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金标准，特别是在中枢神经系统中用于脑活动的高通量结构和功能成像。光学方法的主要优点是光与组织非侵入性地相互作用。然而，现有的光学成像技术无法以高空间分辨率将光递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，使得基于外部光学器件的这种方法限于生物组织的表层。此外，在中枢神经系统的背景下，其具有广泛分布的神经回路，系统范围的询问将需要快速光束转向能力或同时多位点照明。基于来自脑外的光的图案化的最新技术不能深入到组织中，因为当光传播通过组织时，其经历衍射、散射和吸收;结果，光束变宽并且光的强度迅速福尔斯下降到视蛋白和光学报告子的激发阈值以下。拟议的项目旨在通过使用高频声波（超声波）在组织中形成虚拟中继透镜以进入深层组织进行光学成像来解决光学方法的这些缺点。在这项技术中，组织本身变成了一个光学透镜，使成像更深的结构。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，以进行可操纵成像。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，以了解光子学，超声波和神经技术在大脑功能和结构成像中的应用。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大脑内窥镜成像的方法，这种方法通常涉及将梯度折射率（GRIN）透镜植入大脑。非侵入性的超声波将被用于通过限制和引导光深入组织而不必插入物理GRIN透镜来雕刻虚拟光学中继透镜。所提出的对用于中继成像的脑组织内的虚拟可操纵光学透镜的超声雕刻的研究的结果将是通过解决两个未满足的需求来促进用于脑组织的非侵入性成像的基于光的方法的重大突破，即，非侵入式深度穿透和波束控制该超声限定的虚拟透镜可以通过组织的深度传递或收集光。超声换能器的相控阵列将被设计成在组织内形成可重构的虚拟中继透镜。测试和开发这项技术的模型系统是小鼠脑组织。为了进一步扩大拟议项目的影响，开发的声光成像技术也将提供给不同的神经生物学实验室，用于使用大脑成像和刺激的光学方法来测试各种神经科学假设。拟议的项目通过引入一种新的非侵入性深层组织穿透技术和实时光束转向技术来推进光学成像的前沿，以实现深层结构的靶向成像。这可能会改变我们在动物模型中靶向脑组织内特定通路的能力。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。

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.