Age-related macular degeneration (AMD) is a disease that primarily affects the outer retina, with progressive photoreceptor degeneration and atrophy of the retinal pigment epithelium (RPE). Advances in imaging now enable photoreceptor changes to be detected and quantified with unprecedented sensitivity, whereas comparable biomarkers of RPE dysfunction remain less developed. As such, photoreceptor-based biomarkers are increasingly considered potential surrogates for current clinical trial endpoints. This review examines the current imaging modalities-particularly optical coherence tomography (OCT) and modalities enhanced by adaptive optics (AO) -used to evaluate photoreceptor structure in AMD. We explore the intrinsic value of parameters such as outer nuclear layer thickness, external limiting membrane integrity, photoreceptor inner and outer segment thickness, ellipsoid zone (EZ) integrity, and EZ reflectivity on OCT, and cone density and regularity on AO imaging, highlighting their potential and limitations. While OCT-based metrics are the most accessible in clinical settings, their clinical utility is hampered by inconsistent segmentation protocols and methodological heterogeneity. AO imaging offers unmatched resolution but faces practical barriers to widespread adoption. The field is moving in a promising direction with emerging computational tools and artificial intelligence improving accuracy and scalability. However, progress is contingent on establishing consensus definitions, standardized acquisition and analysis protocols, and normative datasets. Future efforts should focus on translating high-resolution imaging into robust, reproducible biomarkers that can be widely adopted in both clinical practice and therapeutic development.

In typical scenes, the available visual information exceeds the processing limits of the visual system. To reduce information, the visual system organizes visual input according to various principles. For example, in visual grouping local elements are grouped into larger wholes. Recently, it was shown how the visual system compresses redundant information by ‘redundancy masking’ which reduces the number of perceived items in repeating patterns. For example, when three identical items are presented in the periphery, observers often report perceiving only two items. In the current study, we examined the role of grouping and segmentation in redundancy masking. In particular, we asked whether visual grouping determines –and precedes— the units in which information is compressed in redundancy masking. Stimuli consisted of arrays of 3-5 vertical lines, briefly presented in the left or right visual field. We varied the contrast polarity of the lines creating the following patterns: uniform arrays, alternating arrays, and subgroups of identical lines with a different line at the stimulus edge. Observers reported the number of lines and then indicated the perceived feature values for each reported line. Our results revealed redundancy masking in all conditions. Importantly, redundancy masking always came after segmentation and grouping: lines were masked predominantly within segmented subgroups of identical lines. The reported patterns were highly systematic, even when redundancy masking occurred: The presence/absence of the two contrast polarities (Contrast), the stimulus edge (Edge) and their ordinal frequencies (Ratio) were largely accurately reported. Hence, important stimulus information remained largely intact. We suggest that redundancy masking comes after grouping and segmentation, and that the visual system compresses redundant information in the visual periphery by reducing the number of perceived identical items while preserving key stimulus features.

Up to very recently, the spatial arrangement of the photoreceptors of the human foveal center and their relationship to vision remained uncharted territory. With adaptive optics photo stimulation techniques that overcome the optical blur of the human eye and at the same time allows precise tracking of each photoreceptor cell as it is actively moved across the image formed on the retina, we can see what the photoreceptors see, and psychophysically study structure-function relationships on foveolar cell level. In this talk I will present recent anatomical and psychophysical results that will show both the similarities and differences in foveal mosaics in humans, and how the highly dynamic and adaptive sampling behavior of an eye aids visual performance.

