• Grant Application - .pdf format

Abstract: DESCRIPTION (provided by applicant): Soon after birth, most infants develop near emmetropic refractive errors that are then maintained in both eyes throughout childhood and into early adult life. However, for reasons not currently understood, a significant and possibly increasing proportion of the population develop abnormal refractive errors (currently about 30% of young adults in the USA have significant refractive errors). Refractive errors are a significant public health concern because in addition to the high costs and the complications associated with traditional optical and surgical correction strategies, refractive errors can lead to permanent sensory disorders and ocular abnormalities causing blindness. The long-term goal of our research program is to provide a better understanding of the etiology of human refractive errors. The specific aims of our proposed research are to determine how visual experience affects refractive development and to characterize the operational properties of the vision-dependent mechanisms that regulate eye growth. Since many of the required experiments can not be conducted in humans, but our purpose is to generate knowledge that can be applied to human development, these experiments will be conducted using rhesus monkeys. Controlled rearing strategies and optical and ultrasonographic measurement techniques will be used to determine: 1) the relative contributions of the central and peripheral retina to emmetropization and vision-dependent changes in eye growth. 2) the impact of peripheral refractive errors on emmetropization, and 3) the spatial integration characteristics of the vision-dependent mechanisms that regulate eye growth. These experiments focus on fundamental issues concerning the role of visual experience that have largely been ignored in previous studies in humans. Overall the proposed studies are an important step in determining how and to what extent visual experience contributes to the genesis of common human refractive errors. The results of these studies will potentially provide the foundation for new treatment and management strategies for human refractive errors.

Thesaurus Terms:
anisometropia, developmental neurobiology, disease /disorder etiology, eye refraction disorder, visual deprivation, visual perception
amblyopia, astigmatism, binocular vision, disease /disorder model, eye accommodation, eye coordination disorder, infant animal, interocular transfer, psychophysics, vision aid, visual feedback
Macaca mulatta, behavioral /social science research tag, electrophysiology, ultrasonography, vision test

Institution: UNIVERSITY OF HOUSTON
4800 CALHOUN RD
HOUSTON, TX 772045037
Fiscal Year: 2006
Department: BASIC SCIENCES
Project Start: 01-FEB-1981
Project End: 31-DEC-2010
ICD: NATIONAL EYE INSTITUTE
IRG: CVP

Brief Daily Periods of Unrestricted Vision Can Prevent Form-Deprivation Amblyopia
 
Janice M. Wensveen,¹ Ronald S. Harwerth,¹ Li-Fang Hung,^1,2 Ramkumar Ramamirtham,^1,2 Chea-su Kee,³ and Earl L. Smith, III<sup>1,2

1</sup>From the College of Optometry, University of Houston, Houston, Texas; the ²Vision CRC, University of South Wales, Sydney, Australia; and the ³New England College of Optometry, Boston, Massachusetts.
 
(Investigative Ophthalmology and Visual Science. 2006;47:2468-2477.)

Subjects
Data are presented for 26 rhesus monkeys (Macaca mulatta). All the infants were obtained at 1 to 3 weeks of age and reared in our primate nursery, which was maintained on a 12-hour light–dark cycle. All the rearing and experimental procedures were approved by the University of Houston’s Institutional Animal Care and Use Committee and were in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.
 
To characterize how the mechanisms that produce unilateral amblyopia in response to interocular imbalances in image quality integrate the effects of normal and abnormal vision over time, we determined how brief daily periods of unrestricted vision influence the development of form-deprivation amblyopia. Form deprivation imposed by diffuser lenses is the ideal amblyogenic stimulus for these experiments because the degree of image degradation cannot be improved by accommodation, changes in fixation distance, or compensating ocular growth. As a consequence, the timing and degree of image degradation can be controlled precisely. Thus, monocular form deprivation was produced in 18 infant monkeys by securing a diffuser spectacle lens in front of one eye and a clear plano lens in front of the fellow eye. The diffuser lenses, which were held in place by a lightweight helmet,40 consisted of a plano carrier lens that was covered with a commercially available occlusion foil (Bangerter Occlusion Foils; Fresnel Prism and Lens Co., Scottsdale, AZ). The occlusion foils were the strongest diffusers that we used in our previous behavioral study on the effects of the degree of image degradation on the depth of amblyopia.9 Measurements of spatial contrast sensitivity obtained through the treatment lenses revealed that these diffusers reduced the contrast sensitivity of normal adult humans by over 1 log unit for grating spatial frequencies of 0.125 cyc/deg with a resulting cutoff spatial frequency near 1 cyc/deg. The lens-rearing regimen was initiated at 3 weeks of age (24.3 ± 2.8 days) and was continued for approximately 18 weeks (144 ± 17 days). At the end of the rearing period, the helmets were removed, and the animals were allowed unrestricted vision until the behavioral experiments were started. We specifically selected this rearing period, because we had previously demonstrated that continuous unilateral form deprivation during this period produced severe amblyopia in infant monkeys without interfering with interocular alignment and that, during this critical period for spatial vision development, even short durations of continuous monocular form deprivation produced severe amblyopia in infant monkeys. During the treatment period, three infants wore the diffusers continuously. For the other form-deprived monkeys, the diffuser lenses were removed each day and replaced with a clear plano lens for unitary periods of 1 (n = 5), 2 (n = 6), or 4 (n = 4) hours. These periods of unrestricted vision were centered near the midpoint of the normal 12-hour lights-on cycle. To control for potential effects associated with the helmet rearing procedures, four infant monkeys were reared with helmets that held clear, zero-powered lenses over both eyes. Additional control data were obtained from four normally reared infants.
 
