Development and Validation of a Novel Mobility Test for Rod-Cone Dystrophies: From Reality to Virtual Reality.

PURPOSE: To validate a novel mobility test (MOST, MObility Standardized Test) and performance outcomes in real (RL) and virtual (VR) environments to be used for interventional clinical studies in order to characterize vision impairment in rod-cone dystrophies, also known as retinitis pigmentosa (RP). DESIGN: Prospective, interventional, noninvasive, reliability and validity analysis. METHODS: We designed MOST to be used in both VR and RL and conducted 3 experimental studies with 89 participants to (1) validate the difficulty of the mobility courses (15 controls), (2) determine the optimal number of light levels and training trials (14 participants with RP), and (3) validate the reproducibility (test-retest), reliability (VR/RL), sensitivity, and construct/content validity of the test (30 participants with RP and 30 controls). A comprehensive ophthalmologic examination was performed in all subjects. Outcomes of interest included MOST performance score, visual acuity, contrast sensitivity, dark adaptation thresholds, visual field parameters, and correlation between the performance score and visual function. RESULTS: The mobility courses exhibited statistically similar difficulty, and 5 trials are sufficient to control for the learning effect. MOST is highly reproducible (test-retest correlations >0.98) and reliable (correlations VR/RL = 0.98). MOST achieved a discrimination between participants with RP and controls (accuracy >95%) and between early and late stages of the disease (82.3% accuracy). The performance score is correlated with visual function parameter (0.57-0.94). CONCLUSION: MOST is a validated mobility test, with the controlled learning effect, excellent reproducibility, and high agreement between RL and VR conditions, as well as sensitivity and specificity to measure disease progression and therapeutic benefit in rod-cone dystrophies.

Landmark-based spatial navigation across the human lifespan.

Human spatial cognition has been mainly characterized in terms of egocentric (body-centered) and allocentric (world-centered) wayfinding bhavior. It was hypothesized that allocentric spatial coding, as a special high-level cognitive ability, develops later and deteriorates earlier than the egocentric one throughout lifetime. We challenged this hypothesis by testing the use of landmarks versus geometric cues in a cohort of 96 deeply phenotyped participants, who physically navigated an equiangular Y maze, surrounded by landmarks or an anisotropic one. The results show that an apparent allocentric deficit in children and aged navigators is caused specifically by difficulties in using landmarks for navigation while introducing a geometric polarization of space made these participants as efficient allocentric navigators as young adults. This finding suggests that allocentric behavior relies on two dissociable sensory processing systems that are differentially affected by human aging. Whereas landmark processing follows an inverted-U dependence on age, spatial geometry processing is conserved, highlighting its potential in improving navigation performance across the lifespan.

Mobility Testing and Other Performance-Based Assessments of Functional Vision in Patients with Inherited Retinal Disease.

In the field of clinical ophthalmology, many of the common visual function study end points do not effectively reflect the significant morbidity of inherited retinal diseases (IRDs) and its effect on the patient's quality of life. In the last decade, emphasis has been placed on the development and implementation of patient-performance or task-focused end points, that may have greater ability to demonstrate the improvement or preservation of the patient's quality of life provided by therapeutic interventions. This article reviews performance-based tools developed to assess functional vision, such as the multi-luminance mobility test (MLMT) or the functional low-vision observer-rated assessment (FLORA), and highlights some of the recent advancements used in clinical development for IRD or ocular interventional therapies.

Driving behaviour and visual compensation in glaucoma patients: Evaluation on a driving simulator.

BACKGROUND: To assess the driving performance and both the visual scanning and driving compensations of glaucoma patients. METHODS: In this case-control pilot study, the driving behaviour and performance of 14 patients with glaucoma and nine healthy age- and sex-similar control subjects were compared in a fixed-base driving simulator. All subjects performed in four scenarios with one to two hazardous situations on urban streets, for a total of five hazards. Measurements taken during the tests included reaction times, longitudinal regulation, lateral control and eye and head movements. RESULTS: Glaucoma patients showed poor driving performance with longer reaction time to hazardous situations than control subjects: pedestrians crossing the road from the left (p < 0.022) or from the right (p = 0.013), and vehicles coming from the left (p = 0.002). Their mean duration of lateral excursion was longer (p = 0.045), and they showed more lane excursions in a wide left curve (p = 0.045). Glaucoma patients also showed a higher standard deviation of time-headway (p = 0.048) with preceding vehicles. Analyses of driving behavioural compensations on curved roads showed that glaucoma patients stayed closer to the centre line in large (p = 0.006) and small (p = 0.025) left curves and on small right curves (p = 0.041). Additionally, on straight roads, as compared to control subjects, glaucoma patients showed longer mean time-headway (p = 0.032) and lower mean speed (p = 0.04). Finally, the glaucoma group exhibited a larger standard deviation of horizontal gaze (p = 0.034) than the control subjects. CONCLUSIONS: In a virtual driving environment, glaucoma patients exhibited unsafe driving behaviours, despite their driving and eye-scanning compensations.