Perception and action are inherently entangled: our world view is shaped by how we explore our environment through complex and variable self-motion. Even when fixating stable stimuli, our eyes undergo small, involuntary movements. Fixational eye movements (FEM) render a stable world jittery on our retinae, which can be expected to harm neural coding. Yet, empirical evidence suggests that FEM help rather than harm human perception of fine detail. Here, we elucidate this paradox by uncovering under which conditions FEM improve or impair retinal coding and human acuity. We combine theory and experiment: model accuracy is directly compared to that of healthy human subjects in a visual acuity task. Acuity is modeled by applying an ideal Bayesian classifier to simulations of retinal spiking activity in the presence of FEM. In addition, empirical FEM are monitored using high-resolution eye-tracking by an adaptive optics scanning laser ophthalmoscope. FEM introduce variability in retinal ganglion cell activity, but they also effectively preprocess inputs to facilitate retinal information encoding. Based on an interplay of these mechanisms, our model predicts a relation between visual acuity, FEM amplitude, and single-trial stimulus size that quantitatively accounts for experimental observations and captures the beneficial effect of FEM. Moreover, we observe that while human subjects' FEM statistics vary with stimulus size, our model suggests that subjects' FEM amplitude remains within a near-optimal range, where acuity is enhanced compared to much larger or smaller amplitudes. Overall, our findings indicate that perception benefits from action even at the fine spatiotemporal scale of FEM.

The prevalence of myopia is increasing worldwide, accompanied by an increase of potentially under-corrected myopes. Because neural pathways are prone to adaptation in relation to the sensory input, we wondered to what extent neural contrast sensitivity (NCS) is altered in the presence of image blur arising from under-correction. No significant differences in NCS were observed between the three groups but were significantly equivalent between emmetropes, well-corrected, and under-corrected myopes (all p < 0.001). Across all healthy participants, NCS variability increased with increasing spatial frequency which could not be explained by variations in foveolar cone density. For an albinism patient, a large difference between the cut-off frequency and central cone density derived Nyquist sampling limit was observed. In conclusion, NCS is unaffected by myopia and remains stable for under-correction of up to 1.5 D. Furthermore, NCS testing can relate visual deficits to an underlying neurological disorder.

Purpose:To study in vivo cone topography of the normal human foveola. Methods:The fovea in both eyes of 30 healthy participants was imaged with adaptive optics scanning light ophthalmoscopy. High-resolution image montages spanning two degrees of visual angle were created and cone center locations annotated. Continuous cone density maps were computed by a Voronoi cell area approach to also yield the topographical center, the cone density centroid (CDC). Cone density profiles were extracted and fit with a four-parameter decay function, D = D0 / (1 + (E/a)b)c, with D as cone density (cones/mm2), D0 as cone density at the CDC, and E as eccentricity (µm). Results:Across eyes, D0 was 175,474 ± 20,543 cones/mm2, on average (range 136,001-216,209 cones/mm2). Density dropped anisotropically along the meridians, shallower horizontally, with average best fit parameters (a, b, c) of 61.95, 2.469, 0.268 for horizontal, and 59.11, 2.012, 0.357, for vertical profiles, respectively. In radially averaged profiles, cone density reached 50% of D0 at 151 ± 17 µm eccentricity (range 128-193 µm). Temporal cone density was slightly higher than nasal. Most topographical metrics were highly correlated between fellow eyes. Conclusions:Despite a 1.6-fold range in absolute cone density, foveolar density profiles could be well described by a sigmoidal decay function across all eyes. This established a normative cone density profile of the healthy foveola. It allowed cone density estimation in cases of only partially available data, which alleviates resolution demands for future studies and renders possible retrospective analyses of foveolar cone topography in sub-optimal imagery.

RationalePeak velocities of saccadic eye movements are reduced after benzodiazepine administration. Even though this is an established effect, past research has only examined it in horizontal prosaccade tasks.ObjectivesThe spectrum of saccadic eye movements, however, is much larger. Therefore, we aimed to make a first attempt at filling this research gap by testing benzodiazepine effects on saccades under different experimental task conditions.Methods1 mg lorazepam or placebo was administered (within-subjects, double-blind, in randomised order) to n = 30 healthy adults. Participants performed an extended version of the prosaccade task, including vertical saccade directions and different stimulus eccentricities, as well as a free viewing task.ResultsResults from the prosaccade task confirmed established effects of benzodiazepines as well as saccade direction on saccadic parameters but additionally showed that the drug effect on peak velocity was independent of saccade direction. Remarkably, in the free viewing task peak velocities as well as other saccade parameters were unaffected by lorazepam. Furthermore, exploration patterns during free viewing did not change under lorazepam.ConclusionsOverall, our findings further consolidate the peak velocity of prosaccades as a biomarker of sedation. Additionally, we suggest that sedative effects of low doses of benzodiazepines may be compensated in tasks that more closely resemble natural eye movement behaviour, possibly due to the lack of time constraints or via neurophysiological processes related to volition.

