Measurement of visual function in infantile nystagmus: a systematic review.

BACKGROUND/AIMS: Recent work has called into question the ability of visual acuity (VA) to accurately represent changes in visual function in infantile nystagmus (IN). This systematic review investigated factors affecting visual performance in IN, to guide development of suitable alternatives to VA. METHODS: Included studies used an experimental manipulation to assess changes in visual function in people with IN. Interventional studies, case series and case studies were excluded. Six databases were searched in August 2023. Selection, detection, attrition and measurement bias were assessed. Due to heterogeneous methodologies, narrative synthesis was undertaken. RESULTS: Eighteen relevant papers were identified, 11 of which complied with the review criteria. Articles were grouped according to the factor manipulated to evoke within-participant changes in performance (motion blur, psychological state, gaze angle or visual crowding). Optotype, image, grating and moving stimuli have been employed under varying lighting conditions and exposure duration. CONCLUSION: Several factors affecting visual performance should be considered when assessing visual function in IN. While maximum VA is a useful metric, its measurement deliberately minimises nystagmus-specific factors such as changes in visual performance with gaze angle and the 'slow to see' phenomenon. Maximum VA can be measured using the null zone, providing unlimited viewing time, reducing stress/mental load and minimising visual crowding. Gaze-dependent functional vision space is a promising measure which quantifies the impact of the null zone but does not consider temporal vision. Although no complete measurement technique has yet been proven, this review provides insights to guide future work towards development of appropriate methods.

Eyetracking-enhanced VEP for nystagmus.

Visual evoked potentials (VEPs) are an important prognostic indicator of visual ability in patients with nystagmus. However, VEP testing requires stable fixation, which is impossible with nystagmus. Fixation instability reduces VEP amplitude, and VEP reliability is therefore low in this important patient group. We investigated whether VEP amplitude can be increased using an eye tracker by triggering acquisition only during slow periods of the waveform. Data were collected from 10 individuals with early-onset nystagmus. VEP was obtained under continuous (standard) acquisition, or triggered during periods of low eye velocity, as detected by an eye tracker. VEP amplitude was compared using Bonferroni corrected paired samples t-tests. VEP amplitude is significantly increased when triggered during low eye velocity (95% CI 1.42-6.83 µV, t(15) = 3.25, p = 0.0053). This study provides proof-of-concept that VEP amplitude (and therefore prognostic reliability) can be increased in patients with early onset nystagmus by connecting an eye tracker and triggering acquisition during periods of lower eye velocity.

Neurodevelopmental dimensional assessment of young children at high genomic risk of neuropsychiatric conditions.

Background: Individuals with 22q11.2 deletion are at considerably increased risk of neurodevelopmental and psychiatric conditions. There have been very few studies investigating how this risk manifests in early childhood and what factors may underlie developmental variability. Insights into this can elucidate transdiagnostic markers of risk that may underlie later development of neuropsychiatric outcomes. Methods: Thirty two children with 22q11.2 Deletion Syndrome (22q11.2DS) (mean age = 4.1 [SD = 1.2] years) and 12 sibling controls (mean age = 4.1 [SD = 1.5] years) underwent in-depth dimensional phenotyping across several developmental domains selected as being potential early indicators of neurodevelopmental and psychiatric liability. Comparisons were conducted of the dimensional developmental phenotype of 22q11.2DS and sibling controls. For autistic traits, both parents and children were phenotyped using the Social Responsiveness Scale. Results: Young children with 22q11.2DS exhibited large impairments (Hedge's g ≥ 0.8) across a range of developmental domains relative to sibling controls, as well as high rates of transdiagnostic neurodevelopmental and psychiatric traits. Cluster analysis revealed a subgroup of children with 22q11.2DS (n = 16; 53%) in whom neurodevelopmental and psychiatric liability was particularly increased and who differed from other children with 22q11.2DS and non-carrier siblings. Exploratory analyses revealed that early motor and sleep impairments indexed liability for neurodevelopmental and psychiatric outcomes. Maternal autism trait scores were predictive of autism traits in children with 22q11.2DS (intraclass correlation coefficients = 0.47, p = 0.046, n = 31). Conclusions: Although psychiatric conditions typically emerge later in adolescence and adulthood in 22q11.2DS, our exploratory study was able to identify a range of early risk indicators. Furthermore, findings indicate the presence of a subgroup who appeared to have increased neurodevelopmental and psychiatric liability. Our findings highlight the scope for future studies of early risk mechanisms and early intervention within this high genetic risk patient group.

