Supernormal foveal photoreceptor density in Alport syndrome: A case report.

PURPOSE: To investigate foveal photoreceptor configuration in Alport syndrome, a rare inherited disease characterized by Collagen IV dysfunction. METHODS: Adaptive optics scanning laser ophthalmoscope (AOSLO) in vivo imaging of the foveal center and quantitative analysis of cone photoreceptor topography in a 17-year-old male patient with Alport syndrome presenting absence of a foveal avascular zone (FAZ) and foveal hypoplasia in both eyes. RESULTS: Cone density analysis based on AOSLO images revealed an unusual linear cone topography profile displaying supernormal densities within the fovea (z-scores up to + 3.57 and + 2.97 in right and left eyes, respectively). CONCLUSION: Foveal hypoplasia has previously been associated with normal or reduced cone density. Our observation is the first case of disease-related supernormal cone density within the foveola, shedding light upon the role of Collagen IV in foveal maturation.

Intergrader agreement of foveal cone topography measured using adaptive optics scanning light ophthalmoscopy.

The foveal cone mosaic can be directly visualized using adaptive optics scanning light ophthalmoscopy (AOSLO). Previous studies in individuals with normal vision report wide variability in the topography of the foveal cone mosaic, especially the value of peak cone density (PCD). While these studies often involve a human grader, there have been no studies examining intergrader reproducibility of foveal cone mosaic metrics. Here we re-analyzed published AOSLO foveal cone images from 44 individuals to assess the relationship between the cone density centroid (CDC) location and the location of PCD. Across 5 graders with variable experience, we found a measurement error of 11.7% in PCD estimates and higher intergrader reproducibility of CDC location compared to PCD location (p < 0.0001). These estimates of measurement error can be used in future studies of the foveal cone mosaic, and our results support use of the CDC location as a more reproducible anchor for cross-modality analyses.

Human gaze is systematically offset from the center of cone topography.

The small physical depression of the human retina, the fovea, is the retinal locus of prime visual resolution, achieved by a peaking topography of the light-sensitive cone photoreceptor outer segments1-3 and a post-receptor wiring scheme preserving high-density sampling.4,5 Humans dynamically direct their gaze such that the retinal images of objects of interest fall onto the foveola, the central one-degree diameter of the fovea,6-8 but it is yet unclear whether a relationship between the individual photoreceptor topography at this location and visual fixation behavior exists.9,10 By employing adaptive optics in vivo imaging and micro-stimulation,11-13 we created topographical maps of the complete foveolar cone mosaics in both eyes of 20 healthy participants while simultaneously recording the retinal location of a fixated visual object in a psychophysical experiment with cellular resolution. We found that the locus of fixation was systematically shifted away from the topographical center toward a naso-superior quadrant on the retina, about 5 min of arc of visual angle on average, with a mirror symmetrical trend between fellow eyes. In cyclopean view, the topographical centers were superior to the fixated target, corresponding to areas in the visual field usually more distant14,15 and thus containing higher spatial frequencies. Given the large variability in foveal topography between individuals, and the surprising precision with which fixation is repeatedly directed to just a small bouquet of cones in the foveola, these findings demonstrate a finely tuned, functionally relevant link between the development of the cellular mosaic of photoreceptors and visual behavior.

The Relationship Between Visual Sensitivity and Eccentricity, Cone Density and Outer Segment Length in the Human Foveola.

Purpose: The cellular topography of the human foveola, the central 1° diameter of the fovea, is strikingly non-uniform, with a steep increase of cone photoreceptor density and outer segment (OS) length toward its center. Here, we assessed to what extent the specific cellular organization of the foveola of an individual is reflected in visual sensitivity and if sensitivity peaks at the preferred retinal locus of fixation (PRL). Methods: Increment sensitivity to small-spot, cone-targeted visual stimuli (1 × 1 arcmin, 543-nm light) was recorded psychophysically in four human participants at 17 locations concentric within a 0.2° diameter on and around the PRL with adaptive optics scanning laser ophthalmoscopy-based microstimulation. Sensitivity test spots were aligned with cell-resolved maps of cone density and cone OS length. Results: Peak sensitivity was at neither the PRL nor the topographical center of the cone mosaic. Within the central 0.1° diameter, a plateau-like sensitivity profile was observed. Cone density and maximal OS length differed significantly across participants, correlating with their peak sensitivity. Based on these results, biophysical simulation allowed to develop a model of visual sensitivity in the foveola, with distance from the PRL (eccentricity), cone density, and OS length as parameters. Conclusions: Small-spot sensitivity thresholds in healthy retinas will help to establish the range of normal foveolar function in cell-targeted vision testing. Because of the high reproducibility in replicate testing, threshold variability not explained by our model is assumed to be caused by individual cone and bipolar cell weighting at the specific target locations.

