The Measurement and Treatment of Suppression in Amblyopia

Amblyopia, a developmental disorder of the visual cortex, is one of the leading causes of visual dysfunction in the working age population. Current estimates put the prevalence of amblyopia at approximately 1-3%^1-3, the majority of cases being monocular². Amblyopia is most frequently caused by ocular misalignment (strabismus), blur induced by unequal refractive error (anisometropia), and in some cases by form deprivation.Although amblyopia is initially caused by abnormal visual input in infancy, once established, the visual deficit often remains when normal visual input has been restored using surgery and/or refractive correction. This is because amblyopia is the result of abnormal visual cortex development rather than a problem with the amblyopic eye itself^4,5 . Amblyopia is characterized by both monocular and binocular deficits^6,7 which include impaired visual acuity and poor or absent stereopsis respectively. The visual dysfunction in amblyopia is often associated with a strong suppression of the inputs from the amblyopic eye under binocular viewing conditions⁸. Recent work has indicated that suppression may play a central role in both the monocular and binocular deficits associated with amblyopia^9,10 .Current clinical tests for suppression tend to verify the presence or absence of suppression rather than giving a quantitative measurement of the degree of suppression. Here we describe a technique for measuring amblyopic suppression with a compact, portable device^11,12 . The device consists of a laptop computer connected to a pair of virtual reality goggles. The novelty of the technique lies in the way we present visual stimuli to measure suppression. Stimuli are shown to the amblyopic eye at high contrast while the contrast of the stimuli shown to the non-amblyopic eye are varied. Patients perform a simple signal/noise task that allows for a precise measurement of the strength of excitatory binocular interactions. The contrast offset at which neither eye has a performance advantage is a measure of the "balance point" and is a direct measure of suppression. This technique has been validated psychophysically both in control^13,14 and patient^6,9,11 populations.In addition to measuring suppression this technique also forms the basis of a novel form of treatment to decrease suppression over time and improve binocular and often monocular function in adult patients with amblyopia^12,15,16 . This new treatment approach can be deployed either on the goggle system described above or on a specially modified iPod touch device¹⁵.     

Visual cortical responses to the input from the amblyopic eye are suppressed during binocular viewing

Amblyopia is a visual disorder caused by an anomalous early visual experience. It has been suggested that suppression of the visual input from the weaker eye might be a primary underlying mechanism of the amblyopic syndrome. However, it is still an unresolved question to what extent neural responses to the visual information coming from the amblyopic eye are suppressed during binocular viewing. To address this question we measured event-related potentials (ERP) to foveal face stimuli in amblyopic patients, both in monocular and binocular viewing conditions. The results revealed no difference in the amplitude and latency of early components of the ERP responses between the binocular and fellow eye stimulation. On the other hand, early ERP components were reduced and delayed in the case of monocular stimulation of the amblyopic eye as compared to the fellow eye stimulation or to binocular viewing. The magnitude of the amblyopic effect measured on the ERP amplitudes was comparable to that found on the fMRI responses in the fusiform face area using the same face stimuli and task conditions. Our findings showing that the amblyopic effects present on the early ERP components in the case of monocular stimulation are not manifested in the ERP responses during binocular viewing suggest that input from the amblyopic eye is completely suppressed already at the earliest stages of visual cortical processing when stimuli are viewed by both eyes.     

The long-term effectiveness of different regimens of occlusion on recovery from early monocular deprivation in kittens.

Although the behavioural effects of an early period of monocular deprivation imposed on kittens can be very severe, resembling an extreme form of the human clinical condition deprivation amblyopia, they are not necessarily irreversible. Considerable behavioural as well as physiological recovery can occur if normal visual input is restored to the deprived eye sufficiently early, particularly if the other (initially non-deprived) eye is occluded at the same time (reverse occlusion). However, past work has shown that in many situations the improvement in the vision of the initially deprived eye that occurs during reverse occlusion is not retained following the subsequent introduction of binocular visual input. Furthermore, the vision of the other eye is often reduced as well, with the result that the eventual outcome is a condition of bilateral amblyopia. This study first examines the consequences of several periods of reverse occlusion whose onset and duration would be thought to maximize the opportunity for good and long-standing recovery of vision in the initially deprived eye. However, only in a very restricted set of exposure conditions did animals acquire good vision in one or both eyes; in most situations the final outcome was one of bilateral amblyopia. A second set of experiments examined the consequences of various regimens of part-time reverse occlusion, where the initially non-deprived eye was occluded for only part of each day to allow a period of binocular visual exposure, on kittens that had been monocularly deprived until 6, 8, 10 or 12 weeks of age. Whereas short or long daily periods of occlusion of the initially non-deprived eye resulted eventually in amblyopia in one, or usually both, eyes, certain intermediate occlusion times (3.5 or 5 h each day) resulted in recovery of normal acuities, contrast sensitivity and vernier acuity in both eyes, in animals that had been monocularly deprived until 6, 8 or 10 weeks of age, but not in animals deprived for longer periods. Experiments were done to establish some of the factors that contributed to the successful outcome associated with certain of the regimens of part-time reverse occlusion. It was established that recovery was just as good in animals in which the visual axes were vertically misaligned by means of prisms during the daily period of binocular visual exposure, thereby indicating that the visual input to the two eyes need not be concordant. However, animals that received equivalent visual exposure of the two eyes each day, but successively rather than simultaneously, all developed very severe bilateral amblyopia.(ABSTRACT TRUNCATED AT 400 WORDS)     

