Human scotopic sensitivity is regulated postreceptorally by changing the speed of the scotopic response.

Sensitivity regulation enables the visual system to function effectively from the absorption of a few photons at the lowest visual threshold to the absorption of enough photons to bleach nearly all the light-sensitive photopigment in the eye. Here, we investigate sensitivity regulation in the rod (or scotopic) range from -3.8 to -0.8 log(10) scotopic trolands. Over most of this range, the rate of photon absorption per rod is too low for sensitivity regulation to be practicable within the rod photoreceptor itself, so that regulation must occur postreceptorally. We measured adaptation-dependent changes in visual sensitivity and visual delay, which together provide a much more complete characterization of the effects of light adaptation than the usual method of measuring sensitivity changes alone. Our results demonstrate clearly that changes in scotopic sensitivity with increasing light levels are achieved in large part by a speeding up of the scotopic response and a decrease in the temporal integration time. Thus, the scotopic and the photopic systems both regulate their steady-state sensitivity using the same strategy, even though the scotopic system does it largely postreceptorally and the photopic system largely receptorally.

The loss of the PDE6 deactivating enzyme, RGS9, results in precocious light adaptation at low light levels.

The GTPase activating protein, RGS9-1, is vital for the deactivation and regulation of the phototransduction cascade (C. K. Chen et al., 2000; C. W. Cowan, R. N. Fariss, I. Sokal, K. Palczewski, & T. G. Wensel, 1998; W. He, C. W. Cowan, & T. G. Wensel, 1998; A. L. Lyubarsky et al., 2001). Its loss through genetic defects in humans has been linked to a slow recovery to changes in illumination (K. M. Nishiguchi et al., 2004). Such a deficit is to be expected because RGS9-1 normally speeds up the deactivation of the activated phosphodiesterase effector molecule, PDE6*, and thus accelerates the turning off of the visual response. Paradoxically, however, we find that the cone response in an observer lacking RGS9-1 is faster at lower light levels than it is in a normal observer. Though surprising, this result is nonetheless consistent with molecular models of light adaptation (e.g., E. N. Pugh, S. Nikonov, & T. D. Lamb, 1999), which predict that the excess of PDE6* resulting from the loss of RGS9-1 will shorten the visual integration time and speed up the visual response at inappropriately low light levels. The gain in speed caused by the superfluity of PDE6* at lower light levels compensates for the loss caused by its slow deactivation; thus quickening the response relative to that in the normal. As the light level is increased and the PDE6* concentration in the normal rises relative to that in the observer lacking RGS9-1, the temporal advantage of the latter is soon lost, leaving only the deficit due to delayed deactivation.

The dependence of luminous efficiency on chromatic adaptation.

We investigated the dependence of luminous efficiency on background chromaticity by measuring 25-Hz heterochromatic flicker photometry (HFP) matches in six genotyped male observers on 21 different 1000-photopic-troland adapting fields: 14 spectral ones ranging from 430 to 670 nm and 7 bichromatic mixtures of 478 and 577 nm that varied in luminance ratio. Each function was analyzed in terms of the best-fitting linear combination of the long- (L) and middle- (M) wavelength sensitive cone fundamentals of A. Stockman and L. T. Sharpe (2000). Taking into account the adapting effects of both the backgrounds and the targets, we found that luminous efficiency between 603 and 535 nm could be predicted by a simple model in which the relative L- and M-cone weights are inversely proportional to the mean cone excitations produced in each cone type multiplied by a single factor, which was roughly independent of background wavelength (and may reflect relative L:M cone numerosity). On backgrounds shorter than 535 nm and longer than 603 nm, the M-cone contribution to luminous efficiency falls short of the proportionality prediction but most likely for different reasons in the two spectral regions.

The effect of sildenafil citrate (Viagra) on visual sensitivity.

