Next generation transcranial ultrasound-based neuromodulation using phase shift nanoemulsions

项目摘要 该提案响应PAR-22-039，旨在开发聚焦超声（FUS）作为下一个 生成高精度的基于设备的药理学神经调节工具，并评估其在非 从人类灵长类动物到人类的转变。当前基于设备的神经调节技术依赖于 与细胞对不同形式能量的内源性敏感性的相互作用。虽然FUS单独克服了 其他非侵入性神经调节方式的空间和深度限制，细胞对 FUS存在局限性，并且可能使可预测的神经调节变得困难。我们力求超越 通过开发FUS结合相移经由内源性敏感性进行调节的范例 纳米乳剂（PSNE）-200 nm的液体颗粒，可以携带药物有效载荷并成为微泡 当暴露于高于阈值的短暂（<1毫秒）FUS脉冲时。通过发展FUS与PSNE相结合， 我们将能够通过局部或局部的方法， 增强血脑屏障（BBB）通透性和注射药物或通过从PSNE释放药物 装满了毒品我们提出了一项研究计划，将推动这些技术在非人类 灵长类动物向人类转化的重要一步。我们首先提出开发一种超声波换能器 这将减少焦点的大小，包括接收元件，这将允许我们映射粒子激活， 穿过头骨我们将把传感器集成到由我们的团队构建的FUS神经调节系统中， BRAIN计划，并开发开源软件，以改善FUS的治疗计划 神经调节我们将应用该系统通过激活PSNE来打开感觉运动区的BBB， 驱动所得微泡并注射抑制药物GABA，其不穿过未打开的微泡， 血脑屏障浓度高到足以抑制神经元。因为打开BBB在许多情况下是不可取的， 我们还将开发可激活的载药PSNE，以局部递送麻醉钠 而不打开血脑屏障我们将描述两种神经调节的抑制作用， 方法使用BOLD功能磁共振成像和评估安全性使用神经成像和行为分析。我们 一个多学科团队拥有MR引导FUS与fMRI反馈的所有专业知识，并将与合作伙伴合作， 研究员代顿的实验室开发了一种基于缩合的PSNE制剂， 赋形剂作为商业批准的造影剂。我们建议开发的声学技术将 提高FUS神经调节的空间能力，探索两种局部药理学方法 在猴子中进行神经调节，包括为翻译铺平道路的安全性评估。

Project Summary This proposal responds to PAR-22-039 and aims to develop focused ultrasound (FUS) as a next generation high precision device-based pharmacological neuromodulation tool and evaluate its use in non- human primates as a translational step to humans. Current device-based neuromodulation technologies rely on interaction with cells’ endogenous sensitivities to different forms of energy. Although FUS alone overcomes spatial and depth limitations of other non-invasive neuromodulation modalities, the diverse response of cells to FUS presents a limitation and can make predictable neuromodulation difficult. We seek to move beyond the paradigm of modulating via endogenous sensitivity by developing FUS in combination with phase shift nanoemulsions (PSNEs)—200 nm liquid particles that can carry a drug payload and become microbubbles when exposed to brief (<1 msec) FUS pulses above a threshold. By developing FUS combined with PSNEs, we will be able to predictably modulate millimeter-scale regions throughout the brain by either locally enhancing blood brain barrier (BBB) permeability and injecting a drug or by releasing drugs from PSNEs loaded with a drug. We propose a research plan that will move these technologies forward in the non-human primate as an important translational step to humans. We first propose to develop an ultrasound transducer that will decrease the focal spot size including receive elements that will allow us to map particle activation through the skull. We will integrate the transducer into a FUS neuromodulation system built by our team under the BRAIN Initiative and develop open-source software that will improve treatment planning for FUS neuromodulation. We will apply this system to open the BBB in the sensorimotor region by activating PSNEs, driving the resultant microbubble and injecting the inhibitory drug GABA, which does not cross the unopened BBB in concentrations high enough to inhibit neurons. Because opening the BBB is not desirable in many scenarios, we will also develop activatable drug-loaded PSNEs to locally deliver the anesthetic sodium pentobarbital without opening the BBB. We will characterize the inhibitory effect of both neuromodulation methods using BOLD fMRI and assess safety using neuroimaging and behavioral analysis. Our multidisciplinary team has all expertise for MR-guided FUS with fMRI feedback and will collaborate with co- investigator Dayton whose laboratory developed a condensation-based PSNE formulation that uses the same excipients as commercially approved contrast agents. The acoustic technologies we propose to develop would improve the spatial capabilities of FUS neuromodulation and explore two approaches for focal pharmacological neuromodulation in the monkey including safety assessments that pave the way for translation.