Dark adaptation of cone photoreceptor responses is revealed by optoretinography

Dark adaptation is the essential process that restores visual sensitivity following exposure to bright light, yet the underlying mechanisms remain incompletely understood. Here, we propose a method for assessing dark adaptation in cones using optoretinography (ORG) based on adaptive optics optical coherence tomography (AO-OCT). ORG quantifies cone functional response by monitoring nano-scale changes in the cone's outer segment occurring over hundreds of milliseconds after visible stimulation. This method consists of sequential measurements of stimulus-evoked cone responses over the course of minutes of dark adaptation. Each response captures optical path length changes in single photoreceptor outer segments over milliseconds during a multi-minute recovery period following a strong photopigment bleach. We parameterized cone ORG responses and proposed an exponential model linking ORG dynamics to pigment regeneration. Parameters of the ORG response exhibited exponential decay behavior during dark adaptation, and were thus fit with exponential functions and quantified by the resulting decay parameter τ. Parameters capturing the amplitude of the ORG responses recovered more slowly than those capturing temporal dynamics of the responses. This difference is consistent with distinct contributions from photopigment regeneration and downstream phototransduction processes. Recovery speed varied by two- to threefold among three normal subjects, suggesting substantial inter-subject physiological diversity. Processes within the cone, including pigment regeneration, are thought to underlie the gains in photopic visual sensitivity that occur in the dark. These findings highlight ORG as an objective and sensitive assay of those cellular mechanisms. While the ORG itself has shown promise as a biomarker of the health of the photoreceptor response to light, the results of this study show that it may also be useful for probing the health of the intra- and intercellular homeostatic mechanisms that support it.