Dennis Levi - US grants

Amblyopia is the most frequent cause of visual loss in childhood and thus is a significant developmental and clinical disorder. Adult amblyopes show marked deficits in position discrimination, which differ between strabismic and anisometropic amblyopes. A conceptual and quantitative framework based upon spatial filtering and spatial sampling has been developed for modelling position discrimination in normal vision. This proposal applies the framework to amblyopic observers. The first goal is to elucidate the mechanisms underlying the abnormal position sense of the amblyopic eye. We propose to make quantitative psychophysical measurements of the components of our model, the "primitives" (contrast response and spatial sampling grain of the putative mechanisms) for position discrimination in normal and amblyopic vision - and to analyze the results in terms of the model. Our hypothesis is that reduced position sensitivity of anisometropic amblyopes is accounted for by their reduced contrast response function and that the additional loss of position acuity shown by strabismic amblyopes is a consequence of spatial undersampling. The second goal is to test the hypothesis that the normal peripheral visual field is an analog for strabismic amblyopia. Our research shows that the normal periphery, like the central field of strabismic amblyopes, has markedly reduced position acuity. Compairsons between normal peripheral versus amblyopic performance will provide insights into the mechanisms underlying amblyopia. We propose to test the hypothesis that both normal peripheral and strabismic amblyopic central visual systems exhibit spatial undersampling. In order to determine how these visual systems may differ, we also propose to compare their spatio-temporal discrimination functions, whcih our preliminary studies suggest may be quite different. A third goal is to test the hypothesis that anisometripic amblyopes have residual stereopsis when the effective contrast in the two eyes is equal, and to examine the effects of degradation upon this stereoscopic position discrimination. The fourth goal is to extend our psychophysical experiments to children with amblyopia. This will enable us to I) increase our data base, II) determining how the laboratory results of adult amblyopes relate to those of young children, III) examine developmental trends to determine whether the sampling losses precede losses in contrast sensitivity and spatial resolution and IV) monitor the effects of treatment on spatial discrimination.

Amblyopia is the most frequent cause of visual loss in childhood and thus is a significant developmental and clinical disorder. Adult amblyopes show marked deficits in position discrimination, which differ between strabismic and anisometropic amblyopes. A conceptual and quantitative framework based upon spatial filtering and spatial sampling has been developed for modelling position discrimination in normal vision. This proposal applies the framework to amblyopic observers. The first goal is to elucidate the mechanisms underlying the abnormal position sense of the amblyopic eye. We propose to make quantitative psychophysical measurements of the components of our model, the "primitives" (contrast response and spatial sampling grain of the putative mechanisms) for position discrimination in normal and amblyopic vision - and to analyze the results in terms of the model. Our hypothesis is that reduced position sensitivity of anisometropic amblyopes is accounted for by their reduced contrast response function and that the additional loss of position acuity shown by strabismic amblyopes is a consequence of spatial undersampling. The second goal is to test the hypothesis that the normal peripheral visual field is an analog for strabismic amblyopia. Our research shows that the normal periphery, like the central field of strabismic amblyopes, has markedly reduced position acuity. Compairsons between normal peripheral versus amblyopic performance will provide insights into the mechanisms underlying amblyopia. We propose to test the hypothesis that both normal peripheral and strabismic amblyopic central visual systems exhibit spatial undersampling. In order to determine how these visual systems may differ, we also propose to compare their spatio-temporal discrimination functions, whcih our preliminary studies suggest may be quite different. A third goal is to test the hypothesis that anisometripic amblyopes have residual stereopsis when the effective contrast in the two eyes is equal, and to examine the effects of degradation upon this stereoscopic position discrimination. The fourth goal is to extend our psychophysical experiments to children with amblyopia. This will enable us to I) increase our data base, II) determining how the laboratory results of adult amblyopes relate to those of young children, III) examine developmental trends to determine whether the sampling losses precede losses in contrast sensitivity and spatial resolution and IV) monitor the effects of treatment on spatial discrimination.

health science research support; university;

