIFUP：增加了ERC的灌注量；增加了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，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MRI来瞄准LIFUP 在能源研究中心。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 连接到大脑皮质(如HC)，以及HC和其他对记忆重要的大脑区域的血液流动。 将其应用于MCI患者，我们将尝试确定LIFUP效应的剂量、助推器效应和持续时间 对大脑和血流、结构和功能的影响，决定这些与LIFUP相关的变化是否有所改善 LIFUP对AD相关血型生物标志物的影响 神经退行性变。了解LIFUP剂量和助推器疗程参数如何影响影响 LIFUP对大脑、生物标记物和记忆性能的持续时间将是迈向 建设综合性临床试验。通过改变大脑区域的活动和血流量的能力 以LIFUP为靶点将是开发非侵入性记忆假体的重要一步 这将对AD的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.