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We provide the first measures of foveal cone density as a function of axial length in living eyes and discuss the physical and visual implications of our findings. We used a new generation Adaptive Optics Scanning Laser Ophthalmoscope to image cones at and near the fovea in 28 eyes of 16 subjects. Cone density and other metrics were computed in units of visual angle and linear retinal units. The foveal cone mosaic in longer eyes is expanded at the fovea, but not in proportion to eye length. Despite retinal stretching (decrease in cones/mm2), myopes generally have a higher angular sampling density (increase in cones/deg2) in and around the fovea compared to emmetropes, offering the potential for better visual acuity. Reports of deficits in best-corrected foveal vision in myopes compared to emmetropes cannot be explained by increased spacing between photoreceptors caused by retinal stretching during myopic progression. The human eye has many different parts that enable sight. The retina is the light sensitive tissue at the back of the eye, and it contains the fovea, the region that provides the clearest vision. Light must be focused on the retina to create images, a feat achieved by the transparent parts at the front of the eye called the cornea and lens. These parts of the eye are called the optics. Between birth and adulthood, significant changes take place in the eye. Most noticeably, the distance between the optics and the fovea grows by about seven millimeters. Cells called cone photoreceptors, which provide light sensitivity, migrate and pack into the fovea. Finally, the eye’s optics adjust to maintain a sharp focus. At the same time, the brain is learning how to process inputs from the eyes to generate mental images that realistically correspond to the physical world around it. The development of the eye is fascinating in its complexity, but for more and more people, the process does not go as expected. Specifically, a growing proportion of the population has eyes that are too long. This means that, for light reflected by far away objects, the eye’s optics form an image in front of the retina instead of on it. As a result, images of distant objects cannot be seen clearly, a condition known as myopia or nearsightedness. Researchers have also discovered that nearsighted people see less clearly than those who do not use glasses, even when given a sharp image to examine at close range. It has been hypothesized that these deficits result from stretching of the retina as the eye becomes bigger. Until recently, testing this hypothesis by looking at cone photoreceptors directly in the eye was impossible. This is because the optics of all eyes have small imperfections that distort the light passing through them, including any light used to take high resolution microscopic images of the fovea. This hurdle can be overcome using adaptive optics, which means adding a deformable mirror to the instrument being used to image the eye that can adjust to correct the distortion. Wang et al. use a new generation Adaptive Optics Scanning Laser Ophthalmoscope to check the density of cones at the fovea in relation to the size of the eye. They show that although the center of the fovea has fewer cones when the eye is bigger, this effect is more than offset because the longer eye increases magnification. So, if a near-sighted person wearing contacts and someone who does not need glasses stood side-by-side admiring the full moon, the near-sighted person would most likely have more cones sampling the image and should therefore have a higher resolution view. These findings rule out reductions in the density of cone photoreceptors as the cause or effect of visual deficits associated with near-sightedness, adding to the understanding of this common condition.

We have used recent measurements of mammalian cone light responses and voltage-gated currents to calculate cone ATP utilization and compare it to that of rods. The largest expenditure of ATP results from ion transport, particularly from removal of Na⁺ entering outer segment light-dependent channels and inner segment hyperpolarization-activated cyclic nucleotide-gated channels, and from ATP-dependent pumping of Ca2+ entering voltage-gated channels at the synaptic terminal. Single cones expend nearly twice as much energy as single rods in darkness, largely because they make more synapses with second-order retinal cells and thus must extrude more Ca2+. In daylight, cone ATP utilization per cell remains high because cones never remain saturated and must continue to export Na⁺ and synaptic Ca2+ even in bright illumination. In mouse and human retina, rods greatly outnumber cones and consume more energy overall even in background light. In primates, however, the high density of cones in the fovea produces a pronounced peak of ATP utilization, which becomes particularly prominent in daylight and may make this part of the retina especially sensitive to changes in energy availability.

