13q32.1 as a candidate region for physiological anisocoria.

BACKGROUND: Physiological anisocoria is an asymmetry of pupil size in the absence of pathology. METHODS: Images of the pupils under standard illumination were collected in the course of a whole-genome association study of a range of visual functions in 1060 healthy adults. DNA for each participant was extracted from saliva samples. RESULTS: We found no relationship between anisocoria and the difference in refraction between the eyes, nor between anisocoria and difference in acuity. There was a small but significant relationship with lightness of the iris, in that the eye with the smaller pupil was associated with the lighter iris. There was a strong association between anisocoria and a local region of chromosome 13 (13q32.1), a region lying between the genes GPR180 and SOX21. The strongest association was with the single-nucleotide polymorphism rs9524583. CONCLUSION: The very specific region associated with anisocoria is one where microdeletions (or microduplications) are known to lead to abnormal development of pupil dilator muscle and hence to the autosomal dominant condition of microcoria. It is possible that alterations at 13q32.1 act by altering the expression of SOX21, which encodes a nuclear transcription factor.

What kind of network is the brain?

The different areas of the cerebral cortex are linked by a network of white matter, comprising the myelinated axons of pyramidal cells. Is this network a neural net, in the sense that representations of the world are embodied in the structure of the net, its pattern of nodes, and connections? Or is it a communications network, where the same physical substrate carries different information from moment to moment? This question is part of the larger question of whether the brain is better modeled by connectionism or by symbolic artificial intelligence (AI), but we review it in the specific context of the psychophysics of stimulus comparison and the format and protocol of information transmission over the long-range tracts of the brain.

Retinal Ganglion Cells-Diversity of Cell Types and Clinical Relevance.

Retinal ganglion cells (RGCs) are the bridging neurons that connect the retinal input to the visual processing centres within the central nervous system. There is a remarkable diversity of RGCs and the various subtypes have unique morphological features, distinct functions, and characteristic pathways linking the inner retina to the relevant brain areas. A number of psychophysical and electrophysiological tests have been refined to investigate this large and varied population of RGCs. Technological advances, such as high-resolution optical coherence tomography imaging, have provided additional tools to define the pattern of RGC involvement and the chronological sequence of events in both inherited and acquired optic neuropathies. The mechanistic insights gained from these studies, in particular the selective vulnerability and relative resilience of particular RGC subtypes, are of fundamental importance as they are directly relevant to the development of targeted therapies for these invariably progressive blinding diseases. This review provides a comprehensive description of the various types of RGCs, the developments in proposed methods of classification, and the current gaps in our knowledge of how these RGCs are differentially affected depending on the underlying aetiology. The synthesis of the current body of knowledge on the diversity of RGCs and the pathways that are potentially amenable to therapeutic modulation will hopefully lead to much needed effective treatments for patients with optic neuropathies.

Color Vision Deficiency Among Doctors: Can We Make Useful Adaptations to the Color Codes Used in the Clinical Environment?

ABSTRACT: Color vision deficiency (formerly known as color blindness) is common as a congenital and as an acquired condition. Some professions, most famously commercial aviation, require their members to demonstrate normal color vision. In the United States and United Kingdom, no restriction is placed on the ability of the color-deficient doctor to practice medicine, although there is evidence that certain clinical discriminations are harder for such doctors. Generally ignored has been the difficulty and the potential for error that arises from the use of color codes in clinical equipment. In this review, we introduce the basic concepts of color deficiency, summarize evidence for the challenges it poses to the doctor, examine global variation in policy, show the potential for confusion among clinical color codes, and suggest how the current situation could be improved to enhance both patient safety and the well-being of the color-deficient doctor.

Individual differences in visual science: What can be learned and what is good experimental practice?

We all pass out our lives in private perceptual worlds. The differences in our sensory and perceptual experiences often go unnoticed until there emerges a variation (such as 'The Dress') that is large enough to generate different descriptions in the coarse coinage of our shared language. In this essay, we illustrate how individual differences contribute to a richer understanding of visual perception, but we also indicate some potential pitfalls that face the investigator who ventures into the field.

Counterphase modulation photometry: comparison of two instruments.

The ratio of long-wavelength to medium-wavelength sensitive cones varies significantly among people. In order to investigate the possible effect of this variation in large numbers of participants, a quick and efficient method to estimate the ratio is required. The OSCAR test has been utilized previously for this purpose, but it is no longer available commercially. Having access to one of the few remaining OSCAR instruments, we compared the observers' mean settings to those obtained with the Medmont C100, a newer but apparently similar device. We also obtained Rayleigh matches for each participant. One hundred volunteers took part in the study. Settings on the OSCAR test were highly correlated with those on the Medmont C100. Both tests appeared to be influenced not only by L∶M cone ratios but also by the spectral positions of the cone photopigments, since anomaloscope midmatch points accounted for a significant proportion of the variance. We conclude that the Medmont C100 can be used as a suitable replacement for the OSCAR test and has a role in the rapid estimation of L∶M cone ratios.