Brain plasticity in the adult: modulation of function in amblyopia with rTMS

Amblyopia is a cortically based visual disorder caused by disruption of vision during a critical early developmental period. It is often thought to be a largely intractable problem in adult patients because of a lack of neuronal plasticity after this critical period [1]; however, recent advances have suggested that plasticity is still present in the adult amblyopic visual cortex [2-6]. Here, we present data showing that repetitive transcranial magnetic stimulation (rTMS) of the visual cortex can temporarily improve contrast sensitivity in the amblyopic visual cortex. The results indicate continued plasticity of the amblyopic visual system in adulthood and open the way for a potential new therapeutic approach to the treatment of amblyopia.     

Critical period revisited: impact on vision

Neural circuits are shaped by experience in early postnatal life. The permanent loss of visual acuity (amblyopia) and anatomical remodeling within primary visual cortex following monocular deprivation is a classic example of critical period development from mouse to man. Recent work in rodents reveals a residual subthreshold potentiation of open eye response throughout life. Resetting excitatory-inhibitory balance or removing molecular 'brakes' on structural plasticity may unmask the potential for recovery of function in adulthood. Novel pharmacological or environmental interventions now hold great therapeutic promise based on a deeper understanding of critical period mechanisms.     

Video-game play induces plasticity in the visual system of adults with amblyopia

Abnormal visual experience during a sensitive period of development disrupts neuronal circuitry in the visual cortex and results in abnormal spatial vision or amblyopia. Here we examined whether playing video games can induce plasticity in the visual system of adults with amblyopia. Specifically 20 adults with amblyopia (age 15–61 y; visual acuity: 20/25–20/480, with no manifest ocular disease or nystagmus) were recruited and allocated into three intervention groups: action videogame group (n = 10), non-action videogame group (n = 3), and crossover control group (n = 7). Our experiments show that playing video games (both action and non-action games) for a short period of time (40–80 h, 2 h/d) using the amblyopic eye results in a substantial improvement in a wide range of fundamental visual functions, from low-level to high-level, including visual acuity (33%), positional acuity (16%), spatial attention (37%), and stereopsis (54%). Using a cross-over experimental design (first 20 h: occlusion therapy, and the next 40 h: videogame therapy), we can conclude that the improvement cannot be explained simply by eye patching alone. We quantified the limits and the time course of visual plasticity induced by video-game experience. The recovery in visual acuity that we observed is at least 5-fold faster than would be expected from occlusion therapy in childhood amblyopia. We used positional noise and modelling to reveal the neural mechanisms underlying the visual improvements in terms of decreased spatial distortion (7%) and increased processing efficiency (33%). Our study had several limitations: small sample size, lack of randomization, and differences in numbers between groups. A large-scale randomized clinical study is needed to confirm the therapeutic value of video-game treatment in clinical situations. Nonetheless, taken as a pilot study, this work suggests that video-game play may provide important principles for treating amblyopia, and perhaps other cortical dysfunctions.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01223716","term_id":"NCT01223716"}}NCT01223716     

Neural mechanisms of recovery following early visual deprivation

Natural patterned early visual input is essential for the normal development of the central visual pathways and the visual capacities they sustain. Without visual input, the functional development of the visual system stalls not far from the state at birth, and if input is distorted or biased the visual system develops in an abnormal fashion resulting in specific visual deficits. Monocular deprivation, an extreme form of biased exposure, results in large anatomical and physiological changes in terms of territory innervated by the two eyes in primary visual cortex (V1) and to a loss of vision in the deprived eye reminiscent of that in human deprivation amblyopia. We review work that points to a special role for binocular visual input in the development of V1 and vision. Our unique approach has been to provide animals with mixed visual input each day, which consists of episodes of normal and biased (monocular) exposures. Short periods of concordant binocular input, if continuous, can offset much longer episodes of monocular deprivation to allow normal development of V1 and prevent amblyopia. Studies of animal models of patching therapy for amblyopia reveal that the benefits are both heightened and prolonged by daily episodes of binocular exposure.     