Eye tracking-based estimation and compensation of chromatic offsets for multi-wavelength retinal microstimulation with foveal cone precision.

Multi-wavelength ophthalmic imaging and stimulation of photoreceptor cells require consideration of chromatic dispersion of the eye, manifesting in longitudinal and transverse chromatic aberrations. Contemporary image-based techniques to measure and correct transverse chromatic aberration (TCA) and the resulting transverse chromatic offset (TCO) in an adaptive optics retinal imaging system are precise but lack compensation of small but significant shifts in eye position occurring during in vivo testing. Here, we present a method that requires only a single measurement of TCO during controlled movements of the eye to map retinal chromatic image shifts to the image space of a pupil camera. After such calibration, TCO can be compensated by continuously monitoring eye position during experimentation and by interpolating correction vectors from a linear fit to the calibration data. The average change rate of TCO per head shift and the correlation between Kappa and the individual foveal TCA are close to the expectations based on a chromatic eye model. Our solution enables continuous compensation of TCO with high spatial precision and avoids high light intensities required for re-measuring TCO after eye position changes, which is necessary for foveal cone-targeted psychophysical experimentation.

Habitual higher order aberrations affect Landolt but not Vernier acuity.

To assess whether the eye's optical imperfections are relevant for hyperacute vision, we measured ocular wave aberrations, visual hyperacuity, and acuity thresholds in 31 eyes of young adults. Although there was a significant positive correlation between the subjects' performance in Vernier- and Landolt-optotype acuity tasks, we found clear differences in how far both acuity measures correlate with the eyes' optics. Landolt acuity thresholds were significantly better in eyes with low higher order aberrations and high visual Strehl ratios (r2 = 0.22, p = 0.009), and significantly positively correlated with axial length (r2 = 0.15, p = 0.03). A retinal image quality metric, calculated as two-dimensional correlation between perfect and actual retinal image, was also correlated with Landolt acuity thresholds (r2 = 0.27, p = 0.003). No such correlations were found with Vernier acuity performance (r2 < 0.03, p > 0.3). Based on these results, hyperacuity thresholds are, contrary to resolution acuity, not affected by higher order aberrations of the eye.

Ultra-high contrast retinal display system for single photoreceptor psychophysics.

Due to the enormous dynamic range of human photoreceptors in response to light, studying their visual function in the intact retina challenges the stimulation hardware, specifically with regard to the displayable luminance contrast. The adaptive optics scanning laser ophthalmoscope (AOSLO) is an optical platform that focuses light to extremely small retinal extents, approaching the size of single photoreceptor cells. However, the current light modulation techniques produce spurious visible backgrounds which fundamentally limit experimental options. To remove unwanted background light and to improve contrast for high dynamic range visual stimulation in an AOSLO, we cascaded two commercial fiber-coupled acousto-optic modulators (AOMs) and measured their combined optical contrast. By compensating for zero-point differences in the individual AOMs, we demonstrate a multiplicative extinction ratio in the cascade that was in accordance with the extinction ratios of both single AOMs. When latency differences in the AOM response functions were individually corrected, single switch events as short as 50 ns with radiant power contrasts up to 1:1010 were achieved. This is the highest visual contrast reported for any display system so far. We show psychophysically that this contrast ratio is sufficient to stimulate single foveal photoreceptor cells with small and bright enough visible targets that do not contain a detectable background. Background-free stimulation will enable photoreceptor testing with custom adaptation lights. Furthermore, a larger dynamic range in displayable light levels can drive photoreceptor responses in cones as well as in rods.