Amblyopic Visual System Research Articles

Invited Session V: Binocular vision and interactions: Harnessing interactions within binocular vision to treat amblyopia.

Inexpensive virtual reality (VR) headsets have enabled at-home therapy for binocular dysfunctions, including amblyopia. Healthy binocular vision is exquisite, which is achieved though interactions among various visual subsystems. As a result, however, binocular vision has multiple points of weakness, so development can go wrong in many different ways. Furthermore, the visual system has many ways it can adapt to dysfunctions to improve vision. It is therefore not surprising that amblyopias are idiosyncratic from one person to the next. Habitual interocular suppression is a typical adaption in amblyopia, and by treating suppression in VR, acuity can be improved by 0.1 to 0.2 logMAR. However, the amblyopic visual system shows complicated patterns of interaction between suppression, acuity, stereopsis, motor vergence, accommodation, and motion perception; and each of those subsystems is itself complex. Thus, to improve acuity and stereopsis in amblyopia, a multifaceted approach would seem more promising. In a VR headset, one can addresses suppression, stereopsis, vergence ability, and even accommodation, simultaneously. I will describe Vivid Vision's approach to this problem, along with preliminary results from independent researchers.

Interocular Transfer: The Dichoptic Flash-Lag Effect in Controls and Amblyopes.

PurposeThe mammalian brain can take into account the neural delays in visual information transmission from the retina to the cortex when accurately localizing the instantaneous position of moving objects by motion extrapolation. In this study, we wanted to investigate whether such extrapolation mechanism operates in a comparable fashion between the eyes in normally sighted and amblyopic observers.MethodsTo measure interocular extrapolation, we adapted a dichoptic version of the flash-lag effect (FLE) paradigm, in which a flashed bar is perceived to lag behind a moving bar when their two positions are physically aligned. Twelve adult subjects with amblyopia and 12 healthy controls participated in the experiment. We measured the FLE magnitude of the subjects under binocular, monocular, and dichoptic conditions.ResultsIn controls, the FLE magnitude of binocular condition was significantly smaller than that of monocular conditions (P ≤ 0.023), but there was no difference between monocular and dichoptic conditions. Subject with amblyopia exhibited a smaller FLE magnitude in the dichoptic condition when the moving bar was presented to the amblyopic eye and the flash to the fellow eye (DA condition) compared to the opposite way around (DF condition), consistent with a delay in the processing of the amblyopic eye (P = 0.041).ConclusionsOur observations confirm that trajectory extrapolation mechanisms transfer between the eyes of normal observers. However, such transfer may be impaired in amblyopia. The smaller FLE magnitude in DA compared to DF in patients with amblyopia could be due to an interocular delay in the amblyopic visual system. The observation that normal controls present a smaller FLE in binocular conditions raises the question whether a larger FLE is or is not an indicator of better motion processing and extrapolation.

Blur Representation in the Amblyopic Visual System Using Natural and Synthetic Images.

PurposeAmblyopia is diagnosed as a reduced acuity in an otherwise healthy eye, which indicates that the deficit is not happening in the eye, but in the brain. One suspected mechanism explaining these deficits is an elevated amount of intrinsic blur in the amblyopic visual system compared to healthy observers. This “internally produced blur” can be estimated by the “equivalent intrinsic blur method”, which measures blur discrimination thresholds while systematically increasing the external blur in the physical stimulus. Surprisingly, amblyopes do not exhibit elevated intrinsic blur when measured with an edge stimulus. Given the fundamental ways in which they differ, synthetic stimuli, such as edges, are likely to generate contrasting blur perception compared to natural stimuli, such as pictures. Because our visual system is presumably tuned to process natural stimuli, testing artificial stimuli only could result in performances that are not ecologically valid.MethodsWe tested this hypothesis by measuring, for the first time, the perception of blur added to natural images in amblyopia and compared discrimination performance for natural images and synthetic edges in healthy and amblyopic groups.ResultsOur results demonstrate that patients with amblyopia exhibit higher levels of intrinsic blur than control subjects when tested on natural images. This difference was not observed when using edges.ConclusionsOur results suggest that intrinsic blur is elevated in the visual system representing vision from the amblyopic eye and that distinct statistics of images can generate different blur perception.

Delayed Correction for Extrapolation in Amblyopia.

