brainlife.io: a decentralized and open-source cloud platform to support neuroscience research.

Neuroscience is advancing standardization and tool development to support rigor and transparency. Consequently, data pipeline complexity has increased, hindering FAIR (findable, accessible, interoperable and reusable) access. brainlife.io was developed to democratize neuroimaging research. The platform provides data standardization, management, visualization and processing and automatically tracks the provenance history of thousands of data objects. Here, brainlife.io is described and evaluated for validity, reliability, reproducibility, replicability and scientific utility using four data modalities and 3,200 participants.

Perspectives of carriers of X-linked retinal diseases on genetic testing and gene therapy: A global survey.

Female carriers of X-linked inherited retinal diseases (IRDs) are burdened with potentially passing their disease-causing variant to future generations, as well as exhibiting signs of retinal disease themselves. This study aimed to investigate carriers' experiences of genetic testing, emotions relating to having affected children, and their knowledge regarding genetic testing and gene therapy. An online survey was advertised to self-identified carriers worldwide. Two hundred and twenty-eight carriers completed the survey with mean age of 51 years (SD ± 15.0). A majority of respondents resided in the United States of America (51%), Australia (19%), and the United Kingdom (14%). Most carriers identified with feelings of guilt (70%), concern (91%), and anxiety (88%) for their child. Female carriers who had given birth to children had significantly greater gene therapy knowledge compared to carriers who had not (p < 0.05). Respondents agreed that their eyecare provider and general practitioner helped them understand their condition (63%), however, few carriers reported receiving psychological counselling (9%) or family planning advice (5%). Most respondents (78%) agreed that gene therapy should be available to carriers. This study emphasises the importance of providing appropriate counselling to female carriers and illustrates the motivation of many to participate in emerging treatment options, such as gene therapy.

Investigating the impact of asymmetric macular sensitivity on visual acuity chart reading in choroideraemia.

INTRODUCTION: Degeneration in choroideraemia, unlike typical centripetal photoreceptor degenerations, is centred temporal to the fovea. Once the fovea is affected, the nasal visual field (temporal retina) is relatively spared, and the preferred retinal locus shifts temporally. Therefore, when reading left to right, only the right eye reads into a scotoma. We investigate how this unique property affects the ability to read an eye chart. METHODS: Standard- and low-luminance visual acuity (VA) for right and left eyes were measured with the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Letters in each line were labelled by column position. The numbers of letter errors for each position across the whole chart were summed to produce total column error scores for each participant. Macular sensitivity was assessed using microperimetry. Central sensitivity asymmetry was determined by the temporal-versus-nasal central macular difference and subsequently correlated to a weighted ETDRS column error score. Healthy volunteers and participants with X-linked retinitis pigmentosa GTPase regulator associated retinitis pigmentosa (RPGR-RP) were used as controls. RESULTS: Thirty-nine choroideraemia participants (median age 44.9 years [IQR 35.7-53.5]), 23 RPGR-RP participants (median age 30.8 years [IQR 26.5-40.5]) and 35 healthy controls (median age 23.8 years [IQR 20.3-29.0]) were examined. In choroideraemia, standard VA in the right eye showed significantly greater ETDRS column errors on the temporal side compared with the nasal side (p = 0.002). This significantly correlated with greater asymmetry in temporal-versus-nasal central macular sensitivity (p = 0.04). No significant patterns in ETDRS column errors or central macular sensitivity were seen in the choroideraemia left eyes, nor in RPGR-RP and control eyes. CONCLUSION: Difficulty in tracking across lines during ETDRS VA testing may cause excess errors independent of true VA. VA assessment with single-letter optotype systems may be more suitable, particularly for patients with choroideraemia, and potentially other retinal diseases with asymmetric central macular sensitivity or large central scotomas including geographic atrophy.

Multimodal Analysis of the Visual Pathways in Friedreich's Ataxia Reveals Novel Biomarkers.

