BOLD Contrast Response Characteristics of Aberrant Voxels with Bilateral Visual Population Receptive Fields in Human Albinism.

Albinism is an inherited disorder characterized by disrupted melanin production in the eye, and often in the skin and hair. This retinal hypopigmentation is accompanied by pathological decussation of many temporal retinal afferents at the optic chiasm during development, ultimately resulting in partially superimposed representations of opposite visual hemifields in each cortical hemisphere. Within these aberrant regions of hemifield overlap, individual voxels have been shown to have bilateral, dual population receptive fields (pRFs) responding to roughly mirror-image locations across the vertical meridian. Nonetheless, how these two conflicting inputs combine to determine a voxel's response to image contrast is still unknown. To address this, we stimulated the right and left hemifields with separately controlled sinusoidal gratings, each having a variety of contrasts (0, 8, 20, 45, 100%), and extracted voxel-wise BOLD response amplitudes to each contrast combination in visual areas V1-V3. We then compared voxels' responses to each hemifield stimulated individually with conditions when both hemifields were stimulated simultaneously. We hypothesized that simultaneous stimulation of the two pRF components will result in either a suppressive or facilitative interaction. However, we found that BOLD responses to simultaneous stimulation appeared to reflect simple summation of the neural activity from the individual hemifield conditions. This suggests that the superimposed opposite hemifield representations do not interact. Thus, dual pRFs in albinism likely reflect two co-localized, but functionally independent populations of neurons each of which respond to a single hemifield. This finding is commensurate with psychophysical studies which have shown no clear perceptual interaction between opposite visual hemifields in human albinism.

Quantitative Foveal Structural Metrics as Predictors of Visual Acuity in Human Albinism.

Purpose: To assess the degree to which quantitative foveal structural measurements account for variation in best-corrected visual acuity (BCVA) in human albinism. Methods: BCVA was measured and spectral domain optical coherence tomography (SD-OCT) images were acquired for 74 individuals with albinism. Categorical foveal hypoplasia grades were assessed using the Leicester Grading System for Foveal Hypoplasia. Foveal anatomical specialization (foveal versus parafoveal value) was quantified for inner retinal layer (IRL) thickness, outer segment (OS) length, and outer nuclear layer (ONL) thickness. These metrics, participant sex, and age were used to build a multiple linear regression of BCVA. This combined linear model's predictive properties were compared to those of categorical foveal hypoplasia grading. Results: The cohort included three participants with type 1a foveal hypoplasia, 23 participants with type 1b, 33 with type 2, ten with type 3, and five with type 4. BCVA ranged from 0.08 to 1.00 logMAR (mean ± SD: 0.53 ± 0.21). IRL ratio, OS ratio, and ONL ratio were measured in all participants and decreased with increasing severity of foveal hypoplasia. The best-fit combined linear model included all three quantitative metrics and participant age expressed as a binary variable (divided into 0-18 years and 19 years or older; adjusted R2 = 0.500). This model predicted BCVA more accurately than a categorical foveal hypoplasia model (adjusted R2 = 0.352). Conclusions: A quantitative model of foveal specialization accounts for more variance in BCVA in albinism than categorical foveal hypoplasia grading. Other factors, such as optical aberrations and eye movements, may account for the remaining unexplained variance.

Extracting spacing-derived estimates of rod density in healthy retinae.

Quantification of the rod photoreceptor mosaic using adaptive optics scanning light ophthalmoscopy (AOSLO) remains challenging. Here we demonstrate a method for deriving estimates of rod density and rod:cone ratio based on measures of rod spacing, cone numerosity, and cone inner segment area. Twenty-two AOSLO images with complete rod visualization were used to validate this spacing-derived method for estimating density. The method was then used to estimate rod metrics in an additional 105 images without complete rod visualization. The spacing-derived rod mosaic metrics were comparable to published data from histology. This method could be leveraged to develop large normative databases of rod mosaic metrics, though limitations persist with intergrader variability in assessing cone area and numerosity.

