Foveal Cone Mosaic Research Articles

Longitudinal Imaging of the Foveal Cone Mosaic in CNGA3-Associated Achromatopsia.

The purpose of this study was to assess the natural history of the foveal cone mosaic in CNGA3-associated achromatopsia (ACHM). Thirteen eyes from 10 genetically confirmed patients underwent longitudinal imaging with optical coherence tomography (OCT) and non-confocal split detection adaptive optics scanning light ophthalmoscopy (AOSLO). OCT scans assessed outer nuclear layer (ONL) thickness, foveal ellipsoid zone (EZ) disruption, and foveal hypoplasia. AOSLO images were analyzed to calculate peak foveal cone density (PCD) and mean inter-cell distance (ICD) between cones. Mixed effects models were used to analyze the rate of annual change of PCD and ICD. Mean (±SD) age at visits was 29 ± 10 years, with a follow-up of 2.6 ± 1 years. There was no change in ONL thickness, degree of EZ disruption, or foveal hypoplasia over the follow-up period. We also observed a stable foveal cone mosaic using AOSLO imaging, with no significant change in PCD or ICD. Mean PCD was 15,346 cones/mm² at the mean age of 29 years old (cf. 64,000-324,000 cones/mm² in previously reported healthy controls), with a mean rate of change of -117.79 cones/mm² (0.8%) per year, P = 0.130. Mean ICD at the mean age was 13.82 µm, with a rate of change of 0.17 µm per year, P = 0.83. CNGA3-associated ACHM displays stable foveal cone structure over time with a similar rate of change to CNGB3-associated ACHM (2% decline per year). The stable PCD, small cohort, and large variability within the cohort means significant age associations were not detected.

Intervisit Reproducibility of Foveal Cone Density Metrics.

To assess longitudinal reproducibility of metrics of foveal density (peak cone density [PCD], cone density centroid [CDC], and 80th percentile centroid area) in participants with normal vision. Participants (n = 19; five male and 14 female) were imaged at two time points (average interval of 3.2years) using an adaptive optics scanning light ophthalmoscope (AOSLO). Foveally centered regions of interest (ROIs) were extracted from AOSLO montages. Cone coordinate matrices were semiautomatically derived for each ROI, and cone mosaic metrics were calculated. On average, there were no significant changes in cone mosaic metrics between visits. The average ± SD PCD was 187,000 ± 20,000 cones/mm2 and 189,000 ± 21,700 cones/mm2 for visits 1 and 2, respectively (P = 0.52). The average ± SD density at the CDC was 183,000 ± 19,000 cones/mm2 and 184,000 ± 20,800 cones/mm2 for visits 1 and 2, respectively (P = 0.78). The average ± SD 80th percentile isodensity contour area was 15,400 ± 1800µm2 and 15,600 ± 1910µm2 for visits 1 and 2, respectively (P = 0.57). Foveal cone mosaic density metrics were highly reproducible in the cohort examined here, although further study is required in more diverse populations. Determination of the normative longitudinal changes in foveal cone topography is key for evaluating longitudinal measures of foveal cone topography in patients with progressive retinal dystrophies.

The effect of sampling window size on topographical maps of foveal cone density.

To characterize the effect of sampling window size on maps of foveal cone density derived from adaptive optics scanning light ophthalmoscope (AOSLO) images of the cone mosaic. Forty-four AOSLO-derived montages of the foveal cone mosaic (300 x 300µm) were used for this study (from 44 individuals with normal vision). Cone photoreceptor coordinates were semi-automatically identified by one experienced grader. From these coordinates, cone density matrices across each foveal montage were derived using 10 different sampling window sizes containing 5, 10, 15, 20, 40, 60, 80, 100, 150, or 200 cones. For all 440 density matrices, we extracted the location and value of peak cone density (PCD), the cone density centroid (CDC) location, and cone density at the CDC. Across all window sizes, PCD values were larger than those extracted at the CDC location, though the difference between these density values decreased as the sampling window size increased (p<0.0001). Overall, both PCD (r=-0.8099, p=0.0045) and density at the CDC (r=-0.7596, p=0.0108) decreased with increasing sampling window size. This reduction was more pronounced for PCD, with a 27.8% lower PCD value on average when using the 200-cone versus the 5-cone window (compared to only a 3.5% reduction for density at the CDC between these same window sizes). While the PCD and CDC locations did not occur at the same location within a given montage, there was no significant relationship between this PCD-CDC offset and sampling window size (p=0.8919). The CDC location was less variable across sampling windows, with an average per-participant 95% confidence ellipse area across the 10 window sizes of 47.56µm² (compared to 844.10µm² for the PCD location, p<0.0001). CDC metrics appear more stable across varying sampling window sizes than PCD metrics. Understanding how density values change according to the method used to sample the cone mosaic may facilitate comparing cone density data across different studies.

