Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina.

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

Cellular and Circuit Mechanisms Shaping the Perceptual Properties of the Primate Fovea.

The fovea is a specialized region of the retina that dominates the visual perception of primates by providing high chromatic and spatial acuity. While the foveal and peripheral retina share a similar core circuit architecture, they exhibit profound functional differences whose mechanisms are unknown. Using intracellular recordings and structure-function analyses, we examined the cellular and synaptic underpinnings of the primate fovea. Compared to peripheral vision, the fovea displays decreased sensitivity to rapid variations in light inputs; this difference is reflected in the responses of ganglion cells, the output cells of the retina. Surprisingly, and unlike in the periphery, synaptic inhibition minimally shaped the responses of foveal midget ganglion cells. This difference in inhibition cannot however, explain the differences in the temporal sensitivity of foveal and peripheral midget ganglion cells. Instead, foveal cone photoreceptors themselves exhibited slower light responses than peripheral cones, unexpectedly linking cone signals to perceptual sensitivity.

Evolutionary and developmental specialization of foveal cell types in the marmoset.

In primates, high-acuity vision is mediated by the fovea, a small specialized central region of the retina. The fovea, unique to the anthropoid lineage among mammals, undergoes notable neuronal morphological changes during postnatal maturation. However, the extent of cellular similarity across anthropoid foveas and the molecular underpinnings of foveal maturation remain unclear. Here, we used high-throughput single-cell RNA sequencing to profile retinal cells of the common marmoset (Callithrix jacchus), an early divergent in anthropoid evolution from humans, apes, and macaques. We generated atlases of the marmoset fovea and peripheral retina for both neonates and adults. Our comparative analysis revealed that marmosets share almost all their foveal types with both humans and macaques, highlighting a conserved cellular structure among primate foveas. Furthermore, by tracing the developmental trajectory of cell types in the foveal and peripheral retina, we found distinct maturation paths for each. In-depth analysis of gene expression differences demonstrated that cone photoreceptors and Müller glia (MG), among others, show the greatest molecular divergence between these two regions. Utilizing single-cell ATAC-seq and gene-regulatory network inference, we uncovered distinct transcriptional regulations differentiating foveal cones from their peripheral counterparts. Further analysis of predicted ligand-receptor interactions suggested a potential role for MG in supporting the maturation of foveal cones. Together, these results provide valuable insights into foveal development, structure, and evolution.

Different temporal dynamics of foveal and peripheral visual processing during fixation.

Humans explore visual scenes by alternating short fixations with saccades directing the fovea to points of interest. During fixation, the visual system not only examines the foveal stimulus at high resolution, but it also processes the extrafoveal input to plan the next saccade. Although foveal analysis and peripheral selection occur in parallel, little is known about the temporal dynamics of foveal and peripheral processing upon saccade landing, during fixation. Here we investigate whether the ability to localize changes across the visual field differs depending on when the change occurs during fixation, and on whether the change localization involves foveal, extrafoveal processing, or both. Our findings reveal that the ability to localize changes in peripheral areas of the visual field improves as a function of time after fixation onset, whereas localization accuracy for foveal stimuli remains approximately constant. Importantly, this pattern holds regardless of whether individuals monitor only foveal or peripheral stimuli, or both simultaneously. Altogether, these results show that the visual system is more attuned to the foveal input early on during fixation, whereas change localization for peripheral stimuli progressively improves throughout fixation, possibly as a consequence of an increased readiness to plan the next saccade.

A circuit motif for color in the human foveal retina.

The neural pathways that start human color vision begin in the complex synaptic network of the foveal retina where signals originating in long (L), middle (M), and short (S) wavelength-sensitive cone photoreceptor types are compared through antagonistic interactions, referred to as opponency. In nonhuman primates, two cone opponent pathways are well established: an L vs. M cone circuit linked to the midget ganglion cell type, often called the red-green pathway, and an S vs. L + M cone circuit linked to the small bistratified ganglion cell type, often called the blue-yellow pathway. These pathways have been taken to correspond in human vision to cardinal directions in a trichromatic color space, providing the parallel inputs to higher-level color processing. Yet linking cone opponency in the nonhuman primate retina to color mechanisms in human vision has proven particularly difficult. Here, we apply connectomic reconstruction to the human foveal retina to trace parallel excitatory synaptic outputs from the S-ON (or "blue-cone") bipolar cell to the small bistratified cell and two additional ganglion cell types: a large bistratified ganglion cell and a subpopulation of ON-midget ganglion cells, whose synaptic connections suggest a significant and unique role in color vision. These two ganglion cell types are postsynaptic to both S-ON and L vs. M opponent midget bipolar cells and thus define excitatory pathways in the foveal retina that merge the cardinal red-green and blue-yellow circuits, with the potential for trichromatic cone opponency at the first stage of human vision.