The effect of sensory uncertainty due to amblyopia (lazy eye) on the planning and execution of visually-guided 3D reaching movements

Background

Impairment of spatiotemporal visual processing in amblyopia has been studied extensively, but its effects on visuomotor tasks have rarely been examined. Here, we investigate how visual deficits in amblyopia affect motor planning and online control of visually-guided, unconstrained reaching movements.

Methods

Thirteen patients with mild amblyopia, 13 with severe amblyopia and 13 visually-normal participants were recruited. Participants reached and touched a visual target during binocular and monocular viewing. Motor planning was assessed by examining spatial variability of the trajectory at 50–100 ms after movement onset. Online control was assessed by examining the endpoint variability and by calculating the coefficient of determination (R²) which correlates the spatial position of the limb during the movement to endpoint position.

Results

Patients with amblyopia had reduced precision of the motor plan in all viewing conditions as evidenced by increased variability of the reach early in the trajectory. Endpoint precision was comparable between patients with mild amblyopia and control participants. Patients with severe amblyopia had reduced endpoint precision along azimuth and elevation during amblyopic eye viewing only, and along the depth axis in all viewing conditions. In addition, they had significantly higher R² values at 70% of movement time along the elevation and depth axes during amblyopic eye viewing.

Conclusion

Sensory uncertainty due to amblyopia leads to reduced precision of the motor plan. The ability to implement online corrections depends on the severity of the visual deficit, viewing condition, and the axis of the reaching movement. Patients with mild amblyopia used online control effectively to compensate for the reduced precision of the motor plan. In contrast, patients with severe amblyopia were not able to use online control as effectively to amend the limb trajectory especially along the depth axis, which could be due to their abnormal stereopsis.     

The Optokinetic Response as a Quantitative Measure of Visual Acuity in Zebrafish

Zebrafish are a proven model for vision research, however many of the earlier methods generally focused on larval fish or demonstrated a simple response. More recently adult visual behavior in zebrafish has become of interest, but methods to measure specific responses are new coming. To address this gap, we set out to develop a methodology to repeatedly and accurately utilize the optokinetic response (OKR) to measure visual acuity in adult zebrafish. Here we show that the adult zebrafish''s visual acuity can be measured, including both binocular and monocular acuities. Because the fish is not harmed during the procedure, the visual acuity can be measured and compared over short or long periods of time. The visual acuity measurements described here can also be done quickly allowing for high throughput and for additional visual procedures if desired. This type of analysis is conducive to drug intervention studies or investigations of disease progression.     

Abnormal Fixational Eye Movements in Amblyopia

Purpose

Fixational saccades shift the foveal image to counteract visual fading related to neural adaptation. Drifts are slow eye movements between two adjacent fixational saccades. We quantified fixational saccades and asked whether their changes could be attributed to pathologic drifts seen in amblyopia, one of the most common causes of blindness in childhood.

Methods

Thirty-six pediatric subjects with varying severity of amblyopia and eleven healthy age-matched controls held their gaze on a visual target. Eye movements were measured with high-resolution video-oculography during fellow eye-viewing and amblyopic eye-viewing conditions. Fixational saccades and drifts were analyzed in the amblyopic and fellow eye and compared with controls.

Results

We found an increase in the amplitude with decreased frequency of fixational saccades in children with amblyopia. These alterations in fixational eye movements correlated with the severity of their amblyopia. There was also an increase in eye position variance during drifts in amblyopes. There was no correlation between the eye position variance or the eye velocity during ocular drifts and the amplitude of subsequent fixational saccade. Our findings suggest that abnormalities in fixational saccades in amblyopia are independent of the ocular drift.

Discussion

This investigation of amblyopia in pediatric age group quantitatively characterizes the fixation instability. Impaired properties of fixational saccades could be the consequence of abnormal processing and reorganization of the visual system in amblyopia. Paucity in the visual feedback during amblyopic eye-viewing condition can attribute to the increased eye position variance and drift velocity.     

Age-dependent ocular dominance plasticity in adult mice

Background

Short monocular deprivation (4 days) induces a shift in the ocular dominance of binocular neurons in the juvenile mouse visual cortex but is ineffective in adults. Recently, it has been shown that an ocular dominance shift can still be elicited in young adults (around 90 days of age) by longer periods of deprivation (7 days). Whether the same is true also for fully mature animals is not yet known.

