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

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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.