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

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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.