Optoretinography: All-optical measures of functional activity in the human retina

项目摘要/摘要 在过去的几十年里，在详细研究支持视力的生理机制方面取得了重大进展。 以及旨在抢救和修复受视网膜疾病影响的神经元的疗法。对于继续 治疗方法的演变及其快速转化到临床，找到一种非侵入性的、全光学的是至关重要的 生物标志物，用于监测疾病的疗效和潜在的治疗药物。为此，我们建议 发展光视网膜图，或称ORG，是目前视网膜电信号(ERG)的光学模拟 人类视网膜功能评估的黄金标准。ORG植根于经典干涉计量学和 能够对神经元如何与光相互作用进行高度敏感的分析。使用这项技术，我们小组已经 展示了在一系列时空分辨率上可视化光驱动的神经活动的能力- 从单个细胞到神经元集合，从微秒到毫秒的时间尺度。在这里，我们的目标是扩大 ORG的能力，并展示其在基础科学和临床应用的有效性。建议数 技术建立在已建立的方法的坚实基础上，并将它们结合在新的 实现速度、分辨率和灵敏度的最佳组合的互补方式 克服人类细胞结构和功能成像所面临的关键挑战。核心技术 相分辨OCT是一种测量毫秒级纳米尺度变化的安全的干涉测量方法吗 体内刻度，自适应光学(AO)，以克服眼睛像差，提高信噪比，并允许 分辨率低至单个细胞和实时眼睛跟踪，以克服眼睛运动并允许定位， 记录单个和一组视网膜神经元的反应并取其平均值。这些都得到了实施 跨越三个ORG平台。在华盛顿大学，我们将改进行扫描相位分辨率OCT 在光学设计和眼球跟踪方面有所改进，并用它来表征 正常人和视网膜病变患者的光传导和视网膜内功能 堕落的人。在斯坦福大学，我们将为啮齿动物开发类似的行扫描系统，并与 转基因模型和药理学，确定了ORG和 为人类录音开发模板。在加州大学伯克利分校，我们将挑战速度和敏感度的极限 通过结合实时眼球跟踪系统来驱动AO-OCT干涉探头，目的是 测量人类视网膜中最微小和最简短的神经元变化。这项生物工程研究 合作伙伴关系将受益于互补的专业知识、研究方向和整个组织的实施 三个网站，并使用图像/数据分析、眼睛跟踪和视觉刺激的共同方法。 归根结底，聚合技术将促进对早期视觉的更深层次的机械理解 加工和眼病，并为加速治疗干预提供了全新的途径。

Project Summary/Abstract The last few decades have seen major inroads into detailing the physiological mechanisms supporting vision as well as therapies aimed at rescue and repair of neurons affected by retinal diseases. For the continued evolution of treatments and their rapid translation to the clinic, it is essential to find a non-invasive, all-optical biomarker to monitor the efficacy of disease and potential therapeutic agents. To this end, we propose to develop the optoretinogram, or ORG, the optical analog to the electroretinogram (ERG) which is the current gold standard for retinal function assessment in humans. The ORG is rooted in classical interferometry and enables a highly sensitive assay of how neurons interact with light. Using this technique, our group has demonstrated the ability to visualize light-driven neural activity across a range of spatiotemporal resolution – from single cells to a collection of neurons, and from µsecs to ms timescales. Here, we aim to expand the capabilities of the ORG and demonstrate its efficacy for basic science and clinical applications. The proposed technology is built upon a solid foundation of established approaches, and combines them in new and complementary ways to achieve an optimal combination of speed, resolution and sensitivity geared towards overcoming the key challenges faced with imaging cellular structure-function in humans. The core technologies are phase-resolved OCT, an eye-safe, interferometric method to measure nm-scale changes at ms time scales in vivo, adaptive optics (AO) to overcome ocular aberrations, increase the signal-to-noise and allow resolution down to single cells and real-time eye tracking to overcome eye motion and allow targeting, recording and averaging of responses from single and a collection of retinal neurons. These are implemented across three ORG platforms. At the University of Washington, we will refine the line-scan phase-resolved OCT with improvements in optical design and eye-tracking and use it to characterize the basic properties of phototransduction and inner retinal function in healthy human volunteers and patients with retinal degenerations. At Stanford University, we will develop a similar line-scan system for rodents, and together with transgenic models and pharmacology, determine the biophysical mechanisms that underlie the ORG and develop templates for human recordings. At UC Berkeley, we will push the envelope of speed and sensitivity by incorporating a real-time eye-tracking system to drive an AO-OCT interferometric probe, with the aim to measure the tiniest and briefest neuronal changes in the human retina. This bioengineering research partnership will benefit from complementary expertise, research direction and ORG implementation across the three sites, and the use of common approaches for image/data analysis, eye tracking and visual stimulation. Ultimately, the aggregate technology will facilitate a deeper mechanistic understanding of early visual processing and eye disease, and provide entirely new avenues for accelerating therapeutic interventions.