Formulae for generating standard and individual human cone spectral sensitivities.

Normal color perception is complicated. But at its initial stage it is relatively simple, since at photopic levels it depends on the activations of just three photoreceptor types: the long- (L-), middle- (M-) and short- (S-) wavelength-sensitive cones. Knowledge of how each type responds to different wavelengths-the three cone spectral sensitivities-can be used to model human color vision and in practical applications to specify color and predict color matches. The CIE has sanctioned the cone spectral sensitivity estimates of Stockman and Sharpe (Stockman and Sharpe, 2000, Vision Res) and their associated measures of luminous efficiency as "physiologically-relevant" standards for color vision (CIE, 2006; 2015). These LMS cone spectral sensitivities are specified at 5- and 1-nm steps for mean "standard" observers with normal cone photopigments and average ocular transparencies, both of which can vary in the population. Here, we provide formulae for the three cone spectral sensitivities as well as for macular and lens pigment density spectra, all as continuous functions of wavelength from 360 to 850 nm. These functions reproduce the tabulated discrete CIE LMS cone spectral sensitivities for 2-deg and 10-deg with little error in both linear and logarithmic units. Furthermore, these formulae allow the easy computation of non-standard cone spectral sensitivities (and other color matching functions) with individual differences in macular, lens and photopigment optical densities, and with spectrally shifted hybrid or polymorphic L- and M-cone photopigments appropriate for either normal or red-green color vision deficient observers.

WFS1-Associated Optic Neuropathy: Genotype-Phenotype Correlations and Disease Progression.

OBJECTIVE: To evaluate the pattern of vision loss and genotype-phenotype correlations in WFS1-associated optic neuropathy (WON). DESIGN: Multicenter cohort study. METHODS: The study involved 37 patients with WON carrying pathogenic or candidate pathogenic WFS1 variants. Genetic and clinical data were retrieved from the medical records. Thirteen patients underwent additional comprehensive ophthalmologic assessment. Deep phenotyping involved visual electrophysiology and advanced psychophysical testing with a complementary metabolomic study. MAIN OUTCOME MEASURES: WFS1 variants, functional and structural optic nerve and retinal parameters, and metabolomic profile. RESULTS: Twenty-two recessive and 5 dominant WFS1 variants were identified. Four variants were novel. All WFS1 variants caused loss of macular retinal ganglion cells (RGCs) as assessed by optical coherence tomography (OCT) and visual electrophysiology. Advanced psychophysical testing indicated involvement of the major RGC subpopulations. Modeling of vision loss showed an accelerated rate of deterioration with increasing age. Dominant WFS1 variants were associated with abnormal reflectivity of the outer plexiform layer (OPL) on OCT imaging. The dominant variants tended to cause less severe vision loss compared with recessive WFS1 variants, which resulted in more variable phenotypes ranging from isolated WON to severe multisystem disease depending on the WFS1 alleles. The metabolomic profile included markers seen in other neurodegenerative diseases and type 1 diabetes mellitus. CONCLUSIONS: WFS1 variants result in heterogenous phenotypes influenced by the mode of inheritance and the disease-causing alleles. Biallelic WFS1 variants cause more variable, but generally more severe, vision and RGC loss compared with heterozygous variants. Abnormal cleftlike lamination of the OPL is a distinctive OCT feature that strongly points toward dominant WON.

A reinterpretation of critical flicker-frequency (CFF) data reveals key details about light adaptation and normal and abnormal visual processing.

Our ability to see flicker has an upper frequency limit above which flicker is invisible, known as the "critical flicker frequency" (CFF), that typically grows with light intensity (I). The relation between CFF and I, the focus of nearly 200 years of research, is roughly logarithmic, i.e., CFF âˆ log(I)-a relation called the Ferry-Porter law. However, why this law should occur, and how it relates to the underlying physiology, have never been adequately explained. Over the past two decades we have measured CFF in normal observers and in patients with retinal gene defects. Here, we reanalyse and model our data and historical CFF data. Remarkably, CFF-versus-I functions measured under a wide range of conditions in patients and in normal observers all have broadly similar shapes when plotted in double-logarithmic coordinates, i.e., log (CFF)-versus-log(I). Thus, the entire dataset can be characterised by horizontal and vertical logarithmic shifts of a fixed-shape template. Shape invariance can be predicted by a simple model of visual processing built from a sequence of low-pass filters, subtractive feedforward stages and gain adjustment (Rider, Henning & Stockman, 2019). It depends primarily on the numbers of visual processing stages that approach their power-law region at a given intensity and a frequency-independent gain reduction at higher light levels. Counter-intuitively, the CFF-versus-I relation depends primarily on the gain of the visual response rather than its speed-a conclusion that changes our understanding and interpretation of human flicker perception. The Ferry-Porter "law" is merely an approximation of the shape-invariant template.

