Table of contentsO1 Changes in peripheral refraction associated with decreased ocular axial growt... more Table of contentsO1 Changes in peripheral refraction associated with decreased ocular axial growth rate in marmosetsAlexandra Benavente-Perez, Ann Nour, Tobin Ansel, Kathleen Abarr, Luying Yan, Keisha Roden, David TroiloO2 PPARα activation suppresses myopia development by increasing scleral collagen synthesis--a new drug target to suppress myopia developmentChanyi Lu, Miaozhen Pan, Min Zheng, Jia Qu, Xiangtian ZhouO3 Evidence and possibilities for local ocular growth regulating signal pathwaysChristine F WildsoetO4 Myopia researches at Eye Hospital of Wenzhou Medical UniversityFan Lu, Xiangtian Zhou, Jie Chen, Jinhua Bao, Liang Hu, Qinmei Wang, Zibing Jin, Jia QuO5 Color, temporal contrast and myopiaFrances Rucker, Stephanie Britton, Stephan Hanowsky, Molly SpatcherO6 The impact of atropine usage on visual function and reading performance in myopic school children in TaiwanHui-Ying Kuo, Ching-Hsiu Ke, I-Hsin Kuo, Chien-Chun Peng, Han-Yin SunO7 Increased time outdoors prevents the on...
On July 26-29, 2010 the 13th International Myopia Conference was held in Tübingen, Germany and in... more On July 26-29, 2010 the 13th International Myopia Conference was held in Tübingen, Germany and included 17 separate symposia, each with 3-5 presentations. Here, in a single paper, the chairs of those Symposia describe the scientific advances noted at the conference and include the full abstracts of the individual myopia papers presented in each symposium along with the authors and their institutions. The 17 Symposia covered 7 topics: Why Study the Mechanisms of Myopia?; Novel Approaches to Risk Factors; Signalling Eye Growth- How Could Basic Biology Be Translated into Clinical Insights?; Where Are Genetic and Proteomic Approaches Leading?; How Does Visual Function Contribute to and Interact with Ametropia?; Does Eye Shape Matter?; Why Ametropia at All?
Myopia is the most frequent cause of distance impairment in the world and is creating an alarming... more Myopia is the most frequent cause of distance impairment in the world and is creating an alarming global epidemic with deleterious ramifications for the quality of life and economic health of individuals and nations as a whole. In addition to being immediately disadvantageous, myopia increases the risk of serious disorders such as myopic macular degeneration, retinal detachment, glaucoma, and cataract and is a leading cause of visual impairment and blindness across many countries. The reduction in age of onset of myopia is of great concern since the earlier the onset, the more myopic the individual will become, with all the attendant increased risks of accompanying debilitating eye conditions. The economic burden is great; both in consequences of uncorrected refractive error and also in the provision of devices for correcting visual acuity. Earlier onset of myopia increases the lifetime economic burden related to loss of productivity and independence, leading to a reduced quality of life. Recent data suggest addressing accommodation per se has little direct amelioration of myopia progression. Pharmacological interventions that effect changes in the sclera show promising efficacy, whereas optical interventions based on a myopic shift in the retinal image are proving to effect up to 55% reduction in the rate of progression of myopia. Early contact lens and spectacle interventions that reduce the rate of progression of myopia are able to significantly reduce the burden of myopia. These nonpharmacological interventions show profound promise in reducing the overall associated morbidity of myopia.
PURPOSE. Early in life, the optical demand associated with the eye's effective refractive state r... more PURPOSE. Early in life, the optical demand associated with the eye's effective refractive state regulates emmetropization in many species, including primates. However, the potential role of optical demand and/or defocus in the genesis of common refractive errors, like myopia, that normally develop much later in life is not known. The purpose of this study was to determine whether chronic optical defocus alters refractive development in monkeys at ages corresponding to when myopia typically develops in children. METHODS. A hyperopic anisometropia was produced in seven adolescent rhesus monkeys by photorefractive keratectomy (PRK) with an excimer laser. Standard treatment algorithms for correcting myopia in humans were used to selectively flatten the central cornea of one eye thereby producing relative hyperopic refractive errors in the treated eyes. The laser ablation zones were 5.0 mm in diameter and centered on the monkeys' pupils. The laser procedures were performed when the monkeys were 2 to 2.5 years old, which corresponded to onset ages between approximately 8 and 10 human years. The ocular effects of the induced anisometropia were assessed by corneal topography, retinoscopy, and A-scan ultrasonography. RESULTS. By approximately 30 days after PRK, the experimentally induced refractive errors had stabilized and the treated eyes were between ϩ0.75 and ϩ2.25 D more hyperopic than their fellow eyes. Subsequently, over the next 300 to 400 days, six of the seven monkeys showed systematic reductions in the degree of anisometropia. Although some regression in corneal power occurred, the compensating refractive changes were primarily due to relative interocular differences in vitreous chamber growth. CONCLUSIONS. Vision-dependent mechanisms that are sensitive to refractive error are still active in adolescent primates and probably play a role in maintaining stable refractive errors in the two eyes. Consequently, conditions that result in consistent hyperopic defocus could potentially contribute to the development of juvenile onset myopia in children. (Invest