Methodology/Principal Findings

We therefore studied the effects of different periods of monocular deprivation (4, 7, 14 days) on ocular dominance in C57Bl/6 mice of different ages (25 days, 90–100 days, 109–158 days, 208–230 days) using optical imaging of intrinsic signals. In addition, we used a virtual optomotor system to monitor visual acuity of the open eye in the same animals during deprivation. We observed that ocular dominance plasticity after 7 days of monocular deprivation was pronounced in young adult mice (90–100 days) but significantly weaker already in the next age group (109–158 days). In animals older than 208 days, ocular dominance plasticity was absent even after 14 days of monocular deprivation. Visual acuity of the open eye increased in all age groups, but this interocular plasticity also declined with age, although to a much lesser degree than the optically detected ocular dominance shift.

Conclusions/Significance

These data indicate that there is an age-dependence of both ocular dominance plasticity and the enhancement of vision after monocular deprivation in mice: ocular dominance plasticity in binocular visual cortex is most pronounced in young animals, reduced but present in adolescence and absent in fully mature animals older than 110 days of age. Mice are thus not basically different in ocular dominance plasticity from cats and monkeys which is an absolutely essential prerequisite for their use as valid model systems of human visual disorders.     

Review of children referred from the school vision screening programme in Kettering during 1976-8.

The progress of 108 children who were identified by the vision screening programme in school as having defective vision (excluding those with puberty onset myopia) was reviewed. Treatment of these children resulted in improvement in visual acuity of the worst eye (two lines or better) for 16 children. Eighteen children had severe amblyopia (6/24 or worse). Among these the vision of only five was improved by treatment. Two thirds of the children had refractive errors in the better eye which required correction. It seems sensible to identify and treat children with bilateral refractive errors, but the need to treat children with lesser degrees of amblyopia is questioned.     

Plasticity of monocular and binocular vision following cerebral blindness: evoked potential evidence

Using monocular and dynamic random dot correlogram (DRDC) stimuli, sequential visual evoked potentials changes were demonstrated in 2 patients following cerebral blindness. The recovery of binocular vision was delayed in comparison to the recovery of monocular vision. The results are not due to simple acuity impairment or convergence deficiency, and thus provide evidence for the vulnerability of postsynaptic cortical mechanisms of human binocular vision.     

Area-specific amblyopic effects in human occipitotemporal object representations

The role of early visual experience in the establishment of human high-order visual areas is poorly understood. Here we investigated this issue using human amblyopia--a developmental visual disorder, which manifests a central vision (acuity) deficit. Previous fMRI studies of amblyopes have described abnormal functional activations in early retinotopic areas. Here we report the surprising finding of a selective object-related abnormality in high-order occipitotemporal cortex. Specifically, we found that face-related cortical areas show a severe disconnection from the amblyopic eye, while building-related regions remain essentially normal. The selectivity of the deficit highlights the differential computations performed in the different object-related areas and is compatible with the suggested association of face regions with analysis of fine detail.     

Visual problems in the elderly population and implications for services.

OBJECTIVE--To determine the prevalence of visual disability and common eye disease among elderly people in inner London. DESIGN--Cross sectional random sample survey. SETTING--Inner London health centre. SUBJECTS--Random sample of people aged 65 and over taken from practice''s computerised age-sex register. MAIN OUTCOME MEASURES--Presenting binocular Snellen 6 m distance acuity and best monocular 3 m Sonksen-Silver acuity to classify prevalence of blindness by World Health Organisation criteria (less than 3/60 in better eye) and American criteria for legal blindness (better eye equal to 6/60 or less) and of low vision by WHO criteria (best acuity 6/18) and visual impairment by American criteria (less than 6/12 or 20/40 but greater than 6/60 or 20/200 in better eye). Principal cause of visual loss by diagnosis, referral indication by cause to hospital eye service, and proportion of cases known to primary care. RESULTS--207 of 288 (72%) eligible people were examined. 17 (8%) housebound subjects were examined at home. The prevalence of blindness was 1% by WHO criteria and 3.9% by American criteria. The prevalence of low vision (WHO criteria) was 7.7%. The prevalence of visual impairment (American criteria) was 10.6%. Cataract accounted for 75% of cases of low vision. Only eight out of 16 patients with low vision were known by their general practitioner to have an eye problem. 56 subjects (27%) would probably have benefited from refraction. Comparisons with studies in the United States and Finland suggested higher rates in this sample, mainly due to the prevalence of disabling cataract. CONCLUSION--There seems to be a considerable amount of undetected ocular disease in elderly people in the community.     