Suggestive association with ocular phoria at chromosome 6p22.

PURPOSE: We conducted a genome-wide association study to identify genetic factors that contribute to the etiology of heterophoria. METHODS: We measured near and far vertical and horizontal phorias in 988 healthy adults aged 16 to 40 using the Keystone telebinocular with plates 5218 and 5219. We regressed degree of phoria against genotype at 642758 genetic loci. To control for false positives, we applied the conservative genome-wide permutation test to our data. RESULTS: A locus at 6p22.2 was found to be associated with the degree of near horizontal phoria (P = 2.3 × 10(-8)). The P value resulting from a genome-wide permutation test was 0.014. CONCLUSIONS: The strongest association signal arose from an intronic region of the gene ALDH5A1, which encodes the mitochondrial enzyme succinic semialdehyde dehydrogenase (SSADH), an enzyme involved in γ-aminobutyric acid metabolism. Succinic semialdehyde dehydrogenase deficiency, resulting from mutations of ALDH5A1, causes a variety of neural and behavioral abnormalities, including strabismus. Variation in ALDH5A1 is likely to contribute to degree of horizontal phoria.

X-linked cone dystrophy and colour vision deficiency arising from a missense mutation in a hybrid L/M cone opsin gene.

In this report, we describe a male subject who presents with a complex phenotype of myopia associated with cone dysfunction and a protan vision deficiency. Retinal imaging demonstrates extensive cone disruption, including the presence of non-waveguiding cones, an overall thinning of the retina, and an irregular mottled appearance of the hyper-reflective band associated with the inner segment ellipsoid portion of the photoreceptor. Mutation screening revealed a novel p.Glu41Lys missense mutation in a hybrid L/M opsin gene. Spectral analysis shows that the mutant opsin fails to form a pigment in vitro and fails to be trafficked to the cell membrane in transfected Neuro2a cells. Extensive sequence and quantitative PCR analysis identifies this mutant gene as the only gene present in the affected subject's L/M opsin gene array, yet the presence of protanopia indicates that the mutant opsin must retain some activity in vivo. To account for this apparent contradiction, we propose that a limited amount of functional pigment is formed within the normal cellular environment of the intact photoreceptor, and that this requires the presence of chaperone proteins that promote stability and normal folding of the mutant protein.

Compatible and incompatible representations in visual sensory storage.

Sensory storage shows a short-lived part-report advantage that survives an aftercoming visual noise pattern (Smithson & Mollon, 2006). We tested whether such an advantage survives different types of high-contrast mask. The target was a 3 × 4 array of digits. The mask could be (a) a noise pattern, (b) an array of eights, or (c) an array of random digits. In a preliminary experiment, target and mask were interleaved (at 140 Hz) and target contrast was varied to determine the level at which performance fell to chance. In the main experiment, target and mask were separated by an inter-stimulus-interval (ISI) of 100, 150, or 200 ms. An auditory part-report cue that was presented 240 ms after target offset supported a part-report advantage at all ISIs for noise masks, at ISIs greater than 100 ms for digit-8 masks, but not at any ISI for random-number masks. Increasing cue delay, in the range 240 to 730 ms, produced a decline in the advantages we measured. The differences in part-report superiority with different types of mask call for revision of the model of visual sensory storage as a single canvas on which successive items are superposed. When mask and target are sufficiently different, a representation of low-contrast target digits can be maintained independently of the representation of an aftercoming, high-contrast mask. However, when the same target is followed by a mask composed of high-contrast random digits, an independent representation of the target does not remain available for access.

Cardinal axes are not independent in color discrimination.

We measured chromatic discrimination under conditions where the target fields could be distinguished only by the ratio of excitation of the long- (L) and middle-wavelength (M) cones. The excitation level of the short-wavelength (S) cones was varied in the experiments, although for any given measurement the S-cone excitation was common to the two target fields and could not be directly used for discrimination. Adaptation was maintained by a steady neutral background metameric to Illuminant D65. Thresholds varied substantially and systematically with the S-cone level of the target probes, but in a complex way: when the ratio of L:M cone excitation was low, an increase in S-cone excitation reduced the thresholds, but when the L:M ratio was higher, an increase in S-cone excitation raised the thresholds. To account for the pattern of results, we postulate a neural channel that draws synergistic inputs from L and S cones and an opposed input from M cones. The proposed channel has a compressive response function and is most sensitive at the point set by the steady background.

Integrity of the cone photoreceptor mosaic in oligocone trichromacy.