Comparison of Cone Mosaic Metrics From Images Acquired With the SPECTRALIS High Magnification Module and Adaptive Optics Scanning Light Ophthalmoscopy.

Purpose: To compare cone mosaic metrics derived from adaptive optics scanning light ophthalmoscopy (AOSLO) images with those derived from Heidelberg Engineering SPECTRALIS High Magnification Module (HMM) images. Methods: Participants with contiguous cone mosaics had HMM imaging performed at locations superior and temporal to the fovea. These images were registered and averaged offline and then aligned to split-detection AOSLO images; 200 × 200-µm regions of interest were extracted from both modalities. Cones were semi-automatically identified by two graders to provide estimates of cone density and spacing. Results: Thirty participants with contiguous cone mosaics were imaged (10 males, 20 females; age range, 11-67 years). Image quality varied, and 80% of our participants had analyzable HMM images. The intergrader intraclass correlation coefficients for cone metrics were good for both modalities (0.688-0.757 for HMM; 0.805-0.836 for AOSLO). Cone density estimates from HMM images were lower by 2661 cones/mm2 (24.1%) on average compared to AOSLO-derived estimates. Accordingly, HMM estimates of cone spacing were increased on average compared to AOSLO. Conclusions: The cone mosaic can be visualized in vivo using the SPECTRALIS HMM, although image quality is variable and imaging is not successful in every individual. Metrics extracted from HMM images can differ from those from AOSLO, although excellent agreement is possible in individuals with excellent optical quality and precise co-registration between modalities. Translational Relevance: Emerging non-adaptive optics-based photoreceptor imaging is more clinically accessible than adaptive optics techniques and has potential to expand high-resolution imaging in a clinical environment.

Retinal alterations in patients with Lafora disease.

PURPOSE: Lafora disease is a genetic neurodegenerative metabolic disorder caused by insoluble polyglucosan aggregate accumulation throughout the central nervous system and body. The retina is an accessible neural tissue, which may offer alternative methods to assess neurological diseases quickly and noninvasively. In this way, noninvasive imaging may provide a means to characterize neurodegenerative disease, which enables earlier identification and diagnosis of disease and the ability to monitor disease progression. In this study, we sought to characterize the retina of individuals with Lafora disease using non-invasive retinal imaging. METHODS: One eye of three individuals with genetically confirmed Lafora disease were imaged with optical coherence tomography (OCT) and adaptive optics scanning light ophthalmoscopy (AOSLO). When possible, OCT volume and line scans were acquired to assess total retinal thickness, ganglion cell-inner plexiform layer thickness, and outer nuclear layer + Henle fiber layer thickness. OCT angiography (OCTA) scans were acquired in one subject at the macula and optic nerve head (ONH). AOSLO was used to characterize the photoreceptor mosaic and examine the retinal nerve fiber layer (RNFL). RESULTS: Two subjects with previous seizure activity demonstrated reduced retinal thickness, while one subject with no apparent symptoms had normal retinal thickness. All other clinical measures, as well as parafoveal cone density, were within normal range. Nummular reflectivity at the level of the RNFL was observed using AOSLO in the macula and near the ONH in all three subjects. CONCLUSIONS: This multimodal retinal imaging approach allowed us to observe a number of retinal structural features in all three individuals. Most notably, AOSLO revealed nummular reflectivity within the inner retina of each subject. This phenotype has not been reported previously and may represent a characteristic change produced by the neurodegenerative process.

Examining Whether AOSLO-Based Foveal Cone Metrics in Achromatopsia and Albinism Are Representative of Foveal Cone Structure.