Glare and Mobility Performance in Glaucoma: A Pilot Study.

PRCIS: Glare disability affects patients with moderate and severe glaucoma. Under glare conditions, mobility performances of glaucoma patients are reduced. PURPOSE: The aim of this study was to evaluate glare disability and its impact on mobility and orientation in glaucoma patients. METHODS: Twenty-two glaucoma patients and 12 age-matched control subjects were included. All patients underwent a clinical evaluation of visual function and halo size measurements to determine glare disability with a glare score (GS) of the best eye and worse eye. Mobility was evaluated by 4 mobility courses on an artificial street (StreetLab) under photopic conditions (P) and mesopic conditions with an additional light source in front of the patient to mimic dazzling conditions (M+G). Mobility time, mobility incidents, trajectory segmentation, distance traveled, preferred walking speed on trial (WS) and percentage of preferred walking speed (PPWS) were recorded, and the Nasa task load index (Nasa-TLX) was evaluated. RESULTS: GS of the worse eye and GS of the best eye were significantly higher in glaucoma patients than in the control group (P=0.001 and 0.003). It was significantly different between moderate glaucoma patients and controls (P=0.001 and 0.010, respectively) and between severe glaucoma patients and controls (P=0.049 and 0.016). In locomotion tasks, comparing performance under M+G and P conditions, mobility performance was significantly different concerning mobility time (P=0.010), distance traveled (P=0.008), WS (P=0.007), PPWS (P=0.006), and Nasa-TLX (P=0.017) in the glaucoma group. Under M+G lighting conditions, mobility performance for glaucoma patients was significantly worse than controls with regard to WS (P=0.038), PPWS (P=0.0498), mobility time (P=0.046), and Nasa-TLX (P=0.006). CONCLUSION: Glare disability was observed in patients with moderate and severe glaucoma and had an impact on their mobility performance.

Assessing Photoreceptor Status in Retinal Dystrophies: From High-Resolution Imaging to Functional Vision.

PURPOSE: To describe the value of integrating phenotype/genotype data, disease staging, and evaluation of functional vision in patient-centered management of retinal dystrophies. METHODS: (1) Cross-sectional structure-function and retrospective longitudinal studies to assess the correlations between standard fundus autofluorescence (FAF), optical coherence tomography, visual acuity (VA), and perimetry (visual field [VF]) examinations to evaluate photoreceptor functional loss in a cohort of patients with rod-cone dystrophy (RCD); (2) flood-illumination adaptive optics (FIAO) imaging focusing on photoreceptor misalignment and orientation of outer segments; and (3) evaluation of the impact of visual impairment in daily life activities, based on functional (visual and mobility) vision assessment in a naturalistic environment in visually impaired subjects with RCD and subjects treated with LuxturnaⓇ for RPE65-related Leber congenital amaurosis before and after therapy. RESULTS: The results of the cross-sectional transversal study showed that (1) VA and macular sensitivity were weakly correlated with the structural variables; and (2) functional impairment (VF) was correlated with reduction of anatomical markers of photoreceptor structure and increased width of autofluorescent ring. The dimensions of the ring of increased FAF evolved faster. Other criteria that differed among groups were the lengths of the ellipsoid zone, the external limiting membrane, and the foveal thickness. FIAO revealed a variety of phenotypes: paradoxical visibility of foveal cones; heterogeneous brightness of cones; dim, inner segment-like, and RPE-like mosaic. Directional illumination by varying orientation of incident light (Stiles-Crawford effect) and the amount of side illumination (gaze-dependent imaging) affected photoreceptor visibility. Mobility assessment under different lighting conditions showed correlation with VF, VA, contrast sensitivity (CS), and dark adaptation, with different predictive values depending on mobility study paradigms and illumination level. At high illumination level (235 lux), VF was a predictor for all mobility performance models. Under low illumination (1 and 2 lux), VF was the most significant predictor of mobility performance variables, while CS best explained the number of collisions and segments. In subjects treated with LuxturnaⓇ, a very favorable impact on travel speed and reduction in the number of collisions, especially at low luminance, was observable 6 months following injection, in both children and adults. CONCLUSIONS: Our results suggest the benefit of development and implementation of quantitative and reproducible tools to evaluate the status of photoreceptors and the impact of both visual impairment and novel therapies in real-life conditions. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Visual brain plasticity induced by central and peripheral visual field loss.