Oral administration of the adenosine receptor (ADOR) antagonist, 7-methylxanthine (7-MX), reduces... more Oral administration of the adenosine receptor (ADOR) antagonist, 7-methylxanthine (7-MX), reduces both formdeprivation and lens-induced myopia in mammalian animal models. We investigated whether topically instilled caffeine, another non-selective ADOR antagonist, retards vision-induced axial elongation in monkeys. Beginning at 24 days of age, a 1.4% caffeine solution was instilled in both eyes of 14 rhesus monkeys twice each day until the age of 135 days. Concurrent with the caffeine regimen, the monkeys were fitted with helmets that held either -3 D (-3D/pl caffeine, n = 8) or +3 D spectacle lenses (+3D/pl caffeine, n = 6) in front of their lens-treated eyes and zero-powered lenses in front of their fellow-control eyes. Refractive errors and ocular dimensions were measured at baseline and periodically throughout the lens-rearing period. Control data were obtained from 8 vehicle-treated animals also reared with monocular -3 D spectacles (-3D/pl vehicle). In addition, historical comparison data were available for otherwise untreated lens-reared controls (-3D/pl controls, n = 20; +3D/pl controls, n = 9) and 41 normal monkeys. The vehicle controls and the untreated lens-reared controls consistently developed compensating axial anisometropias (-3D/pl vehicle = -1.44 ± 1.04 D; -3D/pl controls = -1.85 ± 1.20 D; +3D/pl controls = +1.92 ± 0.56 D). The caffeine regime did not interfere with hyperopic compensation in response to +3 D of anisometropia (+1.93 ± 0.82 D), however, it reduced the likelihood that animals would compensate for -3 D of anisometropia (+0.58 ± 1.82 D). The caffeine regimen also promoted hyperopic shifts in both the lens-treated and fellow-control eyes; 26 of the 28 caffeine-treated eyes became more hyperopic than the median normal monkey (mean (±SD) relative hyperopia = +2.27 ± 1.65 D; range = +0.31 to +6.37 D). The effects of topical caffeine on refractive development, which were qualitatively similar to those produced by oral administration of 7-MX, indicate that ADOR antagonists have potential in treatment strategies for preventing and/or reducing myopia progression.
Although reduced ambient lighting ("dim" light) can cause myopia in emmetropizing chicks, it does... more Although reduced ambient lighting ("dim" light) can cause myopia in emmetropizing chicks, it does not necessarily lead to myopic changes in emmetropizing rhesus monkeys. Because myopia is rarely spontaneous, a question remained whether dim light would hasten the progression of visually induced myopia. To determine the effects of dim light on the development of and recovery from form-deprivation myopia (FDM), seven 3-week-old infant rhesus monkeys were reared under dim light (mean ± SD = 55 ± 9 lx) with monocular diffuser spectacles until ~154 days of age, then maintained in dim light with unrestricted vision until ~337 days of age to allow for recovery. Refractive errors, corneal powers, ocular axial dimensions and sub-foveal choroidal thicknesses were measured longitudinally and compared to those obtained from form-deprived monkeys reared under typical laboratory lighting (504 ± 168 lx). Five of the seven subjects developed FDMs that were similar to those observed among their normal-light-reared counterparts. The average degree of form-deprivation-induced myopic anisometropia did not differ significantly between dim-light subjects (-3.88 ± 3.26D) and normal-light subjects (-4.45 ± 3.75D). However, three of the five dim-light subjects that developed obvious FDM failed to exhibit any signs of recovery and the two monkeys that were isometropic at the end of the treatment period manifest abnormal refractive errors during the recovery period. All refractive changes were associated with alterations in vitreous chamber elongation rates. It appears that dim light is not a strong myopiagenic stimulus by itself, but it can impair the optical regulation of refractive development in primates.
Studies in chickens suggest low intensity ambient lighting causes myopia. The purpose of this exp... more Studies in chickens suggest low intensity ambient lighting causes myopia. The purpose of this experiment was to examine the effects of low intensity ambient lighting (dim light) on normal refractive development in macaque monkeys. Seven infant rhesus monkeys were reared under dim light (room illumination level: ~55 lx) from 24 to ~310 days of age with otherwise unrestricted vision. Refractive error, corneal power, ocular axial dimensions, and choroidal thickness were measured in anesthetized animals at the onset of the experiment and periodically throughout the dim-light-rearing period, and were compared with those of normal-light-reared monkeys. We found that dim light did not produce myopia; instead, dim-light monkeys were hyperopic relative to normal-light monkeys (median refractive errors at ~155 days, OD: +3.13 D vs. +2.31 D; OS: +3.31D vs. +2.44 D; at ~310 days, OD: +2.75D vs. +1.78D, OS: +3.00D vs. +1.75D). In addition, dim-light rearing caused sustained thickening in the choroid, but it did not alter corneal power development, nor did it change the axial nature of the refractive errors. These results showed that, for rhesus monkeys and possibly other primates, low ambient lighting by itself is not necessarily myopiagenic, but might compromise the efficiency of emmetropization.