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.

Featural Representation and Internal Noise Underlie the Eccentricity Effect in Contrast Sensitivity.

Human visual performance for basic visual dimensions (e.g., contrast sensitivity and acuity) peaks at the fovea and decreases with eccentricity. The eccentricity effect is related to the larger visual cortical surface area corresponding to the fovea, but it is unknown if differential feature tuning contributes to this eccentricity effect. Here, we investigated two system-level computations underlying the eccentricity effect: featural representation (tuning) and internal noise. Observers (both sexes) detected a Gabor embedded in filtered white noise which appeared at the fovea or one of four perifoveal locations. We used psychophysical reverse correlation to estimate the weights assigned by the visual system to a range of orientations and spatial frequencies (SFs) in noisy stimuli, which are conventionally interpreted as perceptual sensitivity to the corresponding features. We found higher sensitivity to task-relevant orientations and SFs at the fovea than that at the perifovea, and no difference in selectivity for either orientation or SF. Concurrently, we measured response consistency using a double-pass method, which allowed us to infer the level of internal noise by implementing a noisy observer model. We found lower internal noise at the fovea than that at the perifovea. Finally, individual variability in contrast sensitivity correlated with sensitivity to and selectivity for task-relevant features as well as with internal noise. Moreover, the behavioral eccentricity effect mainly reflects the foveal advantage in orientation sensitivity compared with other computations. These findings suggest that the eccentricity effect stems from a better representation of task-relevant features and lower internal noise at the fovea than that at the perifovea.

Cone-Opponent Ganglion Cells in the Primate Fovea Tuned to Noncardinal Color Directions.

A long-standing question in vision science is how the three cone photoreceptor types-long (L), medium (M), and short (S) wavelength sensitive-combine to generate our perception of color. Hue perception can be described along two opponent axes: red-green and blue-yellow. Psychophysical measurements of color appearance indicate that the cone inputs to the red-green and blue-yellow opponent axes are M vs. L + S and L vs. M + S, respectively. However, the "cardinal directions of color space" revealed by psychophysical measurements of color detection thresholds following adaptation are L vs. M and S vs. L + M. These cardinal directions match the most common cone-opponent retinal ganglion cells (RGCs) in the primate retina. Accordingly, the cone opponency necessary for color appearance is thought to be established in the cortex. While neurons with the appropriate M vs. L + S and L vs. M + S opponency have been reported in the retina and lateral geniculate nucleus, their existence continues to be debated. Resolving this long-standing debate is necessary because a complete account of the cone opponency in the retinal output is critical for understanding how downstream neural circuits process color. Here, we performed adaptive optics calcium imaging to noninvasively measure foveal RGC light responses in the living Macaca fascicularis eye. We confirm the presence of L vs. M + S and M vs. L + S neurons with noncardinal cone opponency and demonstrate that cone-opponent signals in the retinal output are more diverse than classically thought.

Severe distortion in the representation of foveal visual image locations in short-term memory.

The foveal visual image region provides the human visual system with the highest acuity. However, it is unclear whether such a high fidelity representational advantage is maintained when foveal image locations are committed to short-term memory. Here, we describe a paradoxically large distortion in foveal target location recall by humans. We briefly presented small, but high contrast, points of light at eccentricities ranging from 0.1 to 12°, while subjects maintained their line of sight on a stable target. After a brief memory period, the subjects indicated the remembered target locations via computer controlled cursors. The biggest localization errors, in terms of both directional deviations and amplitude percentage overshoots or undershoots, occurred for the most foveal targets, and such distortions were still present, albeit with qualitatively different patterns, when subjects shifted their gaze to indicate the remembered target locations. Foveal visual images are severely distorted in short-term memory.

Comparing Neural Correlates of Memory Encoding and Maintenance for Foveal and Peripheral Stimuli.