PurposeIt has been suggested that amblyopes present impaired motion extrapolation mechanisms. In this study, we used the flash grab effect (FGE), the illusory mislocalization of a briefly flashed stimulus in the direction of a reversing moving background, to investigate whether the amblyopic visual system can correct overextrapolation.MethodsThirteen amblyopes and 13 control subjects participated in the experiment. We measured the monocular FGE magnitude for each subject. Two spatial frequency (2 and 8 cycles), two texture configurations (square wave or sine wave), and two speed conditions (270 degrees/s and 67.5 degrees/s) were tested. In addition, control subjects were further tested in reduced luminance conditions.ResultsCompared with controls, amblyopes exhibited a larger FGE magnitude both in their fellow eye (FE) and amblyopic eye (AE). The FGE magnitude of their AE was significantly larger than that of the FE. In a control experiment, we observed that the FGE magnitude increases with the decreasing of the luminance. The FGE magnitude of amblyopes fall into the same range as that of controls under reduced luminance conditions.ConclusionsWe observed a lager FGE in patients with amblyopia, which indicates that the amblyopic visual system does not accurately correct the overextrapolation when a moving object abruptly reverses its direction. This spatiotemporal processing deficit could be ascribed to delayed visual processing in the amblyopic visual system.

The Flash-lag Effect in Amblyopia.

PurposeAmblyopes suffer a defect in temporal processing, presumably because of a neural delay in their visual processing. By measuring flash-lag effect (FLE), we investigate whether the amblyopic visual system could compensate for the intrinsic neural delay due to visual information transmissions from the retina to the cortex.MethodsEleven adults with amblyopia and 11 controls with normal vision participated in this study. We assessed the monocular FLE magnitude for each subject by using a typical FLE paradigm: a bar moved horizontally, while a flashed bar briefly appeared above or below it. Three luminance contrasts of the flashed bar were tested: 0.2, 0.6, and 1.ResultsAll participants, controls and those with amblyopia, showed a typical FLE. However, the FLE magnitude of participants with amblyopia was significantly shorter than that of the control participants, for both their amblyopic eye (AE) and fellow eye (FE). A nonsignificant difference was found in FLE magnitude between the AE and the FE.ConclusionsWe demonstrate a reduced FLE both in the AE as well as the FE of patients with amblyopia, suggesting a global visual processing deficit. We suggest it may be attributed to a more limited spatiotemporal extent of facilitatory anticipatory activity within the amblyopic primary visual cortex.

Effects of Monocular Perceptual Learning on Binocular Visual Processing in Adolescent and Adult Amblyopia.

SummaryRe-establishing normal binocular visual processing is the key to amblyopia recovery beyond the critical period of visual development. Here, by combining perceptual learning, behavioral testing, and steady-state visually evoked potentials (SSVEPs), we examined how monocular perceptual learning in the amblyopic eye could change binocular visual processing in the adolescent and adult amblyopic visual system. We found that training reduced the interocular difference between amblyopic and fellow eyes and increased the amplitude of a binocular SSVEP component, with a significant negative correlation between the two measures. Our results demonstrate that training in the amblyopic eye primarily improves binocular rather than monocular visual processing in the amblyopic visual system, suggesting that behavioral training could potentially address key neural deficits in adolescent and adult amblyopia.

Globally Normal Bistable Motion Perception of Anisometropic Amblyopes May Profit From an Unusual Coding Mechanism

Anisometropic amblyopia is a neurodevelopmental disorder of the visual system. There is evidence that the neural deficits spread across visual areas, from the primary cortex up to higher brain areas, including motion coding structures such as MT. Here, we used bistable plaid motion to investigate changes in the underlying mechanisms of motion integration and segmentation and, thus, help us to unravel in more detail deficits in the amblyopic visual motion system. Our results showed that (1) amblyopes globally exhibited normal bistable perception in all viewing conditions compared to the control group and (2) decreased contrast led to a stronger increase in percept switches and decreased percept durations in the control group, while the amblyopic group exhibited no such changes. There were few differences in outcomes dependent upon the use of the weak eye, the strong eye, or both eyes for viewing the stimuli, but this was a general effect present across all subjects, not specific to the amblyopic group. To understand the role of noise and adaptation in such cases of bistable perception, we analyzed predictions from a model and found that contrast does indeed affect percept switches and durations as observed in the control group, in line with the hypothesis that lower stimulus contrast enhances internal noise effects. The combination of experimental and computational results presented here suggests a different motion coding mechanism in the amblyopic visual system, with relatively little effect of stimulus contrast on amblyopes' bistable motion perception.

