Human Fovea Research Articles

Alignment, calibration, and validation of an adaptive optics scanning laser ophthalmoscope for high-resolution human foveal imaging.

In prior art, advances in adaptive optics scanning laser ophthalmoscope (AOSLO) technology have enabled cones in the human fovea to be resolved in healthy eyes with normal vision and low to moderate refractive errors, providing new insight into human foveal anatomy, visual perception, and retinal degenerative diseases. These high-resolution ophthalmoscopes require careful alignment of each optical subsystem to ensure diffraction-limited imaging performance, which is necessary for resolving the smallest foveal cones. This paper presents a systematic and rigorous methodology for building, aligning, calibrating, and testing an AOSLO designed for imaging the cone mosaic of the central fovea in humans with cellular resolution. This methodology uses a two-stage alignment procedure and thorough system testing to achieve diffraction-limited performance. Results from retinal imaging of healthy human subjects under 30 years of age with refractive errors of less than 3.5 diopters using either 680 nm or 840 nm light show that the system can resolve cones at the very center of the fovea, the region where the cones are smallest and most densely packed.

Carl Bergmann (1814–1865) and the discovery of the anatomical site in the retina where vision is initiated

ABSTRACT A preeminent quest of nineteenth-century visual neuroscience was to identify the anatomical elements of the retina that respond to light. A major breakthrough came in 1854, when Carl Bergmann discovered through direct observation that the human fovea contains only rods and cones. On this basis, he argued that these must necessarily be the light-sensitive elements (i.e., photoreceptors) that initiate vision. Bergmann also argued that Henle’s fibers form part of the necessary anatomical link between these distal elements and the proximal ganglion cells, which transmit visual signals to the brain via the optic nerve. However, despite his achievement, Heinrich Müller, not Bergmann, is remembered as the discoverer of human photoreceptors in the literature. This article seeks to correct the record. It situates Bergmann’s work alongside that of his contemporaries, sets out his arguments and the critique he received using archival documents, and makes this history more accessible for current readers by comparing what was said to what we know now. We argue that Bergmann’s arguments are at least as compelling as those of Müller, and that he should be recognized as a codiscoverer of the anatomic site in the retina where vision is initiated.

Dynamic changes in ocular shape during human development and its implications for retina fovea formation.

The human fovea is known for its distinctive pit-like appearance, which results from the displacement of retinal layers superficial to the photoreceptors cells. The photoreceptors are found at high density within the foveal region but not the surrounding retina. Efforts to elucidate the mechanisms responsible for these unique features have ruled out cell death as an explanation for pit formation and changes in cell proliferation as the cause of increased photoreceptor density. These findings have led to speculation that mechanical forces acting within and on the retina during development underly the formation of foveal architecture. Here we review eye morphogenesis and retinal remodeling in human embryonic development. Our meta-analysis of the literature suggests that fovea formation is a protracted process involving dynamic changes in ocular shape that start early and continue throughout most of human embryonic development. From these observations, we propose a new model for fovea development.

Non-random fixational drift and sub-cone resolution in the human fovea

Non-random fixational drift and sub-cone resolution in the human fovea

Functional Characteristics of Diverse PAX6 Mutations Associated with Isolated Foveal Hypoplasia.

The human fovea is a specialized pit structure in the central retina. Foveal hypoplasia is a condition where the foveal pit does not fully develop, and it is associated with poor vision. Autosomal dominant isolated foveal hypoplasia (FVH1) is a rare condition of foveal hypoplasia (FH) that lacks any other ocular manifestations. FVH1 is associated with hypomorphic mutations in the PAX6 gene that encodes a sequence-specific DNA-binding transcription factor for morphogenesis and evolution of the eye. We report our findings in 17 patients with PAX6 mutations associated with FVH1 or FH with aniridia and corneal opacities. Patients with three mutations, p.V78E, p.V83F and p.R128H, in the C-terminal subdomain of the paired domain (CTS) consistently have severe FH. Luciferase assays for a single reporter containing a representative PAX6 binding site indicated that the transcriptional activities of these mutations were significantly reduced, comparable to that of the truncation mutation of p.G65Rfs*5. Patients with p.P20S in the N-terminal subdomain of the paired domain, and a patient with p.N365K in the proline-serine-threonine-rich domain (PSTD) had mild FH. A patient with p.Q255L in the homeodomain had severe FH. The P20S and Q255L mutants did not affect the transcriptional activity. Mutant N365K has a retained DNA-binding activity but a reduced transcriptional activity, due to a low PSTD transactivation. These findings demonstrated that mutations associated with FVH1 underlie a functional divergence between DNA-binding ability and transcriptional activity. We conclude that a wide range of mutations in the PAX6 gene is not limited to the CST region and are responsible for FVH1.

Hippocampal spatial view cells, place cells, and concept cells: View representations.