BACKGROUND: Optic neuropathy is a near ubiquitous feature of Friedreich's ataxia (FRDA). Previous studies have examined varying aspects of the anterior and posterior visual pathways but none so far have comprehensively evaluated the heterogeneity of degeneration across different areas of the retina, changes to the macula layers and combined these with volumetric MRI studies of the visual cortex and frataxin level. METHODS: We investigated 62 genetically confirmed FRDA patients using an integrated approach as part of an observational cohort study. We included measurement of frataxin protein levels, clinical evaluation of visual and neurological function, optical coherence tomography to determine retinal nerve fibre layer thickness and macular layer volume and volumetric brain MRI. RESULTS: We demonstrate that frataxin level correlates with peripapillary retinal nerve fibre layer thickness and that retinal sectors differ in their degree of degeneration. We also shown that retinal nerve fibre layer is thinner in FRDA patients than controls and that this thinning is influenced by the AAO and GAA1. Furthermore we show that the ganglion cell and inner plexiform layers are affected in FRDA. Our MRI data indicate that there are borderline correlations between retinal layers and areas of the cortex involved in visual processing. CONCLUSION: Our study demonstrates the uneven distribution of the axonopathy in the retinal nerve fibre layer and highlight the relative sparing of the papillomacular bundle and temporal sectors. We show that thinning of the retinal nerve fibre layer is associated with frataxin levels, supporting the use the two biomarkers in future clinical trials design. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A cross-sectional study to assess the clinical utility of modern visual function assessments in patients with inherited retinal disease: a mixed methods observational study protocol.

BACKGROUND: Treatment options for patients with inherited retinal disease are limited, although research into novel therapies is underway. To ensure the success of future clinical trials, appropriate visual function outcome measures that can assess changes resulting from therapeutic interventions are urgently required. Rod-cone degenerations are the most common type of inherited retinal disease. Visual acuity is a standard measure but is typically preserved until late disease stages, frequently making it an unsuitable visual function marker. Alternative measures are required. This study investigates the clinical utility of a range of carefully selected visual function tests and patient reported outcome measures. The aim is to identify suitable outcome measures for future clinical trials that could be considered for regulatory approval. METHODS: This cross-sectional study involves two participant groups, patients with inherited retinal disease (n = 40) and healthy controls (n = 40). The study has been designed to be flexible and run alongside NHS clinics. The study is split into two parts. Part one includes examining standard visual acuity, low luminance visual acuity, the Moorfields acuity chart visual acuity, mesopic microperimetry and three separate patient reported outcome measures. Part two involves 20 min of dark adaptation followed by two-colour scotopic microperimetry. Repeat testing will be undertaken where possible to enable repeatability analyses. A subset of patients with inherited retinal disease will be invited to participate in a semi-structured interview to gain awareness of participants' thoughts and feelings around the study and different study tests. DISCUSSION: The study highlights a need for reliable and sensitive validated visual function measures that can be used in future clinical trials. This work will build on work from other studies and be used to inform an outcome measure framework for rod-cone degenerations. The study is in keeping with the United Kingdom Department of Health and Social Care research initiatives and strategies for increasing research opportunities for NHS patients as part of their NHS care. TRIAL REGISTRATION: ISRCTN registry, ISRCTN24016133, Visual Function in Retinal Degeneration, registered on 18th August 2022.

Harnessing the potential of practice-based clinical optometry research in the United Kingdom.

Research is the core of evidence-based practice across all healthcare, in order to ensure optimum patient care. The College of Optometrists is a national standard setting institution for optometric practice in the United Kingdom. However, the standards are only as good as the available evidence, and currently there is little evidence relating directly to optometric practice. The National Institute of Health and Care Research, the General Medical Council and The College of Optometrists, amongst others, have published research strategies describing ambitious plans to expand the scope of healthcare research. The aim of this article is to raise awareness of these government initiatives and consider how they may relate to optometric practice. To improve optometrist research engagement, we need to address the barriers to research and implement strategies to overcome them. There are many opportunities to support research, with different degrees of involvement, from signposting patients to research studies, supporting recruitment or collecting data for a multicentre clinical trial, as well as undertaking an individual research project. Healthcare research is changing and there is scope for more practice-based research activities in optometry. Research should not be a solo endeavour but a multi-disciplinary effort. Greater collaborations across all stakeholders, including primary care, secondary care, academia, regulators and industry is needed to make this possible.