Purpose: Adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in patients with achromatopsia (ACHM) and albinism is not always successful. Here, we tested whether optical coherence tomography (OCT) measures of foveal structure differed between patients for whom AOSLO images were either quantifiable or unquantifiable. Methods: The study included 166 subjects (84 with ACHM; 82 with albinism) with previously acquired OCT scans, AOSLO images, and best-corrected visual acuity (BCVA, if available). Foveal OCT scans were assessed for outer retinal structure, outer nuclear layer thickness, and hypoplasia. AOSLO images were graded as quantifiable if a peak cone density could be measured and/or usable if the location of peak density could be identified and the parafoveal mosaic was quantifiable. Results: Forty-nine percent of subjects with ACHM and 57% of subjects with albinism had quantifiable AOSLO images. Older age and better BCVA were found in subjects with quantifiable AOSLO images for both ACHM (P = 0.0214 and P = 0.0276, respectively) and albinism (P = 0.0073 and P < 0.0004, respectively). There was a significant trend between ellipsoid zone appearance and ability to quantify AOSLO (P = 0.0028). In albinism, OCT metrics of cone structure did not differ between groups. Conclusions: Previously reported AOSLO-based cone density measures in ACHM may not necessarily reflect the degree of remnant cone structure in these patients. Translational Relevance: Until AOSLO is successful in all patients with ACHM and albinism, the possibility of the reported data from a particular cohort not being representative of the entire population remains an important issue to consider when interpreting results from AOSLO studies.

Aberrant visual population receptive fields in human albinism.

Retinotopic organization is a fundamental feature of visual cortex thought to play a vital role in encoding spatial information. One important aspect of normal retinotopy is the representation of the right and left hemifields in contralateral visual cortex. However, in human albinism, many temporal retinal afferents decussate aberrantly at the optic chiasm resulting in partially superimposed representations of opposite hemifields in each hemisphere of visual cortex. Previous functional magnetic resonance imaging (fMRI) studies in human albinism suggest that the right and left hemifield representations are superimposed in a mirror-symmetric manner. This should produce imaging voxels which respond to two separate locations mirrored across the vertical meridian. However, it is not yet clear how retino-cortical miswiring in albinism manifests at the level of single voxel population receptive fields (pRFs). Here, we used pRF modeling to fit both single and dual pRF models to the visual responses of voxels in visual areas V1 to V3 of five subjects with albinism. We found that subjects with albinism (but not controls) have sizable clusters of voxels with unequivocal dual pRFs consistently corresponding to, but not fully coextensive with, regions of hemifield overlap. These dual pRFs were typically positioned at locations roughly mirrored across the vertical meridian and were uniquely clustered within a portion of the visual field for each subject.

Optical Coherence Tomography Artifacts Are Associated With Adaptive Optics Scanning Light Ophthalmoscopy Success in Achromatopsia.

Purpose: To determine whether artifacts in optical coherence tomography (OCT) images are associated with the success or failure of adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in subjects with achromatopsia (ACHM). Methods: Previously acquired OCT and non-confocal, split-detector AOSLO images from one eye of 66 subjects with genetically confirmed achromatopsia (15 CNGA3 and 51 CNGB3) were reviewed along with best-corrected visual acuity (BCVA) and axial length. OCT artifacts in interpolated vertical volumes from CIRRUS macular cubes were divided into four categories: (1) none or minimal, (2) clear and low frequency, (3) low amplitude and high frequency, and (4) high amplitude and high frequency. Each vertical volume was assessed once by two observers. AOSLO success was defined as sufficient image quality in split-detector images at the fovea to assess cone quantity. Results: There was excellent agreement between the two observers for assessing OCT artifact severity category (weighted kappa = 0.88). Overall, AOSLO success was 47%. For subjects with OCT artifact severity category 1, AOSLO success was 65%; for category 2, 47%; for category 3, 11%; and for category 4, 0%. There was a significant association between OCT artifact severity category and AOSLO success (P = 0.0002). Neither BCVA nor axial length was associated with AOSLO success (P = 0.07 and P = 0.75, respectively). Conclusions: Artifacts in OCT volumes are associated with AOSLO success in ACHM. Subjects with less severe OCT artifacts are more likely to be good candidates for AOSLO imaging, whereas AOSLO was successful in only 7% of subjects with category 3 or 4 OCT artifacts. These results may be useful in guiding patient selection for AOSLO imaging. Translational Relevance: Using OCT to prescreen patients could be a valuable tool for clinical trials that utilize AOSLO to reduce costs and decrease patient testing burden.

