Cone Plateau Research Articles

LOW-DOSE SUPPLEMENTATION WITH RETINOL IMPROVES RETINAL FUNCTION IN EYES WITH AGE-RELATED MACULAR DEGENERATION BUT WITHOUT RETICULAR PSEUDODRUSEN.

The aim of this study was to determine the functional impact of oral vitamin A supplementation in patients with intermediate age-related macular degeneration with and without reticular pseudodrusen (RPD) demonstrating dysfunction in dark adaptation. Five patients with intermediate age-related macular degeneration and without RPD (AMD group; mean ± SD age 78.0 ± 4.7 years) and seven with RPD (RPD group; age 74.1 ± 11.2 years) were supplemented with 16,000 IU of vitamin A palmitate for 8 weeks. Assessment at baseline, 4, 8, and 12 weeks included scotopic thresholds, dark adaptation, best-corrected and low luminance visual acuities, and the low-luminance quality of life questionnaire. In the linear mixed model, rod intercept time improved significantly in the AMD group (mean [95% CI] change -1.1 minutes [-1.8; -0.5] after 4 weeks ( P < 0.001) and -2.2 min [-2.9 to -1.6] after 8 weeks of vitamin A supplementation ( P < 0.001). The dark adaptation cone plateau also significantly improved (i.e., more sensitive cone threshold) at 4 and 8 weeks ( P = 0.026 and P = 0.001). No other parameters improved in the AMD group, and there was no significant improvement in any parameter in the RPD group despite significantly elevated serum vitamin A levels measurable in both groups after supplementation ( P = 0.024 and P = 0.013). Supplementation with 16,000 IU vitamin A, a lower dose than used in previous studies, partially overcomes the pathophysiologic functional changes in AMD eyes. The lack of improvement in the RPD group may indicate structural impediments to increasing vitamin A availability in these patients and/or may reflect the higher variability observed in the functional parameters for this group.

Evaluation of Cone- and Rod-Mediated Parameters in Dark Adaptation Testing as Outcome Measures in Age-Related Macular Degeneration

To investigate the suitability of 6 rod- or cone-mediated dark adaptation (DA) parameters as outcome measures for clinical trials in age-related macular degeneration (AMD), including their retest reliability, association with age and disease severity, and measurable longitudinal change over time. Prospective, longitudinal study (Clinicaltrials.gov: NCT01352975). A total of 191 patients with AMD and older participants followed longitudinally over 5 years. Dark adaptation testing was performed using the AdaptDx dark adaptometer with a maximum test time of 40 minutes. A 2-part exponential-linear curve was fitted to obtain values for cone decay, cone plateau, time to rod-cone break, rod intercept time (RIT), rod adaptation rate (S2), and area under the curve. Intersession retest reliability was assessed in tests performed within 2 weeks using the Bland-Altman analysis. The relationship of DA parameters with age, AMD severity, and reticular pseudodrusen (RPD) presence was evaluated using linear mixed models. Retest reliability, association with disease severity, and longitudinal change of 6 DA parameters. A total of 1329 DA curves were analyzed. Rod intercept time was the parameter that showed the greatest reliability (intraclass correlation coefficient of 0.88) and greatest association with age, AMD severity, and RPD (marginal R2 of 0.38), followed by the rod-mediated parameters area under the curve and rod-cone break. Cone plateau appeared constant at lower RIT values but increased with progressive rod dysfunction (RIT > 22.8 minutes) with a slope of 0.07 log units per 10 minutes RIT prolongation. Therefore, it might provide additional information in the advanced stages of AMD. Age-related macular degeneration severity and RPD presence are each associated with large differences in multiple DA curve parameters. In addition, substantial differences in some parameters occur with age, even accounting for AMD severity and RPD status. This supports the 2-hit hypothesis of age and disease status on DA (and perhaps AMD pathophysiology itself). Of the DA parameters, RIT has the highest retest reliability, closest correlation with AMD severity and RPD, and largest longitudinal changes. This underscores the suitability of RIT as an outcome measure in clinical trials. The cone plateau increases only in advanced stages of kinetic rod dysfunction, indicating rod dysfunction preceding cone dysfunction and degeneration in the temporal sequence of pathology in AMD.