Clinical vision and molecular loss: Integrating visual psychophysics with molecular genetics reveals key details of normal and abnormal visual processing.

Over the past two decades we have developed techniques and models to investigate the ways in which known molecular defects affect visual performance. Because molecular defects in retinal signalling invariably alter the speed of visual processing, our strategy has been to measure the resulting changes in flicker sensitivity. Flicker measurements provide not only straightforward clinical assessments of visual performance but also reveal fundamental details about the functioning of both abnormal and normal visual systems. Here, we bring together our past measurements of patients with pathogenic variants in the GNAT2, RGS9, GUCA1A, RPE65, OPA1, KCNV2 and NR2E3 genes and analyse the results using a standard model of visual processing. The model treats flicker sensitivity as the result of the actions of a sequence of simple processing steps, one or more of which is altered by the genetic defect. Our analyses show that most defects slow down the visual response directly, but some speed it up. Crucially, however, other steps in the processing sequence can make compensatory adjustments to offset the abnormality. For example, if the abnormal step slows down the visual response, another step is likely to speed up or attenuate the response to rebalance system performance. Such compensatory adjustments are probably made by steps in the sequence that usually adapt to changing light levels. Our techniques and modelling also allow us to tease apart stationary and progressive effects, and the localised molecular losses help us to unravel and characterise individual steps in the normal and abnormal processing sequences.

Light adaptation controls visual sensitivity by adjusting the speed and gain of the response to light.

The range of c. 1012 ambient light levels to which we can be exposed massively exceeds the <103 response range of neurons in the visual system, but we can see well in dim starlight and bright sunlight. This remarkable ability is achieved largely by a speeding up of the visual response as light levels increase, causing characteristic changes in our sensitivity to different rates of flicker. Here, we account for over 65 years of flicker-sensitivity measurements with an elegantly-simple, physiologically-relevant model built from first-order low-pass filters and subtractive inhibition. There are only two intensity-dependent model parameters: one adjusts the speed of the visual response by shortening the time constants of some of the filters in the direct cascade as well as those in the inhibitory stages; the other parameter adjusts the overall gain at higher light levels. After reviewing the physiological literature, we associate the variable gain and three of the variable-speed filters with biochemical processes in cone photoreceptors, and a further variable-speed filter with processes in ganglion cells. The variable-speed but fixed-strength subtractive inhibition is most likely associated with lateral connections in the retina. Additional fixed-speed filters may be more central. The model can explain the important characteristics of human flicker-sensitivity including the approximate dependences of low-frequency sensitivity on contrast (Weber's law) and of high-frequency sensitivity on amplitude ("high-frequency linearity"), the exponential loss of high-frequency sensitivity with increasing frequency, and the logarithmic increase in temporal acuity with light level (Ferry-Porter law). In the time-domain, the model can account for several characteristics of flash sensitivity including changes in contrast sensitivity with light level (de Vries-Rose and Weber's laws) and changes in temporal summation (Bloch's law). The new model provides fundamental insights into the workings of the visual system and gives a simple account of many visual phenomena.

A tour of contemporary color vision research.

The study of color vision encompasses many disciplines, including art, biochemistry, biophysics, brain imaging, cognitive neuroscience, color preferences, colorimetry, computer modelling, design, electrophysiology, language and cognition, molecular genetics, neuroscience, physiological optics, psychophysics and physiological optics. Coupled with the elusive nature of the subjective experience of color, this wide range of disciplines makes the study of color as challenging as it is fascinating. This overview of the special issue Color: Cone Opponency and Beyond outlines the state of the science of color, and points to some of the many questions that remain to be answered in this exciting field.