Low luminance visual acuity as a clinical measure and clinical trial outcome measure: a scoping review.

PURPOSE: The measurement of standard visual acuity (VA) is the most well-known part of any ophthalmic examination to indicate visual function. Despite this, it is insensitive in detecting early disease changes. Therefore, other visual function tests have been developed including low luminance VA (LLVA) and low luminance deficit (LLD). This scoping literature review aims to summarise the current published applications of LLVA and LLD assessments to evaluate their utility as clinical markers and research outcome measures in a variety of ophthalmic conditions. RECENT FINDINGS: Sixty-five peer-reviewed publications were included. LLVA was pioneered for use in geographic atrophy, a subtype of age-related macular degeneration, which remains the mainstay of its clinical application. However, other studies have reported additional useful applications in inherited retinal diseases including rare maculopathies and rod-cone dystrophies. Although there are some variations in testing methodology, use of the standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart with a 2.0 log unit neutral density filter is the most popular approach. The optimal testing luminance is still to be defined. SUMMARY: Overall, LLVA is an earlier clinical marker of change in central retinal function than standard VA. It has been shown to be a risk factor for disease progression and a better indicator of a patient's level of everyday visual function. It is inexpensive and simple to implement using readily available standard ophthalmic equipment.

Early Cone Photoreceptor Outer Segment Length Shortening in RPGR X-Linked Retinitis Pigmentosa.

INTRODUCTION: Introduction of retinal gene therapy requires established outcome measures along with thorough understanding of the pathophysiology. Evidence of early, thinned outer segments in RPGR X-linked retinitis pigmentosa could help understand how the level of cone photoreceptor involvement translates to visual potential. OBJECTIVE: Analysis of foveal photoreceptor outer segment length in a young cohort of RPGR patients to help clarify the reason for absent maximal visual acuity seen. METHODS: Case-control study of RPGR patients. Quantitative measurement of photoreceptor outer segment by OCT. RESULTS: Eighteen male RPGR patients and 30 normal subjects were included. Outer segment thickness differed significantly between the RPGR and normal eyes (p < 0.0005). Mean outer segment values were 35.6 ± 2.3 µm and 35.4 ± 2.6 µm for RPGR right and left eyes, respectively. In normal eyes, the mean outer segment thickness was 61.4 ± 0.7 µm for right eyes and 62.4 ± 0.7 µm for left eyes. CONCLUSIONS: Patients with RPGR X-linked retinitis pigmentosa show thinning of the foveal photoreceptor outer segment thickness early in the disease course, which could be an explanation for the lower maximum visual acuity seen. These findings must be taken into consideration when assessing efficacy outcome measures in retinal gene therapy trials.

The Impact of Progressive Visual Field Constriction on Reading Ability in an Inherited Retinal Degeneration.

BACKGROUND: The ability to read is an important factor in the quality of life. Choroideremia is an inherited retinal degeneration presenting with gradual, progressive constriction of the central visual field, providing a useful disease model to investigate the impact of the visual field on reading ability. OBJECTIVE: The aim of this study was to provide practical guidance on the usefulness of measuring reading ability in patients. METHOD: The Radner Reading Test was administered to 33 patients (65 eyes with choroideremia). To quantify the residual retinal area, the patients underwent microperimetry and imaging. The visual angle subtended by the largest letter read by each subject was calculated using Emsley's Model Eye. RESULTS: A minimum of 1 letter must be seen to allow the eye to read, with preservation of foveal sensitivity. The relationship between reading speed and acuity varies with the visual field. The reading speed is higher in eyes with an intact fovea (p < 0.001 right eye, p = 0.06 left eye). Qualitative analysis of the direction of the intact retina did not indicate any directional impact on measurements. CONCLUSIONS: In order to read, an eye must have enough retinal width close to the fovea to see at least 1 full letter. Direction of print does not impact the ability to read, allowing results from different languages to be combined in clinical trials.

Transcorneal Electrical Stimulation for the Treatment of Retinitis Pigmentosa: A Multicenter Safety Study of the OkuStim® System (TESOLA-Study).