Our long-range objective is to understand the mechanisms that limit spatial vision in humans with amblyopia. We propose to test a number of specific hypotheses and predictions about these factors, and to assess the limits and mechanisms of neural plasticity in adults and children with amblyopia. Aim 1. Crowding. Feature binding and positional uncertainty in amblyopic and peripheral vision: We hypothesize that both crowding and anomalous feature binding in peripheral and amblyopic vision can be explained by limits imposed by early processes in cortical area V1. We propose a series of experiments, using novel methods and modeling, to answer the following questions: i) Do feature binding and crowding share the same spatial properties? ii) Is there mis-mapping of retinal location to perceived visual space in amblyopia, and is this the result ofmis- wiring within feature maps or mis-registration between them? An Adaptive Optics Scanning Laser Ophthalmoscope allows us to deliver point stimuli to precisely identifiable single cones in the retina, and evaluate their perceived location iii)Does crowding impose a critical limit on reading in peripheral and amblyopic vision? Aim 2. Deficits exist at multiple levels in the amblyopic visual system: Recent results lead to the hypothesis that although dysfunction within the amblyopic visual system first occurs in area V1, it is amplified downstream. We will test the prediction that amblyopes will show deficits in "higher level" tasks that cannot be explained by low level considerations: i) second-order processing, ii) contour integration, and iii) temporal, spatial and/or capacity limits of attention. Aim 3. Neural Plasticity in normal and amblyopic vision: There is a surprising degree of neural plasticity in both normal and amblyopic adults as evidenced by perceptual learning, i) We will test the hypothesis that perceptual learning occurs at a high level and reflects the brain learning to attend to and use the most reliable information for the task, ii) Assess the time course, limits and mechanisms of plasticity in adults and young children with amblyopia undergoing both perceptual learning and clinical treatment. We predict that improvement following the successful treatment of amblyopia involves the same mechanisms that improve normal vision following perceptual learning, iii)We will test the prediction that the successful effects of treatment or perceptual learning in amblyopia will lead to increased foveal activation in the visual cortex, as evidenced by alterations in functional MRI.

minority institution research support; secondary schools;

DESCRIPTION: (Applicant's Abstract) This proposal presents a plan to provide ongoing and stable funding for three high-quality and productive vision-research service Modules: Instrument Design, Research Computer Programming, and Biostatistics. These Modules are run by three exceptionally talented principles who have from 3 to 10 years of experience in our Core Center for Vision Research. These Modules provide needed research services to a present group of 22 Core Center vision scientists from 5 departments of the University of Houston (Biochemistry, Biology, Biophysical Sciences, Electrical Engineering, and Optometry). These Core vision scientists have diverse training and research interests; they collaborate effectively with each other, as well as with some 85 other vision researchers at this University and at other institutions. Together, our 22 Core Center investigators receive direct research funding of about $2.6 million annually. An additional $1.2 million is provided annually by the College in support of their vision research. During the past 5 years of P30 funding at this University, the Core Center has created an unusually favorable vision-research environment that has directly contributed to 125 published papers and culminated in the recruitment of 11 new vision investigators, 7 of whom currently have NIH funding, including 3 who have NEI funding. These accomplishments reflect our Core Center's previous and current aims that focus on: stable funding, quality research services, collaborative research, innovative research, new vision researchers, and pilot projects converting into NIH and NEI support. Especially emphasized in the coming 5 years will be innovate research (such as functional magnetic resonance imaging) and recruitment of vision researchers to fill our current 3 open positions, as well as other positions in the future. Our vision researchers and Module principals are a finely tuned team.