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.

Assessing Interocular Symmetry of the Foveal Cone Mosaic.

PurposeTo test the hypothesis that foveal cone topography is symmetrical between contralateral eyes.MethodsWe used adaptive optics scanning light ophthalmoscopy to acquire images of the foveal cone mosaic in each eye of 58 subjects with normal vision (35 female, 23 male). Cones were semiautomatically identified over a 300 × 300-µm foveal area. From these cone coordinates, maps of cone density were derived, and we extracted estimates of peak cone density from each map. Mosaic regularity was assessed using Voronoi cell area regularity (VCAR). Average roundness and average area of the 70%, 75%, 80%, 85%, and 90% of peak density isodensity contours were evaluated.ResultsThe average peak cone density for right eyes was 180,286 cones/mm2 (n = 49) and for left eyes was 182,397 cones/mm2 (n = 45), with a mean absolute difference of 6363 cones/mm2 (n = 43). Peak density, cone spacing, VCAR, and average area within the isodensity contours of fellow eyes were not significantly different (P = 0.60, P = 0.83, P = 0.30, and P = 0.39, respectively). However, the average roundness of the isodensity contours was 2% more circular in the right eyes than in the left eyes (P = 0.02).ConclusionsThere is interocular symmetry of peak foveal cone density, mosaic regularity, and area encompassing the most densely packed cells in subjects with normal vision. The origin and significance of the observed interocular difference in average roundness of the isodensity contours are unclear.

Interocular Symmetry of Foveal Cone Topography in Congenital Achromatopsia

ABSTRACT Purpose: To determine the interocular symmetry of foveal cone topography in achromatopsia (ACHM) using non-confocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). Methods: Split-detector AOSLO images of the foveal cone mosaic were acquired from both eyes of 26 subjects (mean age 24.3 years; range 8–44 years, 14 females) with genetically confirmed CNGA3- or CNGB3-associated ACHM. Cones were identified within a manually delineated rod-free zone. Peak cone density (PCD) was determined using an 80 × 80 μm sampling window within the rod-free zone. The mean and standard deviation (SD) of inter-cell distance (ICD) were calculated to derive the coefficient of variation (CV). Cone density difference maps were generated to compare cone topography between eyes. Results: PCD (mean ± SD) was 17,530 ± 9,614 cones/mm2 and 17,638 ± 9,753 cones/mm2 for right and left eyes, respectively (p = .677, Wilcoxon test). The mean (± SD) for ICD was 9.05 ± 2.55 µm and 9.24 ± 2.55 µm for right and left eyes, respectively (p = .410, paired t-test). The mean (± SD) for CV of ICD was 0.16 ± 0.03 µm and 0.16 ± 0.04 µm for right and left eyes, respectively (p = .562, paired t-test). Cone density maps demonstrated that cone topography of the ACHM fovea is non-uniform with local variations in cone density between eyes. Conclusions: These results demonstrate the interocular symmetry of the foveal cone mosaic (both density and packing) in ACHM. As cone topography can differ between eyes of a subject, PCD does not completely describe the foveal cone mosaic in ACHM. Nonetheless, these findings are of value in longitudinal monitoring of patients during treatment trials and further suggest that both eyes of a given subject may have similar therapeutic potential and non-study eye can be used as a control.

Wide-vergence, multi-spectral adaptive optics scanning laser ophthalmoscope with diffraction-limited illumination and collection.

