Enhanced S-cone Syndrome, a Mini-review.

Enhanced S-cone Syndrome (ESCS) is an autosomal recessive inherited retinal disease mostly associated with disease-causing variants in the NR2E3 gene. During retinal development in ESCS, rod photoreceptor precursors are misdirected to form photoreceptors similar to short-wavelength cones, or S-cones. Compared to a normal human retina, patients with ESCS have no rods and significantly increased numbers of S-cones. Night blindness is the main visual symptom, and visual acuity and color vision can be normal at early disease stages. Histology of donor eyes and adaptive optics imaging revealed increased S-cone density outside of the fovea compared to normal. Visual function testing reveals absent rod function and abnormally enhanced sensitivity to short-wavelength light. Unlike most retinal degenerative diseases, ESCS results in a gain in S-cone photoreceptor function. Research involving ESCS could improve understanding of this rare retinal condition and also shed light on the role of NR2E3 expression in photoreceptor survival.

Impact of cone abundancy ratios and light spectra on emmetropization in chickens.

We had previously found that chicken eyes with normal visual experience grow larger when they have more L cones, relative to M cones. It is not known whether also S cone abundancies may affect eye size, whether cone abundancy ratios can also affect the amount of deprivation myopia that is induced by diffusers in front of the eyes, and whether broadband white light with added energy in the blue may reduce the development of deprivation myopia. Therefore, chickens were monocularly treated with diffusers and raised under three different light conditions with increasing amounts of energy in the blue but with matched total illuminance. L, M and S cones were counted in fresh retinal tissues after the experiments. It was found that adding energy in the blue did not significantly inhibit deprivation myopia, nor did it make uncovered eyes more hyperopic. However, more S cones, relative to L cones, were correlated with more hyperopic refractions in eyes with normal vision. M to L, L to S and M to S cone ratios were also correlated with the amount of induced deprivation myopia. Interestingly, in deprivation myopia, the correlations between cone abundancy ratios with refractive states had reverted signs: eyes with more S cones developed more myopia. Since cone abundancy ratios remained correlated in both eyes, no matter whether eyes had normal vision, were deprived or were exposed to different light spectra, they appear genetically determined. We conclude that, among other factors, inherited cone abundancy ratios determine both normal refractive development and deprivation myopia in the chicken while adding more blue light to a broadband light spectrum had no effect.

Temporal color contrast guides emmetropization in chick.

As a result of longitudinal chromatic aberration (LCA), longer wavelengths are blurred when shorter wavelengths are in focus, and vice versa. As a result, LCA affects the color and temporal aspects of the retinal image with hyperopic defocus. In this experiment, we investigated how the sensitivity to temporal color contrast affects emmetropization. Ten-day-old chicks were exposed for three days to sinusoidal color modulation. The modulation was either blue/yellow flicker (BY) (n = 57) or red/green flicker (RG) (n = 60) simulating hyperopic defocus with and without a blue light component. The color contrasts tested were 0.1, 0.2, 0.3, 0.4, 0.6, and 0.8 Michelson contrast. The mean illuminance of all stimuli was 680 lux. Temporal modulation was either of a high (10 Hz) or low (0.2 Hz) temporal frequency. To test the role of short- and double-cone stimulation, an additional condition silenced these cones in RG_0.4 (D-) and was compared with RG_0.4 (D+) (n = 14). Changes in ocular components and refractive error were measured using Lenstar and a photorefractometer. With high temporal frequency BY representing an in-focus condition for shorter-wavelengths, we found that high temporal frequency BY contrast was positively correlated with vitreous expansion (R2 = 0.87, p < 0.01), expanding the vitreous to compensate for hyperopic defocus. This expansion was offset by low temporal frequency RG, which represented blurred longer wavelengths. The reduction in vitreous expansion in RG_0.4, was enhanced in D+ compared to D- (p < 0.001), indicating a role for short- and/or double-cones. With high temporal frequency RG representing an in-focus condition for longer-wavelengths, we found that high temporal frequency RG contrast was also positively correlated with a linear increase in vitreous chamber depth (R2 = 0.84, p < 0.01) and eye length (R2 = 0.30, p ≤ 0.05), required to compensate for hyperopic defocus, but also with RG sensitive choroidal thickening (R2 = 0.18: p < 0.0001). These increases in the vitreous and eye length were enhanced with D+ compared to D- (p = 0.003) showing the role of short- and double-cones in finessing the vitreous response to hyperopic defocus. Overall, the increase in vitreous chamber depth in RG was offset by reduced expansion in BY, indicating sensitivity to the shorter focal length of blue light and wavelength defocus. Predictable changes in cone contrast and temporal frequency of the retinal image that occur with LCA and defocus result in homeostatic control of emmetropization.