BACKGROUND: Transcorneal electrical stimulation (TES) has been suggested as a possible treatment for retinitis pigmentosa (RP). OBJECTIVE: To expand the safety assessment of repeated applications of an electrical current from a DTL-like electrode in patients with RP. METHODS: This single-arm open label interventional safety trial included a total of 105 RP patients from 11 European centers, who received weekly TES for 6 months on 1 eye followed by observation for another 6 months without stimulation. The primary outcome measure was safety, indicated by the frequency and severity of adverse events. Secondary measures included intraocular pressure and central retinal thickness. Visual field and visual acuity were examined using the methods available at each site. RESULTS: Dry eye sensation was the most common adverse event recorded (37.5%). Serious adverse events secondary to TES were not observed. Most adverse events were mild and all resolved without sequelae. The secondary outcome measures revealed no significant or clinically relevant changes. CONCLUSION: The present results confirm the excellent safety profile of TES. Transient dry eye symptoms were the most common adverse event.

A Randomized Crossover Study to Assess the Usability of Two New Vision Tests in Patients with Low Vision.

SIGNIFICANCE: Well-established charts such as Early Treatment Diabetic Retinopathy Study are able to quantify visual acuity (VA) with a low cutoff of 1.6 logMAR. Below this point, nonquantitative measures, such as count fingers, hand movements, and light perception, are used. There is a need for more reproducible, comparable, and reliable ways to measure VA changes in this patient cohort. PURPOSE: The purpose of this study was to examine and compare the ability of the Berkeley Rudimentary Vision Test (BRVT) and the Freiburg Acuity Test (FrACT) to quantify VA in low-vision patients who score nonnumerical VAs in standard charts. METHODS: Fifty adult participants with VA ≤1.0 logMAR in both eyes were recruited from the Oxford Eye Hospital, Oxford, United Kingdom. Correlation between FrACT and BRVT results and the correlation between VA and daily living activities were analyzed statistically. Potential predictors of differences were investigated. RESULTS: The BRVT was significantly faster to conduct (P = .002), but FrACT was able to quantify vision numerically in a greater proportion of eyes. The κ agreement between tests was 0.26. The difference increased systematically with the VA reduction (P < .0001). The Bland-Altman analysis showed a skew to measurement of lower logMAR VA indicating better vision measured on the FrACT. The only significant predictor of difference between the tests was binocular VA (coefficient, -0.445; P = .001). CONCLUSIONS: Both tests are suitable for a very low-vision population. The BRVT is a faster test to administer, but FrACT provides a numerical result in more eyes. The poor intertest repeatability indicates that they cannot be used interchangeably. The BRVT generally reported poorer vision than did the FrACT. The medium of presentation, such as a computer screen or externally lit print medium, is likely to be the biggest factor in these differences and warrants further investigation.

The elephant in the room: understanding the pathogenesis of Charles Bonnet syndrome.

PURPOSE: Charles Bonnet syndrome (CBS) is a syndrome characterised by complex visual hallucinations in individuals who are cognitively normal, though often elderly and visually impaired. Although first described over 250 years ago, the condition remains poorly understood and difficult to treat. RECENT FINDINGS: Our understanding of CBS pathogenesis has advanced little since it was first described, and much of the recent literature consists of case studies strikingly similar to the first published account of CBS. However, imaging studies have provided some indication as to the cortical areas implicated in the genesis of complex visual hallucinations, and the existence of similar hallucinatory syndromes in other sensory modalities suggests a common underlying mechanism. SUMMARY: This review begins by describing what is currently known about CBS, focusing on epidemiology, clinical presentation and diagnosis. It then explores potential starting points for better understanding the pathogenesis of CBS, namely the existence of similar conditions in other sensory modalities and the reproduction of complex visual hallucinations in sensory deprivation scenarios. Finally, it discusses how CBS should be approached in clinical practice.

Colour discrimination ellipses in choroideremia.