Disorders that specifically affect central and peripheral vision constitute invaluable models to study how the human brain adapts to visual deafferentation. We explored cortical changes after the loss of central or peripheral vision. Cortical thickness (CoTks) and resting-state cortical entropy (rs-CoEn), as a surrogate for neural and synaptic complexity, were extracted in 12 Stargardt macular dystrophy, 12 retinitis pigmentosa (tunnel vision stage), and 14 normally sighted subjects. When compared to controls, both groups with visual loss exhibited decreased CoTks in dorsal area V3d. Peripheral visual field loss also showed a specific CoTks decrease in early visual cortex and ventral area V4, while central visual field loss in dorsal area V3A. Only central visual field loss exhibited increased CoEn in LO-2 area and FG1. Current results revealed biomarkers of brain plasticity within the dorsal and the ventral visual streams following central and peripheral visual field defects.

Cannabis smoking impairs driving performance on the simulator and real driving: a randomized, double-blind, placebo-controlled, crossover trial.

Driving experiments in real conditions are considered as a 'gold standard' to evaluate the effects of drugs on driving performance. Several constraints are difficult to manage in these conditions, so driving simulation appears as the best alternative. A preliminary comparison is crucial before being able to use driving simulation as a valid evaluation method. The aim of this study was to design a driving simulation method for assessing drug effects on driving. We used cannabis (THC) as a positive control and assessed whether THC affects driving performance in simulation conditions and whether these effects are consistent with performance in real driving conditions. A double-blind, placebo-controlled, two successive two-way crossover design was performed using cigarettes containing 20 mg of THC. Healthy occasional users of THC, aged 25-35 years, who had a consistent driving experience were included. The first two sessions were realized in simulation conditions, and the last two sessions were in real driving conditions. Driving performance was estimated through inappropriate line crossings (ILC) and the standard deviation of the vehicle's lateral position. Participants felt significantly drowsier and more tired after THC, whatever the driving condition. Driving stability was significantly impaired after THC, both in simulated and real driving conditions. We also found that ILC were significantly more numerous in driving simulation conditions, as compared to real driving. In conclusion, the driving simulator was proven to be more sensitive for demonstrating THC-induced effects on driving performances. Driving simulation appears to be a good qualitative predictor of driving safety after drug intake.

Adaptive Gaze Strategies for Locomotion with Constricted Visual Field.

In retinitis pigmentosa (RP), loss of peripheral visual field accounts for most difficulties encountered in visuo-motor coordination during locomotion. The purpose of this study was to accurately assess the impact of peripheral visual field loss on gaze strategies during locomotion, and identify compensatory mechanisms. Nine RP subjects presenting a central visual field limited to 10-25° in diameter, and nine healthy subjects were asked to walk in one of three directions-straight ahead to a visual target, leftward and rightward through a door frame, with or without obstacle on the way. Whole body kinematics were recorded by motion capture, and gaze direction in space was reconstructed using an eye-tracker. Changes in gaze strategies were identified in RP subjects, including extensive exploration prior to walking, frequent fixations of the ground (even knowing no obstacle was present), of door edges, essentially of the proximal one, of obstacle edge/corner, and alternating door edges fixations when approaching the door. This was associated with more frequent, sometimes larger rapid-eye-movements, larger movements, and forward tilting of the head. Despite the visual handicap, the trajectory geometry was identical between groups, with a small decrease in walking speed in RPs. These findings identify the adaptive changes in sensory-motor coordination, in order to ensure visual awareness of the surrounding, detect changes in spatial configuration, collect information for self-motion, update the postural reference frame, and update egocentric distances to environmental objects. They are of crucial importance for the design of optimized rehabilitation procedures.

