Investigating fundamental properties and clinical applications of the optoretinogram

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Abstract This grant will investigate the optoretinogram (ORG)–an experimental, all optical assay of human photoreceptor function–and its potential to reveal dysfunction at the cellular level. The ORG is based on adaptive optics optical coherence tomography (AO­OCT), which is the only existing way to produce 3D images of the living human retina with cellular resolution. It leverage our novel observation that light stimuli cause microscopic deformations in the living photoreceptor outer segment (OS), along with OCT’s sensitivity to deformations in the tissue much smaller than the wavelength of the imaging source. Aim 1 investigates the ORG’s ability to measure function in rods and cones, by measuring responses in normal subjects and characterizing the signal’s sensitivity to changes in stimu­ lus energy, and factors affecting this sensitivity, such as spatial and temporal variance in response, computational factors, and photon noise. Aim 2 investigates the mechanisms underlying light­evoked OS deformation. We will rigorously determine the light levels at which the deformations are saturated, the effect of multiple flashes, and the signal’s dependence on retinal eccentricity, all of which provide valuable information about the biochemical processes causing the observed deformations. Aim 3 applies the ORG to well­characterized retinal disease, to determine whether it is able to detect pathological dysfunction in photoreceptors suffering from known deficits. Well­characterized deficits, in turn, offer natural experiments which may shed light on the biochemical and biome­ chanical determinants of the observed light­evoked deformations in the OS.