Visual working memory is believed to rely on top-down attentional mechanisms that sustain active sensory representations in early visual cortex, a mechanism referred to as sensory recruitment. However, both bottom-up sensory input and top-down attentional modulations thereof appear to prioritize the fovea over the periphery, such that initially peripheral percepts may even be assimilated by foveal processes. This raises the question whether and how visual working memory differs for central and peripheral input. To address this, we conducted a delayed orientation recall task in which an orientation was presented either at the center of the screen or at 15° eccentricity to the left or right. Response accuracy, EEG activity, and gaze position were recorded from 30 participants. Accuracy was slightly but significantly higher for foveal versus peripheral memories. Decoding of EEG recordings revealed a clear dissociation between early sensory and later maintenance signals. Although sensory signals were clearly decodable for foveal stimuli, they were not for peripheral input. In contrast, maintenance signals were equally decodable for both foveal and peripheral memories, suggesting comparable top-down components regardless of eccentricity. Moreover, although memory representations were initially spatially specific and reflected in voltage fluctuations, later during the maintenance period, they generalized across locations, as emerged in alpha oscillations, thus revealing a dynamic transformation within memory from separate sensory traces to what we propose are common output-related codes. Furthermore, the combined absence of reliable decoding of sensory signals and robust presence of maintenance decoding indicates that storage activity patterns as measured by EEG reflect signals beyond primary visual cortex. We discuss the implications for the sensory recruitment hypothesis.

Fast and nonuniform dynamics of perisaccadic vision in the central fovea.

Humans use rapid eye movements (saccades) to inspect stimuli with the foveola, the region of the retina where receptors are most densely packed. It is well established that visual sensitivity is generally attenuated during these movements, a phenomenon known as saccadic suppression. This effect is commonly studied with large, often peripheral, stimuli presented during instructed saccades. However, little is known about how saccades modulate the foveola and how the resulting dynamics unfold during natural visual exploration. Here we measured the foveal dynamics of saccadic suppression in a naturalistic high-acuity task, a task designed after primates' social grooming, which-like most explorations of fine patterns-primarily elicits minute saccades (microsaccades). Leveraging on recent advances in gaze-contingent display control, we were able to systematically map the perisaccadic time course of sensitivity across the foveola. We show that contrast sensitivity is not uniform across this region and that both the extent and dynamics of saccadic suppression vary within the foveola. Suppression is stronger and faster in the most central portion, where sensitivity is generally higher and selectively rebounds at the onset of a new fixation. These results shed light on the modulations experienced by foveal vision during the saccade-fixation cycle and explain some of the benefits of microsaccades.

Toward a theory of perspective perception in pictures.

This paper reviews projection models and their perception in realistic pictures, and proposes hypotheses for three-dimensional (3D) shape and space perception in pictures. In these hypotheses, eye fixations, and foveal vision play a central role. Many past theories and experimental studies focus solely on linear perspective. Yet, these theories fail to explain many important perceptual phenomena, including the effectiveness of nonlinear projections. Indeed, few classical paintings strictly obey linear perspective, nor do the best distortion-avoidance techniques for wide-angle computational photography. The hypotheses here employ a two-stage model for 3D human vision. When viewing a picture, the first stage perceives 3D shape for the current gaze. Each fixation has its own perspective projection, but, owing to the nature of foveal and peripheral vision, shape information is obtained primarily for a small region of the picture around the fixation. As a viewer moves their eyes, the second stage continually integrates some of the per-gaze information into an overall interpretation of a picture. The interpretation need not be geometrically stable or consistent over time. It is argued that this framework could explain many disparate pictorial phenomena, including different projection styles throughout art history and computational photography, while being consistent with the constraints of human 3D vision. The paper reviews open questions and suggests new studies to explore these hypotheses.

Foveal neural adaptation to optically induced contrast reduction.

Contrast processing is suggested to interact with eye growth and myopia development. A novel contrast-reducing myopia control lens design decreases image contrast and was shown to slow myopia progression. Limited insights exist regarding neural visual processing following adaptation to image contrast reduction. This study investigated foveal neural contrast sensitivity in 29 young adults following a 30-minute adaptation to scattering using a Bangerter occlusion foil 0.8, +0.5-diopter defocus, and a clear lens control condition. Neural contrast sensitivity at its peak sensitivity of 6 cycles per degree was assessed before and after adaptation to the lens conditions, employing a unique interferometric system. Pre-adaptation measurements were averaged from six replicates and post-adaptation measurements by the first and last three of six replicates. The change in neural contrast sensitivity was largest for scattering across the first and last three post-adaptation measurements (+0.05 ± 0.01 logCS and +0.04 ± 0.01 logCS, respectively) compared with control and defocus (all +0.03 ± 0.01 logCS). For scattering, the observed increase of neural contrast sensitivity within the first three measurements differed significantly from the pre-adaptation baseline (p = 0.04) and was significantly higher compared with the control condition (p = 0.04). The sensitivity increases in the control and defocus conditions were not significant (all p > 0.05). As the adaptation effect diminished, no significant differences were found from baseline or between the conditions in the last three measurements (all p > 0.05). When post-adaptation neural contrast sensitivities were clustered into 25-second sequences, a significant effect was observed between the conditions, with only a significant relevant effect between control and scattering at 25 seconds (p = 0.04) and no further significant effects (all p > 0.05). The alteration in neural contrast sensitivity at peak sensitivity was most pronounced following adaptation to the scattering condition compared with defocus and control, suggesting that induced scattering might be considered for myopia control.

