Contrast Sensitivity of ON and OFF Human Retinal Pathways in Myopia.

The human visual cortex processes light and dark stimuli with ON and OFF pathways that are differently modulated by luminance contrast. We have previously demonstrated that ON cortical pathways have higher contrast sensitivity than OFF cortical pathways and the difference increases with luminance range (defined as the maximum minus minimum luminance in the scene). Here, we demonstrate that these ON-OFF cortical differences are already present in the human retina and that retinal responses measured with electroretinography are more affected by reductions in luminance range than cortical responses measured with electroencephalography. Moreover, we show that ON-OFF pathway differences measured with electroretinography become more pronounced in myopia, a visual disorder that elongates the eye and blurs vision at far distance. We find that, as the eye axial length increases across subjects, ON retinal pathways become less responsive, slower in response latency, less sensitive, and less effective and slower at driving pupil constriction. Based on these results, we conclude that myopia is associated with a deficit in ON pathway function that decreases the ability of the retina to process low contrast and regulate retinal illuminance in bright environments.

Luminance Contrast Shifts Dominance Balance between ON and OFF Pathways in Human Vision.

Human vision processes light and dark stimuli in visual scenes with separate ON and OFF neuronal pathways. In nature, stimuli lighter or darker than their local surround have different spatial properties and contrast distributions (Ratliff et al., 2010; Cooper and Norcia, 2015; Rahimi-Nasrabadi et al., 2021). Similarly, in human vision, we show that luminance contrast affects the perception of lights and darks differently. At high contrast, human subjects of both sexes locate dark stimuli faster and more accurately than light stimuli, which is consistent with a visual system dominated by the OFF pathway. However, at low contrast, they locate light stimuli faster and more accurately than dark stimuli, which is consistent with a visual system dominated by the ON pathway. Luminance contrast was strongly correlated with multiple ON/OFF dominance ratios estimated from light/dark ratios of performance errors, missed targets, or reaction times (RTs). All correlations could be demonstrated at multiple eccentricities of the central visual field with an ON-OFF perimetry test implemented in a head-mounted visual display. We conclude that high-contrast stimuli are processed faster and more accurately by OFF pathways than ON pathways. However, the OFF dominance shifts toward ON dominance when stimulus contrast decreases, as expected from the higher-contrast sensitivity of ON cortical pathways (Kremkow et al., 2014; Rahimi-Nasrabadi et al., 2021). The results highlight the importance of contrast polarity in visual field measurements and predict a loss of low-contrast vision in humans with ON pathway deficits, as demonstrated in animal models (Sarnaik et al., 2014).SIGNIFICANCE STATEMENT ON and OFF retino-thalamo-cortical pathways respond differently to luminance contrast. In both animal models and humans, low contrasts drive stronger responses from ON pathways, whereas high contrasts drive stronger responses from OFF pathways. We demonstrate that these ON-OFF pathway differences have a correlate in human vision. At low contrast, humans locate light targets faster and more accurately than dark targets but, as contrast increases, dark targets become more visible than light targets. We also demonstrate that contrast is strongly correlated with multiple light/dark ratios of visual performance in central vision. These results provide a link between neuronal physiology and human vision while emphasizing the importance of stimulus polarity in measurements of visual fields and contrast sensitivity.

Differences in visual stimulation between reading and walking and implications for myopia development.

Visual input plays an important role in the development of myopia (nearsightedness), a visual disorder that blurs vision at far distances. The risk of myopia progression increases with the time spent reading and decreases with outdoor activity for reasons that remain poorly understood. To investigate the stimulus parameters driving this disorder, we compared the visual input to the retina of humans performing two tasks associated with different risks of myopia progression, reading and walking. Human subjects performed the two tasks while wearing glasses with cameras and sensors that recorded visual scenes and visuomotor activity. When compared with walking, reading black text in white background reduced spatiotemporal contrast in central vision and increased it in peripheral vision, leading to a pronounced reduction in the ratio of central/peripheral strength of visual stimulation. It also made the luminance distribution heavily skewed toward negative dark contrast in central vision and positive light contrast in peripheral vision, decreasing the central/peripheral stimulation ratio of ON visual pathways. It also decreased fixation distance, blink rate, pupil size, and head-eye coordination reflexes dominated by ON pathways. Taken together with previous work, these results support the hypothesis that reading drives myopia progression by understimulating ON visual pathways.

Principles underlying sensory map topography in primary visual cortex.