Visualizing and assessing the function of microscopic retinal structures in the human eye is a challenging task that has been greatly facilitated by ophthalmic adaptive optics (AO). Yet, as AO imaging systems advance in functionality by employing multiple spectral channels and larger vergence ranges, achieving optimal resolution and signal-to-noise ratios (SNR) becomes difficult and is often compromised. While current-generation AO retinal imaging systems have demonstrated excellent, near diffraction-limited imaging performance over wide vergence and spectral ranges, a full theoretical and experimental analysis of an AOSLO that includes both the light delivery and collection optics has not been done, and neither has the effects of extending wavefront correction from one wavelength to imaging performance in different spectral channels. Here, we report a methodology and system design for simultaneously achieving diffraction-limited performance in both the illumination and collection paths for a wide-vergence, multi-spectral AO scanning laser ophthalmoscope (SLO) over a 1.2 diopter vergence range while correcting the wavefront in a separate wavelength. To validate the design, an AOSLO was constructed to have three imaging channels spanning different wavelength ranges (543 ± 11 nm, 680 ± 11 nm, and 840 ± 6 nm, respectively) and one near-infrared wavefront sensing channel (940 ± 5 nm). The AOSLO optics and their alignment were determined via simulations in optical and optomechanical design software and then experimentally verified by measuring the AOSLO's illumination and collection point spread functions (PSF) for each channel using a phase retrieval technique. The collection efficiency was then measured for each channel as a function of confocal pinhole size when imaging a model eye achieving near-theoretical performance. Imaging results from healthy human adult volunteers demonstrate the system's ability to resolve the foveal cone mosaic in all three imaging channels despite a wide spectral separation between the wavefront sensing and imaging channels.

Human foveal cone photoreceptor topography and its dependence on eye length

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.

Sub-Airy Confocal Adaptive Optics Scanning Ophthalmoscopy.

PurposeTo demonstrate the viability of improving transverse image resolution in reflectance scanning adaptive optics ophthalmoscopy using sub-Airy disk confocal detection.MethodsThe foveal cone mosaic was imaged in five human subjects free of known eye disease using two custom adaptive optics scanning light ophthalmoscopes (AOSLOs) in reflectance with 7.75 and 4.30 mm pupil diameters. Confocal pinholes of 0.5, 0.6, 0.8, and 1.0 Airy disk diameters (ADDs) were used in a retinal conjugate plane before the light detector. Average cone photoreceptor intensity profile width and power spectrum were calculated for the resulting images. Detected energy using a model eye was recorded for each pinhole size.ResultsThe cone photoreceptor mosaic is better resolved with decreasing confocal pinhole size, with the high spatial frequency content of the images enhanced in both the large- and small-pupil AOSLOs. The average cone intensity profile width was reduced by ∼15% with the use of a 0.5 ADD pinhole when compared to a 1.0 ADD, with an accompanying reduction in signal greater than a factor of four.ConclusionsThe use of sub-Airy disk confocal pinhole detection without increasing retinal light exposure results in a substantial improvement in image resolution at the cost of larger than predicted signal reduction.Translational RelevanceImprovement in transverse resolution using sub-Airy disk confocal detection is a practical and low-cost approach that is applicable to all point- and line-scanning ophthalmoscopes, including optical coherence tomographers.

Alterations to the Foveal Cone Mosaic of Diabetic Patients.

PurposeWe measured localized changes occurring in the foveal cone photoreceptors and related defects in the cone mosaic to alterations in the nearby retinal vasculature.MethodsThe central 4° of the retina of 54 diabetic (53.7 ± 12.5 years) and 85 control (35.8 ± 15.2 years) participants were imaged with the Indiana adaptive optics scanning laser ophthalmoscope. Foveal cones and overlying retinal capillaries were imaged and infrared scanning laser ophthalmoscopy (IR SLO) images and optical coherence tomography (OCT) B-scans were obtained. Follow-up imaging sessions were performed with intervals from 4 to 50 months for 22 of the 54 diabetic participants.ResultsThe foveal cone mosaics of 49 of 54 diabetic participants were of sufficient quality to assess the absence or presence of small localized defects in the cone mosaic. In 13 of these 49 diabetic participants we found localized defects, visualized as sharp-edged areas of cones with diminished reflectivity. These small, localized areas ranged in size from 10 × 10 μm to 75 × 30 μm. Of these 13 participants with cone defects, 11 were imaged over periods from 4 to 50 months and the defects remained relatively stable. These dark regions were not shadows of overlying retinal vessels, but all participants with these localized defects had alterations in the juxtafoveal capillary network.ConclusionsThe foveal cone mosaic can show localized areas of dark cones that persist over time, that apparently correspond to either missing or nonreflecting cones, and may be related to local retinal ischemia.

Assessing photoreceptor structure after macular hole closure.