PURPOSE: The purpose of this study was to characterise alterations in colour discrimination in a cohort of patients with choroideremia prior to gene therapy, using a test previously validated for use in patients with retinal dystrophies. METHODS: We tested 20 eyes of 10 patients with a diagnosis of choroideremia and an age-matched cohort of 10 eyes of 10 normal controls using the "Cambridge Colour Test" (CCT), in which subjects are required to distinguish the gap in a C presented in one of 4 orientations in a Stilling-type array. Colour discrimination was probed along eight axes in the CIE L*u*v* colour space, and the resulting data were plotted in the CIE 1976 chromaticity diagram and fitted with least-squares ellipses. Subsequently, we estimated the achromatic area for each subject by calculating the area of the resultant discrimination ellipse and calculated sensitivity thresholds along relevant colour confusion axes. RESULTS: Colour discrimination-as quantified by log10 of the ellipse area expressed in square 1/1000th2 units in CIE 1976-was 2.26 (range 1.82 to 2.67) for normal subjects and 3.85 (range 2.35 to 5.41) for choroideremia patients. There was a statistically significant correlation between both achromatic area and red-green colour discrimination at the CCT and BCVA, and to a lesser degree between blue colour discrimination at the CCT and BCVA. The majority of ellipses in choroideremia were aligned close to the tritan axis, and loss of sensitivity was significantly larger in the tritan direction than in the red-green. CONCLUSIONS: The majority of our patients demonstrated greater loss in tritan discrimination than in red-green colour discrimination using the CCT. There was a significant correlation between achromatic area and BCVA. In keeping with our current understanding of the machinery of colour vision, there was a significant correlation between BCVA and colour discrimination thresholds, which was stronger for red-green colour discrimination, than for tritan colour discrimination. We propose that this and similar tests of colour discrimination may prove to be suitable tools for assessing functional outcomes in gene therapy trials for choroideremia.

Real-world refractive outcomes of toric intraocular lens implantation in a United Kingdom National Health Service setting.

BACKGROUND: With increasing availability of toric intraocular lenses (IOL) for cataract surgery, real-world refractive outcome data is needed to aid the counselling of patients regarding lens choice. We aim to assess the outcomes of toric intraocular lens use in the non-specialist environment of a typical United Kingdom NHS cataract service. METHODS: A retrospective cohort study conducted at the Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, UK. All patients who received a toric IOL implant over a 10 months period. Patients underwent pre-operative corneal marking, phacoemulsification and toric IOL implantation. Biometry was obtained using a Zeiss IOLMaster 500 and the toric IOLs were selected using the manufacturers' online calculators. Post-operative refractions were obtained from optometrist's manifest refraction or by autorefraction. The outcome measures were post-operative unaided visual acuity (UVA), spherical equivalent refraction, cylindrical correction and all complications. RESULTS: Thirty-two eyes of 24 patients aged 21-86 years (mean 66.4, SD 14.5) were included. UVA was superior to pre-operative best-corrected visual acuity (BCVA) in 81% of eyes, same in 16% and inferior in 3%, resulting in a median improvement of 0.20 LogMAR (IQR 0.10 to 0.30). 56%, 81%, 94% and 100% of eyes were within ±0.5, ±1.0, ±1.5 and ±2.0 D of predicted spherical equivalent, respectively. Three (9%) eyes required further surgery to rectify significant IOL rotation. CONCLUSIONS: Reduced cylindrical correction and improved UVA could be expected in the majority of patients undergoing toric IOL implantation. Patients should be counselled about the risk of lens rotation.

Effects of pupil dilation on MAIA microperimetry.

BACKGROUND: Macular Integrity Assessment microperimetry assesses macular sensitivity to projected point light sources and maps eye movements to assess fixation stability. Although microperimetry is gaining prominence as an assessment tool in clinical and research settings, there is no consensus on whether it should be performed before or after pupil dilation. No studies to date have examined the effect of pupil dilation on results. The aim of this project was to elucidate the effect of pupil dilation on microperimetry outcomes. DESIGN: Prospective audit. PARTICIPANTS: Twenty healthy patients from postoperative cataract clinic and 10 patients with choroideremia to simulate a disease with peripheral visual field loss. METHODS: Subjects underwent 10-2 68-point field testing using the Macular Integrity Assessment microperimeter on each eye. Subjects then underwent randomized dilation of one eye, and the test was repeated in both eyes. MAIN OUTCOME MEASURES: We compared changes in threshold sensitivity and fixation stability pre-pupil and post-pupil dilation. The undilated eye was analysed for any learning or fatigue effect caused by test repetition. RESULTS: Dilation produced no significant effect on threshold sensitivity (dilation effect: -0.29 decibels, P = 0.23) or fixation stability in healthy controls or in choroideremia patients (dilation effect: +0.08log bivariate contour ellipse area, P = 0.14). There was also no significant learning effect seen in the undilated eye, with no improvement in threshold sensitivity (order of eye testing: +0.03log bivariate contour ellipse area, P = 0.71). CONCLUSIONS: In the clinical setting, patients may be tested for 10 degree microperimetry with or without pupil dilation, as both scenarios yield consistent and interchangeable results.