Reorganization of early visual cortex functional connectivity following selective peripheral and central visual loss.

Behavioral alterations emerging after central or peripheral vision loss suggest that cerebral reorganization occurs for both the afferented and deafferented early visual cortex (EVC). We explored the functional reorganization of the central and peripheral EVC following visual field defects specifically affecting central or peripheral vision. Compared to normally sighted, afferented central and peripheral EVC enhance their functional connectivity with areas involved in visual processing, whereas deafferented central and peripheral EVC increase their functional connectivity with more remote regions. The connectivity pattern of afferented EVC suggests adaptive changes that might enhance the visual processing capacity whereas the connectivity pattern of deafferented EVC may reflect the involvement of these regions in high-order mechanisms. Characterizing and understanding the plastic changes induced by these visual defects is essential for any attempt to develop efficient rehabilitation strategies.

Increased functional connectivity between language and visually deprived areas in late and partial blindness.

In the congenitally blind, language processing involves visual areas. In the case of normal visual development however, it remains unclear whether later visual loss induces interactions between the language and visual areas. This study compared the resting-state functional connectivity (FC) of retinotopic and language areas in two unique groups of late visually deprived subjects: (1) blind individuals suffering from retinitis pigmentosa (RP), (2) RP subjects without a visual periphery but with preserved central "tunnel vision", both of whom were contrasted with sighted controls. The results showed increased FC between Broca's area and the visually deprived areas in the peripheral V1 for individuals with tunnel vision, and both the peripheral and central V1 for blind individuals. These findings suggest that FC can develop in the adult brain between the visual and language systems in the completely and partially blind. These changes start in the deprived areas and increase in size (involving both foveal and peripheral V1) and strength (from negative to positive FC) as the disease and sensory deprivation progress. These observations support the claim that functional connectivity between remote systems that perform completely different tasks can change in the adult brain in cases of total and even partial visual deprivation.

Differences in gaze anticipation for locomotion with and without vision.

Previous experimental studies have shown a spontaneous anticipation of locomotor trajectory by the head and gaze direction during human locomotion. This anticipatory behavior could serve several functions: an optimal selection of visual information, for instance through landmarks and optic flow, as well as trajectory planning and motor control. This would imply that anticipation remains in darkness but with different characteristics. We asked 10 participants to walk along two predefined complex trajectories (limaçon and figure eight) without any cue on the trajectory to follow. Two visual conditions were used: (i) in light and (ii) in complete darkness with eyes open. The whole body kinematics were recorded by motion capture, along with the participant's right eye movements. We showed that in darkness and in light, horizontal gaze anticipates the orientation of the head which itself anticipates the trajectory direction. However, the horizontal angular anticipation decreases by a half in darkness for both gaze and head. In both visual conditions we observed an eye nystagmus with similar properties (frequency and amplitude). The main difference comes from the fact that in light, there is a shift of the orientations of the eye nystagmus and the head in the direction of the trajectory. These results suggest that a fundamental function of gaze is to represent self motion, stabilize the perception of space during locomotion, and to simulate the future trajectory, regardless of the vision condition.

Importance of eye position on spatial localization in blind subjects wearing an Argus II retinal prosthesis.

PURPOSE: With a retinal prosthesis connected to a head-mounted camera (camera-connected prosthesis [CC-P]), subjects explore the visual environment through head-scanning movements. As eye and camera misalignment might alter the spatial localization of images generated by the device, we investigated if such misalignment occurs in blind subjects wearing a CC-P and whether it impacts spatial localization, even years after the implantation. METHODS: We studied three subjects blinded by retinitis pigmentosa, fitted with a CC-P (Argus II) 4 years earlier. Eye/head movements were video recorded as subjects tried to localize a visual target. Pointing coordinates were collected as subjects were requested to orient their gaze toward predetermined directions, and to point their finger to the corresponding perceived spot locations on a touch screen. Finally, subjects were asked to give a history of their everyday behavior while performing visually controlled grasping tasks. RESULTS: Misaligned head and gaze directions occurred in all subjects during free visual search. Pointing coordinates were collected in two subjects and showed that median pointing directions shifted toward gaze direction. Reportedly all subjects were unable to accurately determine their eye position, and they developed adapted strategies to perform visually directed movements. CONCLUSIONS: Eye position affected perceptual localization of images generated by the Argus II prosthesis, and consequently visuomotor coordination, even 4 years following implantation. Affected individuals developed strategies for visually guided movements to attenuate the impact of eye and head misalignment. Our observations provide indications for rehabilitation procedures and for the design of upcoming retinal prostheses. (ClinicalTrials.gov number, NCT00407602.).