Latent binocular function in amblyopia

Recently, psychophysical studies have shown that humans with amblyopia do have binocular function that is not normally revealed due to dominant suppressive interactions under normal viewing conditions. Here we use magnetoencephalography (MEG) combined with dichoptic visual stimulation to investigate the underlying binocular function in humans with amblyopia for stimuli that, because of their temporal properties, would be expected to bypass suppressive effects and to reveal any underlying binocular function.We recorded contrast response functions in visual cortical area V1 of amblyopes and normal observers using a steady state visually evoked responses (SSVER) protocol. We used stimuli that were frequency-tagged at 4Hz and 6Hz that allowed identification of the responses from each eye and were of a sufficiently high temporal frequency (>3Hz) to bypass suppression. To characterize binocular function, we compared dichoptic masking between the two eyes in normal and amblyopic participants as well as interocular phase differences in the two groups.We observed that the primary visual cortex responds less to the stimulation of the amblyopic eye compared to the fellow eye. The pattern of interaction in the amblyopic visual system however was not significantly different between the amblyopic and fellow eyes. However, the amblyopic suppressive interactions were lower than those observed in the binocular system of our normal observers. Furthermore, we identified an interocular processing delay of approximately 20ms in our amblyopic group.To conclude, when suppression is greatly reduced, such as the case with our stimulation above 3Hz, the amblyopic visual system exhibits a lack of binocular interactions.

The Relationship Between Fusion, Suppression, and Diplopia in Normal and Amblyopic Vision.

Single vision occurs through a combination of fusion and suppression. When neither mechanism takes place, we experience diplopia. Under normal viewing conditions, the perceptual state depends on the spatial scale and interocular disparity. The purpose of this study was to examine the three perceptual states in human participants with normal and amblyopic vision. Participants viewed two dichoptically separated horizontal blurred edges with an opposite tilt (2.35°) and indicated their binocular percept: "one flat edge," "one tilted edge," or "two edges." The edges varied with scale (fine 4 min arc and coarse 32 min arc), disparity, and interocular contrast. We investigated how the binocular interactions vary in amblyopic (visual acuity [VA] > 0.2 logMAR, n = 4) and normal vision (VA ≤ 0 logMAR, n = 4) under interocular variations in stimulus contrast and luminance. In amblyopia, despite the established sensory dominance of the fellow eye, fusion prevails at the coarse scale and small disparities (75%). We also show that increasing the relative contrast to the amblyopic eye enhances the probability of fusion at the fine scale (from 18% to 38%), and leads to a reversal of the sensory dominance at coarse scale. In normal vision we found that interocular luminance imbalances disturbed binocular combination only at the fine scale in a way similar to that seen in amblyopia. Our results build upon the growing evidence that the amblyopic visual system is binocular and further show that the suppressive mechanisms rendering the amblyopic system functionally monocular are scale dependent.

Monocular perceptual learning of contrast detection facilitates binocular combination in adults with anisometropic amblyopia.

Perceptual learning in contrast detection improves monocular visual function in adults with anisometropic amblyopia; however, its effect on binocular combination remains unknown. Given that the amblyopic visual system suffers from pronounced binocular functional loss, it is important to address how the amblyopic visual system responds to such training strategies under binocular viewing conditions. Anisometropic amblyopes (n = 13) were asked to complete two psychophysical supra-threshold binocular summation tasks: (1) binocular phase combination and (2) dichoptic global motion coherence before and after monocular training to investigate this question. We showed that these participants benefited from monocular training in terms of binocular combination. More importantly, the improvements observed with the area under log CSF (AULCSF) were found to be correlated with the improvements in binocular phase combination.

Tilt after-effect from high spatial-frequency patterns in the amblyopic eye of adults with anisometropic amblyopia.

