Asymmetries around the visual field: From retina to cortex to behavior

Visual performance varies around the visual field. It is best near the fovea compared to the periphery, and at iso-eccentric locations it is best on the horizontal, intermediate on the lower, and poorest on the upper meridian. The fovea-to-periphery performance decline is linked to the decreases in cone density, retinal ganglion cell (RGC) density, and V1 cortical magnification factor (CMF) as eccentricity increases. The origins of polar angle asymmetries are not well understood. Optical quality and cone density vary across the retina, but recent computational modeling has shown that these factors can only account for a small percentage of behavior. Here, we investigate how visual processing beyond the cone photon absorptions contributes to polar angle asymmetries in performance. First, we quantify the extent of asymmetries in cone density, midget RGC density, and V1 CMF. We find that both polar angle asymmetries and eccentricity gradients increase from cones to mRGCs, and from mRGCs to cortex. Second, we extend our previously published computational observer model to quantify the contribution of phototransduction by the cones and spatial filtering by mRGCs to behavioral asymmetries. Starting with photons emitted by a visual display, the model simulates the effect of human optics, cone isomerizations, phototransduction, and mRGC spatial filtering. The model performs a forced choice orientation discrimination task on mRGC responses using a linear support vector machine classifier. The model shows that asymmetries in a decision maker’s performance across polar angle are greater when assessing the photocurrents than when assessing isomerizations and are greater still when assessing mRGC signals. Nonetheless, the polar angle asymmetries of the mRGC outputs are still considerably smaller than those observed from human performance. We conclude that cone isomerizations, phototransduction, and the spatial filtering properties of mRGCs contribute to polar angle performance differences, but that a full account of these differences will entail additional contribution from cortical representations.

High-Resolution Image Analysis Reveals a Decrease in Lens Thickness and Cone Density in a Cohort of Young Myopic Patients

Purpose: To study the association between axial length (AL) and the thickness of the lens, retina, choroid, and cone density with swept-source optical coherence tomography (SS-OCT) and an adaptive optics (AO) fundus camera.Design: A prospective cross-sectional study.Methods: This study included 136 eyes in 68 subjects. SS-OCT was used to quantify the thickness of the lens, ganglion cell complex (GCC) layer, inner nuclear layer (INL), outer retinal layer (ORL), and choroid layer. Adaptive optics was used to quantify spatial features of the cone photoreceptors, including density, spacing, regularity, and dispersion. The associations among the AL and the thickness of lens, retina, choroid, and cone features were evaluated with linear regression.Results: With the severity of myopia, the increased AL was associated with thinning of the lens (P < 0.001, 95% CI: −100.42 to −49.76). The thickness of the ORL and choroid decreased significantly (all P < 0.001), whereas the thickness of the GCC and INL decreased only in the outer ring (both P < 0.01). There was a significant correlation between the cone density/spacing and AL (both P < 0.001). Although cone density was reduced from 25,160/mm2 to 19,134/mm2 in the inner region and from 17,458/mm2 to 13,896/mm2 in the outer region, the best-corrected visual acuity (BCVA) was 20/20 or greater.Conclusions: We found that the lens thickness (LT), ORL, and cone density decreased in myopia. While decreasing cone density and ORL thickness should be related to axial elongation, decreasing of LT might imply intrinsic physical accommodation. These results provide further morphological changes of myopia.

Cone photoreceptor dysfunction in retinitis pigmentosa revealed by optoretinography

Retinitis pigmentosa (RP) is the most common group of inherited retinal degenerative diseases, whose most debilitating phase is cone photoreceptor death. Perimetric and electroretinographic methods are the gold standards for diagnosing and monitoring RP and assessing cone function. However, these methods lack the spatial resolution and sensitivity to assess disease progression at the level of individual photoreceptor cells, where the disease originates and whose degradation causes vision loss. High-resolution retinal imaging methods permit visualization of human cone cells in vivo but have only recently achieved sufficient sensitivity to observe their function as manifested in the cone optoretinogram. By imaging with phase-sensitive adaptive optics optical coherence tomography, we identify a biomarker in the cone optoretinogram that characterizes individual cone dysfunction by stimulating cone cells with flashes of light and measuring nanometer-scale changes in their outer segments. We find that cone optoretinographic responses decrease with increasing RP severity and that even in areas where cone density appears normal, cones can respond differently than those in controls. Unexpectedly, in the most severely diseased patches examined, we find isolated cones that respond normally. Short-wavelength–sensitive cones are found to be more vulnerable to RP than medium- and long-wavelength–sensitive cones. We find that decreases in cone response and cone outer-segment length arise earlier in RP than changes in cone density but that decreases in response and length are not necessarily correlated within single cones.