Lorazepam impairs highway driving performance more than heavy alcohol consumption.

While research indicates that benzodiazepine (BZD)-like drugs impair driving performance, it remains unclear (i) how far BZDs affect lane-keeping performance, compared with alcohol and (ii) to what extent this impact can realistically be measured in a simulated environment. To clarify these issues, 16 healthy male drivers who had never previously taken BZDs underwent a randomized, crossover, double-blind, placebo-controlled driving paradigm (with the BZD lorazepam) in both real-world and simulated settings. Two lane-keeping variables, namely inappropriate line crossings (ILCs) and standard deviation of lateral position (SDLP), were recorded during the driving sessions. Analyses revealed that (i) a single lorazepam dose (2 mg given by mouth) caused higher SDLP increases than a blood alcohol concentration of above 0.05%, and that (ii) this BZD effect was amplified in the simulated driving setting, mainly for ILCs. As a consequence, we recommend that physicians be made more aware of BZD-related risks and that researchers make a clear distinction between the effects of BZD intake per se and the impact of simulated driving settings.

Path curvature discrimination: dependence on gaze direction and optical flow speed.

Many experimental approaches to the control of steering rely on the tangent point (TP) as major source of information. The TP is a good candidate to control self-motion. It corresponds to a singular and salient point in the subject's visual field, and its location depends on the road geometry, the direction of self-motion relative to the road and the position of the driver on the road. However, the particular status of the TP in the optical flow, as a local minimum of flow speed, has often been left aside. We therefore assume that the TP is actually an optimal location in the dynamic optical array to perceive a change in the trajectory curvature. In this study, we evaluated the ability of human observers to detect variations in their path curvature from optical flow patterns, as a function of their gaze direction in a virtual environment. We simulated curvilinear self-motion parallel to a ground plane. Using random-dot optic flow stimuli of brief duration and a two-alternative forced-choice adaptive procedure, we determined path curvature discrimination thresholds, as a function of gaze direction. The discrimination thresholds are minimal for a gaze directed toward a local minimum of optical flow speed. A model based on Weber fraction of the foveal velocities (ΔV/V) correctly predicts the relationship between experimental thresholds and local flow velocities. This model was also tested for an optical flow computation integrating larger circular areas in central vision. Averaging the flow over five degrees leads to an even better fit of the model to experimental thresholds. We also found that the minimal optical flow speed direction corresponds to a maximal sensitivity of the visual system, as predicted by our model. The spontaneous gazing strategies observed during driving might thus correspond to an optimal selection of relevant information in the optical flow field.

Optokinetic nystagmus is elicited by curvilinear optic flow during high speed curve driving.

When analyzing gaze behavior during curve driving, it is commonly accepted that gaze is mostly located in the vicinity of the tangent point, being the point where gaze direction tangents the curve inside edge. This approach neglects the fact that the tangent point is actually motionless only in the limit case when the trajectory precisely follows the curve's geometry. In this study, we measured gaze behavior during curve driving, with the general hypothesis that gaze is not static, when exposed to a global optical flow due to self-motion. In order to study spatio-temporal aspects of gaze during curve driving, we used a driving simulator coupled to a gaze recording system. Ten participants drove seven runs on a track composed of eight curves of various radii (50, 100, 200 and 500m), with each radius appearing in both right and left directions. Results showed that average gaze position was, as previously described, located in the vicinity of the tangent point. However, analysis also revealed the presence of a systematic optokinetic nystagmus (OKN) around the tangent point position. The OKN slow phase direction does not match the local optic flow direction, while slow phase speed is about half of the local speed. Higher directional gains are observed when averaging the entire optical flow projected on the simulation display, whereas the best speed gain is obtained for a 2° optic flow area, centered on the instantaneous gaze location. The present study confirms that the tangent point is a privileged feature in the dynamic visual scene during curve driving, and underlines a contribution of the global optical flow to gaze behavior during active self-motion.