On the physiological processes underlying optoretinography [Invited].

Optoretinography (ORG) is a label-free imaging of the light-evoked changes in the retina associated with alterations in the cell shape and refractive indices. Its most precise version, the phase-resolved optical coherence tomography (pOCT), exhibited sensitivity of about 10 nm in vivo, limited by the signal-to-noise ratio and accuracy of the tissue registration. While it is yet insufficient for the detection of single action potentials, which are about 1 nm in amplitude, it enables monitoring slower and larger deformations in other retinal layers. In response to a single flash delivered to the dark-adapted retina, photoreceptor outer segments (OS) exhibit rapid (millisecond-scale) contraction, reaching tens of nm in cones and hundreds of nm in rods. This effect can be explained by changes in the membrane tension due to hyperpolarization of the OS discs-that is, the intradiscal space becoming more negatively charged-during the early receptor potential induced by opsins isomerization. In cones, such contraction is followed by a slower elongation by hundreds of nm during hundreds of ms. The proposed underlying mechanisms include osmotic influx of water, swelling of the cone opsin and disc membranes, and conformational changes in phosphodiesterase (PDE6) during phototransduction. ORG also reveals slow deformations in the subretinal space (SRS) and retinal pigment epithelium (RPE), likely induced by light-evoked ionic and osmotic shifts, as well as in the inner plexiform layer (IPL) and ganglion cell layer (GCL). ORG has a high potential as a non-invasive, label-free, and objective assay of retinal health, co-registered with structural images in the same OCT machine. To realize its promise in basic science and clinical assessment of diseases and therapies, its underlying mechanisms need to be delineated. This review summarizes current understanding of the physiological mechanisms behind the ORG.