Signals for defocus arise from longitudinal chromatic aberration in chick.

Chicks respond to two signals from longitudinal chromatic aberration (LCA): a wavelength defocus signal and a chromatic signal. Wavelength defocus predicts reduced axial eye growth in monochromatic short-wavelength light, compared to monochromatic long-wavelength light. Wavelength defocus may also influence growth in broadband light. In contrast, a chromatic signal predicts increased growth when short-wavelength contrast > long-wavelength contrast, but only when light is broadband. We aimed to investigate the influence of blue light, temporal frequency and contrast on these signals under broadband conditions. Starting at 12 to 13 days-old, 587 chicks were exposed to the experimental illumination conditions for three days for 8h/day and spent the remainder of their day in the dark. The stimuli were flickering lights, with a temporal frequency of 0.2 or 10 Hz, low (30%) or high contrast (80%), and a variety of ratios of cone contrast simulating the effects of defocus with LCA. There were two color conditions, with blue contrast (bPlus) and without (bMinus). Stimuli in the "bPlus" condition varied the amounts of long- (L), middle- (M_) and double (D-) cone contrast, relative to short- (S-) and (UV-) cone contrast, to simulate defocus. Stimuli in the "bMinus" condition only varied the relative modulations of the L + D vs. M cones. In all cases, the average of the stimuli was white, with an illuminance of 777 lux, with cone contrast created through temporal modulation. A Lenstar LS 900 and a Hartinger refractometer were used to measure ocular components and refraction. Wavelength defocus signals with relatively high S-cone contrast resulted in reduced axial growth, and more hyperopic refractions, under low-frequency conditions (p = 0.002), in response to the myopic defocus of blue light. Chromatic signals with relatively high S-cone contrast resulted in increased axial growth and more myopic refractions, under high frequency, low contrast, conditions (p < 0.001). We conclude that the chromatic signals from LCA are dependent on the temporal frequency, phase, and relative contrast of S-cone temporal modulation, and recommend broadband spectral and temporal environments, such as the outdoor environment, to optimize the signals-for-defocus in chick.

Mitochondrial absorption of short wavelength light drives primate blue retinal cones into glycolysis which may increase their pace of aging.

Photoreceptors have high energy demands and densely packed mitochondria through which light passes before phototransduction. Old world primates including humans have three cone photoreceptor types mediating color vision with short (S blue), medium (M green), and long (L red) wavelength sensitivities. However, S-cones are enigmatic. They comprise <10% of the total cone population, their responses saturate early, and they are susceptible in aging and disease. Here, we show that primate S-cones actually have few mitochondria and are fueled by glycolysis, not by mitochondrial respiration. Glycolysis has a limited ability to sustain activity, potentially explaining early S-cone saturation. Mitochondria act as optical filters showing reduced light transmission at 400-450 nm where S-cones are most sensitive (420 nm). This absorbance is likely to arise in a mitochondrial porphyrin that absorbs strongly in the Soret band. Hence, reducing mitochondria will improve S-cone sensitivity but result in increased glycolysis as an alternative energy source, potentially increasing diabetic vulnerability due to restricted glucose access. Further, glycolysis carries a price resulting in premature functional decline as seen in aged S-cones. Soret band absorption may also impact on mitochondrial rich M and L cones by reducing sensitivity at the lower end of their spectral sensitivity range resulting in increased differentiation from S-cone responses. These data add to the list of unique characteristic of S-cones and may also explain aspects of their vulnerability.

Laser-induced ocular hypertension in adult rats does not affect non-RGC neurons in the ganglion cell layer but results in protracted severe loss of cone-photoreceptors.