Pyroclastic Density Current Facies in the Millennium Eruption of Tianchi Volcano, Northeast China: Insights From Topography, Stratigraphy, Granulometry, and Petrography

The 946 A.D. Millennium Eruption (ME) of Tianchi volcano produced masses of pyroclastic density current (PDC) deposits that cover an area that extends roughly 50 km from the crater. In order to understand PDC dynamic processes, this study examines the proximal to distal variations in the PDC facies by analysing the topography, stratigraphy, granulometry and petrography. Topography of Tianchi volcano has different slopes, including the cone (>6°), lava shield (2–5°) and lava plateau (20 km) are less than 10 m thick, with coarse-tail layers, ground surge layers, climbing layers, and carbonized woods in the plateau. The degree of PDC welding decreases with the distance from the crater. From the proximal to the distal strata, the emplacement temperature of the PDCs decreased from 740 °C to 280 °C. The medial layers indicate a gravitational differentiation effect and weakened transportation of the PDCs, which led to the formation of thick beds. The distal PDCs demonstrate fluidisation characteristics and a density far lower than those of the proximal and medial strata, which exhibit clear stratification. Grain size data (<64 mm) show that the median diameters decreases with increasing distance from the crater. Rhyolitic and trachytic pumice are found in the PDCs and are assumed to be associated with the composition of the magma chamber. Magmatic mixing structures were confirmed by microscope observations. The volume estimation of PDCs in China is 6.9806 km3. The PDCs exhibit characteristics of high temperatures, large volumes, flowing over long distances, and having the ability to climb hills. The PDCs were the most hazardous volcanic phenomena and can provide a reference for future potential PDC hazards around the Tianchi volcano.

DARK ADAPTATION IN MACULAR TELANGIECTASIA TYPE 2.

To evaluate dark adaptation (DA) in patients with macular telangiectasia Type 2 (MacTel). After a local photobleach (4 × 4° size, 83% bleach), DA was measured using a test stimulus (2° diameter) projected at 5° eccentricity horizontal from the foveal center within the temporal parafovea. Cone plateau, rod intercept time, and rod recovery rate (S2) were calculated from the resulting DA curves. Findings were correlated with disease stages (according to Gass and Blodi), the area of ellipsoid zone loss in optical coherence tomography, and macular pigment loss ("MP-Classes 1-3"). Fifty-nine eyes of 59 patients were compared with 18 eyes of 18 healthy controls. Dark adaptation was significantly impaired in patients with MacTel. Although differences were most pronounced for parameters indicating rod-mediated recovery, cone-mediated recovery was also decreased, yet to a lesser extent. Dark adaptation parameters were only weakly associated with disease stages and ellipsoid zone loss. A better association was found between rod-mediated recovery (S2 and rod intercept time) and macular pigment loss (Kendall's tau for rod intercept time: 0.69 and S2: -0.51; both P < 0.0001). Dark adaptation is significantly impaired in patients with MacTel. Our results indicate an association of reduced macular pigment and rod dysfunction in MacTel.

Automated Light- and Dark-Adapted Perimetry for Evaluating Retinitis Pigmentosa: Filling a Need to Accommodate Multicenter Clinical Trials.