The behavioral data for three of the plano-control animals and the three treated monkeys that wore the diffusers continuously have been previously reported.9 41 In addition, details concerning refractive development for all the animals used in this study have been described previously.42 43 Because the diffuser lenses altered the course of emmetropization in the treated eyes of some monkeys and because these results were potentially important for interpreting our behavioral data, aspects of our animals’ refractive development are also included here.

Observations of the positions of the first Purkinje images relative to the centers of the entrance pupils indicated that all the treated animals maintained normal interocular alignment throughout the observation period.

Psychophysical Methods
When the animals were at least 18 months of age (i.e., after at least 1 year of visual experience without the treatment lenses), spatial contrast sensitivity functions were measured behaviorally for each eye. The basic apparatus and operant procedures were similar to those used in previous investigations.9 44 45 During the daily experimental sessions, the monkeys were seated in a primate chair inside a light-proof, sound-attenuating chamber. The primate chair was fitted with a response lever on the waist plate and a drink spout on the neck plate through which orange drink reinforcement was delivered. The animal’s optimal spectacle correction, which was determined for each eye independently using a subjective refraction procedure,45 was held in a facemask at about a 14-mm vertex distance. For monocular viewing, the lens well for one of the eyes was occluded with an opaque disc.
 
The detection stimuli were vertical sinusoidal gratings that were generated using a graphics board (VSG; Cambridge Research Systems, Cambridge, UK) on a 20-in. video monitor (Nano Flexscan 9080; Eizo Nanao, Cypress, CA) that operated at a 100-Hz frame rate. The usable display subtended a visual angle of 11 x 14 ° at the 114-cm viewing distance and had a space-averaged luminance of 60 cd/m2. The grating stimuli were presented as Gabor patches, which consisted of a carrier grating presented in sine phase with the center of the display. The contrast of the grating was attenuated by a two-dimensional (2-D) Gaussian envelope and declined to a value of 1/e of the maximum contrast at 4 ° from the Gabor’s center. The number of grating cycles within the Gabor varied as a function of spatial frequency. As a result, at low spatial frequencies when a small number of grating cycles were presented, probabilistic concerns may have limited absolute sensitivity by a small amount.46 However, for spatial frequencies above the peak of the monkey’s contrast sensitivity function, the number of grating cycles exceeded the number required for optimal performance. A Pritchard spectrophotometer equipped with an automated scanning spot was used to calibrate the luminance and contrast of the display. The contrast of the grating pattern was defined as (Lmax – Lmin)/(Lmax + Lmin), where Lmax and Lmin represent the maximum and minimum luminances of the grating, respectively.

The behavioral paradigm was a temporal–interval detection task that required the monkey to press and hold down the response lever to initiate a trial and then to release the lever within a criterion response interval (900 ms) after the presentation of the grating stimulus to score a ‘hit’ and to receive a juice reinforcement. The grating stimuli were presented for durations of 500 ms, with equal probability between 250 and 6000 ms after the initial lever press. Contrast detection thresholds were measured as a function of spatial frequency from 0.125 or 0.25 cyc/deg to 16 cyc/deg in 0.15-log-unit intervals. Data were collected using an adaptive decreasing contrast staircase procedure. The decision rules were based on a one-down, two-up strategy where each hit was followed by a 0.05-log-unit reduction in contrast, and two consecutive misses were followed by a 0.6-log-unit increase in contrast. The one-down, two-up strategy caused the staircase reversals to converge to a contrast where the probability of a hit was 25%, and this contrast was taken as the threshold. During a given experimental session, the staircases for 5 to 7 different spatial frequencies were simultaneously interleaved.

Contrast sensitivity functions were generated from the geometric means of a minimum of 10 threshold measurements at each spatial frequency. For descriptive purposes and to calculate an eye’s grating visual acuity, each contrast sensitivity function was fit with a double exponential function (contrast sensitivity = [ks(sf • kf) ^ al] exp(–ah • sf • kf), where sf is spatial frequency; al and ah are parameters that reflect the slopes of the low- and high-spatial frequency portions of the function, respectively; ks and kf are proportional to the peak contrast sensitivity and the optimum spatial frequency, respectively) using an iterative routine that minimized the sum of squared errors.

The effects of the different rearing strategies on spatial vision development were quantified primarily by interocular comparisons between the treated and nontreated eyes and by comparisons of the parameters of the exponential functions fit to the contrast sensitivity data, specifically the peak contrast sensitivities and the optimum and cutoff spatial frequencies. For a global measure of spatial vision, the area under the contrast sensitivity function plotted on log–log coordinates was calculated by integrating the exponential functions that were fit to the data between 0.2 cyc/deg and the cutoff spatial frequency.