With abnormal visual cortical development, amblyopia is generally associated with high spatial frequency deficits in spatial vision. In this study, we aim to answer a critical question: How much high spatial frequency information is available to the amblyopic visual system? We measured the tilt after-effect following adaption to perceptually resolvable and unresolvable sinewave gratings, and showed that gratings with spatial frequency up to 1.5 times the cutoff frequency in grating orientation identification can still produce significant tilt after-effects in adults with amblyopia. Our results suggest that neural connections in the amblyopic visual cortex, at least in V1, may have profoundly developed to represent high spatial frequency information. The demonstration of extant neural connections for high spatial frequencies may have important implications for the development of training protocols for amblyopia treatment. Our paradigm may also serve as a non-invasive probe to diagnose the status of neural connections in other visual deficits.

Occlusion therapy improves phase-alignment of the cortical response in amblyopia

The visual evoked potential (VEP) generated by the amblyopic visual system demonstrates reduced amplitude, prolonged latency, and increased variation in response timing (phase-misalignment). This study examined VEPs before and after occlusion therapy (OT) and whether phase-misalignment can account for the amblyopic VEP deficits. VEPs were recorded to 0.5–4cycles/degree gratings in 10 amblyopic children (2–6years age) before and after OT. Phase-misalignment was measured by Fourier analysis across a limited bandwidth. Signal-to-noise ratios (SNRs) were estimated from amplitude and phase synchrony in the Fourier domain. Responses were compared to VEPs corrected for phase-misalignment (individual epochs shifted in time to correct for the misalignment). Before OT, amblyopic eyes (AE) had significantly more phase-misalignment, latency prolongation, and lower SNR relative to the fellow eye. Phase-misalignment contributed significantly to low SNR but less so to latency delay in the AE. After OT, phase-alignment improved, SNR improved and latency shortened in the AE. Raw averaged waveforms from the AE improved after OT, primarily at higher spatial frequencies. Correcting for phase-misalignment in the AE sharpened VEP peak responses primarily at low spatial frequencies, but could not account for VEP waveform improvements in the AE after OT at higher spatial frequencies. In summary, VEP abnormalities from the AE are associated with phase-misalignment and reduced SNR possibly related to desynchronization of neuronal activity. The effect of OT on VEP responses is greater than that accounted for by phase-misalignment and SNR alone.

Binocular vision in amblyopia: structure, suppression and plasticity

The amblyopic visual system was once considered to be structurally monocular. However, it now evident that the capacity for binocular vision is present in many observers with amblyopia. This has led to new techniques for quantifying suppression that have provided insights into the relationship between suppression and the monocular and binocular visual deficits experienced by amblyopes. Furthermore, new treatments are emerging that directly target suppressive interactions within the visual cortex and, on the basis of initial data, appear to improve both binocular and monocular visual function, even in adults with amblyopia. The aim of this review is to provide an overview of recent studies that have investigated the structure, measurement and treatment of binocular vision in observers with strabismic, anisometropic and mixed amblyopia.

Sensitivity to synchronicity of biological motion in normal and amblyopic vision

Amblyopia is a developmental disorder of spatial vision that results from abnormal early visual experience usually due to the presence of strabismus, anisometropia, or both strabismus and anisometropia. Amblyopia results in a range of visual deficits that cannot be corrected by optics because the deficits reflect neural abnormalities. Biological motion refers to the motion patterns of living organisms, and is normally displayed as points of lights positioned at the major joints of the body. In this experiment, our goal was twofold. We wished to examine whether the human visual system in people with amblyopia retained the higher-level processing capabilities to extract visual information from the synchronized actions of others, therefore retaining the ability to detect biological motion. Specifically, we wanted to determine if the synchronized interaction of two agents performing a dancing routine allowed the amblyopic observer to use the actions of one agent to predict the expected actions of a second agent. We also wished to establish whether synchronicity sensitivity (detection of synchronized versus desynchronized interactions) is impaired in amblyopic observers relative to normal observers. The two aims are differentiated in that the first aim looks at whether synchronized actions result in improved expected action predictions while the second aim quantitatively compares synchronicity sensitivity, or the ratio of desynchronized to synchronized detection sensitivities, to determine if there is a difference between normal and amblyopic observers. Our results show that the ability to detect biological motion requires more samples in both eyes of amblyopes than in normal control observers. The increased sample threshold is not the result of low-level losses but may reflect losses in feature integration due to undersampling in the amblyopic visual system. However, like normal observers, amblyopes are more sensitive to synchronized versus desynchronized interactions, indicating that higher-level processing of biological motion remains intact. We also found no impairment in synchronicity sensitivity in the amblyopic visual system relative to the normal visual system. Since there is no impairment in synchronicity sensitivity in either the non-amblyopic or amblyopic eye of amblyopes, our results suggest that the higher order processing of biological motion is intact.