The erectile dysfunction medicine sildenafil citrate (Viagra) inhibits phosphodiesterase type 6 (PDE6), an essential enzyme involved in the activation and modulation of the phototransduction cascade. Although Viagra might thus be expected to impair visual performance, reports of deficits following its ingestion have so far been largely inconclusive or anecdotal. Here, we adopt tests sensitive to the slowing of the visual response likely to result from the inhibition of PDE6. We measured temporal acuity (critical fusion frequency) and modulation sensitivity in four subjects before and after the ingestion of a 100-mg dose of Viagra under conditions chosen to isolate the responses of either their short-wavelength-sensitive (S-) cone photoreceptors or their long- and middle-wavelength-sensitive (L- and M-) cones. When vision was mediated by S-cones, all subjects exhibited some statistically significant losses in sensitivity, which varied from mild to moderate. The two individuals who showed the largest S-cone sensitivity losses also showed comparable losses when their vision was mediated by the L- and M-cones. Some of the losses appear to increase with frequency, which is broadly consistent with Viagra interfering with the ability of PDE6 to shorten the time over which the visual system integrates signals as the light level increases. However, others appear to represent a roughly frequency-independent attenuation of the visual signal, which might also be consistent with Viagra lengthening the integration time (because it has the effect of increasing the effectiveness of steady background lights), but such changes are also open to other interpretations. Even for the more affected observers, however, Viagra is unlikely to impair common visual tasks, except under conditions of reduced visibility when objects are already near visual threshold.

Human short-wavelength-sensitive cone light adaptation.

The cone-driven visual system is able to regulate its sensitivity effectively from twilight to bright sunlight. On the basis of a novel combination of short-wavelength-sensitive (S-) cone measurements of temporal sensitivity and temporal delay, we show that S-cone light adaptation is achieved not only by trading unwanted sensitivity for speed but also by an additional process that counterintuitively increases the overall sensitivity as the light level rises. Our results are consistent with comparable middle-wavelength-sensitive (M-) cone measurements made in protanopic observers and can be accounted for by the same two-parameter model developed to account for the M-cone data (A. Stockman, M. Langendörfer, H. E. Smithson, & L. T. Sharpe, 2006). Each stage of the model can be linked to molecular mechanisms occurring within the photoreceptor: the speeding up to increases in the rates of decay of active and messenger molecules, the unexpected sensitivity increases to increased rates of molecular resynthesis and changes in channel sensitivity, and the sensitivity decreases to bleaching. Together, these mechanisms act to maintain vision in an optimal operating range and to protect it from overload.

Residual cone vision without alpha-transducin.

Behavioral experiments in humans with a rare genetic mutation that compromises the function of alpha-transducin (Galpha the alpha-subunit of the G-protein in the primary cone phototransduction cascade) reveal a residual cone response only viable at high light levels and at low temporal frequencies. It has three characteristic properties. First, it limits temporal frequency sensitivity to the equivalent of a simple first order reaction with a time constant of approximately 140 ms. Second, it delays the visual response by an amount that is also consistent with such a reaction. Third, it causes temporal acuity to be linearly related to the logarithm of the amount of bleached pigment. We suggest that these properties are consistent with the residual function depending on a sluggishly generated cone photobleaching product, which we tentatively identify as a cone metarhodopsin. By activating the transduction cascade, this bleaching product mimics the effects of real light and is therefore one of the molecular origins of "background equivalence," the long-established observation that the aftereffects of photopigment bleaches and the effects of real background lights are equivalent. Alternative explanations for the residual cone response include the possibilities that there is a secondary phototransduction mechanism that bypasses alpha-transduction, or that the truncated alpha-transduction that results from the mutation retains some minimal functionality.

Transitions between color categories mapped with a reverse Stroop task.

In the reverse Stroop task, observers are instructed to ignore the ink color in which a color word is printed (the distractor color) and to respond to the meaning of the color word (the target). Reaction times (RTs) are faster with congruent combinations when the ink color matches the word than with incongruent combinations when the ink color does not match the word. We manipulated the distracting ink color from congruent to incongruent and measured the transition from facilitation to interference. In Experiment 1, we confirmed that this transition could be assessed independently from the contextual influence of particular sets of stimuli and responses, implying that the color space in which interference and facilitation occurs is generalizable. In Experiment 2, we obtained reverse Stroop data for transitions between red and yellow, yellow and green, green and blue, and blue and red, and compared them with independent estimates of color appearance obtained by hue scaling for the same chromaticity samples. We find that the magnitude of the reverse Stroop effect can provide a reliable index of the similarity of color appearance between the distracting chromaticity and the color category represented by the target color word. Moreover, it will allow us to quantify the mapping between the chromaticity space defined at the cone photoreceptors and a cognitive color space defined at an advanced level of neural processing.

Into the twilight zone: the complexities of mesopic vision and luminous efficiency.

