Evidence for an Association Between a pH-Dependent Potassium Channel, TWIK-1, and the Accuracy of Smooth Pursuit Eye Movements.

Purpose: Within the healthy population there is a large variation in the ability to perform smooth pursuit eye movements. Our purpose was to investigate the genetic and physiological bases for this variation. Methods: We carried out a whole-genome association study, recording smooth pursuit movements for 1040 healthy volunteers by infrared oculography. The primary phenotypic measure was root mean square error (RMSE) of eye position relative to target position. Secondary measures were pursuit gain, frequency of catch-up saccades, and frequency of anticipatory saccades. Ten percent of participants, chosen randomly, were tested twice, giving estimates of test-retest reliability. Results: No significant association was found with three genes previously identified as candidate genes for variation in smooth pursuit: DRD3, COMT, NRG1. A strong association (P = 3.55 × 10-11) was found between RMSE and chromosomal region 1q42.2. The most strongly associated marker (rs701232) lies in an intron of KCNK1, which encodes a two-pore-domain potassium ion channel TWIK-1 (or K2P1) that affects cell excitability. Each additional copy of the A allele decreased RMSE by 0.29 standard deviation. When a psychophysical test of visually perceived motion was used as a covariate in the regression analysis, the association with rs701232 did not weaken (P = 5.38 × 10-12). Conclusions: Variation in the sequence or the expression of the pH-dependent ion channel TWIK-1 is a likely source of variance in smooth pursuit. The variance associated with TWIK-1 appears not to arise from sensory mechanisms, because the use of a perceptual covariate left the association intact.

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.

Individual differences in human eye movements: An oculomotor signature?

Human eye movements are stereotyped and repeatable, but how specific to a normal individual are the quantitative properties of his or her eye movements? We recorded saccades, anti-saccades and smooth-pursuit eye movements in a sample of over 1000 healthy young adults. A randomly selected subsample (10%) of participants were re-tested on a second occasion after a median interval of 18.8days, allowing us to estimate reliabilities. Each of several derived measures, including latencies, accuracies, velocities, and left-right asymmetries, proved to be very reliable. We give normative means and distributions for each measure and describe the pattern of correlations amongst them. We identify several measures that exhibit significant sex differences. The profile of our oculomotor measures for an individual constitutes a personal oculomotor signature that distinguishes that individual from most other members of the sample of 1000.

General and specific factors in the processing of faces.

The ability to recognize faces varies considerably between individuals, but does performance co-vary for tests of different aspects of face processing? For 397 participants (of whom the majority were university students) we obtained scores on the Mooney Face Test, Glasgow Face Matching Test (GFMT), Cambridge Face Memory Test (CFMT) and Composite Face Test. Overall performance was significantly correlated for each pair of tests, and we suggest the term f for the factor underlying this pattern of positive correlations. However, there were large variations in the amount of variance shared by individual tests: The GFMT and CFMT are strongly related, whereas the GFMT and the Mooney test tap largely independent abilities. We do not replicate a frequently reported relationship between holistic processing (from the Composite test) and face recognition (from the CFMT)-indeed, holistic processing does not correlate with any of our tests. We report associations of performance with digit ratio and autism-spectrum quotient (AQ), and from our genome-wide association study we include a list of suggestive genetic associations with performance on the four face tests, as well as with f.

The Oxytocin Receptor Gene ( OXTR) and Face Recognition.

A recent study has linked individual differences in face recognition to rs237887, a single-nucleotide polymorphism (SNP) of the oxytocin receptor gene ( OXTR; Skuse et al., 2014). In that study, participants were assessed using the Warrington Recognition Memory Test for Faces, but performance on Warrington's test has been shown not to rely purely on face recognition processes. We administered the widely used Cambridge Face Memory Test-a purer test of face recognition-to 370 participants. Performance was not significantly associated with rs237887, with 16 other SNPs of OXTR that we genotyped, or with a further 75 imputed SNPs. We also administered three other tests of face processing (the Mooney Face Test, the Glasgow Face Matching Test, and the Composite Face Test), but performance was never significantly associated with rs237887 or with any of the other genotyped or imputed SNPs, after corrections for multiple testing. In addition, we found no associations between OXTR and Autism-Spectrum Quotient scores.

Understanding disability glare: light scatter and retinal illuminance as predictors of sensitivity to contrast.

The presence of a bright light in the visual field has two main effects on the retinal image: reduced contrast and increased retinal illuminance because of scattered light; the latter can, under some conditions, lead to an improvement in retinal sensitivity. The combined effect remains poorly understood, particularly at low light levels. A psychophysical flicker-cancellation test was used to measure the amount and angular distribution of scattered light in the eye for 40 observers. Contrast thresholds were measured using a functional contrast sensitivity test. Pupil-plane glare-source illuminances (i.e., 0, 1.35, and 19.21 lm/m2), eccentricities (5°, 10°, and 15°), and background luminances (1, 2.6, and 26 cd/m2) were investigated. Visual performance was better than predicted, based on a loss of retinal image contrast caused by scattered light, particularly in the mesopic range. Prediction accuracy improved significantly when the expected increase in retinal sensitivity in the presence of scattered light was also incorporated in the model.