PURPOSE: Oligocone trichromacy (OT) is an unusual cone dysfunction syndrome characterized by reduced visual acuity, mild photophobia, reduced amplitude of the cone electroretinogram with normal rod responses, normal fundus appearance, and normal or near-normal color vision. It has been proposed that these patients have a reduced number of normal functioning cones (oligocone). This paper has sought to evaluate the integrity of the cone photoreceptor mosaic in four patients previously described as having OT. METHODS: Retinal images were obtained from two brothers (13 and 15 years) and two unrelated subjects, one male (47 years) and one female (24 years). High-resolution images of the cone mosaic were obtained using high-speed adaptive optics (AO) fundus cameras. Visible structures were analyzed for density using custom software. Additional retinal images were obtained using spectral domain optical coherence tomography (SD-OCT), and the four layers of the photoreceptor-retinal pigment epithelium complex (ELM, IS/OS, RPE1, RPE2) were evaluated. Cone photoreceptor length and the thickness of intraretinal layers were measured and compared to previously published normative data. RESULTS: The adult male subject had infantile onset nystagmus while the three other patients did not. In the adult male patient, a normal appearing cone mosaic was observed. However, the three other subjects had a sparse mosaic of cones remaining at the fovea, with no structure visible outside the central fovea. On SD-OCT, the adult male subject had a very shallow foveal pit, with all major retinal layers being visible, and both inner segment (IS) and outer segment (OS) length were within normal limits. In the other three patients, while all four layers were visible in the central fovea and IS length was within normal limits, the OS length was significantly decreased. Peripherally the IS/OS layer decreased in intensity, and the RPE1 layer was no longer discernable, in keeping with the lack of cone structure observed on AO imaging outside the central fovea. CONCLUSIONS: Findings are consistent with the visual deficits being caused by a reduced number of healthy cones in the two brothers and the adult female. In the unrelated adult subject, no structural basis for the disorder was found. These data suggest two distinct groups on the basis of structural imaging. It is proposed that the former group with evidence of a reduction in cone numbers is more in keeping with typical OT, with the latter group representing an OT-like phenotype. These two groups may be difficult to readily discern on the basis of phenotypic features alone, and high-resolution imaging may be an effective way to distinguish between these phenotypes.

Blue cone monochromacy: causative mutations and associated phenotypes.

PURPOSE: To perform a phenotypic assessment of members of three British families with blue cone monochromatism (BCM), and to determine the underlying molecular genetic basis of disease. METHODS: Affected members of three British families with BCM were examined clinically and underwent detailed electrophysiological and psychophysical testing. Blood samples were taken for DNA extraction. Molecular analysis involved the amplification of the coding regions of the long (L) and medium (M) wave cone opsin genes and the upstream locus control region (LCR) by polymerase chain reaction (PCR). Gene products were directly sequenced and analyzed. RESULTS: In all three families, genetic analysis identified that the underlying cause of BCM involved an unequal crossover within the opsin gene array, with an inactivating mutation. Family 1 had a single 5'-L-M-3' hybrid gene, with an inactivating Cys203Arg (C203R) mutation. Family 3 had an array composed of a C203R inactivated 5'-L-M-3' hybrid gene followed by a second inactive gene. Families 1 and 3 had typical clinical, electrophysiological, and psychophysical findings consistent with stationary BCM. A novel mutation was detected in Family 2 that had a single hybrid gene lacking exon 2. This family presented clinical and psychophysical evidence of a slowly progressive phenotype. CONCLUSIONS: Two of the BCM-causing family genotypes identified in this study comprised different hybrid genes, each of which contained the commonly described C203R inactivating mutation. The genotype in the family with evidence of a slowly progressive phenotype represents a novel BCM mutation. The deleted exon 2 in this family is not predicted to result in a shift in the reading frame, therefore we hypothesize that an abnormal opsin protein product may accumulate and lead to cone cell loss over time. This is the first report of slow progression associated with this class of mutation in the L or M opsin genes in BCM.

X-linked cone dysfunction syndrome with myopia and protanopia.