Assessing Foveal Structure in Individuals with TYR R402Q and S192Y Hypomorphic Alleles.

Purpose: To assess the impact of two TYR hypomorphic alleles (R402Q and S192Y) on foveal pit and foveal avascular zone (FAZ) morphology. Design: Prospective, cross-sectional study. Participants: A total of 164 participants with normal vision (67 male and 97 female; mean ± standard deviation [SD] age = 30.5 ± 12.8 years) were recruited. Methods: Sequencing of more than 100 pigmentation-related genes was performed, and results were reviewed for the presence or absence of the TYR polymorphisms R402Q (rs1126809) and S192Y (rs1042602). Volumetric scans of the macula were obtained for each participant using OCT, and retinal thickness maps were analyzed using custom software. OCT angiography was used to image the FAZ, which was manually segmented and measured. Linear mixed model analysis was used to assess associations between genotype and foveal pit morphology. Main Outcome Measures: Foveal pit depth, diameter, volume, and FAZ area in relation to the presence of hypomorphic alleles R402Q and S192Y on the TYR gene. Results: Heterozygosity for the TYR R402Q allele was associated with decreased pit diameter (P = 0.0094) and decreased FAZ area (P = 0.025). Homozygosity for the TYR R402Q allele was associated with reduced pit volume (P = 0.0005), decreased pit depth (P = 0.007), reduced pit diameter (P = 0.0052), and reduced FAZ area (P = 0.0012). Homozygosity for TYR S192Y was associated with reduced FAZ area (P = 0.016). Heterozygosity for the TYR S192Y allele was not associated with differences in foveal pit depth, diameter, volume, or FAZ area (P > 0.05). Conclusions: Although the role of the TYR R402Q and S192Y hypomorphic alleles in albinism remains controversial, our data suggest that these variants contribute to the extensive inter-individual variability in foveal morphology in the normal population. Our results contribute to the evolving picture of the relationship between ocular pigmentation and foveal morphology.

Preservation of the Foveal Avascular Zone in Achromatopsia Despite the Absence of a Fully Formed Pit.

Purpose: To examine the foveal avascular zone (FAZ) in patients with congenital achromatopsia (ACHM). Methods: Forty-two patients with genetically confirmed ACHM were imaged either with Optovue's AngioVue system or Zeiss's Plex Elite 9000, and the presence or absence of a FAZ was determined. For images where a FAZ was present and could be confidently segmented, FAZ area, circularity index, and roundness were measured and compared with previously published normative values. Structural optical coherence tomography images were acquired to assess the degree of foveal hypoplasia (number and thickness of inner retinal layers present at the fovea). Results: A FAZ was present in 31 of 42 patients imaged (74%), although no determination could be made for 11 patients due to poor image quality (26%). The mean ± SD FAZ area for the ACHM retina was 0.281 ± 0.112 mm2, which was not significantly different from the previously published normative values (P = 0.94). However, their FAZs had decreased circularity (P < 0.0001) and decreased roundness (P < 0.0001) compared to the normative cohort. In the patients with ACHM examined here, the FAZ area decreased as the number and thickness of the retained inner retinal layers increased. Conclusions: Our data demonstrate that despite the presence of foveal hypoplasia, patients with ACHM can have a FAZ. This is distinct from other conditions associated with foveal hypoplasia, which generally show an absence of the FAZ. In ACHM, FAZ formation does not appear to be sufficient for complete pit formation, contrary to some models of foveal development.

The relationship between retinal cone density and cortical magnification in human albinism.