Reliability of gaze-contingent perimetry.

Standard automated perimetry, a psychophysical task performed routinely in eyecare clinics, requires observers to maintain fixation for several minutes at a time in order to measure visual field sensitivity. Detection of visual field damage is confounded by eye movements, making the technique unreliable in poorly attentive individuals and those with pathologically unstable fixation, such as nystagmus. Microperimetry, which utilizes 'partial gaze-contingency' (PGC), aims to counteract eye movements but only corrects for gaze position errors prior to each stimulus onset. Here, we present a novel method of visual field examination in which stimulus position is updated during presentation, which we refer to as 'continuous gaze-contingency' (CGC). In the first part of this study, we present three case examples that demonstrate the ability of CGC to measure the edges of the physiological blind spot in infantile nystagmus with greater accuracy than PGC and standard 'no gaze-contingency' (NoGC), as initial proof-of-concept for the utility of the paradigm in measurements of absolute scotomas in these individuals. The second part of this study focused on healthy observers, in which we demonstrate that CGC has the lowest stimulus positional error (gaze-contingent precision: CGC = ± 0.29°, PGC = ± 0.54°, NoGC = ± 0.81°). CGC test-retest variability was shown to be at least as good as both PGC and NoGC. Overall, CGC is supported as a reliable method of visual field examination in healthy observers. Preliminary findings demonstrate the spatially accurate estimation of visual field thresholds related to retinal structure using CGC in individuals with infantile nystagmus.

Minimal reporting guideline for research involving eye tracking (2023 edition).

A guideline is proposed that comprises the minimum items to be reported in research studies involving an eye tracker and human or non-human primate participant(s). This guideline was developed over a 3-year period using a consensus-based process via an open invitation to the international eye tracking community. This guideline will be reviewed at maximum intervals of 4 years.

Calibration of Perfluorinated Alkyl Acid Uptake Rates by a Tube Passive Sampler in Water.

Per- and polyfluoroalkyl substances (PFAS) are a group of 4000+ man-made compounds of great concern due to their environmental ubiquity and adverse effects. Despite a general interest, few reliable detection tools for integrative passive sampling of PFAS in water are available. A microporous polyethylene tube with a hydrophilic-lipophilic balance sorbent could serve as a flow-resistant passive sampler for PFAS. The tube's sampling rate, Rs, was predicted based on either partitioning and diffusion, or solely diffusion. At 15 °C, the laboratory measured Rs for perfluorohexanoic acid of 100+/-81 mL day-1 were better predicted by a partitioning and diffusion model (48+/-1.8 mL day-1) across 10-60 cm s-1 water flow speeds (15+/-4.2 mL day-1 diffusion only). For perfluorohexane sulfonate, Rs at 15°C were similarly different (110+/-60 mL day-1 measured, 120+/- 63 versus 12+/-3.4 mL day-1 in respective models). Rs values from field deployments were in-between these estimates (46 +/-40 mL day-1 for perfluorohexanoic acid). PFAS uptake was not different for previously biofouled membranes in the laboratory, suggesting the general applicability of the sampler in environmental conditions. This research demonstrates that the polyethylene tube's sampling rates are sensitive to the parameterization of the models used here and partitioning-derived values should be used.

Analysis of Fibroblast Growth Factor 14 (FGF14) structural variants reveals the genetic basis of the early onset nystagmus locus NYS4 and variable ataxia.