Unique yellow shifts for small and brief stimuli in the central retina.

The spectral locus of unique yellow was determined for flashes of different sizes (<11 arcmin) and durations (<500 ms) presented in and near the fovea. An adaptive optics scanning laser ophthalmoscope was used to minimize the effects of higher-order aberrations during simultaneous stimulus delivery and retinal imaging. In certain subjects, parafoveal cones were classified as L, M, or S, which permitted the comparison of unique yellow measurements with variations in local L/M ratios within and between observers. Unique yellow shifted to longer wavelengths as stimulus size or duration was reduced. This effect is most pronounced for changes in size and more apparent in the fovea than in the parafovea. The observed variations in unique yellow are not entirely predicted from variations in L/M ratio and therefore implicate neural processes beyond photoreception.

The role of prediction and visual tracking strategies during manual interception: An exploration of individual differences.

The interception (or avoidance) of moving objects is a common component of various daily living tasks; however, it remains unclear whether precise alignment of foveal vision with a target is important for motor performance. Furthermore, there has also been little examination of individual differences in visual tracking strategy and the use of anticipatory gaze adjustments. We examined the importance of in-flight tracking and predictive visual behaviors using a virtual reality environment that required participants (n = 41) to intercept tennis balls projected from one of two possible locations. Here, we explored whether different tracking strategies spontaneously arose during the task, and which were most effective. Although indices of closer in-flight tracking (pursuit gain, tracking coherence, tracking lag, and saccades) were predictive of better interception performance, these relationships were rather weak. Anticipatory gaze shifts toward the correct release location of the ball provided no benefit for subsequent interception. Nonetheless, two interceptive strategies were evident: 1) early anticipation of the ball's onset location followed by attempts to closely track the ball in flight (i.e., predictive strategy); or 2) positioning gaze between possible onset locations and then using peripheral vision to locate the moving ball (i.e., a visual pivot strategy). Despite showing much poorer in-flight foveal tracking of the ball, participants adopting a visual pivot strategy performed slightly better in the task. Overall, these results indicate that precise alignment of the fovea with the target may not be critical for interception tasks, but that observers can adopt quite varied visual guidance approaches.

Do microsaccades vary with discriminability around the visual field?

Microsaccades-tiny fixational eye movements-improve discriminability in high-acuity tasks in the foveola. To investigate whether they help compensate for low discriminability at the perifovea, we examined microsaccade characteristics relative to the adult visual performance field, which is characterized by two perceptual asymmetries: horizontal-vertical anisotropy (better discrimination along the horizontal than vertical meridian) and vertical meridian asymmetry (better discrimination along the lower than upper vertical meridian). We investigated whether and to what extent microsaccade directionality varies when stimuli are at isoeccentric locations along the cardinals under conditions of heterogeneous discriminability (Experiment 1) and homogeneous discriminability, equated by adjusting stimulus contrast (Experiment 2). Participants performed a two-alternative forced-choice orientation discrimination task. In both experiments, performance was better on trials without microsaccades between ready signal onset and stimulus offset than on trials with microsaccades. Across the trial sequence, the microsaccade rate and directional pattern were similar across locations. Our results indicate that microsaccades were similar regardless of stimulus discriminability and target location, except during the response period-once the stimuli were no longer present and target location no longer uncertain-when microsaccades were biased toward the target location. Thus, this study reveals that microsaccades do not flexibly adapt as a function of varying discriminability in a basic visual task around the visual field.

Microsaccadic suppression of peripheral perceptual detection performance as a function of foveated visual image appearance.