The human fovea lies at the center of the retina and supports high-acuity vision. In normal visual system development, the highest acuity is correlated with both a high density of cone photoreceptors in the fovea and a magnified retinotopic representation of the fovea in the visual cortex. Both cone density and the cortical area dedicated to each degree of visual space-the latter describing cortical magnification (CM)-steadily decrease with increasing eccentricity from the fovea. In albinism, peak cone density at the fovea and visual acuity are decreased, but seem to be within normal limits in the periphery, thus providing a model to explore the correlation between retinal structure, cortical structure, and behavior. Here, we used adaptive optics scanning light ophthalmoscopy to assess retinal cone density and functional magnetic resonance imaging to measure CM in the primary visual cortex of normal controls and individuals with albinism. We find that retinotopic organization is more varied among individuals with albinism than previously appreciated. Additionally, CM outside the fovea is similar to that in controls, but also more variable. CM in albinism and controls exceeds that which might be predicted based on cone density alone, but is more accurately predicted by retinal ganglion cell density. This finding suggests that decreased foveal cone density in albinism may be partially counteracted by nonuniform connectivity between cones and their downstream signaling partners. Together, these results emphasize that central as well as retinal factors must be included to provide a complete picture of aberrant structure and function in albinism.

Assessing Ganglion Cell Layer Topography in Human Albinism Using Optical Coherence Tomography.

Purpose: To test whether ganglion cell layer (GCL) and inner plexiform layer (IPL) topography is altered in albinism. Methods: Optical coherence tomography scans were analyzed in 30 participants with albinism and 25 control participants. Horizontal and vertical line scans were acquired at the fovea, then strip registered and averaged. The Duke Optical Coherence Tomography Retinal Analysis Program was used to automatically segment the combined GCL and IPL and total retinal thickness, followed by program-assisted manual segmentation of the boundary between the GCL and IPL. Layer thickness and area under the curve (AUC) were calculated within 2.5 mm of the fovea. Nasal-temporal and superior-inferior asymmetry were calculated as an AUC ratio in each quadrant. Results: GCL and IPL topography varied between participants. The summed AUC in all quadrants was similar between groups for both the GCL (P = 0.84) and IPL (P = 0.08). Both groups showed nasal-temporal asymmetry in the GCL, but only participants with albinism had nasal-temporal asymmetry in the IPL. Nasal-temporal asymmetry was greater in albinism for both the GCL (P < 0.0001) and the IPL (P = 0.0006). The GCL usually comprised a greater percentage of the combined GCL and IPL in controls than in albinism. Conclusions: The GCL and IPL have greater structural variability than previously reported. GCL and IPL topography are significantly altered in albinism, which suggests differences in the spatial distribution of retinal ganglion cells. This finding provides insight into foveal development and structure-function relationships in foveal hypoplasia.

The Henle Fiber Layer in Albinism: Comparison to Normal and Relationship to Outer Nuclear Layer Thickness and Foveal Cone Density.

Purpose: Directional optical coherence tomography (D-OCT) allows the visualization of the Henle fiber layer (HFL) in vivo. Here, we used D-OCT to characterize the HFL and outer nuclear layer (ONL) in albinism and examine the relationship between true foveal ONL and peak cone density. Methods: Horizontal D-OCT B-scans were acquired, registered, and averaged for 12 subjects with oculocutaneous albinism and 26 control subjects. Averaged images were manually segmented to extract HFL and ONL thickness. Adaptive optics scanning light ophthalmoscopy was used to acquire images of the foveal cone mosaic in 10 subjects with albinism, from which peak cone density was assessed. Results: Across the foveal region, the HFL topography was different between subjects with albinism and normal controls. In particular, foveal HFL thickness was thicker in albinism than in normal controls (P < 0.0001), whereas foveal ONL thickness was thinner in albinism than in normal controls (P < 0.0001). The total HFL and ONL thickness was not significantly different between albinism and controls (P = 0.3169). Foveal ONL thickness was positively correlated with peak cone density in subjects with albinism (r = 0.8061, P = 0.0072). Conclusions: Foveal HFL and ONL topography are significantly altered in albinism relative to normal controls. Our data suggest that increased foveal cone packing drives the formation of Henle fibers, more so than the lateral displacement of inner retinal neurons (which is reduced in albinism). The ability to quantify foveal ONL and HFL may help further stratify grading schemes used to assess foveal hypoplasia.