Nystagmus (involuntary, rhythmical eye movements) can arise due to sensory eye defects, in association with neurological disorders or as an isolated condition. We identified a family with early onset nystagmus and additional neurological features carrying a partial duplication of FGF14, a gene associated with spinocerebellar ataxia type 27 (SCA27) and episodic ataxia. Detailed eye movement analysis revealed oculomotor anomalies strikingly similar to those reported in a previously described four-generation family with early onset nystagmus and linkage to a region on chromosome 13q31.3-q33.1 (NYS4). Since FGF14 lies within NYS4, we revisited the original pedigree using whole genome sequencing, identifying a 161 kb heterozygous deletion disrupting FGF14 and ITGBL1 in the affected individuals, suggesting an FGF14-related condition. Therefore, our study reveals the genetic variant underlying NYS4, expands the spectrum of pathogenic FGF14 variants, and highlights the importance of screening FGF14 in apparently isolated early onset nystagmus.

Eye tracking: empirical foundations for a minimal reporting guideline.

In this paper, we present a review of how the various aspects of any study using an eye tracker (such as the instrument, methodology, environment, participant, etc.) affect the quality of the recorded eye-tracking data and the obtained eye-movement and gaze measures. We take this review to represent the empirical foundation for reporting guidelines of any study involving an eye tracker. We compare this empirical foundation to five existing reporting guidelines and to a database of 207 published eye-tracking studies. We find that reporting guidelines vary substantially and do not match with actual reporting practices. We end by deriving a minimal, flexible reporting guideline based on empirical research (Section "An empirically based minimal reporting guideline").

Voluntary Flutter Presenting During Ophthalmoscopy: A Case Report.

Voluntary flutter (sometimes known as "voluntary nystagmus") is a conjugate saccadic oscillation of the eyes that occurs in some healthy individuals. It has no relation to pathological nystagmus, which can manifest in infancy or become acquired later in life. This report presents an unusual case of voluntary flutter that presented in a 20-year-old male with autism spectrum disorder during ocular examination via direct ophthalmoscopy. Refraction and ocular motor balance were normal, and visual acuity was good in each eye (-0.10 logMAR). During direct ophthalmoscopy, a fine intermittent tremor was initiated. The patient was referred for further assessment, and eye movements were recorded at 1,000 Hz with an EyeLink 1000 eye tracker. Upon request, the patient could manifest voluntary flutter again and sustain the eye movements with effort during convergence. The voluntary flutter consisted of back-to-back saccadic oscillations in a predominantly horizontal direction, with an average frequency of 13 Hz and an amplitude of ∼8°, both reducing over time. We speculate that the discomfort induced by the proximity of the clinician during direct ophthalmoscopy examination may have triggered the eye oscillations. Although the oscillations typically manifest during convergence, atypical forms of voluntary flutter can also occur during divergence. Voluntary flutter can be a useful differential diagnosis in patients with a recently onset apparent "nystagmus," and no other neurological signs and symptoms.

Neural modeling of antisaccade performance of healthy controls and early Huntington's disease patients.

Huntington's disease (HD), a genetically determined neurodegenerative disease, is positively correlated with eye movement abnormalities in decision making. The antisaccade conflict paradigm has been widely used to study response inhibition in eye movements, and reliable performance deficits in HD subjects have been observed, including a greater number and timing of direction errors. We recorded the error rates and response latencies of early HD patients and healthy age-matched controls performing the mirror antisaccade task. HD participants displayed slower and more variable antisaccade latencies and increased error rates relative to healthy controls. A competitive accumulator-to-threshold neural model was then employed to quantitatively simulate the controls' and patients' reaction latencies and error rates and uncover the mechanisms giving rise to the observed HD antisaccade deficits. Our simulations showed that (1) a more gradual and noisy rate of accumulation of evidence by HD patients is responsible for the observed prolonged and more variable antisaccade latencies in early HD; (2) the confidence level of early HD patients making a decision is unaffected by the disease; and (3) the antisaccade performance of healthy controls and early HD patients is the end product of a neural lateral competition (inhibition) between a correct and an erroneous decision process, and not the end product of a third top-down stop signal suppressing the erroneous decision process as many have speculated.