A commentary is provided on issues raised in the Special Issue of Hippocampus (2023) on hippocampal system view representations. First, the evidence for hippocampal and parahippocampal spatial view cells in primates including humans shows that the allocentric representations provided by at least some of these cells are very useful for human memory in that where objects and rewards are seen in the world "out there" is a key component of episodic memory and navigation. Spatial view cell representations provide for memory and navigation to be independent of the place where the individual is currently located and of the egocentric coordinates of the viewed location and the facing direction of the individual. Second, memory and navigation in humans are normally related to the visual cues encoded by spatial view cells that define a location "out there" such as a building, hill, and so forth, not to an unmarked place without local cues and identified only by distant environmental/room cues. Third, "mixed" representations, for example of particular combinations of spatial view and place, can arise if the training has been for only some combinations of place and view, for that is what can then be learned by the hippocampus. Fourth, rodents, with their much less good visual acuity (~1 cycle/° in rats, compared with ~60 cycles/° for the human fovea), and rodents' very wide viewing angle for the world (~270°) might be expected, when using the same computational mechanisms as in primates, to use widely spaced environmental cues to define a place where the rodent is located, supported by inputs about place using local olfactory and tactile cues. Fifth, it is shown how view-point dependent allocentric representations could form a view-point independent allocentric representation for memory and navigation. Sixth, concept cells in humans and primates with connectivity to the hippocampus are compared.

Macular Pigment Carotenoids and Bisretinoid A2E.

Lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) are the three macular pigments (MP) carotenoids that uniquely accumulate in the macula lutea region of the human retina. L and Z are obtained by humans through dietary intake. The third MP, MZ, is rarely present in diet, and its abundance in the human fovea is due to the metabolic conversion of dietary L by the retinal pigment epithelium's RPE65 enzyme. The major functions of MP in ocular health are to filter high-intensity, phototoxic blue light and to act as effective antioxidants for scavenging free radicals. The pyridinium bisretinoid, N-retinylidene-N-retinylethanolamine (A2E), contributes to drusen formation in dry age-related macular degeneration (AMD) and to the autofluorescent flecks in autosomal recessive Stargardt disease (STGD1). Retinal carotenoids attenuate A2E formation and can directly and indirectly alleviate A2E-mediated oxidative damage. In this chapter, we review these more recently recognized interconnections between MP carotenoids and A2E bisretinoids.

Computational simulation of human fovea

Computational simulation of human fovea

Computational simulation of human fovea

Computational simulation of human fovea

Improving the spatial resolution of artificial vision using midget retinal ganglion cell populations modeled at the human fovea

Objective. Retinal prostheses seek to create artificial vision by stimulating surviving retinal neurons of patients with profound vision impairment. Notwithstanding tremendous research efforts, the performance of all implants tested to date has remained rudimentary, incapable of overcoming the threshold for legal blindness. To maximize the perceptual efficacy of retinal prostheses, a device must be capable of controlling retinal neurons with greater spatiotemporal precision. Most studies of retinal stimulation were derived from either non-primate species or the peripheral primate retina. We investigated if artificial stimulation could leverage the high spatial resolution afforded by the neural substrates at the primate fovea and surrounding regions to achieve improved percept qualities. Approach. We began by developing a new computational model capable of generating anatomically accurate retinal ganglion cell (RGC) populations within the human central retina. Next, multiple RGC populations across the central retina were stimulated in-silico to compare clinical and recently proposed neurostimulation configurations based on their ability to improve perceptual efficacy and reduce activation thresholds. Main results. Our model uniquely upholds eccentricity-dependent characteristics such as RGC density and dendritic field diameter, whilst incorporating anatomically accurate features such as axon projection and three-dimensional (3D) RGC layering, features often forgone in favor of reduced computational complexity. Following epiretinal stimulation, the RGCs in our model produced response patterns in shapes akin to the complex and non-trivial percepts reported in clinical trials. Our results also demonstrated that even within the neuron-dense central retina, epiretinal stimulation using a multi-return hexapolar electrode arrangement could reliably achieve spatially focused RGC activation and could achieve single-cell excitation in 56% of all tested locations. Significance. This study establishes an anatomically accurate 3D model of RGC populations within the human central retina and demonstrates the potential for an epiretinal hexapolar configuration to achieve consistent, spatially confined retinal responses, even within the unique and neuron-dense foveal region. Our results and model promote the prospect and optimization of higher spatial resolution in future epiretinal implants.

An efficient hexagonal image framework using pseudo hexagonal pixel for computer vision applications

Nature-inspired computing has been a real source of motivation for the development of many meta-heuristic algorithms. The biological optic system can be patterned as a cascade of sub-filters from the photoreceptors over the ganglion cells in the fovea to some simple cells in the visual cortex. This spark has inspired many researchers to examine the biological retina in order to learn more about information processing capabilities. The photoreceptor cones and rods in the human fovea resemble hexagon more than a rectangular structure. However, the hexagonal meshes provide higher packing density, consistent neighborhood connectivity, and better angular correction compared to the rectilinear square mesh. In this paper, a novel 2-D interpolation hexagonal lattice conversion algorithm has been proposed to develop an efficient hexagonal mesh framework for computer vision applications. The proposed algorithm comprises effective pseudo-hexagonal structures which guarantee to keep align with our human visual system. It provides the hexagonal simulated images to visually verify without using any hexagonal capture or display device. The simulation results manifest that the proposed algorithm achieves a higher Peak Signal-to-Noise Ratio of 98.45 and offers a high-resolution image with a lesser mean square error of 0.59.