Delayed S-cone sensitivity losses following the onset of intense yellow backgrounds linked to the lifetime of a photobleaching product?

Thirty years ago, Mollon, Stockman, & Polden (1987) reported that after the onset of intense yellow 581-nm backgrounds, S-cone threshold rose unexpectedly for several seconds before recovering to the light-adapted steady-state value-an effect they called: "transient-tritanopia of the second kind" (TT2). Given that 581-nm lights have little direct effect on S-cones, TT2 must arise indirectly from the backgrounds' effects on the L- and M-cones. We attribute the phenomenon to the action of an unknown L- and M-cone photobleaching product, X, which acts at their outputs like an "equivalent" background light that then inhibits S-cones at a cone-opponent, second-site. The time-course of TT2 is similar in form to the lifetime of X in a two-stage, first-order biochemical reaction A→X→C with successive best-fitting time-constants of 3.09 ± 0.35 and 7.73 ± 0.70 s. Alternatively, with an additional slowly recovering exponential "restoring-force" with a best-fitting time-constant 23.94 ± 1.42 s, the two-stage best-fitting time-constants become 4.15 ± 0.62 and 6.79 ± 1.00 s. Because the time-constants are roughly independent of the background illumination, and thus the rate of photoisomerization, A→X is likely to be a reaction subsidiary to the retinoid cycle, perhaps acting as a buffer when the bleaching rate is too high. X seems to be logarithmically related to S-cone threshold, which may result from the logarithmic cone-opponent, second-site response compression after multiplicative first-site adaptation. The restoring-force may be the same cone-opponent force that sets the rate of S-cone recovery following the unusual threshold increase following the offset of dimmer yellow backgrounds, an effect known as "transient-tritanopia" (TT1).

Harmonics added to a flickering light can upset the balance between ON and OFF pathways to produce illusory colors.

The neural signals generated by the light-sensitive photoreceptors in the human eye are substantially processed and recoded in the retina before being transmitted to the brain via the optic nerve. A key aspect of this recoding is the splitting of the signals within the two major cone-driven visual pathways into distinct ON and OFF branches that transmit information about increases and decreases in the neural signal around its mean level. While this separation is clearly important physiologically, its effect on perception is unclear. We have developed a model of the ON and OFF pathways in early color processing. Using this model as a guide, we can produce imbalances in the ON and OFF pathways by changing the shapes of time-varying stimulus waveforms and thus make reliable and predictable alterations to the perceived average color of the stimulus-although the physical mean of the waveforms does not change. The key components in the model are the early half-wave rectifying synapses that split retinal photoreceptor outputs into the ON and OFF pathways and later sigmoidal nonlinearities in each pathway. The ability to systematically vary the waveforms to change a perceptual quality by changing the balance of signals between the ON and OFF visual pathways provides a powerful psychophysical tool for disentangling and investigating the neural workings of human vision.

Delayed cone-opponent signals in the luminance pathway.

Cone signals in the luminance or achromatic pathway were investigated by measuring how the perceptual timing of M- or L-cone-detected flicker depended on temporal frequency and chromatic adaptation. Relative timings were measured, as a function of temporal frequency, by superimposing M- or L-cone-isolating flicker on "equichromatic" flicker (flicker of the same wavelength as the background) and asking observers to vary contrast and phase to cancel the perception of flicker. Measurements were made in four observers on up to 35 different backgrounds varying in wavelength and radiance. Observers showed substantial perceptual delays or advances of L- and M-cone flicker that varied systematically with cone class, background wavelength, and radiance. Delays were largest for M-cone-isolating flicker. Although complex, the results can be characterised by a surprisingly simple model in which the representations of L- and M-cone flicker are comprised not only of a fast copy of the flicker signal, but also of a slow copy that is delayed by roughly 30 ms and varies in strength and sign with both background wavelength and radiance. The delays, which are too large to be due to selective cone adaptation by the chromatic backgrounds, must arise postreceptorally. Clear evidence for the slow signals can also be found in physiological measurements of horizontal and magnocellular ganglion cells, thus placing the origin of the slow signals in the retina-most likely in an extended horizontal cell network. Luminance-equated stimuli chosen to isolate chromatic channels may inadvertently generate slow signals in the luminance channel.