DESCRIPTION (provided by applicant): Amblyopia is considered to be a permanent reduction in vision that arises from abnormal visual experience early in life, affecting 2-3% of the general population. The primary treatment for amblyopia in children, for the last 250 years has consisted of patching the fellow eye. Patching is considered to be ineffective in adults and is seldom, if ever used. Our main aim is to develop new interventions that embed visual training in active and rewarding visuomotor tasks for restoring both visual acuity and stereopsis in adults and children with amblyopia and to compare it to the traditional treatment of patching. The first such intervention is action videogame playing. This activity enhances aspects of vision in young healthy eyes that are known to be deficient in amblyopic eyes. We ask whether action video game playing may be useful in restoring visual functions in amblyopic eyes. Specifically we will develop and test a customized videogame which enables the presentation of "designer" targets. An important goal is to promote coordination between the two eyes, therefore we will develop a new interface that uses filtering to degrade the image being sent to the fellow eye in order to match the level of the amblyopic eye. Training will therefore require patients to play an action video game with roughly balanced binocular input. While action games appear most effective in enhancing vision in young adults with normal vision, these games are not appropriate for pediatric populations, thus we also propose to develop and test a videogame that is "child friendly" using the same principles. The second intervention, focused directly on retraining stereopsis, is visually guided hand movements in a virtual-reality environment in which we can manipulate different cues to depth and in which patients receive implicit performance feedback embedded in the task. We ask whether this virtual reality training, which capitalizes on our previous work on how monocular and stereo cues combine to support depth perception, may promote fusion and stereopsis. A strength of this joint proposal between UC Berkeley and U of Rochester is in our outcome measures. We will evaluate and quantify a broad range of visual functions including stereopsis in amblyopic subjects. Our pilot data suggests that improving visual acuity and stereopsis is an achievable goal even in adult patients. A commercially available video game has been adapted to the needs of this project in collaboration with game designers, and will be made freely available to eye clinics for a randomized clinical trial if the project is successful. PUBLIC HEALTH RELEVANCE: Amblyopia is the most frequent cause of vision loss in infants and young children. The primary treatment for amblyopia in young children consists of patching the fellow eye, however, patching is considered to be ineffective in older children and adults. The relevance of this project is in developing new, effective interventions for restoring visual acuity and stereopsis in adults and children with amblyopia.

Project Summary Thirty-two Vision Science preceptors, members of the Group in Vision Science from 9 major departments on the U.C. Berkeley campus (optometry, psychology, public health, molecular and cell biology, neuroscience, public health, computer science, electrical engineering, chemical engineering and physics), seek support for 12 pre- and 4 post-doctoral trainees. Support is sought for 2 years of graduate training toward the PhD, for the pre-doctoral trainees and the 3 health-profession degree seeking trainees (OD, MD etc.), and one year for the post-PhD trainee. The interdisciplinary program in Vision Science has been in existence for over 70 years. There are currently 38 pre-doctoral students engaged in studies leading to the PhD in Vision Science. Among these students there are 5 students who hold an OD degree and one who holds a DVM degree. There are additional 69 postdoctoral fellows currently training in the laboratories of the faculty of the Group in Vision Science. Of the more than 241 trainees who have completed research degree training in Vision Science (almost all PhD) to 2017, the majority are now active vision researchers. Many have successfully competed for independent research funding. Our purpose is to attract outstanding trainees who will develop independent and productive vision research careers. Pre-doctoral and health profession degree trainees, most with additional formal basic science training (e.g., cell biology, immunology, neurobiology, or epidemiology, biostatistics), will earn Ph.D. (Vision Science) degrees. Each pre-doctoral trainee will receive stipend support during the first two years from the NIH Training Grant supplemented by Departmental and University fellowships. After the initial first two years, the support will be provided entirely from resources of the University of California (primarily through individual faculty research grants). Health professional trainees will receive 3 years of support on the Training Grant. Trainees will meet formal course and teaching requirements and will be trained in laboratory research techniques in both basic sciences and vision science. The training is augmented by the extensive resources of the Berkeley campus and the technical support provided to the Group in Vision Science by the NEI Core Grant.