Of all the functions that define visual performance, the mesopic luminous efficiency function is probably the most complex and hardest to standardise or model. Complexities arise because of the substantial and often rapid visual changes that accompany the transition from scotopic to photopic vision. These are caused not only by the switch from rod to cone photoreceptors, but also by switches between different post-receptoral pathways through which the rod and cone signals are transmitted. In this review, we list several of the complexities of mesopic vision, such as rod-cone interactions, rod saturation, mixed photoreceptor spectral sensitivities, different rod and cone retinal distributions, and the changes in the spatial properties of the visual system as it changes from rod- to cone-mediated. Our main focus, however, is the enormous and often neglected temporal changes that occur in the mesopic range and their effect on luminous efficiency. Even before the transition from rod to cone vision is complete, a transition occurs within the rod system itself from a sluggish, sensitive post-receptoral pathway to a faster, less sensitive pathway. As a consequence of these complexities, any measure of mesopic performance will depend not only on the illumination level, but also on the spectral content of the stimuli used to probe performance, their retinal location, their spatial frequency content, and their temporal frequency content. All these should be considered when attempting to derive (or to apply) a luminous efficiency function for mesopic vision.

Spectrophotometry for cerebrospinal fluid pigment analysis.

The use of spectrophotometry for the analysis of the cerebrospinal fluid (CSF) is reviewed. The clinically relevant CSF pigments--oxyhemoglobin and bilirubin--are introduced and discussed with regard to clinical differential diagnosis and potentially confounding variables (the four T's: traumatic tap, timing, total protein, and total bilirubin). The practical laboratory aspects of spectrophotometry and automated techniques are presented in the context of analytical and clinical specificity and sensitivity. The perceptual limitations of human color vision are highlighted and the use of visual assessment of the CSF is discouraged in light of recent evidence from a national audit in the United Kingdom. Finally, future perspectives including the need for longitudinal CSF profiling and routine spectrophotometric calibration are outlined.

Advantages and disadvantages of human dichromacy.

We compared the visual detection thresholds for cone-isolating stimuli of trichromats (those with normal color vision) with those of X-linked dichromats, who lack either the long-wavelength-sensitive (L) cones (protanopes) or middle-wavelength-sensitive (M) cones (deuteranopes). At low (1 Hz) temporal frequencies, dichromats have significantly higher (twofold) thresholds for all colored stimuli than trichromats; whereas at high (16 Hz) temporal frequencies, they perform as well or better than trichromats. The advantages of dichromats in detecting high temporally modulated targets can be related to an increased number, through replacement, of the remaining L- or M-cone type. However, their disadvantages in detecting low temporally modulated targets, even in directions of color space where their increased number of cone photoreceptors might be expected to be beneficial, are best explained in terms of the loss of L-M cone opponency and the inability of the visual pathways to reorganize to allow the detection of low-frequency luminance modulation.

Visual acuity and X-linked color blindness.

PURPOSE: Optimal sampling for visual acuity requires a fine array of cones with identical sensitivity. Thus, dichromats, whose inner fovea is made up of cones having the same spectral sensitivity, may have better than normal visual acuity. We investigated this by comparing the visual acuities of trichromats and X-linked dichromats, while taking into account the different molecular genetics underlying the disorder. METHODS: Our subjects were age- and refraction-matched groups of normals (n=8) and X-linked dichromats (n=13). The dichromats (four protanopes and nine deuteranopes) were genotyped and classified according to whether they carried a single (n=6) or multiple (n=7) visual pigment genes on their X-chromosome. Visual acuity was measured in both eyes with the Freiburger Visual Acuity Test. RESULTS: Normal trichromats and ungenotyped dichromats do not significantly differ in visual acuity, nor do ungenotyped protanopes and deuteranopes. However, multi-gene dichromats, who possess more than one photopigment gene in the array, all of which encode for the same long- or middle-wavelength sensitive photopigment, have significantly higher visual acuity than either normal trichromats or dichromats who have only a single-gene. CONCLUSIONS: Multi-gene dichromats may benefit from a reduction in chromatic aberration and chromatic noise in the high acuity channel, normally a consequence of combining signals from different cone photoreceptor types and of cone-specific patterns of retinal image defocus and blur. Single-gene dichromats may not share in the advantage because of other molecular differences that influence the development of the retinal mosaic and/or its visual pathways.

Human cone light adaptation: from behavioral measurements to molecular mechanisms.