Linear-nonlinear models of the red-green chromatic pathway.

The mean hue of flickering waveforms comprising only the first two harmonics depends on their temporal alignment. We evaluate explanatory models of this hue-shift effect using previous data obtained using L- and M-cone-isolating stimuli together with chromatic sensitivity and hue discrimination data. The key questions concerned what type of nonlinearity produced the hue shifts, and where the nonlinearities lay with respect to the early band-pass and late low-pass temporal filters in the chromatic pathways. We developed two plausible models: (a) a slew-rate limited nonlinearity that follows both early and late filters, and (b) a half-wave rectifying nonlinearity-consistent with the splitting of the visual input into ON- and OFF-channels-that lies between the early and late filters followed by a compressive nonlinearity that lies after the late filter.

Hue shifts produced by temporal asymmetries in chromatic signals.

Observers viewed M- or L-cone-isolating stimuli and compared slowly-on and slowly-off sawtooth waveforms of the same mean chromaticity and luminance. Between 6 and 13 Hz, the mean hue of slowly-on L-cone and slowly-off M-cone sawtooth flicker appeared redder, and the mean hue of slowly-off L-cone and slowly-on M-cone sawtooth stimuli appeared greener-despite all the waveforms' having the same mean, near-yellow-appearing chromaticity. We measured the effect of the modulation depth and the slope of the sawtooth on the mean hue shifts as a function of temporal frequency. The results are complex but show that discriminability depended mainly on the second harmonic of the waveforms. We considered several models with combinations of linear and nonlinear stages. First, we considered models in which a nonlinear stage limits the rate of change of hue and restricts the steep slope of the sawtooth waveform more than its shallow slope, thus shifting the mean hue in the direction of the shallower slope (such a nonlinearity is also known as a slew-rate limit). Second, we considered saturation models in which the nonlinear stage compresses hue signals and thus shifts the mean of asymmetrical waveforms with or without differentiation before the nonlinearity. Overall, our modeling and results suggest that the hue shift occurs at some nonlinear mechanism in the chromatic pathway; and that, in terms of the Fourier components of the various waveforms, the effect of the nonlinearity depends crucially on the timing of the second harmonic relative to the first.

Hue shifts produced by temporal asymmetries in chromatic signals depend on the alignment of the first and second harmonics.

When M- or L-cone-isolating sawtooth waveforms flicker at frequencies between 4 and 13.3 Hz, there is a mean hue shift in the direction of the shallower sawtooth slope. Here, we investigate how this shift depends on the alignment of the first and second harmonics of sawtooth-like waveforms. Below 4 Hz, observers can follow hue variations caused by both harmonics, and reliably match reddish and greenish excursions. At higher frequencies, however, the hue variations appear as chromatic flicker superimposed on a steady light, the mean hue of which varies with second-harmonic alignment. Observers can match this mean hue against a variable-duty-cycle rectangular waveform and, separately, set the alignment at which the mean hue flips between reddish and greenish. The maximum hue shifts were approximately frequency independent and occurred when the peaks or troughs of the first and second harmonics roughly aligned at the visual input-consistent with the hue shift's being caused by an early instantaneous nonlinearity that saturates larger hue excursions. These predictions, however, ignore phase delays introduced within the chromatic pathway between its input and the nonlinearity that produces the hue shifts. If the nonlinearity follows the substantial filtering implied by the chromatic temporal contrast-sensitivity function, phase delays will alter the alignment of the first and second harmonics such that at the nonlinearity, the waveforms that produce the maximum hue shifts might well be those with the largest differences in rising and falling slopes-consistent with the hue shift's being caused by a central nonlinearity that limits the rate of hue change.

The Pattern of Retinal Ganglion Cell Loss in OPA1-Related Autosomal Dominant Optic Atrophy Inferred From Temporal, Spatial, and Chromatic Sensitivity Losses.

