CAREER: All-Acoustic Image-Guided Implantable Microscopic Ultrasound Neuromodulation

神经调节有可能映射神经功能；增强我们的感知、运动和认知能力；并恢复因受伤或疾病而丧失的感觉和运动功能。尽管经过了几十年的研究和开发，最先进的非侵入性神经调节技术仍然存在空间分辨率低(超过几毫米)的问题，而通过极具侵入性的实质植入，具有较高空间分辨率的可植入电学和光学方法只能有限地覆盖数百到数千个神经元。这些限制是根本的，这些技术的进一步优化不能同时满足最小侵入性、微观空间分辨率(数百微米及以下)和全脑覆盖的关键要求。该计划包括对一种激进方法的科学研究，该方法探索超声波作为一种前所未有的大规模显微分辨率神经调节的微创植入性手段，已经在亚厘米分辨率的经颅神经调节中发挥作用。这项拟议的研究将为一套全面的微创神经接口提供独特的构建块。它将在神经科学中打开新的机会，在空间分辨率和大脑神经调节的覆盖范围方面有重大改进，最初是在动物身上。最终，它还将在人类的许多临床应用中具有巨大的翻译潜力，例如治疗神经和精神疾病以及脑机接口。利用这项研究的多学科性质，该计划还包括一个综合外展和教育部分，围绕“故障排除和基于探究的学习(TIL)框架”创建，以加强学生在不同教育水平上学习原则和研究技能。用TIL框架改造本科电路课程将提高许多本科生的研究技能、解决问题的能力和创造性思维。一年一度的为期一周的教师暑期工作坊将为教师提供基于TIL的教育实践和基于课堂电脑游戏的模块，以教育K-12教师及其学生，这些教师和学生来自本研究中科学、技术、工程和数学(STEM)领域代表性较低的地区。一个以TIL为基础的预科女生“超声转歌”实践模块，将吸引她们投身工程专业，并在本研究中对她们进行教育。一门新的医疗器械课程将培养这一领域的研究生。该项目将探索植入式显微超声刺激(IuUS)，对整个大脑进行微创调制，空间分辨率在数百微米及以下。该计划将为IuUS奠定基础，即在脑表面(部分切除的头骨)植入超声换能器阵列，在没有实质穿透的情况下，以电子方式将高度聚焦的超声束引导到不同的神经目标。这样的系统可用于基础神经科学实验，以解决超声神经调节中最基本的科学问题：潜在机制、有效性和安全性。这项工作将探索和建立振动声学，以实现IuUS的高能效。它将通过开发基于波动方程的数值和计算模型来研究IuUS的空间分辨率和覆盖范围的基本限制以及能量效率，以探索不同换能器几何形状、频率和配置的影响以及它们与组织和电子设备的相互作用。为了管理植入后的不确定性(例如微动)，这项工作将探索和创建一种基于学习的全声图像引导系统，以实现准确的解剖定位。将开发一种带有离线训练的芯片上机器学习模型，以快速而准确的方式将声束轮廓的变化动态映射到微动和组织变化。还将为IuUS开发一种具有新颖电路的感应询问闭环(记录和刺激)片上系统。最后，系统级别的演示将为IUS奠定基本基础。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Neuromodulation has the potential to map neural functions; enhance our perceptual, motor, and cognitive capabilities; and restore sensory and motor functions lost through injury or disease. Despite several decades of research and development, state-of-the-art noninvasive neuromodulation techniques still suffer from poor spatial resolution (more than several millimeters), while implantable electrical and optical methods with finer spatial resolution only provide a limited coverage of hundreds to thousands of neurons through extremely invasive parenchymal implantation. These limitations are fundamental, and further optimization of these technologies cannot simultaneously meet the critical requirements of minimal invasiveness, microscopic spatial resolution (hundreds of micrometers and below), and whole brain coverage. This program includes scientific research in a radical approach that explores ultrasound, which has already been effective in transcranial neuromodulation with sub-centimeter resolution, as a minimally invasive implantable means for unprecedented microscopic-resolution neuromodulation at large scale. The proposed research will yield a unique building block for a comprehensive set of minimally invasive neural interfaces. It will open new opportunities in neuroscience with significant improvements in spatial resolution and coverage of neuromodulation of the brain, initially in animals. Ultimately, it will also have huge translational potential for many clinical applications in humans, such as the treatment of neurological and psychiatric disorders and brain-machine interfaces. Leveraging the multidisciplinary nature of the research, this program also includes an integrated outreach and educational component created around a "Troubleshooting and Inquiry-based Learning (TIL) Framework" to enhance students' learning of principles and research skills at different education levels. Transforming an undergraduate circuit course with the TIL framework will enhance the research skills, problem solving, and creative thinking of many undergraduate students. An annual week-long summer workshop for teachers with educational TIL-based hands-on and in-class computer-game-based modules will educate K-12 teachers and their students from districts underrepresented in the science, technology, engineering, and mathematics (STEM) fields in this research. A TIL-based "Ultrasonically Transferred Song" hands-on module for pre-college female students will attract them to the engineering profession and educate them in this research. A new medical-device course will educate graduate students in this field.This program will explore implantable microscopic ultrasound stimulation (IuUS) with minimally invasive modulation of the whole brain with the spatial resolution of hundreds of micrometers and below. This program will establish the fundamental basis for IuUS, in which an ultrasound transducer array is implanted on the brain surface (partially removed skull) with no parenchymal penetration to electronically steer highly focused ultrasound beams towards different neural targets. Such a system can be utilized in basic neuroscience experiments to address the most fundamental scientific questions in ultrasound neuromodulation: underlying mechanism, efficacy, and safety. This work will explore and establish vibro-acoustography for high energy efficiency in IuUS. It will investigate fundamental limits of spatial resolution and coverage as well as energy efficiency in IuUS by developing numerical and computational models based on wave equations to explore effects of different transducer geometries, frequencies, and configurations as well as their interactions with tissue and electronics. To manage post-implantation uncertainties (e.g. micromotions), this work will explore and create a learning-based all-acoustic image-guided system for accurate anatomical targeting. An on-chip machine-learning model with offline training will be developed to dynamically map changes in the profile of acoustic beams to micromotions and tissue changes in a fast and accurate fashion. An inductively interrogated closed-loop (recording and stimulation) system-on-chip with novel circuitry will also be developed for IuUS. Finally, a system-level demonstration will establish the fundamental basis for IuUS.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.