Cortical hyperexcitability and sensitivity to discomfort glare.

It is well established that there are two main aspects to glare, the visual impairment and the discomfort, known as disability and discomfort glare, respectively. In contrast to the case of disability glare we understand very little about the underlying mechanisms or physiology of discomfort glare. This study attempts to elucidate the neural mechanisms involved using fMRI and glare sources with controlled levels of retinal illuminance. Prior to carrying out the fMRI experiment, we determined each participant's discomfort glare threshold. The participants were then divided into two groups of equal size based on their ranked sensitivity to discomfort glare, a low and high sensitivity group. In the fMRI experiment each participant was presented with three levels of glare intensity whilst simultaneously required to carry out a simple behavioral task. We compared BOLD responses between the two groups and found that the group more sensitive to glare had an increased response that was localized at three discrete, bilateral cortical locations: one in the cunei, one in the lingual gyri and one in the superior parietal lobules. This increased response was present for all light levels tested, whether or not they were intense enough to cause discomfort glare. Based on the results, we present the case that discomfort glare may be a response to hyperexcitability or saturation of visual neurons.

Mechanisms for discomfort glare in central vision.

PURPOSE: The presence of a bright light source in the visual field can generate visual discomfort. Based on empirical observations we can predict to a reasonable degree of accuracy how uncomfortable a given lighting installation is likely to be; yet very little is known about the mechanism or physiological underpinnings that lead to visual discomfort. This study attempts to elucidate some of the underlying mechanisms by controlling the amount of light reaching the retina and by varying photometric properties of the glare source. METHODS: The participants were required to view a source of light presented against a simulated residential street background in the form of uniform flashes of light of varying intensity. Discomfort-glare thresholds were estimated using a staircase procedure; the dependent variable was retinal illuminance. The size of the glare source and the luminance of the surrounding background were varied systematically. RESULTS: Across glare-source sizes or background luminances the discomfort-glare threshold varied less in terms of retinal illuminance than it did in terms of pupil-plane illuminance or light flux. A two-stage model based on saturation of photoreceptors followed by summation of an edge response signal that defines the edges of the glare-source accurately predicted the data. CONCLUSIONS: Discomfort glare in central vision is more closely associated with the spatial properties of the glare source, such as contrast-defined edges, than the overall amount of light entering the eye. The results suggest that discomfort glare in lighting installations could be reduced while maintaining adequate illuminance levels by an appropriate choice of illuminant source size.

An online version of the Mooney Face Test: phenotypic and genetic associations.

The Mooney Face Test is a widely used test of face perception, but was originally designed to be administered by personal interview. We have developed a three-alternative forced-choice version for online testing. We tested 397 healthy adults between the ages of 18 and 42 (M=24 years). There was a wide range of performance (64-100% correct; M=89.6%). We observed a significant sex difference favoring males (.31 standard deviation; p =.004). In addition, independently of sex, higher 2D:4D digit ratios were significantly associated with higher scores (ρ=.14, p=.006). A genome-wide association study (GWAS) for a subset of 370 participants identified an association between Mooney performance and a polymorphism in the RAPGEF5 gene (rs1522280; p=9.68×10(-8)). This association survives a permutation test (p=.031).

Individual differences provide psychophysical evidence for separate on- and off-pathways deriving from short-wave cones.

Distinct neural populations carry signals from short-wave (S) cones. We used individual differences to test whether two types of pathways, those that receive excitatory input (S+) and those that receive inhibitory input (S-), contribute independently to psychophysical performance. We also conducted a genome-wide association study (GWAS) to look for genetic correlates of the individual differences. Our psychophysical test was based on the Cambridge Color Test, but detection thresholds were measured separately for S-cone spatial increments and decrements. Our participants were 1060 healthy adults aged 16-40. Test-retest reliabilities for thresholds were good (ρ=0.64 for S-cone increments, 0.67 for decrements and 0.73 for the average of the two). "Regression scores," isolating variability unique to incremental or decremental sensitivity, were also reliable (ρ=0.53 for increments and ρ=0.51 for decrements). The correlation between incremental and decremental thresholds was ρ=0.65. No genetic markers reached genome-wide significance (p<5×10(-7)). We identified 18 "suggestive" loci (p<10(-5)). The significant test-retest reliabilities show stable individual differences in S-cone sensitivity in a normal adult population. Though a portion of the variance in sensitivity is shared between incremental and decremental sensitivity, over 26% of the variance is stable across individuals, but unique to increments or decrements, suggesting distinct neural substrates. Some of the variability in sensitivity is likely to be genetic. We note that four of the suggestive associations found in the GWAS are with genes that are involved in glucose metabolism or have been associated with diabetes.

