Explaining the variability in focused ultrasound neuromodulation

项目摘要 虽然非侵入性脑刺激的常规电磁方法在其空间上是有限的， 分辨率和穿透深度，超声波神经调节具有毫米级的潜力 刺激大脑深部区域而无需手术。大量证据表明，低强度 聚焦超声刺激（FUS）调节大脑活动。然而，有几份报告称， 对超声波的神经反应有很大的差异，相同的"剂量"产生不同的效果。 了解变异性的来源对于利用FUS在基础神经科学中的巨大潜力至关重要， 神经病学和精神病学。 这项研究的长期目标是将FUS发展成为一种个性化的闭环技术， 可以将大脑活动推向理想状态。作为实现这一目标的第一步， 建议是确定FUS神经元反应变异性的主要来源。基于我们小组的 根据初步数据，我们的中心假设是，对FUS的反应受大脑状态的影响很大， 通过考虑神经活动的动力学 导致刺激。在拟议的工作中，我们将彻底测试的概念，即FUS是国家依赖的 通过探测睡眠和清醒状态期间振荡动力学和细胞类型的影响。我们的具体 目的是：（1）确定基线LFP动力学和睡眠期间神经元反应之间的关系，（2） 确定细胞类型在睡眠期间对FUS的反应中的作用，以及（3）确定神经元的决定因素。 在清醒状态下对FUS的反应。我们将对麻醉和头部固定的清醒大鼠进行研究， 并且将用FUS靶向海马体，同时捕获电生理活动。 所提出的工作是有意义的，因为它解决了超声波的核心问题 神经调节：如何使其效果更强大和可预测。这项研究是创新的，因为它 明确地将导致刺激的神经动力学与随后对FUS的反应联系起来。 这项研究的产品有可能解决FUS的一个核心问题： 反应通过描述导致稳健效应的条件，这项研究将使FUS领域成为一个 更接近闭环能力，这显然需要可预测的反应。而且还要 通过考虑FUS的神经生物学底物， 在这项研究中确定的响应国家。例如，如果我们确认FUS反应与 基线伽马，这将阐明FUS正在调制的（伽马生成）电路。这 这些知识也将立即通知快速增长的FUS神经调节研究社区 作为未来神经病学和精神病学的试点研究。

PROJECT SUMMARY While conventional electromagnetic approaches to non-invasive brain stimulation are limited in their spatial resolution and penetration depth, ultrasonic neuromodulation carries the potential of millimeter scale stimulation of deep brain regions without the need for surgery. Abundant evidence shows that low intensity focused ultrasound stimulation (FUS) modulates brain activity. However, there have been several reports of substantial variability in the neural response to ultrasound, with the same "dose" producing disparate effects. Understanding the source of variability is critical to harnessing the vast potential of FUS in basic neuroscience, neurology, and psychiatry. The long term goal of this research is to develop FUS into a personalized, closed loop technology that can drive brain activity towards desirable states. As the first step towards this goal, the overall objective of this proposal is to identify the primary source of the variability in neuronal responses to FUS. Based on our group's preliminary data, our central hypothesis is that response to FUS is greatly influenced by brain state, and that the outcome of stimulation may be accurately predicted by taking into account the dynamics of neural activity leading up to stimulation. In the proposed work, we will thoroughly test the notion that FUS is state dependent by probing the influence of oscillatory dynamics and cell type during both sleep and wake states. Our specific aims are: (1) Identify the relationship between baseline LFP dynamics and neuronal response during sleep, (2) Identify the role of cell type in response to FUS during sleep, and (3) Identify the determinants of neuronal response to FUS in the awake state. We will work with both urethane-anesthetized and head-fixed awake rats, and will target the hippocampus with FUS while simultaneously capturing electrophysiological activity. The proposed work is significant because it addresses the central problem with ultrasonic neuromodulation: how to make its effects more robust and predictable. This research is innovative because it explicitly links neural dynamics leading up to stimulation with the subsequent response to FUS. The products of this research have the potential to solve a central problem in FUS: variability of response. By delineating the conditions that lead to robust effects, this research will bring the FUS field one step closer to closed-loop capabilities, which clearly necessitate predictable responses. Moreover, we will obtain a clearer understanding of the mechanism of FUS by considering the neurobiological substrates of the responsive states identified in this research. For example, if we do confirm a link between FUS response and baseline gamma, this will shed light on the (gamma generating) circuits that FUS is modulating. This knowledge will then immediately inform the rapidly growing FUS neuromodulation research community as well as future pilot studies in neurology and psychiatry.