? DESCRIPTION (provided by applicant): Amblyopia is a deficit that arises from abnormal visual experience early in life, most commonly when the two eyes are not aligned (strabismus) or have unequal refractive error (anisometropia). It has long been thought to develop into a permanent deficit unless properly treated early in life; however, recent studies call this into question [1-8]. Adult amblyopes can recover some visual functions. Thus, amblyopia provides a useful model for understanding how to unlock adult neural plasticity. Our main aim is to develop new interventions for restoring visual acuity and stereopsis in adults with amblyopia by embedding visual training in active and rewarding visuomotor tasks that require stereopsis. Our work during the current grant period indicates that playing action-packed video games enhances several aspects of vision in amblyopic adults. Training either monocularly or under dichoptic conditions results in improved visual acuity and reduced suppression in adults with amblyopia. However, it is now clear that both perceptual learning (PL) and videogame play (VGP), whether monocular or dichoptic, result in only a modest improvement in visual acuity (by one to two lines), and only limited improvement in stereopsis [1,3-8]. Much recent work has focused on the role of binocular suppression, as the key to recovering visual functions in amblyopia. Specifically, it has been suggested that treatment should be dichoptic - and aimed at eliminating suppression - rather than monocular [5-8]. However, our pilot studies call this approach into question, and suggest a more direct approach to improving both visual acuity and stereopsis: training under 3D conditions. By forcing the two eyes to coordinate and integrate their signal in the service of a common output, stereopsis provides a unique common teaching signal to the two eyes that may be central to overcoming amblyopia. Our emphasis on stereopsis is novel, but it is based on: (1) our pilot data, showing that in adults with amblyopia training stereopsis directly resulted not only in improved stereopsis, but also in improved visual acuity and contrast sensitivity, as well as reduced inter-ocular suppression and (2) the loss of stereopsis has demonstrable negative effects on everyday activities that can significantly impact individual's quality of life as well as limit their career choices and activities. The most noticeble qualitative deficit associated with amblyopia is impaired or complete loss of stereoscopic depth perception. Thus, the Aims of this proposal are: 1) To develop an integrated, immersive 3D videogame training program for adults with amblyopia; 2) Develop a battery of outcome measures to evaluate the effectiveness, mechanisms and real world impact of training 3) Evaluate the effectiveness of direct training of stereopsis on vision recovery in adult amblyopes.

Levi, Dennis M. PROJECT SUMMARY/ABSTRACT Amblyopia is a developmental disorder of spatial vision usually associated with the presence of strabismus, anisometropia or form deprivation early in life. It affects visual acuity, contrast sensitivity and position acuity. Amblyopia is clinically important because, aside from refractive error, it is the most frequent cause of vision loss in infants and young children, and amblyopia is of basic interest because it reflects the neural impairment which can occur when normal visual development is disrupted. The long-range objectives of this research are to understand the mechanisms that limit spatial vision in humans with amblyopia, with the ultimate goal of developing new approaches aimed at more effective treatment. While our focus in past studies has been on the sensory losses, here we propose the application of a number of innovative methods that will enable us to test specific hypotheses about the role of eye-movements in limiting spatial vision in amblyopia. Aim 1 tests the hypothesis that abnormal spatial vision is at least in part a consequence of fixational eye movements. Specifically we ask how both the retinal image motion induced by these abnormal fixational eye movements, and the eye movements per se, influence visual resolution, visual acuity, crowding and the precision and accuracy of spatial localization. We will use a high-resolution video eye tracker, the Tracking Scanning Laser Ophthalmoscope (TSLO) which allows stimuli to be delivered to precisely identifiable locations on the retina, to test our hypothesis using three different approaches: i) We will measure, model and characterize fixational eye movements in normal and amblyopic adults while performing visual tasks that are compromised in amblyopia. ii) We will assess the role of retinal image motion by comparing visual performance on these tasks under stabilized, unstabilized and ?playback? (i.e., superimposing the amblyopic eye's retinal image motion on the nonamblyopic eye) conditions. iii) We will assess the role of eye movements per se by evaluating visual performance around the time of occurrence of drifts and microsaccades. Compared to normal observers, strabismic amblyopes have significantly longer saccadic and manual latencies to stimuli seen with their amblyopic eyes, compared to their fellow eyes. Aim 2 tests the hypothesis that for strabismic amblyopes, the frequent microsaccades and accompanying saccadic suppression and attentional shifts made while strabismics struggle to maintain fixation with their amblyopic eyes, result in all types of reaction times being irreducibly delayed, commensurate with the degree of unsteadiness. Because the degree of unsteadiness is correlated with LogMAR acuity, it follows that reaction time and saccadic latency are also correlated with LogMAR acuity. Aim 2 tests a number of specific hypotheses regarding the role of microsaccades in reaction time and visual search. 1

PROJECT SUMMARY This is a request for a Research Supplement to promote Diversity in Health-Related Research for grant R21EY030609. Specifically this Supplement is requested to support my graduate student, Angelica (Angie) Godinez for a period of 13 months (August 1 2020 ? August 31, 2021) to complete her Ph.D.