The purpose of this investigation was to determine the effects of narrow band, long-wavelength li... more The purpose of this investigation was to determine the effects of narrow band, long-wavelength lighting on normal refractive development and the phenomena of lens compensation and formdeprivation myopia (FDM) in infant rhesus monkeys. Starting at 24 and continuing until 151 days of age, 27 infant rhesus monkeys were reared under long-wavelength LED lighting (630 nm; illuminance = 274 ± 64 lux) with unrestricted vision (Red Light (RL) controls, n = 7) or a +3 D (+3D-RL, n = 7), -3 D (-3D-RL, n = 6) or diffuser lens (From Deprivation (FD-RL), n = 7) in front of one eye and a plano lens in front of the fellow eye. Refractive development, corneal power, and vitreous chamber depth were measured by retinoscopy, keratometry, and ultrasonography, respectively. Comparison data were obtained from normal monkeys (Normal Light (NL) controls, n = 39) and lens-(+3D-NL, n = 9; -3D-NL, n = 18) and diffuser-reared controls (FD-NL, n = 16) housed under white fluorescent lighting. At the end of the treatment period, median refractive errors for both eyes of all RL groups were significantly more hyperopic than that for NL groups (P = 0.0001 to 0.016). In contrast to fluorescent lighting, red ambient lighting greatly reduced the likelihood that infant monkeys would develop either FDM or compensating myopia in response to imposed hyperopic defocus. However, as in the +3D-NL monkeys, the treated eyes of the +3D-RL monkeys exhibited relative hyperopic shifts resulting in significant anisometropias that compensated for the monocular lens-imposed defocus (P = 0.001). The red-light-induced alterations in refractive development were associated with reduced vitreous chamber elongation and increases in choroidal thickness. The results suggest that chromatic cues play a role in vision-dependent emmetropization in primates. Narrow-band, long-wavelength lighting prevents the axial elongation typically produced by either form deprivation or hyperopic defocus, possibly by creating direction signals normally associated with myopic defocus.
To systematically analyse the differences between cycloplegic and noncycloplegic refractive error... more To systematically analyse the differences between cycloplegic and noncycloplegic refractive errors (RE) in children and to determine if the predictive value of noncycloplegic RE in categorizing RE can be improved. Random cluster sampling was used to select 6825 children aged 4-15 years. Autorefraction was performed under both noncycloplegic and cycloplegic (induced with 1% cyclopentolate drops) conditions. Paired differences between noncycloplegic and cycloplegic spherical equivalent (SE) RE were determined. A general linear model was developed to determine whether cycloplegic SE can be predicted using noncycloplegic SE, age and uncorrected visual acuity (UCVA). Compared to cycloplegia, noncycloplegia resulted in a more myopic SE (paired difference: -0.63 ± 0.65D, 95% CI: -0.612 to -0.65D, 6017 eligible right eyes) with greater differences observed in younger participants and in eyes with more hyperopic RE and smaller AL. Using raw noncycloplegic data resulted in only 61% of the eye...
We investigated the potential causal relationships between anisometropia, amblyopia and strabismu... more We investigated the potential causal relationships between anisometropia, amblyopia and strabismus, specifically to determine whether either amblyopia or strabismus interfered with emmetropization. We analyzed data from non-human primates that were relevant to the coexistence of anisometropia, amblyopia and strabismus in children. We relied on interocular comparisons of spatial vision and refractive development in animals reared with 1) monocular form deprivation; 2) anisometropia optically imposed by either contact lenses or spectacle lenses; 3) organic amblyopia produced by laser ablation of the fovea; and 4) strabismus that was either optically imposed with prisms or produced by either surgical or pharmacological manipulation of the extraocular muscles. Hyperopic anisometropia imposed early in life produced amblyopia in a dose-dependent manner. However, when potential methodological confounds were taken into account, there was no support for the hypothesis that the presence of amblyopia interferes with emmetropization or promotes hyperopia or that the degree of image degradation determines the direction of eye growth. To the contrary, there was strong evidence that amblyopic eyes were able to detect the presence of a refractive error and alter ocular growth to eliminate the ametropia. On the other hand, early onset strabismus, both optically and surgically imposed, disrupted the emmetropization process producing anisometropia. In surgical strabismus, the deviating eyes were typically more hyperopic than their fellow fixating eyes. The results show that early hyperopic anisometropia is a significant risk factor for amblyopia. Early esotropia can trigger the onset of both anisometropia and amblyopia. However, amblyopia, in isolation, does not pose a significant risk for the development of hyperopia or anisometropia.