The purpose of this study was to develop a convenient means to measure rod (and cone) function by automated perimetry in patients with inherited retinal degenerations (IRDs). A currently available automated perimeter was used to determine sensitivity (in decibels) to a blue target in the dark-adapted (DA) state and a white target in the light-adapted (LA) state. Normal subjects and IRD patients were evaluated with a full-threshold 71-locus strategy (the retinitis pigmentosa [RP] test) and a size III target. Comparisons were made with results from the more commonly used methods of two-color DA perimetry and middle/long-wavelength LA perimetry in the same patients. Rod function using the blue target and the RP test was determined for normal subjects by measuring DA sensitivities. If patients detected the blue stimulus in the DA state, it was determined whether the value was rod mediated by using normal data acquired during the cone plateau phase of dark adaptation. If rod mediated, rod sensitivity loss (RSL) was calculated and mapped across the visual field. Light-adapted sensitivities in normal subjects were also measured, permitting cone sensitivity losses (CSL) to be calculated for the patients. Multiple methods were used to compare RSL and CSL results with those from two-color DA perimetry and chromatic LA perimetry, and there was close correspondence between the methods. The unmodified automated static perimeter used in the DA and LA states presents a practical approach to accomplish current goals of treatment trials in IRDs. This proof-of-principle study is an initial step toward establishing a clinical method to gather reproducible data on photoreceptor-mediated sensitivity.

Spectral sensitivity measurements reveal partial success in restoring missing rod function with gene therapy

Rod visual function can be established with some certainty by demonstrating that dark-adapted visual spectral sensitivity has the shape of the rod (scotopic) spectral sensitivity function and that this scotopic shape collapses to a cone (photopic) shape when cones, but not rods, have recovered following an intense bleach. We used these tests to assess retinal function in eight young adult and child patients with early-onset severe retinal dystrophy enrolled in phase II of a clinical gene therapy trial for RPE65 deficiency, an isomerase, the lack of which disrupts the “visual cycle” upon which rods solely depend for regenerating visual pigment after light exposure. The trial involved subretinal delivery of a recombinant adeno-associated viral vector expressing RPE65. After gene therapy, substantial improvements in 1-Hz dark-adapted flicker sensitivity were found in two of the eight patients. One patient showed up to a 1000-fold improvement in sensitivity 4 months after treatment, and the second, up to a 100-fold improvement 6 months after treatment. In both cases, the spectral sensitivity after treatment was rod-like after normal periods of dark adaptation, but remained cone-like during the cone plateau after an intense bleach. The dark-adapted spectral sensitivities of the other six patients were cone-like both before and after treatment with only minimal sensitivity changes. It is not clear why restored rod function was evident in only some patients, but the response may be limited by the extent of retinal degeneration at the locus tested. Meeting abstract presented at VSS 2015

PSYCHOPHYSICAL MEASUREMENT OF ROD AND CONE THRESHOLDS IN STARGARDT DISEASE WITH FULL-FIELD STIMULI

To investigate psychophysical thresholds in Stargardt disease with the full-field stimulus test (FST). Visual acuity, spectral domain optical coherence tomography, full-field electroretinogram, and FST measurements were made in 1 eye of 24 patients with Stargardt disease. Dark-adapted rod FST thresholds were measured with short-wavelength stimuli, and cone FST thresholds were obtained from the cone plateau phase of dark adaptation using long-wavelength stimuli. Correlation coefficients were calculated for FST thresholds versus macular thickness, visual acuity, and electroretinogram amplitudes. The Stargardt disease patients' FST cone thresholds correlated significantly with visual acuity, macular thickness, and electroretinogram cone response amplitudes (all P < 0.01). The patients' FST rod thresholds correlated with electroretinogram rod response amplitudes (P < 0.01) but not macular thickness (P = 0.05). All patients with Stargardt disease with flecks confined to the macula, and most of the patients with flecks extending outside of the macula had normal FST thresholds. All patients with extramacular atrophic changes had elevated FST cone thresholds and most had elevated FST rod thresholds. Full-field stimulus test rod and cone threshold elevation in patients with Stargardt disease correlated well with measures of structure and function, as well as ophthalmoscopic retinal appearance. The Full-field stimulus test appears to be a useful tool for assessing rod and cone function in Stargardt disease.