单眼远视性弱视儿童P-VEP检查的临床研究

目的:分析单眼远视性弱视儿童图形视觉诱发电位(P-VEP)检查情况,探讨外周发病机制,为临床诊疗提供依据。方法:选取2013年1月到2015年10月我院收治的单眼远视性弱视儿童75例(75只眼),另选取同期正常儿童32例(64只眼)为对照组,根据病情将弱视儿童分为轻度(A组)和对侧健眼组(B组),中度(C组)和对侧健眼组(D组),重度(E组)和对侧健眼组(F组),应用P-VEP检查各组P100波及振幅。结果:A组、C组、E组P100波潜伏期较B组、D组、F组和对照组延长(P0.05),振幅较B组、D组、F组和对照组降低(P0.05),A组、C组和、E组P100波潜伏期和振幅比较具有统计学意义(P0.05),B组、D组、F组P100波潜伏期与对照组无统计学意义(P0.05),B组、D组、F组振幅显著低于对照组(P0.05),B组、D组、F组P100波潜伏期和振幅比较无统计学意义(P0.05)。结论:单眼远视性弱视儿童弱视眼会出现P100波潜伏期延长,振幅降低,对侧健康眼会出现振幅降低。     

Lateralized visual behavior in bottlenose dolphins (Tursiops truncatus) performing audio-visual tasks: the right visual field advantage

Analyzing cerebral asymmetries in various species helps in understanding brain organization. The left and right sides of the brain (lateralization) are involved in different cognitive and sensory functions. This study focuses on dolphin visual lateralization as expressed by spontaneous eye preference when performing a complex cognitive task; we examine lateralization when processing different visual stimuli displayed on an underwater touch-screen (two-dimensional figures, three-dimensional figures and dolphin/human video sequences). Three female bottlenose dolphins (Tursiops truncatus) were submitted to a 2-, 3- or 4-, choice visual/auditory discrimination problem, without any food reward: the subjects had to correctly match visual and acoustic stimuli together. In order to visualize and to touch the underwater target, the dolphins had to come close to the touch-screen and to position themselves using monocular vision (left or right eye) and/or binocular naso-ventral vision. The results showed an ability to associate simple visual forms and auditory information using an underwater touch-screen. Moreover, the subjects showed a spontaneous tendency to use monocular vision. Contrary to previous findings, our results did not clearly demonstrate right eye preference in spontaneous choice. However, the individuals' scores of correct answers were correlated with right eye vision, demonstrating the advantage of this visual field in visual information processing and suggesting a left hemispheric dominance. We also demonstrated that the nature of the presented visual stimulus does not seem to have any influence on the animals' monocular vision choice.     

Ten days of darkness causes temporary blindness during an early critical period in felines

Extended periods of darkness have long been used to study how the mammalian visual system develops in the absence of any instruction from vision. Because of the relative ease of implementation of darkness as a means to eliminate visually driven neural activity, it has usually been imposed earlier in life and for much longer periods than was the case for other manipulations of the early visual input used for study of their influences on visual system development. Recently, it was shown that following a very brief (10 days) period of darkness imposed at five weeks of age, kittens emerged blind. Although vision as assessed by measurements of visual acuity eventually recovered, the time course was very slow as it took seven weeks for visual acuity to attain normal levels. Here, we document the critical period of this remarkable vulnerability to the effects of short periods of darkness by imposing 10 days of darkness on nine normal kittens at progressively later ages. Results indicate that the period of susceptibility to darkness extends only to about 10 weeks of age, which is substantially shorter than the critical period for the effects of monocular deprivation in the primary visual cortex, which extends beyond six months of age.     

Visual acuity and hyperacuity in 11- to 17-year-old secondary school students

Visual acuity and hyperacuity of 11- to 17-year-old secondary school students with normal vision were measured and compared. The estimations of hyperacuity and acuity were made using the vernier stimuli, Landolt Cs, and Tumbling Es. When test stimuli were located in the tables, visual acuity estimations measured using Landolt Cs were significantly higher by a factor of 1.1 than that measured using Tumbling Es. Visual hyperacuity was 1.25?C4.1 times higher than visual acuity. The estimations of visual hyperacuity were almost 2 times higher in 16-year-old than 13-year-old secondary school students, in contrast to the estimations of visual acuity that did not change with age. The binocular visual acuity estimations were 1.05 times higher than the monocular ones and did not depend on the age. The ratio of binocular visual hyperacuity to monocular visual hyperacuity in 13-year-old secondary school students was 1.9, whereas, in senior secondary school students, it was 1.2. The contribution of binocular vision to the development of the mechanisms of visual acuity and hyperacuity in ontogenesis and the differences between the mechanisms of visual acuity and hyperacuity are discussed.