PPARα activation suppresses myopia development by increasing scleral collagen synthesis-a new dru... more PPARα activation suppresses myopia development by increasing scleral collagen synthesis-a new drug target to suppress myopia development
propose that the absence of "violet" light (VL, near ultraviolet (UV), below 400 nm) in our indus... more propose that the absence of "violet" light (VL, near ultraviolet (UV), below 400 nm) in our industrialized world is a major contributing factor for the recent epidemic increase in myopia. They conclude from their study that artificial lighting should be revised to include a UV component, as in sunlight. The proposal is provocative since short wavelength light exposure has been a topic of research for decades and has been shown to induce photo-oxidation and retinal degeneration. Their conclusion is based on three lines of studies (1) experiments in chickens showing that form deprivation and negative lens induced myopia were reduced when chicks were exposed to light containing near UV and that transcription of retinal genes involved in myopia inhibition was stimulated, (2) measurements of gene expression in mouse photoreceptor cell cultures with and without UV exposure, and (3) analyses of myopia progression in students and children who wore either UV blocking or UV transmitting correcting lenses. We believe that important limitations of the study should be kept in mind.
Although increased intrinsic noise is thought to be responsible for a range of perceptual deficit... more Although increased intrinsic noise is thought to be responsible for a range of perceptual deficits in amblyopic humans, the neural basis for the elevated perceptual noise in amblyopic primates is not known. Here, we tested the idea that perceptual noise is linked to the neuronal spiking noise (variability) resulting from developmental alterations in cortical circuitry. To assess spiking noise, we analyzed the contrast-dependent dynamics of spike counts and spiking irregularity by calculating the square of the coefficient of variation in interspike intervals (CV 2 ) and the trial-to-trial fluctuations in spiking, or mean matched Fano factor (m-FF) in visual area V2 of monkeys reared with chronic monocular defocus. In amblyopic neurons, the contrast versus response functions and the spike count dynamics exhibited significant deviations from comparable data for normal monkeys. The CV 2 was pronounced in amblyopic neurons for highcontrast stimuli and the m-FF was abnormally high in amblyopic neurons for low-contrast gratings. The spike count, CV 2 , and m-FF of spontaneous activity were also elevated in amblyopic neurons. These contrast-dependent spiking irregularities were correlated with the level of binocular suppression in these V2 neurons and with the severity of perceptual loss for individual monkeys. Our results suggest that the developmental alterations in normalization mechanisms resulting from early binocular suppression can explain much of these contrast-dependent spiking abnormalities in V2 neurons and the perceptual performance of our amblyopic monkeys.
Investigative ophthalmology & visual science, Aug 1, 2016
We investigated how the relative surface area devoted to the more positive-powered component in d... more We investigated how the relative surface area devoted to the more positive-powered component in dual-focus lenses influences emmetropization in rhesus monkeys. From 3 to 21 weeks of age, macaques were reared with binocular dual-focus spectacles. The treatment lenses had central 2-mm zones of zero-power and concentric annular zones that had alternating powers of either +3.0 diopters (D) and 0 D (+3 D/pL) or -3.0 D and 0 D (-3 D/pL). The relative widths of the powered and plano zones varied from 50:50 to 18:82 between treatment groups. Refractive status, corneal curvature, and axial dimensions were assessed biweekly throughout the lens-rearing period. Comparison data were obtained from monkeys reared with binocular full-field single-vision lenses (FF+3D, n = 6; FF-3D, n = 10) and from 35 normal controls. The median refractive errors for all of the +3 D/pL lens groups were similar to that for the FF+3D group (+4.63 D versus +4.31 D to +5.25 D; P = 0.18-0.96), but significantly more hyp...
ABSTRACT A contact lens (10) for use in controlling or retarding the progression of myopia in an ... more ABSTRACT A contact lens (10) for use in controlling or retarding the progression of myopia in an eye has a central optical zone (20) approximating the normal diameter of the pupil of the eye (22) that gives clear central vision at distance for the wearer. An annular peripheral optical zone 24 that is substantially outside the diameter of the pupil is formed around the central optical zone (20) with greater refractive power than that of the central zone (22) so that oblique rays entering the eye through the peripheral optical zone (24) will be brought to focus at a focal plane that is substantially on or anterior to the peripheral region of the retina. Preferably, the rear surface (16) of the lens is shaped to conform to the cornea of the eye and the front surface (18) of the lens (10) is shaped to provide—in conjunction with the rear surface (16)—the desired optical properties of the central and peripheral optical zones. The front surface (18) is also preferably contoured to form a smooth transition (30) between the junction of the central optical zone (20) and the peripheral optical zone (24), with or without designed optical properties such as progressive power.
Normative data on the systematic changes in visual sensitivity as a function of retinal eccentric... more Normative data on the systematic changes in visual sensitivity as a function of retinal eccentricity have provided the basis for efficient threshold strategies and data analysis routines for static perimetry. The standard methods of assessing visual field changes in patients also could be used for monkeys with experimentally induced ocular disorders if the normal visual fields of monkeys and humans were similar. Normal visual field data from three rhesus monkeys were compared to data from eight human subjects using the standard threshold programs of the Humphrey Field Analyzer. The experimental paradigm developed for these measurements provided excellent behavioral control for the monkeys, with reliability indices well within acceptable limits. The visual field data from monkeys were comparable to those from humans with respect to: (1) sensitivity as a function of stimulus field size; (2) the derived Statpac global indices; and (3) the variance of threshold measurements across the visual field. The visual fields of monkeys and humans are similar, and the techniques of computerized perimetry may be applied to monkey subjects without significant modification.