To describe photoreceptor structure and recovery after macular hole (MH) closure with pars plana vitrectomy (PPV) using adaptive optics scanning light ophthalmoscopy and spectral domain optical coherence tomography. A pilot imaging study of four eyes from four subjects undergoing PPV for MH was conducted. Imaging with spectral domain optical coherence tomography and adaptive optics scanning light ophthalmoscopy was performed at varying time points after PPV. Despite successful MH closure, disruption of the foveal inner segment ellipsoid zone was seen in all patients when imaged at a mean of 117 days after PPV. Disruption of the photoreceptor mosaic was seen using adaptive optics scanning light ophthalmoscopy at locations corresponding to regions of ellipsoid zone disruption on spectral domain optical coherence tomography. Cone density immediately surrounding these disruptions was normal, except for one patient. In 2 patients who were imaged serially up to 516 days after PPV, recovery of cone cells within regions of mosaic disruption could be detected over time. Photoreceptor disruption exists even after apparent MH closure. Remodeling of the foveal cone mosaic continues for many months after surgery, perhaps accounting for the delayed postoperative improvements of visual acuity in some patients. Spectral domain optical coherence tomography and adaptive optics scanning light ophthalmoscopy are useful tools for monitoring photoreceptor recovery after surgical closure of MH.

Relationship Between Foveal Cone Structure and Clinical Measures of Visual Function in Patients With Inherited Retinal Degenerations

To study the relationship between cone spacing and density and clinical measures of visual function near the fovea. High-resolution images of the photoreceptor mosaic were obtained with adaptive optics scanning laser ophthalmoscopy from 26 patients with inherited retinal degenerations. Cone spacing measures were made close to or at the foveal center (mean [SD] eccentricity, 0.02 [0.03] degree; maximum eccentricity, 0.13 degree) and were converted to Z-scores, fraction of cones, and percentage-of-cones-below-average compared with normal values for each location (based on 37 age-similar visually normal eyes). Z-scores and percentage of cones below average were compared with best-corrected visual acuity (VA) and foveal sensitivity. Visual acuity was significantly correlated with cone spacing (Spearman rank correlation ρ = -0.60, P = 0.003) and was preserved (≥ 80 letters), despite cone density measures that were 52% below normal. Foveal sensitivity showed significant correlation with cone spacing (ρ = -0.47, P = 0.017) and remained normal (≥ 35 decibels), despite density measures that were approximately 52% to 62% below normal. Cone density was reduced by up to 62% below normal at or near the fovea in eyes with VA and sensitivity that remained within normal limits. Despite a significant correlation with foveal cone spacing, VA and sensitivity are insensitive indicators of the integrity of the foveal cone mosaic. Direct, objective measures of cone structure may be more sensitive indicators of disease severity than VA or foveal sensitivity in eyes with inherited retinal degenerations.

Modeling the foveal cone mosaic imaged with adaptive optics scanning laser ophthalmoscopy.

To better understand the limitations of high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO), we describe an imaging model that examines the smallest cone photoreceptors in the fovea of normal human subjects and analyze how different factors contribute to their resolution. The model includes basic optical factors such as wavelength and pupil size, and defines limits caused by source coherence which are specific to the AOSLO imaging modality as well as foveal cone structure. The details of the model, its implications for imaging, and potential techniques to circumvent the limitations are discussed in this paper.

Intersubject Variability of Foveal Cone Photoreceptor Density in Relation to Eye Length

Adaptive optics scanning laser ophthalmoscopy (AOSLO) under optimized wavefront correction allows for routine imaging of foveal cone photoreceptors. The intersubject variability of foveal cone density was measured and its relation to eye length evaluated. AOSLO was used to image 18 healthy eyes with axial lengths from 22.86 to 28.31 mm. Ocular biometry and an eye model were used to estimate the retinal magnification factor. Individual cones in the AOSLO images were labeled, and the locations were used to generate topographic maps representing the spatial distribution of density. Representative retinal (cones/mm(2)) and angular (cones/deg(2)) cone densities at specific eccentricities were calculated from these maps. The entire foveal cone mosaic was resolved in four eyes, whereas the cones within 0.03 mm eccentricity remained unresolved in most eyes. The preferred retinal locus deviated significantly (P < 0.001) from the point of peak cone density for all except one individual. A significant decrease in retinal density (P < 0.05) with increasing axial length was observed at 0.30 mm eccentricity but not closer. Longer, more myopic eyes generally had higher angular density near the foveal center than the shorter eyes, but by 1°, this difference was nullified by retinal expansion, and so angular densities across all eyes were similar. The AOSLO can resolve the smallest foveal cones in certain eyes. Although myopia causes retinal stretching in the fovea, its effect within the foveola is confounded by factors other than cone density that have high levels of intersubject variability.