The ability of the cone visual system to regulate its sensitivity from twilight to bright sunlight is an extraordinary feat of biology. Here, we investigate the changes in visual processing that accompany cone light adaptation over a 5 log10 unit intensity range by combining measures of temporal sensitivity made in one eye with measures of the temporal delay between the two eyes in different states of adaptation. This combination of techniques, which provides more complete information than has been available before, leads to a simple model of steady-state light adaptation. At high light levels, visual sensitivity is maintained mainly by photopigment bleaching. At low-to-moderate light levels, it is maintained by trading unwanted sensitivity for speed and by an additional process that paradoxically increases the overall sensitivity as the light level rises. Each stage of the model can be linked to molecular mechanisms within the photoreceptor: The speeding up can be linked to faster rates of decay of activated molecules; the paradoxical sensitivity increases can be linked to faster rates of molecular resynthesis and to changes in channel sensitivity; and the sensitivity decreases can be linked to bleaching. Together, these mechanisms act to maintain the cone visual system in an optimal operating range and to protect it from overload.

Dose-dependency and time-course of electrophysiologic short-term effects of VIAGRA: a case study.

The dose-dependency and time-course of the short-term visual effects of sildenafil citrate (VIAGRA) were tested in two subjects. Blood pressure was measured and samples of blood taken at 30 min intervals before and after drug administration. In the first experiment, prolongations of the implicit times of the scotopic maximum a-wave, cone a- and b-wave, 33 Hz flicker, ON-response a- and b-wave and 3.3 Hz a- and b-wave electroretinogram (ERG) recordings and of the oscillatory potentials OP1, OP2, and OP3 were observed for both eyes of both subjects, following 100 or 200 mg dosings. Interestingly, no prolongation was found for OP4, to which the OFF-bipolar cell pathway significantly contributes. In the second experiment, in which visual function was repeatedly assessed following a 200 mg dose, similar prolongations were found in both eyes of one subject for the implicit times of the oscillatory potential OP2, the cone b-wave response and the 3.3 Hz a-wave. Moreover, the steady-state (A0) and immediate extinction (B0) blue target thresholds of transient tritanopia were raised relative to the pre-drug administration baseline effects. While the maximum lowering of both systolic and diastolic blood pressure approximately correlated with the peak plasma concentration of sildenafil (c. 30-60 min after administration), the peak magnitudes of most visual effects were found at c. 110 min, consistent with a second compartment kinetic.

CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia.

Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack of color discrimination, low visual acuity (<0.2), photophobia, and nystagmus. Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder. Here, we analyzed the spectrum and prevalence of CNGB3 gene mutations in a cohort of 341 independent patients with achromatopsia. In 163 patients, CNGB3 mutations could be identified. A total of 105 achromats carried apparent homozygous mutations, 44 were compound (double) heterozygotes, and 14 patients had only a single mutant allele. The derived CNGB3 mutation spectrum comprises 28 different mutations including 12 nonsense mutations, eight insertions and/or deletions, five putative splice site mutations, and three missense mutations. Thus, the majority of mutations in the CNGB3 gene result in significantly altered and/or truncated polypeptides. Several mutations were found recurrently, in particular a 1 bp deletion, c.1148delC, which accounts for over 70% of all CNGB3 mutant alleles. In conclusion, mutations in the CNGB3 gene are responsible for approximately 50% of all patients with achromatopsia. This indicates that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent.

A luminous efficiency function, V*(lambda), for daylight adaptation.

We propose a new luminosity function, V*(lambda), that improves upon the original CIE 1924 V(lambda) function and its modification by D. B. Judd (1951) and J. J. Vos (1978), while being consistent with a linear combination of the A. Stockman & L. T. Sharpe (2000) long-wavelength-sensitive (L) and middle-wavelength-sensitive (M) cone fundamentals. It is based on experimentally determined 25 Hz, 2 degrees diameter, heterochromatic (minimum) flicker photometric data obtained from 40 observers (35 males, 5 females) of known genotype, 22 with the serine variant L(ser180), 16 with the alanine L(ala180) variant, and 2 with both variants of the L-cone photopigment. The matches, from 425 to 675 nm in 5-nm steps, were made on a 3 log troland xenon white (correlated color temperature of 5586 K but tritanopically metameric with CIE D65 standard daylight for the Stockman and Sharpe L- and M-cone fundamentals in quantal units) adapting field of 16 degrees angular subtense, relative to a 560-nm standard. Both the reference standard and test lights were kept near flicker threshold so that, in the region of the targets, the total retinal illuminance averaged 3.19 log trolands. The advantages of the new function are as follows: it forms a consistent set with the new proposed CIE cone fundamentals (which are the Stockman & Sharpe 2000 cone fundamentals); it is based solely on flicker photometry, which is the standard method for defining luminance; it corresponds to a central 2 degrees viewing field, for which the basic laws of brightness matching are valid for flicker photometry; its composition of the serine/alanine L-cone pigment polymorphism (58:42) closely matches the reported incidence in the normal population (56:44; Stockman & Sharpe, 1999); and it specifies luminance for a reproducible, standard daylight condition. V*(lambda) is defined as 1.55L(lambda) + M(lambda), where L(lambda) and M(lambda) are the Stockman & Sharpe L- & M-cone (quantal) fundamentals. It is extrapolated to wavelengths shorter than 425 nm and longer than 675 nm using the Stockman & Sharpe cone fundamentals.