Table of contentsO1 Changes in peripheral refraction associated with decreased ocular axial growt... more Table of contentsO1 Changes in peripheral refraction associated with decreased ocular axial growth rate in marmosetsAlexandra Benavente-Perez, Ann Nour, Tobin Ansel, Kathleen Abarr, Luying Yan, Keisha Roden, David TroiloO2 PPARα activation suppresses myopia development by increasing scleral collagen synthesis--a new drug target to suppress myopia developmentChanyi Lu, Miaozhen Pan, Min Zheng, Jia Qu, Xiangtian ZhouO3 Evidence and possibilities for local ocular growth regulating signal pathwaysChristine F WildsoetO4 Myopia researches at Eye Hospital of Wenzhou Medical UniversityFan Lu, Xiangtian Zhou, Jie Chen, Jinhua Bao, Liang Hu, Qinmei Wang, Zibing Jin, Jia QuO5 Color, temporal contrast and myopiaFrances Rucker, Stephanie Britton, Stephan Hanowsky, Molly SpatcherO6 The impact of atropine usage on visual function and reading performance in myopic school children in TaiwanHui-Ying Kuo, Ching-Hsiu Ke, I-Hsin Kuo, Chien-Chun Peng, Han-Yin SunO7 Increased time outdoors prevents the on...
On July 26-29, 2010 the 13th International Myopia Conference was held in Tübingen, Germany and in... more On July 26-29, 2010 the 13th International Myopia Conference was held in Tübingen, Germany and included 17 separate symposia, each with 3-5 presentations. Here, in a single paper, the chairs of those Symposia describe the scientific advances noted at the conference and include the full abstracts of the individual myopia papers presented in each symposium along with the authors and their institutions. The 17 Symposia covered 7 topics: Why Study the Mechanisms of Myopia?; Novel Approaches to Risk Factors; Signalling Eye Growth- How Could Basic Biology Be Translated into Clinical Insights?; Where Are Genetic and Proteomic Approaches Leading?; How Does Visual Function Contribute to and Interact with Ametropia?; Does Eye Shape Matter?; Why Ametropia at All?
Myopia is the most frequent cause of distance impairment in the world and is creating an alarming... more Myopia is the most frequent cause of distance impairment in the world and is creating an alarming global epidemic with deleterious ramifications for the quality of life and economic health of individuals and nations as a whole. In addition to being immediately disadvantageous, myopia increases the risk of serious disorders such as myopic macular degeneration, retinal detachment, glaucoma, and cataract and is a leading cause of visual impairment and blindness across many countries. The reduction in age of onset of myopia is of great concern since the earlier the onset, the more myopic the individual will become, with all the attendant increased risks of accompanying debilitating eye conditions. The economic burden is great; both in consequences of uncorrected refractive error and also in the provision of devices for correcting visual acuity. Earlier onset of myopia increases the lifetime economic burden related to loss of productivity and independence, leading to a reduced quality of life. Recent data suggest addressing accommodation per se has little direct amelioration of myopia progression. Pharmacological interventions that effect changes in the sclera show promising efficacy, whereas optical interventions based on a myopic shift in the retinal image are proving to effect up to 55% reduction in the rate of progression of myopia. Early contact lens and spectacle interventions that reduce the rate of progression of myopia are able to significantly reduce the burden of myopia. These nonpharmacological interventions show profound promise in reducing the overall associated morbidity of myopia.
PURPOSE. Early in life, the optical demand associated with the eye's effective refractive state r... more PURPOSE. Early in life, the optical demand associated with the eye's effective refractive state regulates emmetropization in many species, including primates. However, the potential role of optical demand and/or defocus in the genesis of common refractive errors, like myopia, that normally develop much later in life is not known. The purpose of this study was to determine whether chronic optical defocus alters refractive development in monkeys at ages corresponding to when myopia typically develops in children. METHODS. A hyperopic anisometropia was produced in seven adolescent rhesus monkeys by photorefractive keratectomy (PRK) with an excimer laser. Standard treatment algorithms for correcting myopia in humans were used to selectively flatten the central cornea of one eye thereby producing relative hyperopic refractive errors in the treated eyes. The laser ablation zones were 5.0 mm in diameter and centered on the monkeys' pupils. The laser procedures were performed when the monkeys were 2 to 2.5 years old, which corresponded to onset ages between approximately 8 and 10 human years. The ocular effects of the induced anisometropia were assessed by corneal topography, retinoscopy, and A-scan ultrasonography. RESULTS. By approximately 30 days after PRK, the experimentally induced refractive errors had stabilized and the treated eyes were between ϩ0.75 and ϩ2.25 D more hyperopic than their fellow eyes. Subsequently, over the next 300 to 400 days, six of the seven monkeys showed systematic reductions in the degree of anisometropia. Although some regression in corneal power occurred, the compensating refractive changes were primarily due to relative interocular differences in vitreous chamber growth. CONCLUSIONS. Vision-dependent mechanisms that are sensitive to refractive error are still active in adolescent primates and probably play a role in maintaining stable refractive errors in the two eyes. Consequently, conditions that result in consistent hyperopic defocus could potentially contribute to the development of juvenile onset myopia in children. (Invest