To investigate the long-term effects of laser-photocoagulation (LP)-induced ocular hypertension (OHT) in the innermost and outermost (outer-nuclear and outer segment)-retinal layers (ORL). OHT was induced in the left eye of adult rats. To investigate the ganglion cell layer (GCL) wholemounts were examined at 1, 3 or 6 months using Brn3a-immunodetection to identify retinal ganglion cells (RGCs) and DAPI-staining to detect all nuclei in this layer. To study the effects of LP on the ORL up to 6 months, retinas were: i) fresh extracted to quantify the levels of rod-, S- and L-opsin; ii) cut in cross-sections for morphometric analysis, or; iii) prepared as wholemounts to quantify and study retinal distributions of entire populations of RGCs (retrogradely labeled with fluorogold, FG), S- and L-cones (immunolabeled). OHT resulted in wedge-like sectors with their apex on the optic disc devoid of Brn3a(+)RGCs but with large numbers of DAPI(+)nuclei. The levels of all opsins diminished by 2 weeks and further decreased to 20% of basal-levels by 3 months. Cross-sections revealed focal areas of ORL degeneration. RGC survival at 15 days represented approximately 28% and did not change with time, whereas the S- and L-cone populations diminished to 65% and 80%, or to 20 and 35% at 1 or 6 months, respectively. In conclusion, LP induces in the GCL selective RGCs loss that does not progress after 1 month, and S- and L-cone loss that progresses for up to 6 months. Thus, OHT results in severe damage to both the innermost and the ORL.

Low luminance contrast's effect on the color appearance of S-cone patterns.

There is a surprisingly strong effect on color appearance when low levels of luminance contrast are added to visual targets in which only S-cones are modulated. This phenomenon can be studied with checkerboard patterns composed of alternating S-cone-modulated checks and gray checks. + S checks look purple when surrounded by slightly brighter gray checks but look highly desaturated (lavender, almost white) when surrounded by darker gray checks. -S checks change in hue with luminance contrast; they look yellow when surrounded by darker gray checks but are greener when surrounded by lighter checks. Psychophysical paired comparisons confirm these perceptions. Furthermore, visual evoked potentials (VEPs) recorded from human posterior cortex indicate that signals evoked by low luminance contrast interact nonlinearly with S-cone-evoked signals in early cortical color processing. Our new psychophysics and electrophysiology results prove that human perception of color appearance is not based on neural computations within a separate, isolated color system. Rather, signals evoked by color contrast and luminance contrast interact to produce the colors we see.

Mechanisms of the dimming and brightening aftereffects.

Dimming and brightening aftereffects occur after exposure to a temporal luminance sawtooth stimulus: A subsequently presented steady test field appears to become progressively dimmer or brighter, depending on the polarity of the adapting sawtooth. Although described as "dimming" and "brightening," it is plausible that a component of the aftereffects is based on contrast changes rather than on luminance changes. We conducted two experiments to reveal any contrast component. In the first we investigated whether the aftereffects result from the same mechanism that causes a polarity-selective loss in contrast sensitivity following luminance sawtooth adaptation. We manipulated test contrast: If a component of the aftereffect results from a polarity selective loss of contrast sensitivity we would expect that the aftereffects would differ in magnitude depending on the contrast polarity of the test fields. We found no effect of test-field polarity. In the second experiment we used an adapting sawtooth with a polarity consistent in contrast but alternating in luminance in order to induce a potential equivalent aftereffect of contrast. Again, we found no evidence that the aftereffects result from contrast adaptation. In a third experiment, we used S-cone isolating stimuli to discover whether there are S-cone dimming and brightening aftereffects. We found no aftereffects. However, in a fourth experiment we replicated Krauskopf and Zaidi's (1986) finding that adaptation to S-cone sawtooth stimuli affects thresholds for increment and decrement detection. The mechanism underlying the dimming and brightening aftereffects thus seems to be independent of the mechanism underlying the concurrent polarity selective reductions in contrast sensitivity.

Neuronal Responses to Short Wavelength Light Deficiency in the Rat Subcortical Visual System.