The Relationship Between Perifoveal L-Cone Isolating Visual Acuity and Cone Photoreceptor Spacing—Understanding the Transition Between Healthy Aging and Early AMD

Background: Age-related macular degeneration (AMD) is a multifactorial degenerative disorder that can lead to irreversible loss of visual function, with aging being the prime risk factor. However, knowledge about the transition between healthy aging and early AMD is limited. We aimed to examine the relationship between psychophysical measures of perifoveal L-cone acuity and cone photoreceptor structure in healthy aging and early AMD.Methods and Results: Thirty-nine healthy participants, 10 with early AMD and 29 healthy controls were included in the study. Multimodal high-resolution retinal images were obtained with adaptive-optics scanning-light ophthalmoscopy (AOSLO), optical-coherence tomography (OCT), and color fundus photographs. At 5 degrees retinal eccentricity, perifoveal L-cone isolating letter acuity was measured with psychophysics, cone inner segment and outer segment lengths were measured using OCT, while cone density, spacing, and mosaic regularity were measured using AOSLO. The Nyquist sampling limit of cone mosaic (Nc) was calculated for each participant. Both L-cone acuity and photoreceptor inner segment length declined with age, but there was no association between cone density nor outer segment length and age. A multiple regression showed that 56% of the variation in log L-cone acuity was accounted for by Nc when age was taken into account. Six AMD participants with low risk of progression were well within confidence limits, while two with medium-to-severe risk of progression were outliers. The observable difference in cone structure between healthy aging and early AMD was a significant shortening of cone outer segments.Conclusion: The results underscore the resilience of cone structure with age, with perifoveal functional changes preceding detectable changes in the cone photoreceptor mosaic. L-cone acuity is a sensitive measure for assessing age-related decline in this region. The transition between healthy aging of cone structures and changes in cone structures secondary to early AMD relates to outer segment shortening.

Hydroxychloroquine’s Early Impact on Cone Density

Purpose. To evaluate early effects of hydroxychloroquine (HCQ) on the retina using adaptive optics (AO). Methods. This was a prospective observational single-center study of 29 eyes of 29 patients who had been treated with HCQ for the first time and followed with AO for a minimum of two years. Cone counting was performed in 4 quadrants, nasal, temporal, superior, and inferior, at 0.75 mm from the foveal center. The changes of cone density on AO, visual acuity, and foveal thickness within two years of use were analyzed. The changes of mean cone density of patients whose cumulative dose was over 200 g in 2 years were also assessed. We evaluated the correlation between cone density and cumulative dose of HCQ. Results. There was no significant decrease in cone density in the first 2 years of HCQ use. VA and foveal thickness did not show obvious change, either. Among 9 patients whose cumulative dose was over 200 g in 2 years, the mean cone density showed no significant change at 6, 12, 18, and 24 months compared with baseline ( P = 0.381 , P = 0.380 , P = 0.281 , and P = 0.534 , respectively). There was no correlation between cone density and cumulative dose of HCQ at two years (Spearman’s correlation coefficient, r = −0.0553, P = 0.780 ; n = 29). Conclusion. AO showed no change in cone density in the first two years of HCQ use.

Computer-assisted photoreceptor assessment on Heidelberg Engineering Spectralis™ High Magnification Module™ images

Purpose To evaluate reliability and repeatability of computer-assisted measurements of cone photoreceptor metrics on Heidelberg Engineering Spectralis™ High Magnification Module (HMM™) Automatic Real-time Tracking (ART™) images. Methods We analyzed HMM™ images in three separate study arms. Computer-assisted cone identification software was validated using an open-access adaptive optics (AO) dataset. We compared results of the first arm to data from AO and histology. We evaluated intersession repeatability of our computer-assisted cone analysis in the second arm. We assessed the capability of HMM™ to visualize cones in the presence of pathology in the third arm. Results We included 10 healthy subjects in the first arm of our study, 5 additional healthy participants in the second arm and 5 patients in the third arm. In total, we analyzed 225 regions of interest on HMM™ images. We were able to automatically identify cone photoreceptors and assess corresponding metrics at all eccentricities between 2 and 9° from the fovea. Cone density significantly declined with increasing eccentricity (p = 4.890E-26, Friedman test). With increasing eccentricity, we found a significant increase in intercell distance (p = 2.196E-25, Friedman test) and nearest neighbor distance (p = 1.997E-25, Friedman test). Cone hexagonality ranged between 71 and 85%. We found excellent automated intersession repeatability of cone density counts and spacing measurements. In pathology, we were also able to repeatedly visualize photoreceptors. Conclusion Computer-assisted cone photoreceptor analysis on Spectralis™ HMM™ images is feasible, and most cone metrics show excellent repeatability. HMM™ imaging may be useful for photoreceptor analysis as progression marker in outer retinal disease.