Beyond Visual Acuity: Development of a Simple Test of the Slow-To-See Phenomenon in Children with Infantile Nystagmus Syndrome.

PURPOSE: Conventional static visual acuity testing profoundly underestimates the impact of infantile nystagmus on functional vision. The slow-to-see phenomenon explains why many patients with nystagmus perform well in non-time restricted acuity tests but experience difficulty in certain situations. This is often observed by parents when their child struggles to recognise familiar faces in crowded scenes. A test measuring more than visual acuity could permit a more real-world assessment of visual impact and provide a robust outcome measure for clinical trials. METHODS: Children with nystagmus and, age and acuity matched controls attending Southampton General Hospital were recruited for two tasks. In the first, eye-tracking measured the time participants spent looking at an image of their mother when alongside a stranger, this was then repeated with a sine grating and a homogenous grey box. Next, a tablet-based app was developed where participants had to find and press either their mother or a target face from up to 16 faces. Here, the response time was measured. The tablet task was refined over multiple iterations. RESULTS: In the eye-tracking task, controls spent significantly longer looking at their mother and the grating (P < .05). Interestingly, children with nystagmus looked significantly longer at the grating (P < .05) but not their mother (P > .05). This confirmed a facial target was key to further development. The tablet-based task demonstrated that children with nystagmus take significantly longer to identify the target; this was most pronounced using a 3-min test with 12-face displays. CONCLUSION: This study has shown a facial target is key to identifying the time-to-see deficit in infantile nystagmus and provides the basis for an outcome measure for use in clinical treatment trials.

An automated segmentation approach to calibrating infantile nystagmus waveforms.

Infantile nystagmus (IN) describes a regular, repetitive movement of the eyes. A characteristic feature of each cycle of the IN eye movement waveform is a period in which the eyes are moving at minimal velocity. This so-called "foveation" period has long been considered the basis for the best vision in individuals with IN. In recent years, the technology for measuring eye movements has improved considerably, but there remains the challenge of calibrating the direction of gaze in tracking systems when the eyes are continuously moving. Identifying portions of the nystagmus waveform suitable for calibration typically involves time-consuming manual selection of the foveation periods from the eye trace. Without an accurate calibration, the exact parameters of the waveform cannot be determined. In this study, we present an automated method for segmenting IN waveforms with the purpose of determining the foveation positions to be used for calibration of an eye tracker. On average, the "point of regard" was found to be within 0.21° of that determined by hand-marking by an expert observer. This method enables rapid clinical quantification of waveforms and the possibility of gaze-contingent research paradigms being performed with this patient group.

An augmented reality sign-reading assistant for users with reduced vision.

People typically rely heavily on visual information when finding their way to unfamiliar locations. For individuals with reduced vision, there are a variety of navigational tools available to assist with this task if needed. However, for wayfinding in unfamiliar indoor environments the applicability of existing tools is limited. One potential approach to assist with this task is to enhance visual information about the location and content of existing signage in the environment. With this aim, we developed a prototype software application, which runs on a consumer head-mounted augmented reality (AR) device, to assist visually impaired users with sign-reading. The sign-reading assistant identifies real-world text (e.g., signs and room numbers) on command, highlights the text location, converts it to high contrast AR lettering, and optionally reads the content aloud via text-to-speech. We assessed the usability of this application in a behavioral experiment. Participants with simulated visual impairment were asked to locate a particular office within a hallway, either with or without AR assistance (referred to as the AR group and control group, respectively). Subjective assessments indicated that participants in the AR group found the application helpful for this task, and an analysis of walking paths indicated that these participants took more direct routes compared to the control group. However, participants in the AR group also walked more slowly and took more time to complete the task than the control group. The results point to several specific future goals for usability and system performance in AR-based assistive tools.

The role of Peripheral Vision in the Flashed Face Distortion Effect.

