Retinal opto-physiology is the physiological response of the retina to a visible light stimulus, reflecting the function of the retina to a certain extent. Optoretinography, also termed optoretinogram (ORG), is a newly developed functional imaging technique for precisely quantifying the opto-physiological response of the retina. It uses optical coherence tomography combined with controllable light stimulus, to accurately measure retinal morphology and optical property changes in response to a light stimulus by detecting the peak position and scattering intensity alternations in optical coherence tomography (OCT) images. Moreover, ORG can achieve microscale lateral resolution, nanoscale axial resolution, and millisecond temporal resolution by combining adaptive optics and phase analysis techniques, and be used to measure opto-physiological functions of the retina at the cellular level. To perform ORG, only an optical stimulus unit is required to be added to the existing OCT system. Currently, it is still in the stage of technology development and mechanism exploration. Once standards are established, ORG may be used in broad ophthalmic research and clinical practice. In this study, the history of OCT functional imaging development for probing the retinal opto-physiological signal is systematically reviewed, the latest progress in ORG technology is summarized, and several future directions of ORG technology are discussed.

Because of the excellent spatial resolution of OCT and its extensive use in basic research, clinical diagnosis, and treatment, researchers have been committed to capturing the functional response of nerve cells to a visible light stimulus using OCT. Early studies of OCT photo-physiological functional imaging focused on finding the changes in retinal scattering signals after light stimulation. With the gradual improvement of OCT performance (such as resolution and imaging speed) and the wide application of in vivo imaging technology, a series of breakthroughs have been made in the field of OCT retinal functional imaging in recent years. The optical path difference changes of cone outer segment in living human retina after a light stimulus [Fig. 2(a)-(c)] were successfully measured using high-speed full-field OCT combined with phase analysis technology. Subsequently, Zhang et al. used OCT to observe the function signals of mouse retina in response to the light stimulation with different intensities. They reported the changes in the thickness of the rod outer segment at a micron level and changes in scattering signal intensities of several retinal layers [Fig. 2(d)-(h)]. Moreover, they confirmed that the response signals came from the visual photo-transduction process using gene knockout mice. Furthermore, due to the advantages of adaptive optics enhanced OCT (AO-OCT) in imaging resolution, researchers have successfully measured the photo-physiological signal at the level of a single cone cell in the human eye. For example, Zhang et al. measured the functional response of human cone cells after light stimulation using AO-OCT in 2019 and successfully distinguished three types of cone cells in the human eyes via different cone cell responses to different color stimuli (Fig. 3). In the recent studies, several experimental groups have conducted the diseases or mechanism research on the retina from a physiological perspective. Qian et al. changed the mouse retina through transgenic or drug methods to carry out controlled experiments with conventional wild mice. They found that changes in the thickness of the mouse’s external retina after light stimulation were affected by the base level of mitochondrial respiration and oxidative stress reaction. This suggests the favorable conditions for the clinical application of OCT-based photo-physiological functional imaging.

The method based on OCT retinal opto-physiological functional imaging and visible light stimulation is collectively called optoretinogram. ORG is a new technology in which the obtained opto-physiological signals can reflect the function of retinal tissue. This addresses the limitation of conventional OCT imaging technology which can only provide details of the retinal structure. Moreover, studies of human and animal retina indicate that retinal responses to light stimulation involve subtle changes in several structures including the rod, cone, retinal pigment epithelium, Bruch's membrane, and choroid. All are closely related to the structures affected by various retinal diseases. Thus, to some extent, early retinopathy may affect the intensity and change rate of retinal opto-physiological function signal. Therefore, this can provide a new diagnostic basis for detection of early disease by measuring the abnormal changes in the opto-physiological function signal.

Future developments of ORG may include the following four aspects: 1) realizing the local analytical capability of ORG while maintaining wide-field macroscopic imaging; 2) further enhancement of the sensitivity of OCT to enable detection of weaker functional signals; 3) extracting the functional signal quickly and automatically and exploring the characteristic functional signal of early retinopathy; and 4) optimization and standardization of experimental methods.