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

视网膜检光术：人类视网膜功能活动的全光学测量

• 批准号: 10295296
• 负责人: DANIEL V PALANKER
• 金额: $ 103.79万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295296
• 关键词: Action Potentials; Affect; Age; Animals; Automobile Driving; Basic Science; Biological Assay; Biological Markers; Biomedical Engineering; Biophysical Process; Cell Culture Techniques; Cell model; Cells; Cellular Structures; Clinic; Clinical; Collection; Computer Models; Cone; Data; Data Analyses; Detection; Diagnosis; Disease; Electrophysiology (science); Electroretinography; Elements; Event; Evolution; Eye; Eye diseases; Foundations; Functional disorder; Generations; Goals; Gold; Grant; Human; Human Volunteers; Image; Individual; Interferometry; Ions; Lateral; Light; Location; Machine Learning; Measurement; Measures; Membrane; Methods; Monitor; Motion; Natural regeneration; Neurons; Noise; Optics; Patients; Pharmacology; Phase; Photic Stimulation; Photoreceptors; Phototransduction; Physiological; Physiology; Plant Roots; Positioning Attribute; Property; Research; Resolution; Retina; Retinal Cone; Retinal Degeneration; Retinal Diseases; Rodent; Rodent Model; Scanning; Signal Transduction; Site; Solid; Speed; Stimulus; System; Techniques; Technology; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Transgenic Model; Translations; Treatment Efficacy; Universities; Vision; Visual system structure; Washington; adaptive optics; adaptive optics scanning laser ophthalmoscopy; analog; base; cell type; cellular imaging; clinical application; computerized data processing; data acquisition; design; efficacy evaluation; ganglion cell; imaging approach; in vivo; inherited retinal degeneration; millisecond; multi-electrode arrays; mutant; nanometer; non-invasive imaging; patch clamp; relating to nervous system; repaired; response; retinal neuron; spatiotemporal; temporal measurement; tool; visual dysfunction; visual processing; visual tracking; Action Potentials; Affect; Age; Animals; Automobile Driving; Basic Science; Biological Assay; Biological Markers; Biomedical Engineering; Biophysical Process; Cell Culture Techniques; Cell model; Cells; Cellular Structures; Clinic; Clinical; Collection; Computer Models; Cone; Data; Data Analyses; Detection; Diagnosis; Disease; Electrophysiology (science); Electroretinography; Elements; Event; Evolution; Eye; Eye diseases; Foundations; Functional disorder; Generations; Goals; Gold; Grant; Human; Human Volunteers; Image; Individual; Interferometry; Ions; Lateral; Light; Location; Machine Learning; Measurement; Measures; Membrane; Methods; Monitor; Motion; Natural regeneration; Neurons; Noise; Optics; Patients; Pharmacology; Phase; Photic Stimulation; Photoreceptors; Phototransduction; Physiological; Physiology; Plant Roots; Positioning Attribute; Property; Research; Resolution; Retina; Retinal Cone; Retinal Degeneration; Retinal Diseases; Rodent; Rodent Model; Scanning; Signal Transduction; Site; Solid; Speed; Stimulus; System; Techniques; Technology; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Transgenic Model; Translations; Treatment Efficacy; Universities; Vision; Visual system structure; Washington; adaptive optics; adaptive optics scanning laser ophthalmoscopy; analog; base; cell type; cellular imaging; clinical application; computerized data processing; data acquisition; design; efficacy evaluation; ganglion cell; imaging approach; in vivo; inherited retinal degeneration; millisecond; multi-electrode arrays; mutant; nanometer; non-invasive imaging; patch clamp; relating to nervous system; repaired; response; retinal neuron; spatiotemporal; temporal measurement; tool; visual dysfunction; visual processing; visual tracking

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.

项目摘要/摘要 在过去的几十年中 以及旨在营救和修复受残留疾病的神经元的疗法。继续 治疗的演变及其快速转化为诊所，必须找到无创的全光学 生物标志物监测疾病和潜在治疗剂的效率。为此，我们建议 开发对电图（ERG）的光学图或组织的光学类似物（ERG）是电流 人类残留功能评估的金标准。该组织植根于经典干扰和 对神经元如何与光相互作用进行高度敏感的评估。使用这种技术，我们的小组有 证明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 - 从单个细胞到集合神经元，从µSEC到MS时标。在这里，我们旨在扩大 组织的功能，并证明了其对基础科学和临床应用的有效性。提议 技术建立在既定方法的坚实基础上，并将它们结合在新的和 完全实现速度，分辨率和灵敏度的最佳组合的方法 克服成像人类中细胞结构功能的关键挑战。核心技术 是相位分辨的OCT，一种眼部安全的干涉方法，用于测量MS时NM尺度变化 体内鳞片，自适应光学元件（AO）克服眼畸变，增加信噪比并允许 分辨到单个单元格和实时的眼睛跟踪，以克服眼睛运动并允许靶向， 记录和平均单个和一系列残留神经元的响应。这些已实现 跨三个组织平台。在华盛顿大学，我们将完善线扫相分辨的Oct 随着光学设计和眼睛跟踪的改进，并使用它来表征 健康的人类志愿者和残留患者的光转传和内部残留功能 退化。在斯坦福大学，我们将为啮齿动物开发类似的线扫描系统，并与 转基因模型和药理学，确定构成组织和组织的生物物理机制 开发用于人类记录的模板。在加州大学伯克利分校，我们将推动速度和灵敏度的信封 通过合并实时的眼交系统来驱动AO-O-OCT干涉探针，目的是 测量人视网膜中最微小，最短的神经元变化。这项生物工程研究 伙伴关系将受益于完善专业知识，研究方向和组织实施 三个站点，以及用于图像/数据分析，眼睛跟踪和视觉刺激的通用方法。 最终，总体技术将有助于对早期视觉的更深入的理解 加工和眼部疾病，为加速治疗干预提供了全新的途径。