The amount and spectral composition of light changes considerably during the day, with dawn and dusk being the most crucial moments when light is within the mesopic range and short wavelength enriched. It was recently shown that animals use both cues to adjust their internal circadian clock, thereby their behavior and physiology, with the solar cycle. The role of blue light in circadian processes and neuronal responses is well established, however, an unanswered question remains: how do changes in the spectral composition of light (short wavelengths blocking) influence neuronal activity? In this study we addressed this question by performing electrophysiological recordings in image (dorsal lateral geniculate nucleus; dLGN) and non-image (the olivary pretectal nucleus; OPN, the suprachiasmatic nucleus; SCN) visual structures to determine neuronal responses to spectrally varied light stimuli. We found that removing short-wavelength from the polychromatic light (cut off at 525 nm) attenuates the most transient ON and sustained cells in the dLGN and OPN, respectively. Moreover, we compared the ability of different types of sustained OPN neurons (either changing or not their response profile to filtered polychromatic light) to irradiance coding, and show that both groups achieve it with equal efficacy. On the other hand, even very dim monochromatic UV light (360 nm; log 9.95 photons/cm2/s) evokes neuronal responses in the dLGN and SCN. To our knowledge, this is the first electrophysiological experiment supporting previous behavioral findings showing visual and circadian functions disruptions under short wavelength blocking environment. The current results confirm that neuronal activity in response to polychromatic light in retinorecipient structures is affected by removing short wavelengths, however, with type and structure - specific action. Moreover, they show that rats are sensitive to even very dim UV light.

The Psychophysical Assessment of Hierarchical Magno-, Parvo- and Konio-Cellular Visual Stream Dysregulations in Migraineurs.

INTRODUCTION: Although conscious, image-forming illusions have been noted in migraine, few studies have specifically sought to collectively evaluate the role of all three parallel visual processing streams in the retinogeniculostriate pathway involved with image-forming vision and their implications in the development of migraine symptoms. METHODS: We psychophysically assessed the functionality of the inferred magnocellular (MC), parvocellular (PC), and koniocellular (KC) streams at different hierarchical loci across three clinical groups: individuals who experience migraine with aura (MA; n=13), experience migraine without aura (MWO; n=14), and Controls (n=15). Participants completed four experiments: Experiment 1 designed to assess retinal short-wavelength-sensitive (S-) cone sensitivities; Experiment 2 intended to measure postretinal temporal and spatiochromatic contrast sensitivities; Experiment 3 intended to assess postretinal spatiotemporal achromatic contrast sensitivities; and Experiment 4 designed to measure thalamocortical color discriminations along the three cone-excitation axes. RESULTS: S-cone deficits were revealed with greater retinal areas being affected in MA compared to MWO participants. Findings across the four experiments suggest a prominent retinal locus of dysfunction in MA (lesser in MWO) with potential feedforward compensations occurring within the KC visual stream. CONCLUSION: Complex, integrative network compensations need to be factored in when considering the dysregulating influences of migraine along the visual pathway.

Asymmetric high-contrast masking in S cone increment and decrement pathways.

Physiological, anatomical, and psychophysical evidence points to important differences between visual processing of short-wave cone increments and decrement (S+ and S-) stimuli. The present study uses the pedestal discrimination paradigm to investigate potential differences, using S+ and S- tests presented on (L)ong-wave, (M)edium-wave, S, L+M, L-M, and achromatic pedestals, of both contrast polarities. Results show that high contrast 'purplish' (S+ or -(L+M)) pedestals produce substantially more masking of both S+ and S- tests than 'yellowish' (S- or +(L+M)) pedestals do. The other pedestals produce no masking. These findings suggest greater nonlinearity - either a static nonlinearity or contrast gain control - in the mechanisms responsible for the 'purplish' polarity, likely the S ON pathway.

Immunohistochemical profile of long-standing traumatic retinal detachment in atrophic globe in a young patient.

Photoreceptor cell death is the ultimate cause of irreversible vision loss in retinal detachment (RD). The present study aimed to investigate the retinal changes in a case of long-standing traumatic RD in a young patient. The RD-induced atrophic globe was examined following enucleation. A control eye acquired from a deceased donor (normal histology; age- and sex-matched) was evaluated correspondingly. Frozen sections of retina tissue were assessed by immunofluorescence staining. The atrophic retina demonstrated structural disruption along with reduction in the retinal outer nuclear layer/inner nuclear layer thickness ratio. Photoreceptor degeneration was noted with complete loss of the outer segment of short-wavelength sensitive (S) cones. In addition, Müller cell hypertrophy was observed across the retinal nuclear layers. These results indicate that RD without successful medical treatment may lead to retinal atrophy associated with disruption of retinal integrity, dramatic S cones loss and subretinal gliosis. Further clarifications of the mechanisms underlying photoreceptor cell death and glial cell reprogramming may facilitate the design of novel therapeutic strategies for RD.