Automated analysis of differential interference contrast microscopy images of the foveal cone mosaic

An algorithm is presented for processing and analysis of differential interference contrast (DIC) microscopy images of the fovea to study the cone mosaic. The algorithm automatically locates the cones and their boundaries in such images and is assessed by comparison with results from manual analysis. Additional algorithms are presented that analyze the cone positions to extract information on cone neighbor relationships as well as the short-range order and domain structure of the mosaic. The methods are applied to DIC images of the human fovea.

Modelling the effect of microsaccades on retinal responses to stationary contrast patterns

We have modelled the effect of microsaccades on retinal responses to achromatic borders and lines using physiologically realistic parameters. Typical microsaccade movement sequences were applied to the retinal image of stationary spatial contrast patterns as projected on the foveal cone mosaic after being passed through the optical transfer function of the eye. The resulting temporal contrast modulation over a cone receptive field was convolved with an analytical expression for the response waveform of primate cones (photocurrent: [Schnapf, J. L., Nunn, B. J., Meister, M. & Baylor, D. A. (1990). Visual transduction in cones of the monkey Macaca fascicularis. Journal of Physiology, 427, 681–713]; photovoltage: [Schneeweis, D. M. & Schnapf, J. L. (1999). The photovoltage of macaque cone photoreceptors: Adaptation, noise, and kinetics. Journal of Neuroscience, 19, 1203–1216]). The input to the ganglion cell was derived from the cone responses by the difference-of-Gaussians receptive field model of Donner and Hemilä [Donner, K. & Hemilä, S. (1996). Modelling the spatio-temporal modulation response of ganglion cells with difference-of-Gaussians receptive fields: Relation to photoreceptor response kinetics. Visual Neuroscience, 13, 173–186]. The modelled response waveforms suggest that microsaccades may significantly enhance sensitivity to edges, “re-sharpen” the image and, most interestingly, improve resolution of two closely spaced lines. The reason is that fine spatial structure of the retinal image when moving at suitable velocities is translated into a correlated temporal structure of responses of single cones and ganglion cells. The information content of the signal is not strongly dependent on positional accuracy and the effect is thus distinct from the presumed retinal basis of vernier acuity. Other eye movements (drift) with velocity distributions similar to that of the microsaccade’s slow return phase might be similarly useful, although the microsaccade has some distinguishing features that could be functionally significant, e.g., the neural motor control and the biphasic movement pattern.

The locus of fixation and the foveal cone mosaic

High-resolution retinal imaging with adaptive optics was used to record the position of a light stimulus on the cone mosaic, with an error at least five times smaller than the diameter of the smallest foveal cones. We discuss the factors that limit the accuracy with which absolute retinal position can be determined. In five subjects, the standard deviation of fixation positions measured in discrete trials ranged from 2.1 to 6.3 arcmin, with an average of 3.4 arcmin (about 17 microm), in agreement with previous studies (R. W. Ditchburn, 1973; R. M. Steinman, G. M. Haddad, A. A. Skavenski, & D. Wyman, 1973). The center of fixation, based on the mean retinal position for each of three subjects, was displaced from the location of highest foveal cone density by an average of about 10 arcmin (about 50 microm), indicating that cone density alone does not drive the location on the retina selected for fixation. This method can be used in psychophysical studies or medical applications requiring submicron registration of stimuli with respect to the retina or in delivering light to retinal features as small as single cells.

The role of opsin expression and apoptosis in determination of cone types in human retina