Optical coherence tomography in children with inherited retinal disease.

Recent advances have led to therapeutic options becoming available for people with inherited retinal disease. In particular, gene therapy has been shown to hold great promise for slowing vision loss from inherited retinal disease. Recent studies suggest that gene therapy is likely to be most effective when implemented early in the disease process, making consideration of paediatric populations important. It is therefore necessary to have a comprehensive understanding of retinal imaging in children with inherited retinal diseases, in order to monitor disease progression and to determine which early retinal biomarkers may be used as outcome measures in future clinical trials. In addition, as many optometrists will review children with an inherited retinal disease, an understanding of the expected imaging outcomes can improve clinical care. This review focuses on the most common imaging modality used in research assessment of paediatric inherited retinal diseases: optical coherence tomography. Optical coherence tomography findings can be used in both the clinical and research setting. In particular, the review discusses current knowledge of optical coherence tomography findings in eight paediatric inherited retinal diseases - Stargardt disease, Bests disease, Leber's congenital amaurosis, choroideremia, RPGR related retinitis pigmentosa, Usher syndrome, X-linked retinoschisis and, Batten disease.

Retinal characteristics of female choroideremia carriers: Multimodal imaging, microperimetry and genetics.

PURPOSE: Describe visual function and retinal features of female carriers of choroideremia (CHM), using multimodal imaging and microperimetry. DESIGN: Cross-sectional cohort study PARTICIPANTS AND CONTROLS: CHM carriers seen in Australia (Melbourne or Perth) or United Kingdom (Oxford or Cambridge) between 2012 and 2023. Healthy age-matched controls seen in Melbourne, Australia, between 2022 and 2023. METHODS: Participants had visual acuity, fundus-tracked microperimetry, optical coherence tomography (OCT), and fundus autofluorescence (FAF) imaging performed. CHM carriers were either genetically and/or clinically confirmed (i.e., obligate carriers). CHM carriers were grouped according to their retinal phenotype and compared to healthy controls. Statistical analyses were performed on StataBE (v18.0). MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), average retinal sensitivity, volume of macular hill of vision (HoV), inner retinal thickness (IRT), and photoreceptor complex (PRC) thickness. RESULTS: Eighty-six eyes of 43 CHM carriers and 60 eyes of 30 healthy controls were examined using multimodal imaging and microperimetry. Median age was 54 and 48.5 years for CHM carriers and controls, respectively (p=0.18). Most CHM carriers (86%) were genetically confirmed. CHM carriers and controls had strong inter-eye correlation between eyes for BCVA and average retinal sensitivity (p<0.001). LLVA and macular HoV tests were sensitive tests to detect changes in CHM carriers with mild phenotypes (i.e., fine and coarse). CHM carriers with geographic and/or male pattern phenotypes had reduced BCVA, LLVA, retinal sensitivity, and retinal thinning, compared to healthy controls. Retinal thickening of the inner retina was observed in the central 1 degree, despite generalised thinning of the PRC in the central 7 degrees, indicating retinal remodelling in CHM carriers, compared to controls. There were no genotype-phenotype correlations observed. CONCLUSIONS: Female carriers of CHM with severe retinal phenotypes (i.e., geographic or male pattern) have significantly decreased visual function and retinal structural changes, when compared to age-matched controls and those carriers with milder phenotypes. LLVA and volumetric measures of the macular HoV were found to be the most sensitive functional tests to detect milder retinal disease (fine and coarse phenotypes) in CHM carriers.