Oral administration of the adenosine receptor (ADOR) antagonist, 7-methylxanthine (7-MX), reduces... more Oral administration of the adenosine receptor (ADOR) antagonist, 7-methylxanthine (7-MX), reduces both formdeprivation and lens-induced myopia in mammalian animal models. We investigated whether topically instilled caffeine, another non-selective ADOR antagonist, retards vision-induced axial elongation in monkeys. Beginning at 24 days of age, a 1.4% caffeine solution was instilled in both eyes of 14 rhesus monkeys twice each day until the age of 135 days. Concurrent with the caffeine regimen, the monkeys were fitted with helmets that held either -3 D (-3D/pl caffeine, n = 8) or +3 D spectacle lenses (+3D/pl caffeine, n = 6) in front of their lens-treated eyes and zero-powered lenses in front of their fellow-control eyes. Refractive errors and ocular dimensions were measured at baseline and periodically throughout the lens-rearing period. Control data were obtained from 8 vehicle-treated animals also reared with monocular -3 D spectacles (-3D/pl vehicle). In addition, historical comparison data were available for otherwise untreated lens-reared controls (-3D/pl controls, n = 20; +3D/pl controls, n = 9) and 41 normal monkeys. The vehicle controls and the untreated lens-reared controls consistently developed compensating axial anisometropias (-3D/pl vehicle = -1.44 ± 1.04 D; -3D/pl controls = -1.85 ± 1.20 D; +3D/pl controls = +1.92 ± 0.56 D). The caffeine regime did not interfere with hyperopic compensation in response to +3 D of anisometropia (+1.93 ± 0.82 D), however, it reduced the likelihood that animals would compensate for -3 D of anisometropia (+0.58 ± 1.82 D). The caffeine regimen also promoted hyperopic shifts in both the lens-treated and fellow-control eyes; 26 of the 28 caffeine-treated eyes became more hyperopic than the median normal monkey (mean (±SD) relative hyperopia = +2.27 ± 1.65 D; range = +0.31 to +6.37 D). The effects of topical caffeine on refractive development, which were qualitatively similar to those produced by oral administration of 7-MX, indicate that ADOR antagonists have potential in treatment strategies for preventing and/or reducing myopia progression.
Although reduced ambient lighting ("dim" light) can cause myopia in emmetropizing chicks, it does... more Although reduced ambient lighting ("dim" light) can cause myopia in emmetropizing chicks, it does not necessarily lead to myopic changes in emmetropizing rhesus monkeys. Because myopia is rarely spontaneous, a question remained whether dim light would hasten the progression of visually induced myopia. To determine the effects of dim light on the development of and recovery from form-deprivation myopia (FDM), seven 3-week-old infant rhesus monkeys were reared under dim light (mean ± SD = 55 ± 9 lx) with monocular diffuser spectacles until ~154 days of age, then maintained in dim light with unrestricted vision until ~337 days of age to allow for recovery. Refractive errors, corneal powers, ocular axial dimensions and sub-foveal choroidal thicknesses were measured longitudinally and compared to those obtained from form-deprived monkeys reared under typical laboratory lighting (504 ± 168 lx). Five of the seven subjects developed FDMs that were similar to those observed among their normal-light-reared counterparts. The average degree of form-deprivation-induced myopic anisometropia did not differ significantly between dim-light subjects (-3.88 ± 3.26D) and normal-light subjects (-4.45 ± 3.75D). However, three of the five dim-light subjects that developed obvious FDM failed to exhibit any signs of recovery and the two monkeys that were isometropic at the end of the treatment period manifest abnormal refractive errors during the recovery period. All refractive changes were associated with alterations in vitreous chamber elongation rates. It appears that dim light is not a strong myopiagenic stimulus by itself, but it can impair the optical regulation of refractive development in primates.
Studies in chickens suggest low intensity ambient lighting causes myopia. The purpose of this exp... more Studies in chickens suggest low intensity ambient lighting causes myopia. The purpose of this experiment was to examine the effects of low intensity ambient lighting (dim light) on normal refractive development in macaque monkeys. Seven infant rhesus monkeys were reared under dim light (room illumination level: ~55 lx) from 24 to ~310 days of age with otherwise unrestricted vision. Refractive error, corneal power, ocular axial dimensions, and choroidal thickness were measured in anesthetized animals at the onset of the experiment and periodically throughout the dim-light-rearing period, and were compared with those of normal-light-reared monkeys. We found that dim light did not produce myopia; instead, dim-light monkeys were hyperopic relative to normal-light monkeys (median refractive errors at ~155 days, OD: +3.13 D vs. +2.31 D; OS: +3.31D vs. +2.44 D; at ~310 days, OD: +2.75D vs. +1.78D, OS: +3.00D vs. +1.75D). In addition, dim-light rearing caused sustained thickening in the choroid, but it did not alter corneal power development, nor did it change the axial nature of the refractive errors. These results showed that, for rhesus monkeys and possibly other primates, low ambient lighting by itself is not necessarily myopiagenic, but might compromise the efficiency of emmetropization.
