Next generation transcranial ultrasound-based neuromodulation using phase shift nanoemulsions

使用相移纳米乳剂的下一代经颅超声神经调节

基本信息

批准号：
10577371
负责人：
Charles F Caskey
金额：
$ 81.24万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577371
关键词：
Acoustics Anesthetics Automobile Driving Autopsy BRAIN initiative Behavioral Blood - brain barrier anatomy Brain Brain region Cells Cephalic Characteristics Clinical Trials Collaborations Computer software Contrast Media Data Development Devices Drug Delivery Systems Elements Excipients Exposure to Feedback Focused Ultrasound Focused Ultrasound Therapy Formulation Functional Magnetic Resonance Imaging Goals Growth Human Image Inflammation Laboratories Liquid substance Magnetic Resonance Imaging Maps Methods Microbubbles Modality Molecular Monitor Monkeys Neurons Patients Pentobarbital Sodium Pharmaceutical Preparations Phase Physical condensation Physiologic pulse Procedures Publishing Rattus Research Research Personnel Risk Rodent Safety Scheme Spottings System Technology Time Transducers Translating Translations Ultrasonic Transducer Work blood oxygen level dependent blood-brain barrier permeabilization cranium design gamma-Aminobutyric Acid image guided improved millimeter millisecond multidisciplinary nanoemulsion neuroimaging neuroregulation next generation nonhuman primate open source particle patient population pharmacologic pressure putamen response safety assessment sensorimotor system side effect software development somatosensory tool translational model treatment planning ultrasound

Acoustics Anesthetics Automobile Driving Autopsy BRAIN initiative Behavioral Blood - brain barrier anatomy Brain Brain region Cells Cephalic Characteristics Clinical Trials Collaborations Computer software Contrast Media Data Development Devices Drug Delivery Systems Elements Excipients Exposure to Feedback Focused Ultrasound Focused Ultrasound Therapy Formulation Functional Magnetic Resonance Imaging Goals Growth Human Image Inflammation Laboratories Liquid substance Magnetic Resonance Imaging Maps Methods Microbubbles Modality Molecular Monitor Monkeys Neurons Patients Pentobarbital Sodium Pharmaceutical Preparations Phase Physical condensation Physiologic pulse Procedures Publishing Rattus Research Research Personnel Risk Rodent Safety Scheme Spottings System Technology Time Transducers Translating Translations Ultrasonic Transducer Work blood oxygen level dependent blood-brain barrier permeabilization cranium design gamma-Aminobutyric Acid image guided improved millimeter millisecond multidisciplinary nanoemulsion neuroimaging neuroregulation next generation nonhuman primate open source particle patient population pharmacologic pressure putamen response safety assessment sensorimotor system side effect software development somatosensory tool translational model treatment planning ultrasound

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项目摘要

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.

项目摘要该建议对PAR-22-039的回应，旨在发展重点超声（FUS）产生高精度的基于设备的药物神经调节工具，并评估其在非 - 非 - 人类素数是对人类的转化步骤。当前基于设备的神经调节技术依赖与细胞对不同形式能量的内源性敏感性相互作用。虽然单独的FUS克服了其他非侵入性神经调节方式的空间和深度限制，细胞对潜水员的反应 FUS提出了一个局限性，可以使可预测的神经调节变得困难。我们试图超越通过内源性敏感性调制的范式通过与相移结合形成FUS 纳米乳液（PSNE） - 可以携带药物有效载荷并成为微泡的200 nm液体颗粒当暴露于阈值以上的简短（<1毫秒）脉冲时。通过开发FUS与PSNE相结合，我们将能够可预测地调节整个大脑的毫米级区域增强血脑屏障（BBB）渗透性并注入药物或通过释放PSNE的药物装有药物。我们提出了一项研究计划，将这些技术推向非人类灵长类动物是对人类的重要转化步骤。我们首先建议开发超声传感器这将降低焦点大小，包括接收元素，使我们能够绘制粒子激活穿过头骨。我们将将换能器集成到由我们的团队建立的FUS神经调节系统大脑计划和开发开源软件，可以改善FUS的治疗计划神经调节。我们将通过激活PSNE，将此系统应用于感觉运动区域的BBB。驱动最终的微泡并注入抑制性药物GABA，该药物不会跨越未打开 BBB的浓度足够高以抑制神经元。因为打开BBB是不可取的场景，我们还将开发可激活的药物psnes，以局部提供麻醉钠戊巴比妥不打开BBB。我们将表征两种神经调节的抑制作用使用BOLD FMRI和使用神经影像学和行为分析的评估安全性的方法。我们的多学科团队拥有FMRI反馈的MR引导FUS的所有专业知识，并将与共同合作研究人员代顿的实验室开发了一种基于冷凝的PSNE公式，该公式使用相同赋形剂作为商业批准的对比剂。我们建议开发的声学技术将提高FUS神经调节的空间能力，并探索两种局灶性药理方法猴子中的神经调节，包括为翻译铺平道路的安全评估。