Optogenetic therapies for vision restoration aim to confer intrinsic light sensitivity to retinal ganglion cells when photoreceptors have degenerated and light sensitivity has been irreversibly lost. We combine adaptive optics ophthalmoscopy with calcium imaging to optically record optogenetically restored retinal ganglion cell activity in the fovea of the living primate. Recording from the intact eye of a living animal, we compare the patterns of activity evoked by the optogenetic actuator ChrimsonR with natural photoreceptor mediated stimulation in the same retinal ganglion cells. Optogenetic responses are recorded more than one year following administration of the therapy and two weeks after acute loss of photoreceptor input in the living animal. This in vivo imaging approach could be paired with any therapy to minimize the number of primates required to evaluate restored activity on the retinal level, while maximizing translational benefit by using an appropriate pre-clinical model of the human visual system. Non-human primate models are important for the development of high quality vision restoration therapies for blindness. Here, the authors demonstrate restoration of light responses in foveal retinal ganglion cells of the living macaque following optogenetic gene therapy.

Most irreversible blindness results from retinal disease. To advance our understanding of the etiology of blinding diseases, we used single-cell RNA-sequencing (scRNA-seq) to analyze the transcriptomes of ~85,000 cells from the fovea and peripheral retina of seven adult human donors. Utilizing computational methods, we identified 58 cell types within 6 classes: photoreceptor, horizontal, bipolar, amacrine, retinal ganglion and non-neuronal cells. Nearly all types are shared between the two retinal regions, but there are notable differences in gene expression and proportions between foveal and peripheral cohorts of shared types. We then used the human retinal atlas to map expression of 636 genes implicated as causes of or risk factors for blinding diseases. Many are expressed in striking cell class-, type-, or region-specific patterns. Finally, we compared gene expression signatures of cell types between human and the cynomolgus macaque monkey, Macaca fascicularis . We show that over 90% of human types correspond transcriptomically to those previously identified in macaque, and that expression of disease-related genes is largely conserved between the two species. These results validate the use of the macaque for modeling blinding disease, and provide a foundation for investigating molecular mechanisms underlying visual processing.

To investigate repeatability and reproducibility of thickness of eight individual retinal layers at axial and lateral foveal locations, as well as foveal width, measured from Spectralis spectral domain optical coherence tomography (SD-OCT) scans using newly available retinal layer segmentation software. High-resolution SD-OCT scans were acquired for 40 eyes of 40 young healthy volunteers. Two scans were obtained in a single visit for each participant. Using new Spectralis segmentation software, two investigators independently obtained thickness of each of eight individual retinal layers at 0°, 2° and 5° eccentricities nasal and temporal to foveal centre, as well as foveal width measurements. Bland-Altman Coefficient of Repeatability (CoR) was calculated for inter-investigator and inter-scan agreement of all retinal measurements. Spearman's ρ indicated correlation of manually located central retinal thickness (RT0) with automated minimum foveal thickness (MFT) measurements. In addition, we investigated nasal-temporal symmetry of individual retinal layer thickness within the foveal pit. Inter-scan CoR values ranged from 3.1 μm for axial retinal nerve fibre layer thickness to 15.0 μm for the ganglion cell layer at 5° eccentricity. Mean foveal width was 2550 μm ± 322 μm with a CoR of 13 μm for inter-investigator and 40 μm for inter-scan agreement. Correlation of RT0 and MFT was very good (ρ = 0.97, P < 0.0005). There were no significant differences in thickness of any individual retinal layers at 2° nasal compared to temporal to fovea (P > 0.05); however this symmetry could not be found at 5° eccentricity. We demonstrate excellent repeatability and reproducibility of each of eight individual retinal layer thickness measurements within the fovea as well as foveal width using Spectralis SD-OCT segmentation software in a young, healthy cohort. Thickness of all individual retinal layers were symmetrical at 2°, but not at 5° eccentricity away from the fovea.

Across saccades, neurons in retinotopically organized visual representations experience drastically different images, but visual percepts remain stable. Here we investigated whether such stability can be mediated, in part, via prediction-error signaling by neurons processing post-saccadic visual images. We specifically recorded from foveal superior colliculus (SC) neurons when a visual image only overlapped with their response fields (RF’s) after foveating saccades but not pre-saccadically. When we rapidly changed the target features intra-saccadically, the foveal neurons’ post-saccadic visual reafferent responses were elevated, even though the neurons did not directly sample the pre-saccadic extrafoveal target features. This effect did not occur in the absence of saccades, and it also scaled with the extent of the introduced intra-saccadic image feature discrepancies. These results suggest that foveal SC neurons may signal a trans-saccadic prediction error when the foveated image stimulating them is inconsistent with that expected from pre-saccadic extrafoveal representations, a potential perceptual stability mechanism.