Restoration of rod function following gene therapy in patients with mutations in the gene encoding the RPE65 protein required for recycling all-trans-retinal to 11-cis-retinal

Rod visual function can be confirmed unequivocally by demonstrating that visual performance measured as a function of wavelength has a rod spectral sensitivity. We have used this test to assess retinal function in some of the patients with early onset severe retinal dystrophy enrolled in an ongoing phase-I/II dose-escalation clinical trial of gene therapy for RPE65 deficiency. The therapy involves subretinal delivery of a recombinant adeno-associated viral vector expressing RPE65. The particular visual performance task used was the threshold detection of 1-Hz flicker following 40 minutes of dark adaptation. The flickering target was 3.55-deg in diameter presented 10-deg in the superior retina (close to the treatment site). We made spectral sensitivity measurements prior to gene therapy and then at 2-monthly intervals following gene therapy in the last five patients enrolled in the trial (to date). Prior to gene therapy, no clear evidence of rod function was found in the spectral sensitivity measurements. The flicker spectral sensitivity functions in all patients were cone-like and similar to those found during the cone plateau after an intense bleach. After gene therapy, however, substantial improvements in flicker sensitivity were found in the first two patients tested. One patient showed a 1000-fold improvement in dark-adapted flicker sensitivity at 500 nm, 4 months after treatment and the second a 100-fold improvement, 6 months after treatment. In both cases, the spectral sensitivity became clearly rod-like, indicative of restored rod function. To date, the other patients have not shown an improvement using this test. The trial is ongoing.

Unique hue loci differ with methodology

Studies investigating the effect of rods on unique hue loci in the peripheral retina generally obtain measures at two time points associated with the dark adaptation function - the cone plateau and the rod plateau. In comparison, this study used a color-naming procedure to identify the loci of unique green and unique yellow as a function of time associated with the entire dark adaptation function. The unique hue loci derived by this procedure were then compared to those obtained directly with a staircase procedure. Hue-scaling functions were obtained for monochromatic stimuli for four observers using the '4 + 1' procedure. Data were collected every 4 min following extinction of a bleaching stimulus. These hue-scaling functions were then converted to uniform appearance diagrams (UADs) to derive unique green and unique yellow loci. Unique green and unique yellow loci were also obtained from the same observers via a staircase procedure at 4-9 min post-bleach (minimal rod input) and after 28 min dark adaptation (maximal rod input). Measurements were made in the peripheral retina at 10° temporal retinal eccentricity and at the fovea. Unique green loci derived from UADs are at longer wavelengths compared to those measured directly with the staircase procedure. In addition, unique green loci derived from UADs show a progressive shift to longer wavelengths as time post-bleach increases; whereas, unique green loci obtained from the staircase procedure differ little between the rod-bleach and no-bleach conditions. Unique yellow loci are similar across both experimental procedures. Unique green loci derived from UADs are not the same as those measured with traditional psychophysical procedures. These differences may be due to the different response criteria used by observers in the color-naming and staircase procedures. The unique green loci obtained from UADs indicate that rod signals shift unique green loci to longer wavelengths as time post-bleach increases. More direct methods need to be employed to determine if this rod effect is valid.

Time course of rod influences on hue perception

Stimulation of dark-adapted rods can shift the hues associated with specific wavelengths throughout the spectrum: Rods exert a green bias (strengthen green relative to red) at longer wavelengths and a blue bias (strengthen blue relative to yellow) at short-to-middle wavelengths. A third rod influence at shorter wavelengths is more complicated because it has been shown to reverse direction with change of stimulus duration. Thus, for 30-ms stimuli, rods exert a green bias like that observed at longer wavelengths. However, for 1-s stimuli, rods exert a red bias that is observed nowhere else in the spectrum. We examined the latency (time course) of rod hue biases by measuring the shifts of the three spectral unique hues under dark-adapted versus bleached (cone plateau) conditions. The rod green bias at unique yellow (mean 10 nm) and, in contrast to some prior studies, the rod blue bias at unique green (mean 21 nm) were not systematically affected by test stimulus duration. A quick rod green bias (mean 5 nm) was shown at unique blue for two of three observers but was dominated by a slower rod red bias (mean 11 nm) after 30-50 ms of rod stimulation. These opposing rod influences may reflect competing effects of rod signals on ML-cone and S-cone pathways.