The primary visual cortex contains a detailed map of the visual scene, which is represented according to multiple stimulus dimensions including spatial location, ocular dominance and stimulus orientation. The maps for spatial location and ocular dominance arise from the spatial arrangement of thalamic afferent axons in the cortex. However, the origins of the other maps remain unclear. Here we show that the cortical maps for orientation, direction and retinal disparity in the cat (Felis catus) are all strongly related to the organization of the map for spatial location of light (ON) and dark (OFF) stimuli, an organization that we show is OFF-dominated, OFF-centric and runs orthogonal to ocular dominance columns. Because this ON-OFF organization originates from the clustering of ON and OFF thalamic afferents in the visual cortex, we conclude that all main features of visual cortical topography, including orientation, direction and retinal disparity, follow a common organizing principle that arranges thalamic axons with similar retinotopy and ON-OFF polarity in neighbouring cortical regions.

Diversity of Ocular Dominance Patterns in Visual Cortex Originates from Variations in Local Cortical Retinotopy.

The primary visual cortex contains a detailed map of retinal stimulus position (retinotopic map) and eye input (ocular dominance map) that results from the precise arrangement of thalamic afferents during cortical development. For reasons that remain unclear, the patterns of ocular dominance are very diverse across species and can take the shape of highly organized stripes, convoluted beads, or no pattern at all. Here, we use a new image-processing algorithm to measure ocular dominance patterns more accurately than in the past. We use these measurements to demonstrate that ocular dominance maps follow a common organizing principle that makes the cortical axis with the slowest retinotopic gradient orthogonal to the ocular dominance stripes. We demonstrate this relation in multiple regions of the primary visual cortex from individual animals, and different species. Moreover, consistent with the increase in the retinotopic gradient with visual eccentricity, we demonstrate a strong correlation between eccentricity and ocular dominance stripe width. We also show that an eye/polarity grid emerges within the visual cortical map when the representation of light and dark stimuli segregates along an axis orthogonal to the ocular dominance stripes, as recently demonstrated in cats. Based on these results, we propose a developmental model of visual cortical topography that sorts thalamic afferents by eye input and stimulus polarity, and then maximizes the binocular retinotopic match needed for depth perception and the light-dark retinotopic mismatch needed to process stimulus orientation. In this model, the different ocular dominance patterns simply emerge from differences in local retinotopic cortical topography.SIGNIFICANCE STATEMENT Thalamocortical afferents segregate in primary visual cortex by eye input and light-dark polarity. This afferent segregation forms cortical patterns that vary greatly across species for reasons that remain unknown. Here we show that the formation of ocular dominance patterns follows a common organizing principle across species that aligns the cortical axis of ocular dominance segregation with the axis of slowest retinotopic gradient. Based on our results, we propose a model of visual cortical topography that sorts thalamic afferents by eye input and stimulus polarity along orthogonal axes with the slowest and fastest retinotopic gradients, respectively. This organization maximizes the binocular retinotopic match needed for depth perception and the light-dark retinotopic mismatch needed to process stimulus orientation in carnivores and primates.

Amblyopia Affects the ON Visual Pathway More than the OFF.

Visual information reaches the cerebral cortex through parallel ON and OFF pathways that signal the presence of light and dark stimuli in visual scenes. We have previously demonstrated that optical blur reduces visual salience more for light than dark stimuli because it removes the high spatial frequencies from the stimulus, and low spatial frequencies drive weaker ON than OFF cortical responses. Therefore, we hypothesized that sustained optical blur during brain development should weaken ON cortical pathways more than OFF, increasing the dominance of darks in visual perception. Here we provide support for this hypothesis in humans with anisometropic amblyopia who suffered sustained optical blur early after birth in one of the eyes. In addition, we show that the dark dominance in visual perception also increases in strabismic amblyopes that have their vision to high spatial frequencies reduced by mechanisms not associated with optical blur. Together, we show that amblyopia increases visual dark dominance by 3-10 times and that the increase in dark dominance is strongly correlated with amblyopia severity. These results can be replicated with a computational model that uses greater luminance/response saturation in ON than OFF pathways and, as a consequence, reduces more ON than OFF cortical responses to stimuli with low spatial frequencies. We conclude that amblyopia affects the ON cortical pathway more than the OFF, a finding that could have implications for future amblyopia treatments.SIGNIFICANCE STATEMENT Amblyopia is a loss of vision that affects 2-5% of children across the world and originates from a deficit in visual cortical circuitry. Current models assume that amblyopia affects similarly ON and OFF visual pathways, which signal light and dark features in visual scenes. Against this current belief, here we demonstrate that amblyopia affects the ON visual pathway more than the OFF, a finding that could have implications for new amblyopia treatments targeted at strengthening a weak ON visual pathway.

Cortical Balance Between ON and OFF Visual Responses Is Modulated by the Spatial Properties of the Visual Stimulus.