The primate foveola, with its high cone density and magnified cortical representation, is exquisitely specialized for high-resolution spatial vision. However, uncovering the wiring of retinal circuitry responsible for this performance has been challenging due to the difficulty in recording receptive fields of foveal retinal ganglion cells (RGCs) in vivo. In this study, we use adaptive optics scanning laser ophthalmoscopy (AOSLO) to image the calcium responses of RGCs in the living primate, with a stable, high precision visual stimulus that allowed us to localize the receptive fields of hundreds of foveal ganglion cells. This approach revealed a precisely radial organization of foveal RGCs, despite the many distortions possible during the extended developmental migration of foveal cells. By back projecting the line connecting RGC somas to their receptive fields, we have been able to define the 'physiological center' of the foveola, locating the vertical meridian separating left and right hemifields in vivo.

Visual resolution is best at the center of the retina, where the cones are packed together most closely, and decreases outside of this area, where cones are farther apart. Combining adaptive optics imaging and psychophysical testing, the authors reveal that resolution actually falls off much more quickly than cone spacing would predict. Visual resolution decreases rapidly outside of the foveal center. The anatomical and physiological basis for this reduction is unclear. We used simultaneous adaptive optics imaging and psychophysical testing to measure cone spacing and resolution across the fovea, and found that resolution was limited by cone spacing only at the foveal center. Immediately outside of the center, resolution was worse than cone spacing predicted and better matched the sampling limit of midget retinal ganglion cells.

Though the responses of the rich variety of retinal ganglion cells (RGCs) reflect the totality of visual processing in the retina and provide the sole conduit for those processed responses to the brain, we have much to learn about how the brain uses these signals to guide behavior. An impediment to developing a comprehensive understanding of the role of retinal circuits in behavior is the paucity of causal studies in the intact primate visual system. Here, we demonstrate the ability to optogenetically activate individual RGCs with flashes of light focused on single RGC somas in vivo, with no evidence for activation of neighboring cells. The ability to selectively activate specific cells is the first step toward causal experiments that directly link retinal circuits to visual experience and behavior.

To analyse the distribution of macular ganglion cell layer thickness (GCLT) in patients with foveal hypoplasia (FH) with or without albinism to obtain new insights into visual pathway anomalies in albinos. Patients with FH who presented at our institution between 2013 and 2018 were retrospectively drawn for analysis. Mean GCLT was calculated after automated segmentation of spectral domain-optical coherence tomography (SD-OCT) scans. Patients with FH due to albinism (n = 13, termed 'albinism FH') or other kinds (n = 10, termed 'non-albinism FH') were compared with control subjects (n = 15). The areas: fovea (central), parafovea (nasal I, temporal I) and perifovea (nasal II, temporal II) along the horizontal meridian were of particular interest. Primary endpoints of this study were the ratios (GCLT-I- and GCLT-II-Quotient) between the GCLT measured in the temporal I or II and nasal I or II areas. There was a significant difference between the GCLT-I-Quotient of healthy controls and albinism FH (p<0.001), as well as between non-albinism FH and albinism FH (p = 0.004). GCLT-II-Quotient showed significant differences between healthy controls and albinism FH (p<0.001) and between non-albinism FH and albinism FH (p = 0.006). The best measure for distinguishing between non-albinism FH and albinism FH was the calculation of GCLT-II-Quotient (area temporal II divided by area nasal II), indicating albinism at a cut-off of <0.7169. The estimated specificity and sensitivity for this cut-off were 84.6% and 100.0%, respectively. The estimated area under the curve (AUC) was 0.892 [95%CI: 0.743-1.000, p = 0.002]. Macular GCLT-distribution showed a characteristic temporal to central shift in patients with FH due to albinism. Calculation of the GCLT-II-Quotient at a cut-off of <0.7169 presents a new diagnostic criterion for identification of ocular albinism.