In primates, short wavelength sensitive cones (S cones) and medium- or long-wavelength-sensitive cones (L/M cones) are two separate populations. Each cone type has a different developmental timecourse, contributes to different intra-retinal circuits, and transmits different types of information to the brain. However, in fetal human retina a significant population of cones express both S and L/M opsin (S+L/M cones), raising questions about whether S+L/M cones die or change opsin expression during development. We have utilized fetal, postnatal and adult human retinae to study the immunohistochemical distribution and morphology of S+L/M cones during development. Because S cones appear to be at higher density in fetal compared to adult retinae, we used antibodies to S opsin and alpha-transducin to estimate the proportion of S-cones, and TUNEL labelling to detect apoptotic death in the L/M, S or S+L/M population during development. S cones were present in central retina from fetal week (Fwk)11 and covered the retina by Fwk20. L/M cones appeared in the foveal cone mosaic 3–4 weeks after S-opsin was first detected, and covered the retina by birth. S+L/M cones were detected in all retinae older than Fwk14. They were most numerous at the retinal eccentricity where L/M opsin was just appearing; i.e. at the ’front’ of L/M opsin expression. In this region, five morphological types of cones were present. (1) Heavily labelled S cones had thick cell bodies, a thick basal axon and pedicle, and a nucleus at any level of the outer nuclear layer (ONL). (2) Heavily labelled L/M cones were wine goblet shaped with a small round cell body, a large nucleus at the outer ONL edge, and a thin axon with a prominent synaptic pedicle. (3) Goblet-shaped S+L/M cones. (4) Goblet-shaped cones lightly labelled for S-opsin. (5) Cones that were not immunoreactive to either opsin. Only type 1 S cones were present peripheral to the L/M expression front, and their labelling intensity, morphology and distribution indicates that these are the ‘true blue’ cones of the adult mosaic. Only type 2 L/M cones were present in the foveal cone mosaic. Types 3 and 4 were most numerous within 500–750 μm of the L/M expression front, but type 3 S+L/M cones were also scattered throughout more central regions in fetal, infant and adult retinae. S+L/M cones comprised 5–10% of opsin immunoreactive cones at the L/M front in fetal and early postnatal retinas but 0·01–0·03% throughout P8mo and adult retinae. We found no evidence of significant levels of apoptosis in L/M cones at the expression front, suggesting that this decrease was not due to cell death. The findings suggest that goblet-shaped cones destined to express L or M opsin may initially and transiently express S opsin. Near the optic disc, at Fwk17 S cone density was around 2000 cells mm −2, which dropped 50% by Fwk20 and stabilized at around 500 cells mm −2 by birth. Double labelling with alpha-transducin showed that throughout this period 8–10% of all cones expressed S opsin. TUNEL labelling found no significant apoptosis in the S cone population. The decrease in S cone density near the optic disc occurs in the absence of apoptosis, and is likely due to other developmental events acting on the photoreceptor layer, including displacement of cones towards the fovea.

Ontogeny of the primate fovea:a central issue in retinal development

The formation of the primate fovea has fascinated a substantial number of histologists, pathologists, ophthalmologists and physiologists for more than a century. In this article, using data from the literature as well as our own observations, we identify events which we believe are crucial in this process and present a developmental neurobiologist's view of the formation of the primate fovea. The fovea is a region of the retina specialized for diurnal, high acuity functions which require a high spatial density of cone photoreceptors as well as a large number of inner retinal cells in order to establish the distinct retinofugal pathways (ganglion cell axons) receiving from individual cones in the foveal cone mosaic. A unique feature of the fovea is the displacement of cells connected to the foveal cones onto the rim of the fovea. It is generally believed that this displacement counteracts the problems caused by the scattering of the incoming light by cells and blood vessels of the inner retina. We believe that one of the crucial events in the formation of the primate fovea is the early centripetal migration of photoreceptors towards the central area (centripetal displacement). This process, initiated early in development, continues throughout intrauterine life until some months or years postnatal. We propose that the displacement of cells from the inner layers is related to the earlier developmental accumulation of photoreceptors and inner retinal cells centrally. This, we propose, leads to metabolic “starvation” of the inner retina, resulting from the complete absence of retinal vessels from the vicinity of the incipient fovea. It is suggested that these factors in turn trigger centrifugal displacement of inner retinal cells towards the encroaching perifoveal capillary network and lead to the formation of the foveal depression.

Imaging the foveal cones in vivo through ocular speckle interferometry:theory and numerical simulations

New high-resolution imaging techniques have recently been developed for resolving the foveal cone mosaic in the living human eye. We present a theoretical analysis and numerical predictions of the performance and limitations of ocular speckle interferometry and related methods. Images were computer generated, simulating short-exposure recordings of a model of the cone mosaic imaged through the optics of the eye. Cases of both coherent and incoherent illumination are analyzed. Theoretical predictions are in good agreement with published experimental results. Our analysis and computer simulations validate these methods and successfully explain different observed effects. The simulation predicts a slight underestimation of the experimentally measured cone mosaic characteristic spatial frequency and how this effect can be compensated by deconvolution with a speckle transfer function. Other experimental observations, such as the improvement of the results after a preselection of the best images, the effect of both the defocus and changes in fixation, and the influence of the size of the illuminating spot, have been reproduced.