Purpose: Progressive retinal ganglion cell (RGC) loss is the pathological hallmark of autosomal dominant optic atrophy (DOA) caused by pathogenic OPA1 mutations. The aim of this study was to conduct an in-depth psychophysical study of the visual losses in DOA and to infer any selective vulnerability of visual pathways subserved by different RGC subtypes. Methods: We recruited 25 patients carrying pathogenic OPA1 mutations and age-matched healthy individuals. Spatial contrast sensitivity functions (SCSFs) and chromatic contrast sensitivity were quantified, the latter using the Cambridge Colour Test. In 11 patients, long (L) and short (S) wavelength-sensitive cone temporal acuities were measured as a function of target illuminance, and L-cone temporal contrast sensitivity (TCSF) as a function of temporal frequency. Results: Spatial contrast sensitivity functions were abnormal, with the loss of sensitivity increasing with spatial frequency. Further, the highest L-cone temporal acuity fell on average by 10 Hz and the TCSFs by 0.66 log10 unit. Chromatic thresholds along the protan, deutan, and tritan axes were 8, 9, and 14 times higher than normal, respectively, with losses increasing with age and S-cone temporal acuity showing the most significant age-related decline. Conclusions: Losses of midget parvocellular, parasol magnocellular, and bistratified koniocellular RGCs could account for the losses of high spatial frequency sensitivity and protan and deutan sensitivities, high temporal frequency sensitivity, and S-cone temporal and tritan sensitivities, respectively. The S-cone-related losses showed a significant deterioration with increasing patient age and could therefore prove useful biomarkers of disease progression in DOA.

Psychophysical measures of visual function and everyday perceptual experience in a case of congenital stationary night blindness.

An appreciation of the relation between laboratory measures of visual deficit and everyday perceptual experience is fundamental to understanding the impact of a visual condition on patients and so to a fuller characterization of the disorder. This study aims to understand better the interpretative processes by which modified sensory information is perceived by a patient with congenital stationary night blindness and the adaptive strategies that are devised to deal with their measurable visual loss. Psychophysical measurements of temporal resolution, spectral sensitivity, and color discrimination were conducted on a 78-year-old male patient with the condition, who was also interviewed at length about the ways in which his diagnosis affected his daily life. Narrative analysis was employed to identify the relation between his subjective perceptual experiences and functional deficits in identifiable components of the visual system. Psychophysical measurements indicated a complete lack of rod perception and substantially reduced cone sensitivity. Two particular effects of this visual loss emerged during interviews: 1) the development of navigational techniques that relied on light reflections and point sources of light and 2) a reluctance to disclose the extent of visual loss and resulting lifelong psychosocial consequences. This study demonstrates the valuable complementary role that rich descriptive patient testimony can play, in conjunction with laboratory and clinical measurements, in more fully characterizing a disorder and in reaching a more complete understanding of the experience of vision loss. It also evidences the particular suitability of filmmaking techniques as a means of accessing and communicating subjective patient experience.

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

Restored rod visual function after gene therapy can be established unequivocally by demonstrating that, after dark adaptation, spectral sensitivity has the shape characteristic of rods and that this shape collapses to a cone-like shape before rods have recovered after an intense bleach. We used these tests to assess retinal function in eight young adults and children with early-onset severe retinal dystrophy from Phase II of a clinical gene-therapy trial for RPE65 deficiency that involved the subretinal delivery of a recombinant adeno-associated viral vector carrying RPE65. We found substantial improvements in rod sensitivity in two participants: dark-adapted spectral sensitivity was rod-like after treatment and was cone-like before rods had recovered after a bleach. After 40 min of dark adaptation, one participant showed up to 1,000-fold sensitivity improvements 4 months after treatment and the second up to 100-fold improvements 6 months after treatment. The dark-adapted spectral sensitivities of the other six participants remained cone-like and showed little improvement in sensitivity.

Long-term effect of gene therapy on Leber's congenital amaurosis.

BACKGROUND: Mutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. METHODS: We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. RESULTS: Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. CONCLUSIONS: Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.).

Nature of the visual loss in observers with Leber's congenital amaurosis caused by specific mutations in RPE65.

