Molecular Functional Ultrasound for Non-Invasive Imaging and Image-Guided Recording and Modulation of Neural Activity

研究复杂的神经功能和疾病需要成像技术， 具有高时空分辨率的哺乳动物大脑的全面视图。理想情况下，这些技术 应该可以从啮齿动物的小脑区域扩展到更大生物体的全脑成像，如非 人类灵长类动物它们应提供内源性信号（如血流动力学）的通路，并能够 使用靶向成像技术对神经元特异性信号如钙和活性依赖性基因表达进行成像 记者说它们还应该与自由移动的受试者兼容，以便进行行为研究，并且应该 允许同时进行电生理学和靶向调节。最后，它们应该是非侵入性的， 微创，使未来的临床翻译的可能性。现有技术无法满足这些要求 标准，因为光学和电生理技术在缩放方面面临固有的限制，而功能 磁共振成像具有相对低的时空分辨率 范例最近，功能性超声作为一种革命性的技术被引入， 活动的非侵入性与超过一个数量级的改善时空分辨率相比， fMRI（<100µm和<10 ms），使用可以安装在自由移动动物身上的传感器。在啮齿类动物中，fUS 已经被用于成像与癫痫发作、胡须刺激、嗅觉、 感知和静息状态连接，研究正在进行中，以证明fUS在更大的 动物和儿科患者。在其目前的形式中，fUS跟踪由神经血管引起的血流变化， 偶合器.虽然这已经提供了前所未有的大脑成像性能，但它受到相对 内在血流动力学信号强度低，缺乏报告者将超声更直接地连接到 神经活动在这里，我们建议采取下一个重大飞跃，超声功能成像的大脑， 开发将fUS信号增强两个数量级以上的生物分子成像剂， 能够直接成像活性依赖性基因表达和钙信号传导的基因靶向 神经元作为这项工作的一部分，我们还将证明fUS在非人类大脑活动中成像的能力。 与电记录和药理学调制相结合的灵长类动物。如果我们在这些方面取得成功， 目标，由此产生的技术将为神经科学研究人员提供真正革命性的能力， 特别是对于大型动物模型的研究。此外，这项技术与 超声波神经调节（使用不同的频率和强度）将打开 全声学接口同时成像和控制自由移动中的神经活动的可能性 科目

Studying complex neurological function and disease requires imaging technologies that can provide a comprehensive view of the mammalian brain with high spatiotemporal resolution. Ideally, these technologies should be scalable from small brain regions in rodents to whole-brain imaging in larger organisms such as non- human primates. They should provide access to endogenous signals such as hemodynamics, and be able to image neuron-specific signals such as calcium and activity-dependent gene expression using targeted reporters. They should also be compatible with freely moving subjects to enable behavioral studies, and should allow simultaneous electrophysiology and targeted modulation. Finally, they should be non-invasive or minimally invasive to enable the possibility of future clinical translation. No existing technology fulfills these criteria because optical and electrophysiological techniques face inherent limitations in scaling, while functional magnetic resonance imaging has relatively low spatiotemporal resolution and severely constrains behavioral paradigms. Recently, functional ultrasound was introduced as a revolutionary technique that can image neural activity non-invasively with more than an order of magnitude improved spatiotemporal resolution compared to fMRI (<100µm and <10ms), using transducers that can be mounted on freely moving animals. In rodents, fUS has been used to image activity patterns associated with epileptic seizures, whisker stimulation, olfactory perception and resting state connectivity, and studies are underway to demonstrate the use of fUS in larger animals and pediatric patients. In its present form, fUS tracks changes in blood flow arising from neurovascular coupling. While this already provides unprecedented brain imaging performance, it is limited by the relatively low strength of intrinsic hemodynamic signals and the lack of reporters to connect ultrasound more directly to neural activity. Here, we propose to take the next major leap in ultrasonic functional imaging of the brain by developing biomolecular imaging agents that enhance fUS signals by more than two orders of magnitude and enable direct imaging of activity-dependent gene expression and calcium signaling in genetically targeted neurons. As part of this work, we will also demonstrate the ability of fUS to image brain activity in non-human primates in combination with electrical recording and pharmacological modulation. If we are successful in these goals, the resulting technology will provide neuroscience researchers with truly revolutionary capabilities, especially for the study of larger animal models. Furthermore, the potential merger of of this technology with ultrasonic neuromodulation (which uses a different regime of frequencies and intensities) will open the possibility of all-acoustic interfaces to simultaneously image and control neural activity in freely moving subjects.