The purpose of this investigation was to determine the effects of narrow band, long-wavelength li... more The purpose of this investigation was to determine the effects of narrow band, long-wavelength lighting on normal refractive development and the phenomena of lens compensation and formdeprivation myopia (FDM) in infant rhesus monkeys. Starting at 24 and continuing until 151 days of age, 27 infant rhesus monkeys were reared under long-wavelength LED lighting (630 nm; illuminance = 274 ± 64 lux) with unrestricted vision (Red Light (RL) controls, n = 7) or a +3 D (+3D-RL, n = 7), -3 D (-3D-RL, n = 6) or diffuser lens (From Deprivation (FD-RL), n = 7) in front of one eye and a plano lens in front of the fellow eye. Refractive development, corneal power, and vitreous chamber depth were measured by retinoscopy, keratometry, and ultrasonography, respectively. Comparison data were obtained from normal monkeys (Normal Light (NL) controls, n = 39) and lens-(+3D-NL, n = 9; -3D-NL, n = 18) and diffuser-reared controls (FD-NL, n = 16) housed under white fluorescent lighting. At the end of the treatment period, median refractive errors for both eyes of all RL groups were significantly more hyperopic than that for NL groups (P = 0.0001 to 0.016). In contrast to fluorescent lighting, red ambient lighting greatly reduced the likelihood that infant monkeys would develop either FDM or compensating myopia in response to imposed hyperopic defocus. However, as in the +3D-NL monkeys, the treated eyes of the +3D-RL monkeys exhibited relative hyperopic shifts resulting in significant anisometropias that compensated for the monocular lens-imposed defocus (P = 0.001). The red-light-induced alterations in refractive development were associated with reduced vitreous chamber elongation and increases in choroidal thickness. The results suggest that chromatic cues play a role in vision-dependent emmetropization in primates. Narrow-band, long-wavelength lighting prevents the axial elongation typically produced by either form deprivation or hyperopic defocus, possibly by creating direction signals normally associated with myopic defocus.
To systematically analyse the differences between cycloplegic and noncycloplegic refractive error... more To systematically analyse the differences between cycloplegic and noncycloplegic refractive errors (RE) in children and to determine if the predictive value of noncycloplegic RE in categorizing RE can be improved. Random cluster sampling was used to select 6825 children aged 4-15 years. Autorefraction was performed under both noncycloplegic and cycloplegic (induced with 1% cyclopentolate drops) conditions. Paired differences between noncycloplegic and cycloplegic spherical equivalent (SE) RE were determined. A general linear model was developed to determine whether cycloplegic SE can be predicted using noncycloplegic SE, age and uncorrected visual acuity (UCVA). Compared to cycloplegia, noncycloplegia resulted in a more myopic SE (paired difference: -0.63 ± 0.65D, 95% CI: -0.612 to -0.65D, 6017 eligible right eyes) with greater differences observed in younger participants and in eyes with more hyperopic RE and smaller AL. Using raw noncycloplegic data resulted in only 61% of the eye...
We investigated the potential causal relationships between anisometropia, amblyopia and strabismu... more We investigated the potential causal relationships between anisometropia, amblyopia and strabismus, specifically to determine whether either amblyopia or strabismus interfered with emmetropization. We analyzed data from non-human primates that were relevant to the coexistence of anisometropia, amblyopia and strabismus in children. We relied on interocular comparisons of spatial vision and refractive development in animals reared with 1) monocular form deprivation; 2) anisometropia optically imposed by either contact lenses or spectacle lenses; 3) organic amblyopia produced by laser ablation of the fovea; and 4) strabismus that was either optically imposed with prisms or produced by either surgical or pharmacological manipulation of the extraocular muscles. Hyperopic anisometropia imposed early in life produced amblyopia in a dose-dependent manner. However, when potential methodological confounds were taken into account, there was no support for the hypothesis that the presence of amblyopia interferes with emmetropization or promotes hyperopia or that the degree of image degradation determines the direction of eye growth. To the contrary, there was strong evidence that amblyopic eyes were able to detect the presence of a refractive error and alter ocular growth to eliminate the ametropia. On the other hand, early onset strabismus, both optically and surgically imposed, disrupted the emmetropization process producing anisometropia. In surgical strabismus, the deviating eyes were typically more hyperopic than their fellow fixating eyes. The results show that early hyperopic anisometropia is a significant risk factor for amblyopia. Early esotropia can trigger the onset of both anisometropia and amblyopia. However, amblyopia, in isolation, does not pose a significant risk for the development of hyperopia or anisometropia.