Size of the foveal blue scotoma related to the shape of the foveal pit but not to macular pigment.

When the eye is covered with a filter that transmits light below 480 nm and a blue field is observed on a computer screen that is modulated in brightness at about 1 Hz, the fovea is perceived as small irregular dark spot. It was proposed that the "foveal blue scotoma" results from the lack of S-cones in the foveal center. The foveal blue scotoma is highly variable among subjects. Possible factors responsible for the variability include differences in S-cone distribution, in foveal shape, and in macular pigment distribution. Nine young adult subjects were instructed to draw their foveal blue scotomas on a clear foil that was attached in front of the computer screen. The geometry of their foveal pit was measured in OCT images in two dimensions. Macular pigment distribution was measured in fundus camera images. Finally, blue scotomas were compared with Maxwell's spot which was visualized with a dichroic filter and is commonly assumed to reflect the macular pigment distribution. The diameters of the foveal blue scotomas varied from 15.8 to 76.4 arcmin in the right eyes and 15.5 to 84.7 arcmin in the left and were highly correlated in both eyes. It was found that the steeper the foveal slopes and the narrower the foveal pit, the larger the foveal blue scotoma. There was no correlation between foveal blue scotoma and macular pigment distribution or Maxwell's spot. The results are therefore in line with the assumption that the foveal blue scotoma is a consequence of the lack of S-cones in the foveal center. Unlike the foveal blue scotoma, Maxwell's spot is based on macular pigment as previously proposed.

Temporal Visual Mechanisms May Mediate Compensation for Macular Pigment.

Macular pigment (MP) is a pre-receptoral filter that is diet derived and deposited in relatively high optical density in the foveal region of the retina. Due to its yellow coloration, MP absorbs light of relatively short wavelengths, ranging from 400 nm to 520 nm. Despite the spectral and spatial nonuniformity imposed upon the sensory retina by MP, perception appears to be relatively uniform across the central visual field. MP therefore offers an opportunity to determine experimentally potential mechanisms responsible for mediating this uniformity. After assessing, in 14 subjects, MP's effects on the temporal sensitivity of both the short-wavelength- and middle-/long-wavelength-sensitive visual pathways, it appears that the visual system compensates for absorption of short-wavelength light by MP by slowing the sampling rate of short-wavelength cones and by increasing the processing speed of middle-/long-wavelength-sensitive cones. This mechanism could work via temporal summation or a temporal neural code, whereby slower response dynamics lead to amplification of relatively weak signals.

The role of the collicular pathway in the salience-based progression of visual attention.

Visual attention has been shown to progress from the most to the least salient item in a given scene. Cognitive and physiological models assume that this orienting of covert attention relies on the collicular pathway, involving the superior colliculus and the pulvinar. Recent studies questioned this statement as they described attentional capture by visual items invisible to the superior colliculus. Electrophysiological studies shown that there is no direct projections from short-wave receptors to the superior colliculus. S-cone stimuli can thus be employed to assess visual processing without the involvement of the collicular pathway. We have attempted to investigate whether this pathway is involved in the salience-based orientation of attention by presenting S-cone stimuli. Volunteers were asked to make a judgment regarding a target among two distractors (all items of unequal sizes). Items' location and size varied randomly, as well as color, randomly black or calibrated for each subject to activate exclusively S-cones. The hierarchical pattern testifying of the salience-based orientation of attention was only found with black stimuli, arguing in favor of an implication of the collicular pathway in salience. In a second experiment, one item was presented at a time in order to test the item-multiplicity effect by comparing experiments. Performance was the most penalized when presenting multiple stimuli in the black condition. Results were interpreted in terms of distinct modes of processing by the collicular and geniculate pathways. The establishment of salience that determines attentional progression appeared to be only possible when the collicular pathway was solicited.