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.

Genetic association suggests that SMOC1 mediates between prenatal sex hormones and digit ratio.

Men and women differ statistically in the relative lengths of their index and ring fingers; and the ratio of these lengths has been used as a biomarker for prenatal testosterone. The ratio has been correlated with a wide range of traits and conditions including prostate cancer, obesity, autism, ADHD, and sexual orientation. In a genome-wide association study of 979 healthy adults, we find that digit ratio is strongly associated with variation upstream of SMOC1 (rs4902759: P = 1.41 × 10(-8)) and a meta-analysis of this and an independent study shows a probability of P = 1.5 × 10(-11). The protein encoded by SMOC1 has recently been shown to play a critical role in limb development; its expression in prostate tissue is dependent on sex hormones, and it has been implicated in the sexually dimorphic development of the gonads. We put forward the hypothesis that SMOC1 provides a link between prenatal hormone exposure and digit ratio.

Do different 'magnocellular tasks' probe the same neural substrate?

The sensory abnormalities associated with disorders such as dyslexia, autism and schizophrenia have often been attributed to a generalized deficit in the visual magnocellular-dorsal stream and its auditory homologue. To probe magnocellular function, various psychophysical tasks are often employed that require the processing of rapidly changing stimuli. But is performance on these several tasks supported by a common substrate? To answer this question, we tested a cohort of 1060 individuals on four 'magnocellular tasks': detection of low-spatial-frequency gratings reversing in contrast at a high temporal frequency (so-called frequency-doubled gratings); detection of pulsed low-spatial-frequency gratings on a steady luminance pedestal; detection of coherent motion; and auditory discrimination of temporal order. Although all tasks showed test-retest reliability, only one pair shared more than 4 per cent of variance. Correlations within the set of 'magnocellular tasks' were similar to the correlations between those tasks and a 'non-magnocellular task', and there was little consistency between 'magnocellular deficit' groups comprising individuals with the lowest sensitivity for each task. Our results suggest that different 'magnocellular tasks' reflect different sources of variance, and thus are not general measures of 'magnocellular function'.

Colored-speech synaesthesia is triggered by multisensory, not unisensory, perception.

Although it is estimated that as many as 4% of people experience some form of enhanced cross talk between (or within) the senses, known as synaesthesia, very little is understood about the level of information processing required to induce a synaesthetic experience. In work presented here, we used a well-known multisensory illusion called the McGurk effect to show that synaesthesia is driven by late, perceptual processing, rather than early, unisensory processing. Specifically, we tested 9 linguistic-color synaesthetes and found that the colors induced by spoken words are related to what is perceived (i.e., the illusory combination of audio and visual inputs) and not to the auditory component alone. Our findings indicate that color-speech synaesthesia is triggered only when a significant amount of information processing has occurred and that early sensory activation is not directly linked to the synaesthetic experience.

Synaesthesia and cortical connectivity.

Synaesthesia is a heritable condition of involuntary sensory cross-activation whereby the presentation of a particular stimulus elicits a secondary sensory-perceptual experience. It is thought to be caused by aberrant cross-activation of one cortical area by another, but models differ as to whether this reflects functional or structural differences in the brains of synaesthetes. Here we consider these models in light of recent experimental findings and argue for structural differences in the brains of synaesthetes, which might be more widespread than expected. We also discuss several plausible developmental mechanisms that could link a putative genetic variant to altered cortical connectivity and illustrate how synaesthesia could be an informative model to investigate how patterns of connectivity between cortical areas are established.

Familial patterns and the origins of individual differences in synaesthesia.

The term synaesthesia has been applied to a range of different sensory-perceptual and cognitive experiences, yet how these experiences are related to each other is not well understood. Not only are there disparate types of synaesthesia, but even within types there are vast individual differences in the way that stimuli induce synaesthesia and in the subjective synaesthetic experience. An investigation of the inheritance patterns of different types of synaesthesia is likely to elucidate whether a single underlying mechanism can explain all types. This study is the first to systematically survey all types of synaesthesia within a familial framework. We recruited 53 synaesthetes and 42% of these probands reported a first-degree relative with synaesthesia. We then directly contacted as many first-degree relatives as possible and collected complete data on synaesthetic status for all family members for 17 families. We found that different types of synaesthesia can occur within the same family and that the qualitative nature of the experience can differ between family members. Our findings strongly indicate that various types of synaesthesia are fundamentally related at the genetic level, but that the explicit associations and the individual differences between synaesthetes are influenced by other factors. Synaesthesia thus provides a good model to explore the interplay of all these factors in the development of cognitive traits in general.