Retinal factors of visual sensitivity in the human fovea

Humans direct their gaze towards visual objects of interest such that the retinal images of fixated objects fall onto the fovea, a small anatomically and physiologically specialized region of the retina displaying highest visual fidelity. One striking anatomical feature of the fovea is its non-uniform cellular topography, with a steep decline of cone photoreceptor density and outer segment length with increasing distance from its center. We here assessed in how far the specific cellular organization of the foveola is reflected in visual function. Increment sensitivity to small spot visual stimuli (1 x 1 arcmin, 543 nm light) was recorded psychophysically in 4 human participants at 17 locations placed concentric within a 0.2-degree diameter around the preferred retinal locus of fixation with adaptive optics scanning laser ophthalmoscopy based microstimulation. While cone density as well as maximum outer segment length differed significantly among the four tested participants, the range of observed threshold was similar, yielding an average increment threshold of 3.3 ± 0.2 log10 photons at the cornea. Thresholds were correlated with retinal eccentricity, as well as cone density and outer segment length. Biophysical simulation allowed to develop a model of foveal sensitivity based on these parameters, explaining at least 37% of the observed threshold variability. Based on high reproducibility in replicate testing, the residual variability is assumed to be caused by individual cone and bipolar cell weighting at the specific target locations.

Persistent Dark Cones in Oligocone Trichromacy Revealed by Multimodal Adaptive Optics Ophthalmoscopy

Dark cone photoreceptors, defined as those with diminished or absent reflectivity when observed with adaptive optics (AO) ophthalmoscopy, are increasingly reported in retinal disorders. However, their structural and functional impact remain unclear. Here, we report a 3-year longitudinal study on a patient with oligocone trichromacy (OT) who presented with persistent, widespread dark cones within and near the macula. Diminished electroretinogram (ERG) cone but normal ERG rod responses together with normal color vision confirmed the OT diagnosis. In addition, the patient had normal to near normal visual acuity and retinal sensitivity. Occasional dark gaps in the photoreceptor layer were observed on optical coherence tomography, in agreement with reflectance AO scanning light ophthalmoscopy, which revealed that over 50% of the cones in the fovea were dark, increasing to 74% at 10° eccentricity. In addition, the cone density was 78% lower than normal histologic value at the fovea, and 20–40% lower at eccentricities of 5–15°. Interestingly, color vision testing was near normal at locations where cones were predominantly dark. These findings illustrate how a retina with predominant dark cones that persist over at least 3 years can support near normal central retinal function. Furthermore, this study adds to the growing evidence that cones can continue to survive under non-ideal conditions.

Assessment of fundus autofluorescence and adaptive optics high-resolution images in macular disorders

Purpose This study analyzed and compared the results of adaptive optics (AO) and fundus autofluorescence (FAF) in various maculopathies. Methods The study included four different types of maculopathy: central serous chorioretinopathy (CSC), retinitis pigmentosa (RP), Stargardt disease (STGD) and phototoxic retinopathy. In all four cases cone mosaic and cone density were obtained using AO fundus camera. Further the high resolution images were compared with the FAF and optical coherence tomography (OCT) results. Results In CSC, FAF and AO were able to show changes in the macula even two years after the subretinal fluid resorption, as opposed to a normal OCT. The improvement of FAF and cone mosaic appearance was concomitant with the visual acuity growth. Several cone mosaic phenotypes were observed in RP and STGD. In RP the cone density was 24.240cones/mm2 in the center, and decreased to 8.163cones/mm2 in the parafoveolar area. In STGD the cone density was lower in the center, 9.219cones/mm2, and higher at the periphery, 12.594cones/mm2. In the case of phototoxic retinopathy, AO and OCT were more effective than FAF in highlighting the photoreceptor and retinal pigment epithelium lesions. Conclusions FAF and AO are very useful tools in macular pathologies examination. FAF can give us a true picture about metabolic changes in the macula while AO allows us to view changes up to the cellular level.