Microsaccades are known to be associated with a deficit in perceptual detection performance for brief probe flashes presented in their temporal vicinity. However, it is still not clear how such a deficit might depend on the visual environment across which microsaccades are generated. Here, and motivated by studies demonstrating an interaction between visual background image appearance and perceptual suppression strength associated with large saccades, we probed peripheral perceptual detection performance of human subjects while they generated microsaccades over three different visual backgrounds. Subjects fixated near the center of a low spatial frequency grating, a high spatial frequency grating, or a small white fixation spot over an otherwise gray background. When a computer process detected a microsaccade, it presented a brief peripheral probe flash at one of four locations (over a uniform gray background) and at different times. After collecting full psychometric curves, we found that both perceptual detection thresholds and slopes of psychometric curves were impaired for peripheral flashes in the immediate temporal vicinity of microsaccades, and they recovered with later flash times. Importantly, the threshold elevations, but not the psychometric slope reductions, were stronger for the white fixation spot than for either of the two gratings. Thus, like with larger saccades, microsaccadic suppression strength can show a certain degree of image dependence. However, unlike with larger saccades, stronger microsaccadic suppression did not occur with low spatial frequency textures. This observation might reflect the different spatiotemporal retinal transients associated with the small microsaccades in our study versus larger saccades.

Maturation and refinement of the maculae and foveae in the Anolis sagrei lizard.

The fovea is a pit in the center of the macula, which is a region of the retina with a high concentration of photoreceptor cells, which accounts for a large degree of visual acuity in primates. The maturation of this primate visual acuity area is characterized by the shallowing and widening of the foveal pit, a decrease in the diameter of the rod-free zone, and an increase in photoreceptor cells packing after birth. Maturation occurs concurrently with progressing age, increasing eye size, and retinal length/area. These observations have led to the hypothesis that the maturation of the fovea might be a function of mechanical variables that remodel the retina. However, this has never been explored outside of primates. Here, we take advantage of the Anolis sagrei lizard, which has a bifoveated retina, to study maturation of the fovea and macula. Eyes were collected from male and female lizards-hatchling, 2-month, 4-month, 6-month, and adult. We found that Anolis maculae undergo a maturation process somewhat different than what has been observed in primates. Anole macular diameters actually increase in size and undergo minimal photoreceptor cell packing, possessing a near complete complement of these cells at the time of hatching. As the anole eye expands, foveal centers experience little change in overall retina cell density with most cell redistribution occurring at macular borders and peripheral retina areas. Gene editing technology has recently been developed in lizards; this study provides a baseline of normal retina maturation for future genetic manipulation studies in anoles.

Modulations of foveal vision associated with microsaccade preparation.

It is known that attention shifts prior to a saccade to start processing the saccade target before it lands in the foveola, the high-resolution region of the retina. Yet, once the target is foveated, microsaccades, tiny saccades maintaining the fixated object within the fovea, continue to occur. What is the link between these eye movements and attention? There is growing evidence that these eye movements are associated with covert shifts of attention in the visual periphery, when the attended stimuli are presented far from the center of gaze. Yet, microsaccades are primarily used to explore complex foveal stimuli and to optimize fine spatial vision in the foveola, suggesting that the influences of microsaccades on attention may predominantly impact vision at this scale. To address this question we tracked gaze position with high precision and briefly presented high-acuity stimuli at predefined foveal locations right before microsaccade execution. Our results show that visual discrimination changes prior to microsaccade onset. An enhancement occurs at the microsaccade target location. This modulation is highly selective and it is coupled with a drastic impairment at the opposite foveal location, just a few arcminutes away. This effect is strongest when stimuli are presented closer to the eye movement onset time. These findings reveal that the link between attention and microsaccades is deeper than previously thought, exerting its strongest effects within the foveola. As a result, during fixation, foveal vision is constantly being reshaped both in space and in time with the occurrence of microsaccades.

Achromatic doublet electrowetting prism array for beam steering device in foveated display.

A foveated display is a technology that can solve the problem of insufficient angular resolution (relative to the human eye) for near-eye display. In a high-resolution foveated display, a beam steering element is required to track the human gaze. An electrowetting prism array is a transmissive non-mechanical beam steering device, that allows a light and compact optical system to be configured and a large aperture possible. However, the view is obstructed by the sidewall of the prism array. When the size of the cell prism is 7mm, the prism array has an 87% fill-factor. To push the fill-factor to 100%, the cell prisms were magnified using a lens array. Image processing was performed such that the image produced by the lens array was identical to the original. Beam steering by refraction is accompanied by chromatic dispersion, which causes chromatic aberration, making colors appear blurry. The refractive index condition to reduce chromatic dispersion was obtained using the doublet structure of the electrowetting prism. The chromatic dispersion was reduced by 70% on average.