PPARα activation suppresses myopia development by increasing scleral collagen synthesis-a new dru... more PPARα activation suppresses myopia development by increasing scleral collagen synthesis-a new drug target to suppress myopia development
propose that the absence of "violet" light (VL, near ultraviolet (UV), below 400 nm) in our indus... more propose that the absence of "violet" light (VL, near ultraviolet (UV), below 400 nm) in our industrialized world is a major contributing factor for the recent epidemic increase in myopia. They conclude from their study that artificial lighting should be revised to include a UV component, as in sunlight. The proposal is provocative since short wavelength light exposure has been a topic of research for decades and has been shown to induce photo-oxidation and retinal degeneration. Their conclusion is based on three lines of studies (1) experiments in chickens showing that form deprivation and negative lens induced myopia were reduced when chicks were exposed to light containing near UV and that transcription of retinal genes involved in myopia inhibition was stimulated, (2) measurements of gene expression in mouse photoreceptor cell cultures with and without UV exposure, and (3) analyses of myopia progression in students and children who wore either UV blocking or UV transmitting correcting lenses. We believe that important limitations of the study should be kept in mind.
Although increased intrinsic noise is thought to be responsible for a range of perceptual deficit... more Although increased intrinsic noise is thought to be responsible for a range of perceptual deficits in amblyopic humans, the neural basis for the elevated perceptual noise in amblyopic primates is not known. Here, we tested the idea that perceptual noise is linked to the neuronal spiking noise (variability) resulting from developmental alterations in cortical circuitry. To assess spiking noise, we analyzed the contrast-dependent dynamics of spike counts and spiking irregularity by calculating the square of the coefficient of variation in interspike intervals (CV 2 ) and the trial-to-trial fluctuations in spiking, or mean matched Fano factor (m-FF) in visual area V2 of monkeys reared with chronic monocular defocus. In amblyopic neurons, the contrast versus response functions and the spike count dynamics exhibited significant deviations from comparable data for normal monkeys. The CV 2 was pronounced in amblyopic neurons for highcontrast stimuli and the m-FF was abnormally high in amblyopic neurons for low-contrast gratings. The spike count, CV 2 , and m-FF of spontaneous activity were also elevated in amblyopic neurons. These contrast-dependent spiking irregularities were correlated with the level of binocular suppression in these V2 neurons and with the severity of perceptual loss for individual monkeys. Our results suggest that the developmental alterations in normalization mechanisms resulting from early binocular suppression can explain much of these contrast-dependent spiking abnormalities in V2 neurons and the perceptual performance of our amblyopic monkeys.
Investigative ophthalmology & visual science, Aug 1, 2016
We investigated how the relative surface area devoted to the more positive-powered component in d... more We investigated how the relative surface area devoted to the more positive-powered component in dual-focus lenses influences emmetropization in rhesus monkeys. From 3 to 21 weeks of age, macaques were reared with binocular dual-focus spectacles. The treatment lenses had central 2-mm zones of zero-power and concentric annular zones that had alternating powers of either +3.0 diopters (D) and 0 D (+3 D/pL) or -3.0 D and 0 D (-3 D/pL). The relative widths of the powered and plano zones varied from 50:50 to 18:82 between treatment groups. Refractive status, corneal curvature, and axial dimensions were assessed biweekly throughout the lens-rearing period. Comparison data were obtained from monkeys reared with binocular full-field single-vision lenses (FF+3D, n = 6; FF-3D, n = 10) and from 35 normal controls. The median refractive errors for all of the +3 D/pL lens groups were similar to that for the FF+3D group (+4.63 D versus +4.31 D to +5.25 D; P = 0.18-0.96), but significantly more hyp...
ABSTRACT A contact lens (10) for use in controlling or retarding the progression of myopia in an ... more ABSTRACT A contact lens (10) for use in controlling or retarding the progression of myopia in an eye has a central optical zone (20) approximating the normal diameter of the pupil of the eye (22) that gives clear central vision at distance for the wearer. An annular peripheral optical zone 24 that is substantially outside the diameter of the pupil is formed around the central optical zone (20) with greater refractive power than that of the central zone (22) so that oblique rays entering the eye through the peripheral optical zone (24) will be brought to focus at a focal plane that is substantially on or anterior to the peripheral region of the retina. Preferably, the rear surface (16) of the lens is shaped to conform to the cornea of the eye and the front surface (18) of the lens (10) is shaped to provide—in conjunction with the rear surface (16)—the desired optical properties of the central and peripheral optical zones. The front surface (18) is also preferably contoured to form a smooth transition (30) between the junction of the central optical zone (20) and the peripheral optical zone (24), with or without designed optical properties such as progressive power.
Normative data on the systematic changes in visual sensitivity as a function of retinal eccentric... more Normative data on the systematic changes in visual sensitivity as a function of retinal eccentricity have provided the basis for efficient threshold strategies and data analysis routines for static perimetry. The standard methods of assessing visual field changes in patients also could be used for monkeys with experimentally induced ocular disorders if the normal visual fields of monkeys and humans were similar. Normal visual field data from three rhesus monkeys were compared to data from eight human subjects using the standard threshold programs of the Humphrey Field Analyzer. The experimental paradigm developed for these measurements provided excellent behavioral control for the monkeys, with reliability indices well within acceptable limits. The visual field data from monkeys were comparable to those from humans with respect to: (1) sensitivity as a function of stimulus field size; (2) the derived Statpac global indices; and (3) the variance of threshold measurements across the visual field. The visual fields of monkeys and humans are similar, and the techniques of computerized perimetry may be applied to monkey subjects without significant modification.
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