PURPOSE: To perform a detailed clinical, psychophysical, and molecular assessment of members of 4 families with an unusual X-linked cone dysfunction syndrome associated with myopia. PARTICIPANTS: Affected and unaffected members of 4 British nonconsanguineous families. METHODS: Subjects underwent both detailed clinical examination and psychophysical testing. After informed consent was obtained, blood samples were taken for DNA extraction, and molecular genetic analysis was performed. The strategy for molecular analysis was to amplify the coding regions of the long and middle wavelength-sensitive cone opsin genes and the upstream locus control region by polymerase chain reaction and to examine these fragments for mutations by sequencing of DNA. RESULTS: The phenotype was almost identical in all 4 families, consisting of moderate to high myopia, astigmatism, moderately reduced acuity, and normal fundi. Electroretinography showed abnormal cone but normal rod responses. Psychophysical testing showed a selective impairment of long cones in combination with well-preserved middle cone and short cone function. There was no evidence to suggest that the phenotype was progressive. Molecular analysis of the X-linked opsin gene array in the 4 families indicated that affected males have inherited the same X-chromosome from their mother. In 2 families, a long/middle hybrid gene was detected. In a third family, the commonly described deleterious Cys203Arg amino acid substitution was identified in both the long and middle opsin genes. In the fourth family, the only abnormality was absence of a middle opsin exon 2; the cause of the protanopia in this family is uncertain. CONCLUSIONS: The X-linked cone dysfunction syndrome associated with myopia and dichromacy described here has many similarities to Bornholm eye disease, a condition previously mapped to Xq28. Except for the Cys203Arg substitution in one family, no alterations in the opsin gene array were identified that could underlie the cone dysfunction. It is therefore possible that the cone dysfunction may have a genetic origin different from that of the dichromacy.

Progressive cone dystrophy associated with mutation in CNGB3.

PURPOSE: To determine the molecular basis for phenotypic variability in a three-generation consanguineous family containing a single individual with complete achromatopsia and three individuals with progressive cone dystrophy. METHODS: Four affected individuals underwent ophthalmic examination, electrophysiological assessment, color fundus photography, and psychophysical testing. Blood samples were obtained for DNA extraction and mutation screening of the cone-specific cGMP-gated (CNG) channel protein gene CNGB3 was undertaken. RESULTS: The clinical findings in one family member were consistent with a diagnosis of complete achromatopsia, with nystagmus, photophobia, and poor visual acuity from early infancy and complete color-blindness, normal fundi, and absent cone responses with normal rod responses on electroretinography (ERG). Mutation analysis revealed her to be homozygous for the common CNGB3 achromatopsia mutation, 1148delC (Thr383fs). In contrast, the three other symptomatic individuals in the family had findings consistent with progressive cone dystrophy. Their visual problems began later in childhood (ranging from 3 to 14 years of age) and there was evidence of progressive deterioration in cone function. All three had a marked tritanopic color vision defect and fundoscopy revealed bilateral macular atrophy. Electrophysiological testing of these three subjects demonstrated clear evidence of progressive deterioration of cone responses over time; rod responses were normal. All three individuals with this progressive phenotype were found to be compound heterozygotes for the 1148delC (Thr383fs) frameshift mutation and a novel Arg403Gln missense mutation in CNGB3. CONCLUSIONS: Mutations in CNGB3, which have been shown to cause achromatopsia, are now shown to be associated with autosomal recessive progressive cone dystrophy. In this study, a novel Arg403Gln mutation was identified, located in the middle of the pore domain of the cone CNG cation channel beta-subunit, which when associated with the nonsense mutation Thr383fs, resulted in progressive cone dystrophy.

Comparison at a distance.

The visual system is known to contain hard-wired mechanisms that compare the values of a given stimulus attribute at adjacent positions in the visual field; but how are comparisons performed when the stimuli are not adjacent? We ask empirically how well a human observer can compare two stimuli that are separated in the visual field. For the stimulus attributes of spatial frequency, contrast, and orientation, we have measured discrimination thresholds as a function of the spatial separation of the discriminanda. The three attributes were studied in separate experiments, but in all cases the target stimuli were briefly presented Gabor patches. The Gabor patches lay on an imaginary circle, which was centred on the fixation point and had a radius of 5 deg of visual angle. Our psychophysical procedures were designed to ensure that the subject actively compared the two stimuli on each presentation, rather than referring just one stimulus to a stored template or criterion. For the cases of spatial frequency and contrast, there was no systematic effect of spatial separation up to 10 deg. We conclude that the subject's judgment does not depend on discontinuity detectors in the early visual system but on more central codes that represent the two stimuli individually. In the case of orientation discrimination, two naive subjects performed as in the cases of spatial frequency and contrast; but two highly trained subjects showed a systematic increase of threshold with spatial separation, suggesting that they were exploiting a distal mechanism designed to detect the parallelism or non-parallelism of contours.

Conditions under which stereopsis and motion perception are blind.

We describe modified random-dot stereograms in which the corresponding elements differ from non-corresponding elements in colour, size, and luminance. Despite these visible differences between the elements, depth perception collapses when the spatially integrated luminous flux is similar for the corresponding and non-corresponding elements. Our results suggest that a low-pass spatial filter precedes the mechanism that recognises disparity. A similar phenomenon is observed for the perception of coherent motion in random-dot kinematograms. Our modified stereograms and kinematograms may find other uses when experimenters wish to study the contribution of colour to visual processes and require a method of eliminating edge artifacts.