Assessment of photoreceptor function is important in the diagnosis of visual impairment in the retina. A recent publication describes work by researchers at University of California, Davis, that aims to use optical coherency tomography to determine changes at the photoreceptor level in the retina.¹ Here, Retinal Physician speaks with study author Ravi S. Jonnal, PhD, as well as Glenn Yiu, MD, PhD, principal investigator in the UC Davis Health Eye Center lab, about this research.

Q. Could you give a brief overview of your research?

A. We have discovered a way to measure functional responses from photoreceptors using OCT. This method is called optoretinography (ORG). The technology is based on the microscopic contraction and elongation of photoreceptor outer segments that occur when photoreceptors sense light. Acquired data provide information about both structural and functional changes caused by photoreceptor disease. The functional measurement is multifaceted and may provide diagnostic cues for different kinds of photoreceptor disease. This discovery may lead to new diagnostic tools in the clinic and also to novel disease biomarkers for use in clinical trials.

Q. Tell us a bit about how this research developed.

A. I [Ravi] have been working on noninvasive optical techniques for observing neural responses in human photoreceptors since I was a PhD student. After joining the faculty at the UC Davis Eye Center, I sought clinician researchers with similar interests. I have active collaborations with retina specialists like Drs. Paul Sieving, Suanna Park, Glenn Yiu, and Ala Moshiri. The inherited retinal degenerations studied by Drs. Sieving, Park, and Moshiri are of great interest, but the ORG’s broadest impacts are likely to be in clinical management and treatments for age-related macular degeneration (AMD), which is nearly 100 times more prevalent. Dr. Yiu studies AMD imaging in patients, mice, and nonhuman primates, and he is also involved in gene therapy research. He has taught me much about the disease and has been instrumental in designing preliminary ORG experiments for patients. I believe our collaboration will be long and fruitful.

Q. What is unique about the technology?

A. Several teams around the world, including mine, have demonstrated methods for measuring photoreceptor function using adaptive optics. Adaptive optics provides cellular resolution and permits measurement of these responses from single cells, where they are least confounded by variables such as optical blur and acellular contributions. However, adaptive optics OCT imaging systems are costly, physically large, and require multiple expert personnel to use and maintain. The main achievement described in our paper is the development of a way to measure ORG using an OCT system very much like those found in most clinics today. The work illustrates how ORG technology could be integrated into commercial OCT technology, analogous to how angiography has been over the past 10 years.

Q. What are the potential benefits of this modality for retina specialists and retina patients?

A. Retina specialists rely on structural imaging technologies like OCT, which do not measure function. Functional tests like microperimetry and multifocal electroretinography provide some spatial assessment of photoreceptor function, but they lack the resolution of OCT imaging. The ability to functionally measure specific regions of the retina with OCT-level resolution could alert clinicians of disease progression before structural changes are seen, or stratify clinical trial patients based on likelihood of progression. The technology may also help explain vision loss in patients in the absence of anatomic retinal changes. Importantly, photoreceptor function assessed on ORGs can be spatially correlated with the structural portion of the OCT. We see ORGs as a game changer in how visual function will be measured in the future.

Q. Are there challenges or barriers to overcome before this can be used in a widespread way?

A. The main challenge in ORG development now is optimization for clinical use. This includes the design of stimuli that improve the speed of testing and the development of clinical figures of merit that can be calculated from the raw neural responses. One of my lab’s current projects is to investigate these areas. The next challenge will be amassing normative data and providing statistical analysis of these, which will lead to estimates of the method’s dynamic range and sensitivity to disease-related dysfunction. Then we will move on to deployment in clinical sites for real-world testing. RP

REFERENCE

1. Vienola KV, Valente D, Zawadski RJ, Jonnal RS. Velocity-based optoretinography for clinical applications. Optica. 2022;9(10):1100-1108. doi:10.1101/2022.05.10.491416