Optoretinography (ORG), a technique that allows in vivo observation of cellular movement in the eye at the nanoscale, could provide a robust, noninvasive way to evaluate retinal health and detect blinding eye diseases, like age-related macular degeneration, earlier.
An international research team, led by Nanyang Technological University, Singapore (NTU Singapore), tested the feasibility of using ORG as a tool to access the optical expression of electrical activity within the eye’s rod photoreceptors — specifically, the rod early receptor potential generated in the disk membranes, which is challenging to access in electrophysiology. Rod photoreceptors are the cells that support vision in low light, and are often the first to deteriorate at the onset of retinal disease.
The researchers investigated whether rod photoreceptors exhibit an early receptor potential that produces a rapid, minute electromechanical contraction. They found that rod photoreceptors undergo a rapid contraction of up to 200 nm within about 10 milliseconds of light reaching the retina.
When the researchers combined these measurements with biophysical modeling, they further found that the rapid rod photoreceptor movements are initiated when rhodopsin — the eye’s light-sensitive molecule — is light-activated. Rhodopsin activation is an initial step in the body’s conversion of light into electrical signals that the brain can interpret as vision.
“The ‘twitch’ of the eye’s night-vision cells is akin to the ignition spark of vision,” professor Tong Ling said. “We have long known that these cells produce electrical signals when they absorb light, but no one had, until now, ever reported the accompanying mechanical contraction of these cells inside the living eyes of humans or rodents. The findings reveal a fundamental step in the process by which rod photoreceptors detect light and send visual information to the brain. These cells make up about 95% of all photoreceptors in the human retina.”
The researchers used an ultrahigh-resolution point-scan OCT system to image light-triggered electrical activity in rodent rod photoreceptors in vivo. They combined OCT with an unsupervised learning approach to separate the light-evoked response of the rod’s outer segment tips from the retinal pigment epithelium-Bruch’s membrane complex.
In humans, the researchers used ORG with an adaptive optics line-scan OCT to facilitate high-speed recordings in rod photoreceptors.
By enabling noninvasive, in vivo optical imaging of rhodopsin activation, OCT could extend the diagnostic capability of ORG, allowing personalized, objective assessment of rod dysfunction in inherited and age-related eye diseases.
Existing tools to study and measure rod photoreceptor function are inadequate. The in vivo techniques are limited in their sensitivity, specificity, and cellular resolution, while the ex vivo approaches are too invasive to be used on patients.
“This is the first time we’ve been able to see this phenomenon in rod cells in a living eye,” professor Ramkumar Sabesan said. “Rod dysfunction is one of the earliest signs of many retinal diseases, including AMD and retinitis pigmentosa. Being able to directly monitor the rods’ response to light gives us a powerful tool for disease detection and tracking treatment responses earlier and with greater sensitivity than any conventional diagnostic instrument.”
The ability to accurately measure rod photoreceptor viability will allow researchers to assess the structural and functional integrity of rods with high sensitivity and resolution. Together with a technique developed by the team in 2024, which measures the rod photoreceptors’ relatively slow movements in response to dim visual stimuli, the new approach will provide valuable method for clinicians to detect and monitor rod function.
ORG also allows researchers to visualize the movements of other types of cells in a living person’s eye. This could lead to a better understanding of how retinal cells work and their relationship with neighboring cells. From a clinical standpoint, it could allow more detailed, and potentially earlier, diagnoses of retinal diseases, especially those that primarily affect the photoreceptors.
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