In-situ Ultrasonically Sculpted Virtual Light Paths for Steerable Neural Imaging and Stimulation

组织的光学成像是生物医学成像的黄金标准，特别是在中枢神经系统中，可以高通量地对大脑活动进行结构和功能成像。光学方法的主要优点是光与组织的非侵入性相互作用。然而，现有的光学成像技术无法以高空间分辨率将光传送和收集到组织深处。光在组织中的散射限制了分辨率和穿透深度，使得这些方法基于仅限于生物组织表层的外部光学。此外，在拥有广泛分布的神经回路的中枢神经系统的背景下，系统范围的询问将需要快速的光束转向能力或同时的多点照明。最新的基于脑外光线模式的技术无法深入组织，因为当光线在组织中传播时，它会经历衍射、散射和吸收；结果，光束变宽，光线强度迅速降至光学蛋白和光学记者的激发阈值以下。该项目旨在解决光学方法的这些缺点，利用高频声波(超声波)在组织中形成一个虚拟的中继镜，以进入深层组织进行光学成像。在这种技术中，组织本身被转化为光学透镜，从而能够对更深层次的结构进行成像。这种超声定义的透镜可以在不干扰组织的情况下四处移动，进行可操纵的成像。这个多学科项目为研究生和本科生提供了一个独特的教育和培训环境，让他们了解当代光子学、超声学和神经技术在脑功能和结构成像中的应用。来自少数族裔的学生将通过这个研究项目接受培训。在这个跨学科的项目中，研究人员将开发一种非侵入性的替代脑部内窥镜成像的方法，通常涉及将分级折射率(GRIN)透镜植入大脑。非侵入性超声波将被用来通过限制和引导光线深入组织来雕刻虚拟光学中继镜，而不必插入物理GRIN透镜。本文提出的在脑组织内进行接力成像的虚拟可操控光学透镜超声造型的研究成果将是一项重大突破，将通过解决两个尚未满足的需求，即无创深穿透和波束控制，促进基于光的方法进行脑组织的非侵入性成像。这种超声定义的虚拟透镜可以通过组织的深度传递或收集光线。超声换能器的相控阵将被设计成在组织内形成可重新配置的虚拟中继透镜。测试和开发这项技术的一个模型系统是小鼠脑组织。为了进一步扩大拟议项目的影响，还将向不同的神经生物学实验室提供开发的声光成像技术，以使用脑成像和刺激的光学方法测试各种神经科学假说。拟议的项目通过引入一种非侵入性深层组织穿透和实时光束控制的新技术来推动光学成像的前沿，从而能够对深层结构进行定向成像。这可能会改变我们在动物模型中针对脑组织内特定路径的能力。这一结果将对人类产生间接的临床影响。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。

Optical imaging of tissue is the gold standard of biomedical imaging, especially in the central nervous system for high throughput structural and functional imaging of brain activity. The key advantage of optical methods is that light interacts with tissue non-invasively. Existing optical imaging techniques, however, suffer from an inability to deliver and collect light deep into the tissue with high spatial resolution. Scattering of light in tissue limits the resolution and penetration depth, rendering such methods based on external optics limited to the superficial layers of biological tissues. Additionally, in the context of the central nervous system, which harbors widely distributed neural circuits, system-wide interrogation would require either fast optical beam-steering capability or simultaneous multi-site illumination. Recent techniques based on patterning of light from outside the brain cannot reach deep into the tissue, since as light propagates through tissue, it undergoes diffraction, scattering, and absorption; as a result, the beam widens and the intensity of light rapidly falls below the threshold of excitation of opsins and optical reporters. The proposed project aims to address these shortcomings of the optical methods by using high frequency sound waves (ultrasound) to form a virtual relay lens in the tissue to access deep tissue for optical imaging. In this technique, the tissue itself is turned into an optical lens that enables imaging deeper structures. This ultrasonically defined lens can be moved around without disturbing the tissue for steerable imaging. This multidisciplinary project provides a unique educational and training environment for graduate and undergraduate students to learn about contemporary concepts in photonics, ultrasonics, and neural technologies for applications in functional and structural imaging of brain. Students from underrepresented minority groups will be trained through this research program.In this interdisciplinary project, the researchers will develop a non-invasive alternative to endoscopic imaging of brain that usually involve implanting a graded-index (GRIN) lens into the brain. Non-invasive ultrasonic waves will be used to sculpt virtual optical relay lenses by confining and steering light deep into the tissue without having to insert physical GRIN lenses. The result of the proposed research on ultrasonic sculpting of virtual steerable optical lenses within the brain tissue for relay imaging will be a significant breakthrough to facilitate light-based methods for non-invasive imaging of brain tissue by addressing two unmet needs, i.e., noninvasive deep penetration and beam steering. This ultrasonically defined virtual lens can both deliver or collect light through the depth of the tissue. A phased array of ultrasonic transducers will be designed to form reconfigurable virtual relay lenses within the tissue. A model system in which to test and develop this technology is the mouse brain tissue. To further amplify the impact of the proposed project, the developed acousto-optic imaging technique will also be provided to different neurobiology labs for testing various neuroscience hypotheses using optical methods for brain imaging and stimulation. The proposed project advances frontiers of optical imaging by introducing a novel technique for non-invasive deep tissue penetration and real-time optical beam steering to enable targeted imaging of deep structures. This can potentially transform our ability to target specific pathways within the brain tissue in animal models. The results will have indirect clinical implications for humans.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.