Effect of stimulus intensity on the sizes of chromatic perceptive fields

The effects of intensity on chromatic perceptive field size were investigated along the horizontal meridian at 10 degrees temporal eccentricity by manipulating stimulus intensity from 0.3 to 3.3 log trolands. Following light adaptation, observers described the hue and saturation of monochromatic stimuli (440-660 nm, in 10 nm steps) for a series of test sizes (0.098-3 degrees) presented along the time period associated with the cone plateau of the dark-adaptation function. Perceptive field sizes of the four elemental hues (red, green, yellow, and blue) and the saturation component were estimated by three observers at each intensity level for each wavelength. In general, perceptive field sizes of blue and red are the smallest, and yellow and green are the largest. Furthermore, perceptive field sizes of all four hues decrease with increasing stimulus intensity, though the absolute change is largest for green and yellow. The decrease in size with increase in intensity cannot be completely explained in terms of saturation or rod signals and is likely, then, attributable to a cone-based mechanism.

Measurements of chromatic sensitivity in the mesopic range

We measured chromatic threshold sensitivity in the mesopic range using a combination of techniques that mask the detection of photopic and scotopic luminance contrast signals. The measurements were carried out at a number of light levels in the range 45–0.004 cd/m2, both foveally and with the stimulus centered 3.5° in the periphery. In order to investigate the effect of rod signals on chromatic detection thresholds in the near periphery of the visual field, we measured chromatic threshold ellipses when fully dark-adapted and during the cone plateau region of the dark-adaptation curve. The results confirm a number of previous observations and reveal new findings: © 2000 John Wiley & Sons, Inc. Col Res Appl, 26, S36–S42, 2001

Rods affect S-cone discrimination on the Farnsworth–Munsell 100-hue test

Rod influence on hue discrimination was assessed by the Farnsworth–Munsell 100-hue test. Rod influence was taken as the difference in error scores obtained after complete dark adaptation and during the cone plateau at three mesopic (23, 9, 3 td) and one standard (158 td) light level. On the FM 100, rods produced a differential discrimination loss along a tritan axis as compared with a red–green axis without any bias toward a rod confusion axis. Rods appear to impair discrimination mediated by S-cone pathways, which at moderate levels of illumination can differentially elevate tritan errors on the FM 100.

Rod influence on hue-scaling functions

Rod influence on hue appearance of spectral lights was characterized by comparing the scaling of red, green, yellow, and blue hue sensations for an 8°-diameter, 7°-eccentric test spot under conditions that minimized (cone plateau) and maximized (dark adapted) rod influence at two mesopic light levels (1.5 and 3.0 log scoptic trolands). At the lower light level, the hue-scaling functions showed that rod signals influenced the spectral range and magnitude of all four primary hues. The rod influence could not be characterized as a ubiquitous augmentation or diminution of any hue over the entire spectrum. This constrains models of rod influence on color vision.

Unique hue judgments as a function of test size in the fovea and at 20-deg temporal eccentricity

Unique hue loci were measured for four observers in the fovea and at 20-deg temporal eccentricity as a function of test size. Eccentric measurements were made on the cone plateau following a rod bleach. The results indicate that unique yellow remains approximately invariant with respect to test size and retinal eccentricity, whereas unique blue and unique green shift to longer wavelengths with increasing test size. The locus of unique blue in the periphery reaches an asymptote at approximately the same wavelength as that from the foveal measurements, whereas unique green measured in the periphery is consistently at shorter wavelengths than in the fovea. In general, the data are best described by a model in which the short-wavelength-sensitive cone input to the two opponent-color channels decreases with decreasing test size and increasing retinal eccentricity.