PURPOSE: To characterize visual losses associated with genetic mutations in the RPE65 gene that cause defects in the RPE-specific isomerase, RPE65. RPE65 is an important component of the retinoid cycle that restores 11-cis-retinal after its photoisomerization to its all-trans form. The defects investigated here cause Leber's congenital amaurosis (LCA2), an autosomal, recessively-inherited, severe, congenital-onset rod-cone dystrophy. METHODS: Vision was assessed in nine patients and 10 normal controls by measuring: (1) long-wavelength sensitive (L-) cone temporal acuity (critical flicker fusion frequency or cff) as a function of target illuminance, and (2) L-cone temporal contrast sensitivity as a function of temporal frequency at a fixed-target illuminance. Measurements were made by modulating either a 650-nm light superimposed on a 480-nm background or the red phosphor of a color monitor on a background produced by the monitor's blue phosphor. RESULTS: RPE65-mutant observers have severely reduced cffs with shallower cff versus log illuminance functions that rise with a mean slope of 4.53 Hz per decade of illuminance compared with 8.69 Hz in normal controls. Consistent with the cff differences, RPE65-mutant observers show losses in temporal contrast sensitivity that increase rapidly with temporal frequency. CONCLUSIONS: All RPE65-mutant observers have consistent and substantial losses in temporal acuity and sensitivity compared with normal observers. The losses can be characterized by the addition of two sluggish filters within the mutant visual pathway, both filters with a time constant of 29.5 ms (i.e., low-pass filters with cut-off frequencies of 5.40 Hz).

Color and brightness encoded in a common L- and M-cone pathway with expansive and compressive nonlinearities.

Lights near 560 nm appear brighter when flickered, whereas lights near 520 or 650 nm appear yellower. Both effects are consistent with signal distortion within the visual pathway--brightness changes at an expansive nonlinearity, and hue shifts at a compressive one. We previously manipulated the distortion products generated by each nonlinearity to extract the temporal properties of stages of the L- and M-cone pathways that signal brightness and color before (early stages) and after (late stages) each nonlinearity. We find that the attenuation characteristics of the early and late stages are virtually identical in both pathways: The early temporal stage acts like a band-pass filter peaking at 10-15 Hz, while the late stage acts like low-pass filter with a cut-off frequency near 3 Hz. We propose a physiologically relevant model that accounts for the filter shapes and incorporates both nonlinearities within a common parvocellular pathway. The shape of the early band-pass filter is consistent with antagonism between center signals and more sluggish and delayed surround signals, while the late filter is consistent with a simple two-stage low-pass filter. Modeling suggests that the brightness change and hue shift are both initially caused by the half-wave rectification and partition of signals into ON and OFF components. However, the hue shift is probably caused by the additional effects of a later nonlinearity that compresses chromatic red and green signals. Plausible sites for the expansive half-wave rectifying nonlinearity are after surround antagonism, possibly from horizontal cells, but the compressive nonlinearity is likely to be after the late filter.

Visual consequences of molecular changes in the guanylate cyclase-activating protein.

PURPOSE: We characterized and modeled changes in visual performance associated with a Tyr99Cys mutation in guanylate cyclase-activating protein-1 (GCAP1) in four family members aged between 39 and 55 years old. Guanylate cyclase and its activating protein are molecules in the visual transduction pathway that restore cyclic GMP (cGMP) following its light-activated hydrolysis. The mutation causes an excess of cGMP in the dark and results in progressive photoreceptor loss. METHODS: L-cone temporal acuity was measured as a function of target irradiance, and L-cone temporal contrast sensitivity was measured as a function of temporal frequency. RESULTS: All four mutant GCAP1 family members showed sensitivity or acuity losses relative to normal observers. The data for the youngest family member are consistent with an abnormal speeding up of the visual response relative to that in normals, but those for the older members showed a progressively higher-frequency sensitivity loss consistent with a slowing down of their response. CONCLUSIONS: The speeding up of the visual response in the youngest observer is consistent with the Tyr99Cys mutation that results in the more rapid replacement of cGMP after light exposure and, thus, in a reduction of temporal integration and relative improvement in high-frequency sensitivity compared to normals. The high-frequency losses in the older observers are consistent with their vision being limited by the interposition of some sluggish process. This might result from some residual or malfunctioning molecular process limiting transduction within damaged photoreceptors or from an active or passive postreceptoral reorganization caused by the paucity of functioning photoreceptors.