Human Foveal Cone and RPE Cell Topographies and Their Correspondence With Foveal Shape.

PurposeTo characterize the association between foveal shape and cone and retinal pigment epithelium (RPE) cell topographies in healthy humans.MethodsMultimodal adaptive scanning light ophthalmoscopy and optical coherence tomography (OCT) were used to acquire images of foveal cones, RPE cells, and retinal layers in eyes of 23 healthy participants with normal foveas. Distributions of cone and RPE cell densities were fitted with nonlinear mixed-effects models. A linear mixed-effects model was used to examine the relationship between cone and RPE inter-cell distances and foveal shape as obtained from the OCT scans of retinal thickness.ResultsThe best-fit model to the cone densities was a power function with a nasal–temporal asymmetry. There was a significant linear relationship among cone and RPE cell spacing, foveal shape, and foveal cell topography. The model predictions of the central 10° show that the contributions of both the cones and RPE cells are necessary to account for foveal shape.ConclusionsThe results indicate that there is a strong relationship between cone and RPE cell spacing and the shape of the human adolescent and adult fovea. This finding adds to the existing evidence of the critical role that the RPE serves in fetal foveal development and through adolescence, possibly via the imposition of constraints on the number and distribution of foveal cones.

Wide range retina-like scanning based on liquid crystal optical phased array

A retina-like scanning method based on liquid crystal optical phased array (LCOPA) is proposed to improve field of view and efficiency. The functions of human retina, lens and fovea gaze control are achieved with optimized designed scanning strategy. Beam splitting method and angular magnification system are used to meet the requirements of the efficient scanning and large FOV. The models are verified by several experiments and the results show that the scanning performance well with the flexible retina-like strategy, especially for eccentric fovea. The scanning FOV is magnified 2.2 times and the average scanning error is less than 5%.

LIFE: A Generalizable Autodidactic Pipeline for 3D OCT-A Vessel Segmentation.

Optical coherence tomography (OCT) is a non-invasive imaging technique widely used for ophthalmology. It can be extended to OCT angiography (OCT-A), which reveals the retinal vasculature with improved contrast. Recent deep learning algorithms produced promising vascular segmentation results; however, 3D retinal vessel segmentation remains difficult due to the lack of manually annotated training data. We propose a learning-based method that is only supervised by a self-synthesized modality named local intensity fusion (LIF). LIF is a capillary-enhanced volume computed directly from the input OCT-A. We then construct the local intensity fusion encoder (LIFE) to map a given OCT-A volume and its LIF counterpart to a shared latent space. The latent space of LIFE has the same dimensions as the input data and it contains features common to both modalities. By binarizing this latent space, we obtain a volumetric vessel segmentation. Our method is evaluated in a human fovea OCT-A and three zebrafish OCT-A volumes with manual labels. It yields a Dice score of 0.7736 on human data and 0.8594 ± 0.0275 on zebrafish data, a dramatic improvement over existing unsupervised algorithms.

Circuit Reorganization Shapes the Developing Human Foveal Midget Connectome toward Single-Cone Resolution

The human visual pathway is specialized for the perception of fine spatial detail. The neural circuitry that determines visual acuity begins in the retinal fovea, where the resolution afforded by a dense array of cone photoreceptors is preserved in the retinal output by a remarkable non-divergent circuit: cone → midget bipolar interneuron → midget ganglion cell (the "private line"). How the private line develops is unknown; it could involve early specification of extremely precise synaptic connections or, by contrast, emerge slowly in concordance with the gradual maturation of foveal architecture and visual sensitivity. To distinguish between these hypotheses, we reconstructed the midget circuitry in the fetal human fovea by serial electron microscopy. We discovered that the midget private line is sculpted by synaptic remodeling beginning early in fetal life, with midget bipolar cells contacting a single cone by mid-gestation and bipolar cell-ganglion cell connectivity undergoing a more protracted period of refinement.

Cell Atlas of The Human Fovea and Peripheral Retina

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.

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.

Foveal scanning based on an optical-phases array.

We utilize the space-variant structure of the human fovea as a basis for a novel, to the best of our knowledge, foveal approach based on optical-phases array (OPA). This approach can be used to solve issues in 3D imaging and achieve a large field of view and high resolution with real-time application. A foveal scanning model based on the OPA is established. Simulations and experiments are performed to verify the models and illustrate the advantages of foveal scanning compared with traditional raster scanning. Simulations agree well with the theory, and the foveal approach has higher efficiency than traditional raster scanning. These results can serve as a reference for developing biomimetic sensors that mimic the human eye.

Spatial summation in the human fovea measured with adaptive optics

Spatial summation in the human fovea measured with adaptive optics

Visual perception in the human fovea: functional evaluation of cone diseases by neurophysiological methods.

Visual perception in the human fovea: functional evaluation of cone diseases by neurophysiological methods.