The flashed face distortion effect is a phenomenon whereby images of faces, presented at 4-5 Hz in the visual periphery, appear distorted. It has been hypothesized that the effect is driven by cortical, rather than retinal, components. Here, we investigated the role of peripheral viewing on the effect. Normally sighted participants viewed the stimulus peripherally, centrally, and centrally with a blurring lens (to match visual acuity in the peripheral location). Participants rated the level of distortion using a Visual Analogue Scale. Although optical defocus did have a significant effect on distortion ratings, peripheral viewing had a much greater effect, despite matched visual acuity. We suggest three potential mechanisms for this finding: increased positional uncertainty in the periphery, reduced deployment of attention to the visual periphery, or the visual crowding effect.

Sixteen diverse laboratory mouse reference genomes define strain-specific haplotypes and novel functional loci.

We report full-length draft de novo genome assemblies for 16 widely used inbred mouse strains and find extensive strain-specific haplotype variation. We identify and characterize 2,567 regions on the current mouse reference genome exhibiting the greatest sequence diversity. These regions are enriched for genes involved in pathogen defence and immunity and exhibit enrichment of transposable elements and signatures of recent retrotransposition events. Combinations of alleles and genes unique to an individual strain are commonly observed at these loci, reflecting distinct strain phenotypes. We used these genomes to improve the mouse reference genome, resulting in the completion of 10 new gene structures. Also, 62 new coding loci were added to the reference genome annotation. These genomes identified a large, previously unannotated, gene (Efcab3-like) encoding 5,874 amino acids. Mutant Efcab3-like mice display anomalies in multiple brain regions, suggesting a possible role for this gene in the regulation of brain development.

Low-Level Nighttime Light Therapy for Age-Related Macular Degeneration: A Randomized Clinical Trial.

Purpose: To investigate the safety, acceptability, and effectiveness of light therapy on the progression of AMD over 12 months. Methods: This was a phase I/IIa, prospective, proof-of-concept, single-center, unmasked randomized controlled trial. Sixty participants (55 to 88 years) with early AMD in the study eye and neovascular AMD (nAMD) in the fellow eye were recruited from a hospital nAMD clinic. Eligible participants were randomized (ratio 1:1) to receive light therapy or to an untreated control group. Light therapy was delivered via a light-emitting mask (peak 505 nm, 23 scotopic Td), which was worn each night for 12 months. Co-primary outcome measures were disease progression (onset of nAMD or increased drusen volume beyond test-retest limits) and change in time constant of cone dark adaptation. Other main outcomes included adverse events, compliance, and subjective sleep quality data. Results: Disease progression over 12 months was seen in 38.1% (18.1%-61.6% confidence interval [CI]) of intervention participants and 48.3% (29.4%-67.5% CI) of controls (Mantel-Haenszel test, common odds ratio = 0.763, P = 0.495). A significantly larger delay in cone adaptation was observed in the intervention group (1.66 ± 0.61 minutes) than in the control group (0.66 ± 0.49 minutes) over the follow-up period. No reported adverse events were deemed to be associated with the intervention. Conclusions: Although acceptable to the patients, light therapy did not have a substantial effect on the progression of early AMD over 12 months. Further investigation is necessary to discover the permanency and cause of the adverse effect of light therapy on dark adaptation.

Lateral visual occlusion does not change walking trajectories.

Difficulties with walking are often reported following brain damage that causes a lateralized loss of awareness on one side. Whether lateralized loss of awareness has a direct causal impact on walking is unknown. A review of the literature on visually guided walking suggests several reasons why a lateralized loss of visual awareness might be expected to lead to difficulties walking. Here, we isolated and examined the effect of lateralized vision loss on walking behavior in real and virtual environments. Healthy young participants walked to a target placed within a real room, in a virtual corridor, or on a virtual ground plane. In the ground-plane condition, the scene either was empty or contained three obstacles. We reduced vision on one side by occluding one eye (Experiment 1 and 2) or removing one hemifield, defined relative to either the head or trunk (Experiment 2), through use of eye patching (Experiment 1) and a virtual-reality system (Experiment 2). Visual-field restrictions did not induce significant deviations in walking paths in any of the occlusion conditions or any of the environments. The results provide further insight into the visual information that guides walking in humans, and suggest that lateralized vision loss on its own is not the primary cause of walking difficulties.