Objective: Lesions characterized as complete retinal pigment epithelium and outer retinal atrophy (cRORA) are linked to the progression of intermediate age-related macular degeneration (iAMD). However, the extent of functional impairment of such precursor lesions remains uncertain. Methods: In this cross-sectional study, 4 participants (mean age ± standard deviation: 71.5 ± 2.1 years) underwent extensive multimodal imaging and psychophysical testing of cRORA lesions secondary to iAMD. Lesion-specific functional testing was performed using patient individualized testing grids with clinical conventional available (Stimulus size: 0.43°, ~125 µm) and experimental adaptive optics scanning light ophthalmoscope (AOSLO, stimulus size 0.07°, ~20 µm) based microperimetry (MP). One cRORA lesion site and one in-eye control region were tested per patient, respectively. Results: AOSLO imaging revealed an overall decrease in photoreceptor reflectivity, areas of hyporeflectivity over drusen, interspersed with hyperreflective foci, and disrupted photoreceptor mosaic in regions of cRORA. Localized retinal sensitivity assessment with clinical conventional MP yielded an average loss of −14.0 ± 3.3 dB at cRORA lesions compared to the in-eye control regions. In contrast, localized visual impairment assessed by high-resolution AOSLO-MP with smaller test stimuli (20 µm) revealed a sensitivity loss of −15.1 ± 5.1 dB at cRORA lesions (p < 0.01). Notably, also the area surrounding cRORA lesions can be impacted. Conclusions: We demonstrated that cRORA lesions are associated with severe localized functional impairment. cRORA precursor lesions may thus be considered as a surrogate outcome measure in future interventional iAMD trials.

Neural information processing requires accurately timed action potentials arriving from presynaptic neurons at the postsynaptic neuron. However, axons of ganglion cells in the human retina feature low axonal conduction speeds and vastly different lengths, which poses a challenge to the brain for constructing a temporally coherent image over the visual field. Combining results from microelectrode array recordings, human behavioral measurements, transmission electron microscopy, and mathematical modelling of the retinal nerve fiber layer, we demonstrate that axonal propagation speeds compensate for variations in axonal length across the human retina including the fovea. The human brain synchronizes the arrival times of action potentials at the optic disc by increasing the diameters of longer axons, which increases their propagation speeds. ### Competing Interest Statement The authors have declared no competing interest.

Lesions of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) are associated with disease progression in age-related macular degeneration. However, the corresponding functional impact of these precursor lesions is unknown.We present a cross-sectional study of four patients employing clinical-grade MAIA (stimulus size: 0.43°, ~125 µm) and adaptive optics scanning light ophthalmoscope (AOSLO, stimulus size 0.07°, ~20 µm) based microperimetry (MP) to assess the specific impact of iRORA lesions on retinal sensitivity.AOSLO imaging showed overall reduced photoreceptor reflectivity and patches of hyporeflective regions at drusen with interspersed hyper-reflective foci in iRORA regions. MAIA-MP yielded an average retinal sensitivity loss of -7.3±3.1 dB at iRORA lesions compared with the in-eye control. With AOSLO-MP, the corresponding sensitivity loss was 20.1±4.8 dB.We demonstrated that iRORA lesions are associated with a severe impairment in retinal sensitivity. Larger cohort studies will be necessary to validate our findings.