The Nagel anomaloscope: its calibration and recommendations for diagnosis and research.

BACKGROUND: The Nagel anomaloscope Model I is the definitive clinical instrument for classifying phenotypic variations in X-linked color-vision disorders. Its system of classification is based on the Rayleigh equation: the relative amounts of red and green primary lights required to match a yellow primary. Our aim was to characterize how changes in mains voltage and ambient temperature influence the wavelength and intensity of each primary and alter the Rayleigh matches of normal and anomalous trichromats. METHODS: A Nagel Model I anomaloscope was calibrated in wavelength and intensity while varying the temperature of its prism housing and the mains voltage. Three normal, three protanomalous and three deuteranomalous trichromats made Rayleigh matches at various temperatures and voltages. RESULTS: The intensities of the green and red primaries show an exponential growth with mains voltage. Additionally, the wavelengths and intensities of all three primaries change with prism housing temperature. As a result, the R-G match midpoints of normal and anomalous trichromats shift with increasing mains voltage, and more markedly with increasing prism housing temperature, to higher R-G settings. CONCLUSIONS: Rayleigh matches obtained with the Nagel I anomaloscope are sensitive to changes in voltage supply and prism housing temperature, arising largely from thermal effects of the internal light sources. However, the instrument may still be safely used for diagnostic and research purposes provided that: (1) a stable voltage supply is used; (2) it is kept at a constant temperature; and (3) the match midpoint of the reference population has been established under identical conditions.

Visual short-term effects of Viagra: double-blind study in healthy young subjects.

PURPOSE: To investigate short-term visual effects of a single 100-mg dose of Viagra (sildenafil citrate) in healthy men. DESIGN: Randomized, double-blind, placebo-controlled clinical trial of drug effects on normal volunteers conducted by a single center. METHODS: Twenty men, aged 20 to 40 years, were treated with either a placebo or 100 mg sildenafil. Visual function tests included electroretinogram (ERG) recordings, on-/off- and 3.3 Hz-flicker-ERG recordings, anomaloscope matches, and measurements of cone contrast sensitivities and transient tritanopia. RESULTS: Most visual tests did not differ between the sildenafil and placebo groups. However, statistically significant increases in sensitivity during transient tritanopia were observed as well as significant prolongations in the implicit times of scotopic a-wave, photopic b-wave, and 3.3 Hz-flicker a-wave and b-wave ERG recordings. The magnitude of the differences correlated with peak sidenafil plasma concentration. Although rod amplitudes of the ERG recordings tended to be higher and cone amplitudes lower in the sildenafil group after drug ingestion, the differences were nonsignificant. There were no reports of visual side effects, and all electrophysiologic and psychophysical measurements returned to the normal range within 24 hours. CONCLUSIONS: A single oral dose of 100-mg sildenafil given to healthy young men led to small but statistically significant transient changes of outer and inner retinal function, as detected by ERG and psychophysical methods. Although the acute effects were fully reversible within 24 hours, it would be worthwhile to compare them with those induced by other PDE5 and PDE6 inhibitors.

Molecular basis of an inherited form of incomplete achromatopsia.

Mutations in the genes encoding the CNGA3 and CNGB3 subunits of the cyclic nucleotide-gated (CNG) channel of cone photoreceptors have been associated with autosomal recessive achromatopsia. Here we analyze the molecular basis of achromatopsia in two siblings with residual cone function. Psychophysical and electroretinographic analyses show that the light sensitivity of the cone system is lowered, and the signal transfer from cones to secondary neurons is perturbed. Both siblings carry two mutant CNGA3 alleles that give rise to channel subunits with different single-amino acid substitutions. Heterologous expression revealed that only one mutant forms functional channels, albeit with grossly altered properties, including changes in Ca2+ blockage and permeation. Surprisingly, coexpression of this mutant subunit with CNGB3 rescues the channel phenotype, except for the Ca2+ interaction. We argue that these alterations are responsible for the perturbations in light sensitivity and synaptic transmission.