Surface color naming in dichromats

In previous experiments, Montag and Boynton [(1987) Vision Research, 27, 2153–2162] found that many dichromats can categorize colors using color naming in fair agreement with color-normal subjects. The contribution of rods to color vision was suspected as underlying this ability. Here we follow up on these experiments by having dichromats name colors under various conditions. When the stimuli are limited to a brief presentation time (60 msec) the dichromats' categorization in the three dimensions of the OSA color space is impaired. Using high light levels so that the rods are saturated does not impair performance. The dichromats named colors during the period of the cone plateau following a rod bleach. Contrary to Montag and Boynton (1987) there was no deficit. These results suggest that an anomalous third cone pigment is responsible for the categorization in three dimensions. It is concluded that the receptors containing the anomalous pigment require greater temporal and spatial summation in order to contribute to the dichromats' color categorization.

Red–green color discrimination as a function of stimulus field size in peripheral vision

Red-green color-discrimination thresholds were measured at eccentricities of 10 and 25 deg in the nasal retina. Thresholds were measured as a function of stimulus field size both during the cone plateau and after dark adaptation. During the cone plateau, threshold decreased with increasing field size, but the effect of field size was dependent on the color of the test stimulus. The decrease in threshold was greater for yellow and orange test stimuli than for red and green tests. Two factors, summation and opponent-mechanism adaptation, appear to affect the relation between threshold and field size. An equation suggested by Boynton and Kambe in 1980 [Color Res. Appl. 5, 13 (1980)] provides a good description of the variation in thresholds with field size and eccentricity. After dark adaptation, thresholds increased for all test colors, suggesting that rod signals reduce discrimination. The dark-adapted thresholds could be described well by the addition of a rod term to the Boynton-Kambe equation.

Effect of yellow-tinted lenses on brightness

Magnitude estimates of brightness were obtained for small (5-deg diameter) and large (15 deg X 20 deg) targets viewed through yellow-tinted lenses (ytl's) and luminance-matched neutral lenses. The results indicate that brightness perception with ytl's is up to 40% greater than that with neutral lenses when the spatial extent of the stimulus exceeds the fovea. The onset of the enhancement effect is coincident with the chromatic threshold, and its end point is coincident with psychophysical estimates of rod saturation. In a second experiment, brightness estimates were obtained for the ytl's and neutral lenses during the cone plateau of the dark adaptation curve when rods, but not cones, were desensitized by bleach. The brightness-enhancement effect was negligible. These results confirm the subjective impression that brightness perception is enhanced by ytl's and indicate that this effect is mediated, in large part, by the contribution of rod signals to the chromatic pathway.

Rod and cone system contributions to oscillatory potentials: An explanation for the conditioning flash effect

The oscillatory potentials (OPs) of the human electroretinogram (ERG) are smaller in response to the initial flash of a series than to subsequent flashes. To investigate a possible rod system contribution to this “conditioning flash effect,” we have examined OPs in normals and rod monochromats. The OPs recorded from rod monochromats were similar to those recorded from normals under test conditions that selectively stimulate rods. However, under conditions that in normals stimulate both rods and cones and that result in maximal amplitude of the OPs, the rod monochromats exhibit markedly reduced OPs. This finding suggests that the initial (conditioning) flash operates by adapting the rod system contribution to the OPs, so that the OPs in response to subsequent flashes result primarily from the cone system. In agreement with this hypothesis, the conditioning flash effect did not occur when flashes were presented against a background which eliminated the rod system response nor during the cone plateau phase of dark adaptation.

Rod-cone interaction in the dark-adapted fovea.

The foveal cone threshold was significantly lower after 45 min of dark adaptation than it was near the start of the cone plateau of the dark-adaptation curve. A concentric rod background subsequently raised the threshold by an amount correlated wit the difference between the cone plateau and the dark-adapted thresholds. Paradoxically, the rod background also lowered the cone threshold by an amount that differed from subject to subject. This sensitizing effect was identifiable by its relatively small variability across sessions. These results show that adaptation of parafoveal rods by either real light or dark light can change foveal cone thresholds.