The primary visual cortex of carnivores and primates is dominated by the OFF visual pathway and responds more strongly to dark than light stimuli. Here, we demonstrate that this cortical OFF dominance is modulated by the size and spatial frequency of the stimulus in awake primates and we uncover a main neuronal mechanism underlying this modulation. We show that large grating patterns with low spatial frequencies drive five times more OFF-dominated than ON-dominated neurons, but this pronounced cortical OFF dominance is strongly reduced when the grating size decreases and the spatial frequency increases, as when the stimulus moves away from the observer. We demonstrate that the reduction in cortical OFF dominance is not caused by a selective reduction of visual responses in OFF-dominated neurons but by a change in the ON/OFF response balance of neurons with diverse receptive field properties that can be ON or OFF dominated, simple, or complex. We conclude that cortical OFF dominance is continuously adjusted by a neuronal mechanism that modulates ON/OFF response balance in multiple cortical neurons when the spatial properties of the visual stimulus change with viewing distance and/or optical blur.

Neuronal nonlinearity explains greater visual spatial resolution for darks than lights.

Astronomers and physicists noticed centuries ago that visual spatial resolution is higher for dark than light stimuli, but the neuronal mechanisms for this perceptual asymmetry remain unknown. Here we demonstrate that the asymmetry is caused by a neuronal nonlinearity in the early visual pathway. We show that neurons driven by darks (OFF neurons) increase their responses roughly linearly with luminance decrements, independent of the background luminance. However, neurons driven by lights (ON neurons) saturate their responses with small increases in luminance and need bright backgrounds to approach the linearity of OFF neurons. We show that, as a consequence of this difference in linearity, receptive fields are larger in ON than OFF thalamic neurons, and cortical neurons are more strongly driven by darks than lights at low spatial frequencies. This ON/OFF asymmetry in linearity could be demonstrated in the visual cortex of cats, monkeys, and humans and in the cat visual thalamus. Furthermore, in the cat visual thalamus, we show that the neuronal nonlinearity is present at the ON receptive field center of ON-center neurons and ON receptive field surround of OFF-center neurons, suggesting an origin at the level of the photoreceptor. These results demonstrate a fundamental difference in visual processing between ON and OFF channels and reveal a competitive advantage for OFF neurons over ON neurons at low spatial frequencies, which could be important during cortical development when retinal images are blurred by immature optics in infant eyes.

Neuronal mechanisms underlying differences in spatial resolution between darks and lights in human vision.

Artists and astronomers noticed centuries ago that humans perceive dark features in an image differently from light ones; however, the neuronal mechanisms underlying these dark/light asymmetries remained unknown. Based on computational modeling of neuronal responses, we have previously proposed that such perceptual dark/light asymmetries originate from a luminance/response saturation within the ON retinal pathway. Consistent with this prediction, here we show that stimulus conditions that increase ON luminance/response saturation (e.g., dark backgrounds) or its effect on light stimuli (e.g., optical blur) impair the perceptual discrimination and salience of light targets more than dark targets in human vision. We also show that, in cat visual cortex, the magnitude of the ON luminance/response saturation remains relatively constant under a wide range of luminance conditions that are common indoors, and only shifts away from the lowest luminance contrasts under low mesopic light. Finally, we show that the ON luminance/response saturation affects visual salience mostly when the high spatial frequencies of the image are reduced by poor illumination or optical blur. Because both low luminance and optical blur are risk factors in myopia, our results suggest a possible neuronal mechanism linking myopia progression with the function of the ON visual pathway.

The role of thalamic population synchrony in the emergence of cortical feature selectivity.

In a wide range of studies, the emergence of orientation selectivity in primary visual cortex has been attributed to a complex interaction between feed-forward thalamic input and inhibitory mechanisms at the level of cortex. Although it is well known that layer 4 cortical neurons are highly sensitive to the timing of thalamic inputs, the role of the stimulus-driven timing of thalamic inputs in cortical orientation selectivity is not well understood. Here we show that the synchronization of thalamic firing contributes directly to the orientation tuned responses of primary visual cortex in a way that optimizes the stimulus information per cortical spike. From the recorded responses of geniculate X-cells in the anesthetized cat, we synthesized thalamic sub-populations that would likely serve as the synaptic input to a common layer 4 cortical neuron based on anatomical constraints. We used this synchronized input as the driving input to an integrate-and-fire model of cortical responses and demonstrated that the tuning properties match closely to those measured in primary visual cortex. By modulating the overall level of synchronization at the preferred orientation, we show that efficiency of information transmission in the cortex is maximized for levels of synchronization which match those reported in thalamic recordings in response to naturalistic stimuli, a property which is relatively invariant to the orientation tuning width. These findings indicate evidence for a more prominent role of the feed-forward thalamic input in cortical feature selectivity based on thalamic synchronization.