Decoupling orientation specificity from perceptual learning in amblyopic vision

Perceptual learning (PL) has been shown to improve many visual functions in amblyopes, but this learning is often specific to the trained orientation, possibly implying neural plasticity in the amblyopic early visual cortex. However, orientation specificity in normal vision can be decoupled from PL with a training-plus-exposure (TPE) technique (Zhang et al., JNS2010). Specifically, PL transfers to an untrained orthogonal orientation when training is accompanied by additional exposure of the transfer orientation when an irrelevant task is performed. The transfer suggests PL occurs in higher brain areas. Here we used the TPE technique in adults with amblyopia to investigate whether PL reflects V1 plasticity or improved high-level decision making in the amblyopic brain. Eighteen adult amblyopes participated. Similar to normal vision we found: (1) PL of contrast discrimination in the fovea of amblyopic eyes (AEs) did not transfer to an orthogonal orientation. However, AEs were then exposed to the orthogonal transfer orientation through irrelevant orientation discrimination training at the transfer orientation, which enabled contrast learning to transfer to the orthogonal orientation. (2) We found similar transfer in the AEs after the non-amblyopic eyes (NAEs) were exposed. (3) Orientation specificity in Vernier and orientation learning was also eliminated by exposure of the transfer orientation in AEs or NAEs through irrelevant orientation or contrast training. (4) Surprisingly, orientation specificity in NAE Vernier learning was eliminated after AEs were exposed to the orthogonal transfer orientation, indicating that the AE can teach the NAE. TPE enabled learning transfer across orientations suggests that perceptual learning in amblyopic vision may not reflect plasticity in local circuits in the amblyopic early visual cortex. Rather it may result from improved readout of noisy stimulus inputs at the decision stage that, at least in part, compensates for the functional deficits in the amblyopic visual system. Meeting abstract presented at VSS 2012

Prentice Award Lecture 2011

Experience-dependent plasticity is closely linked with the development of sensory function. Beyond this sensitive period, developmental plasticity is actively limited; however, new studies provide growing evidence for plasticity in the adult visual system. The amblyopic visual system is an excellent model for examining the "brakes" that limit recovery of function beyond the critical period. While amblyopia can often be reversed when treated early, conventional treatment is generally not undertaken in older children and adults. However, new clinical and experimental studies in both animals and humans provide evidence for neural plasticity beyond the critical period. The results suggest that perceptual learning and video game play may be effective in improving a range of visual performance measures and importantly the improvements may transfer to better visual acuity and stereopsis. These findings, along with the results of new clinical trials, suggest that it might be time to reconsider our notions about neural plasticity in amblyopia.

The Pattern of Learned Visual Improvements in Adult Amblyopia

Although amblyopia is diagnosed in terms of a monocular letter acuity loss, individuals typically present with deficits on a wide range of spatial tasks. Many of these deficits can be collapsed along two basic visual dimensions (visual acuity and contrast sensitivity) that together account for most of the variability in performance of the amblyopic visual system. In this study, this space was exploited, to target the main deficits and fully characterize the pattern of learned visual improvements in adult amblyopic subjects. Twenty-six amblyopic subjects (mean age, 39 ±12 years) were trained on one of four tasks, categorized as either visual acuity (letter or grating acuity) or contrast sensitivity (letter or grating contrast) tasks. Performance was measured on all tasks before and after training, to quantify learning along each dimension and generalization to the other dimension. Performance in 35 visually normal subjects (mean, age 24 ± 5 years) was used to establish normal variation in visual performance along each dimension, against which the learned improvements in amblyopic subjects was compared. Training on the contrast sensitivity tasks produced substantial within-task learning and generalization to measures of visual acuity. The learned improvements in performance after training on the letter acuity task were also substantial, but did not generalize to contrast sensitivity. Mapping the pattern of learning onto the known deficit space for amblyopia enabled the identification of tasks and stimulus configurations that optimized learning, guiding further development of learning-based interventions in this clinical group.

Can Human Amblyopia be Treated in Adulthood?

Amblyopia is a common visual disorder that results in a spatial acuity deficit in the affected eye. Orthodox treatment is to occlude the unaffected eye for lengthy periods, largely determined by the severity of the visual deficit at diagnosis. Although this treatment is not without its problems (poor compliance, potential to reduce binocular function, etc) it is effective in many children with moderate to severe amblyopia. Diagnosis and initiation of treatment early in life are thought to be critical to the success of this form of therapy. Occlusion is rarely undertaken in older children (more than 10 years old) as the visual benefits are considered to be marginal. Therefore, in subjects where occlusion is not effective or those missed by mass screening programs, there is no alternative therapy available later in life. More recently, burgeoning evidence has begun to reveal previously unrecognized levels of residual neural plasticity in the adult brain and scientists have developed new genetic, pharmacological, and behavioral interventions to activate these latent mechanisms in order to harness their potential for visual recovery. Prominent amongst these is the concept of perceptual learning—the fact that repeatedly practicing a challenging visual task leads to substantial and enduring improvements in visual performance over time. In the normal visual system the improvements are highly specific to the attributes of the trained stimulus. However, in the amblyopic visual system, learned improvements have been shown to generalize to novel tasks. In this paper we ask whether amblyopic deficits can be reduced in adulthood and explore the pattern of transfer of learned improvements. We also show that developing training protocols that target the deficit in stereo acuity allows the recovery of normal stereo function even in adulthood. This information will help guide further development of learning-based interventions in this clinical group.

Training in Contrast Detection Improves Motion Perception of Sinewave Gratings in Amblyopia

PURPOSE. One critical concern about using perceptual learning to treat amblyopia is whether training with one particular stimulus and task generalizes to other stimuli and tasks. In the spatial domain, it has been found that the bandwidth of contrast sensitivity improvement is much broader in amblyopes than in normals. Because previous studies suggested the local motion deficits in amblyopia are explained by the spatial vision deficits, the hypothesis for this study was that training in the spatial domain could benefit motion perception of sinewave gratings. METHODS. Nine adult amblyopes (mean age, 22.1 ± 5.6 years) were trained in a contrast detection task in the amblyopic eye for 10 days. Visual acuity, spatial contrast sensitivity functions, and temporal modulation transfer functions (MTF) for sinewave motion detection and discrimination were measured for each eye before and after training. Eight adult amblyopes (mean age, 22.6 ± 6.7 years) served as control subjects. RESULTS. In the amblyopic eye, training improved (1) contrast sensitivity by 6.6 dB (or 113.8%) across spatial frequencies, with a bandwidth of 4.4 octaves; (2) sensitivity of motion detection and discrimination by 3.2 dB (or 44.5%) and 3.7 dB (or 53.1%) across temporal frequencies, with bandwidths of 3.9 and 3.1 octaves, respectively; (3) visual acuity by 3.2 dB (or 44.5%). The fellow eye also showed a small amount of improvement in contrast sensitivities and no significant change in motion perception. Control subjects who received no training demonstrated no obvious improvement in any measure. CONCLUSIONS. The results demonstrate substantial plasticity in the amblyopic visual system, and provide additional empirical support for perceptual learning as a potential treatment for amblyopia.

Removing Brakes on Adult Brain Plasticity: From Molecular to Behavioral Interventions

Adult brain plasticity, although possible, remains more restricted in scope than during development. Here, we address conditions under which circuit rewiring may be facilitated in the mature brain. At a cellular and molecular level, adult plasticity is actively limited. Some of these "brakes" are structural, such as perineuronal nets or myelin, which inhibit neurite outgrowth. Others are functional, acting directly upon excitatory-inhibitory balance within local circuits. Plasticity in adulthood can be induced either by lifting these brakes through invasive interventions or by exploiting endogenous permissive factors, such as neuromodulators. Using the amblyopic visual system as a model, we discuss genetic, pharmacological, and environmental removal of brakes to enable recovery of vision in adult rodents. Although these mechanisms remain largely uncharted in the human, we consider how they may provide a biological foundation for the remarkable increase in plasticity after action video game play by amblyopic subjects.