Multiple Short Daily Periods of Normal Binocular Vision Preserve Stereopsis in Strabismus.

Purpose: Infantile strabismus impedes the development of stereopsis. In optically strabismic monkeys, 2 continuous hours of normal binocular vision per day has been shown to preserve near-normal stereopsis. In this study, we investigated whether, as in learning, multiple shorter periods of intervention would further boost performance. Methods: To simulate infantile esotropia, infant monkeys were reared with 30 prism diopters base-in starting at 4 weeks of age. Daily periods of normal binocular vision were provided by replacing prisms with plano lenses. Altogether, 14 monkeys were prism reared: 2 with continuous prism, 2 with 2 continuous hours of normal binocular vision per day, 6 with 2 noncontinuous hours, and 4 with 1 noncontinuous hour of binocular vision each day. Seven normally reared monkeys provided control data. Behavioral methods were employed to measure spatial contrast sensitivity, eye alignment, and stereopsis. Results: One monkey reared with continuous prism had poor stereopsis, and the other had no stereopsis. Ten of the 12 monkeys reared with periods of normal binocular vision had stereopsis, and those with longer and more continuous periods of binocular vision had stereopsis approaching that of normally reared monkeys. Conclusions: During early development, multiple short periods of binocular vision were effective in preserving clinically significant stereopsis in monkeys. These results suggest that by providing relatively short multiple daily intervention periods, stereopsis may be preserved in strabismic human children.

Observations on the relationship between anisometropia, amblyopia and strabismus.

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 co-existence 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.

Noisy Spiking in Visual Area V2 of Amblyopic Monkeys.

Interocular decorrelation of input signals in developing visual cortex can cause impaired binocular vision and amblyopia. 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 (CV2) 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 CV2 was pronounced in amblyopic neurons for high-contrast stimuli and the m-FF was abnormally high in amblyopic neurons for low-contrast gratings. The spike count, CV2, 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. SIGNIFICANCE STATEMENT: Amblyopia is a common developmental vision disorder in humans. Despite the extensive animal studies on how amblyopia emerges, we know surprisingly little about the neural basis of amblyopia in humans and nonhuman primates. Although the vision of amblyopic humans is often described as being noisy by perceptual and modeling studies, the exact nature or origin of this elevated perceptual noise is not known. We show that elevated and noisy spontaneous activity and contrast-dependent noisy spiking (spiking irregularity and trial-to-trial fluctuations in spiking) in neurons of visual area V2 could limit the visual performance of amblyopic primates. Moreover, we discovered that the noisy spiking is linked to a high level of binocular suppression in visual cortex during development.

Early monocular defocus disrupts the normal development of receptive-field structure in V2 neurons of macaque monkeys.

Experiencing different quality images in the two eyes soon after birth can cause amblyopia, a developmental vision disorder. Amblyopic humans show the reduced capacity for judging the relative position of a visual target in reference to nearby stimulus elements (position uncertainty) and often experience visual image distortion. Although abnormal pooling of local stimulus information by neurons beyond striate cortex (V1) is often suggested as a neural basis of these deficits, extrastriate neurons in the amblyopic brain have rarely been studied using microelectrode recording methods. The receptive field (RF) of neurons in visual area V2 in normal monkeys is made up of multiple subfields that are thought to reflect V1 inputs and are capable of encoding the spatial relationship between local stimulus features. We created primate models of anisometropic amblyopia and analyzed the RF subfield maps for multiple nearby V2 neurons of anesthetized monkeys by using dynamic two-dimensional noise stimuli and reverse correlation methods. Unlike in normal monkeys, the subfield maps of V2 neurons in amblyopic monkeys were severely disorganized: subfield maps showed higher heterogeneity within each neuron as well as across nearby neurons. Amblyopic V2 neurons exhibited robust binocular suppression and the strength of the suppression was positively correlated with the degree of hereogeneity and the severity of amblyopia in individual monkeys. Our results suggest that the disorganized subfield maps and robust binocular suppression of amblyopic V2 neurons are likely to adversely affect the higher stages of cortical processing resulting in position uncertainty and image distortion.

Objective and subjective refractive error measurements in monkeys.

PURPOSE: To better understand the functional significance of refractive-error measures obtained using common objective methods in laboratory animals, we compared objective and subjective measures of refractive error in adolescent rhesus monkeys. METHODS: The subjects were 20 adolescent monkeys. Spherical-equivalent spectacle-plane refractive corrections were measured by retinoscopy and autorefraction while the animals were cyclopleged and anesthetized. The eye's axial dimensions were measured by A-Scan ultrasonography. Subjective measures of the eye's refractive state, with and without cycloplegia, were obtained using psychophysical methods. Specifically, we measured spatial contrast sensitivity as a function of spectacle lens power for relatively high spatial frequency gratings. The lens power that produced the highest contrast sensitivity was taken as the subjective refraction. RESULTS: Retinoscopy and autorefraction consistently yielded higher amounts of hyperopia relative to subjective measurements obtained with or without cycloplegia. The subjective refractions were not affected by cycloplegia and on average were 1.42 ± 0.61 D and 1.24 ± 0.62 D less hyperopic than the retinoscopy and autorefraction measurements, respectively. Repeating the retinoscopy and subjective measurements through 3 mm artificial pupils produced similar differences. CONCLUSIONS: The results show that commonly used objective methods for assessing refractive errors in monkeys significantly overestimate the degree of hyperopia. It is likely that multiple factors contributed to the hyperopic bias associated with these objective measurements. However, the magnitude of the hyperopic bias was in general agreement with the "small-eye artifact" of retinoscopy.

Effects of brief daily periods of unrestricted vision during early monocular form deprivation on development of visual area 2.

PURPOSE: Providing brief daily periods of unrestricted vision during early monocular form deprivation reduces the depth of amblyopia. To gain insights into the neural basis of the beneficial effects of this treatment, the binocular and monocular response properties of neurons were quantitatively analyzed in visual area 2 (V2) of form-deprived macaque monkeys. METHODS: Beginning at 3 weeks of age, infant monkeys were deprived of clear vision in one eye for 12 hours every day until 21 weeks of age. They received daily periods of unrestricted vision for 0, 1, 2, or 4 hours during the form-deprivation period. After behavioral testing to measure the depth of the resulting amblyopia, microelectrode-recording experiments were conducted in V2. RESULTS: The ocular dominance imbalance away from the affected eye was reduced in the experimental monkeys and was generally proportional to the reduction in the depth of amblyopia in individual monkeys. There were no interocular differences in the spatial properties of V2 neurons in any subject group. However, the binocular disparity sensitivity of V2 neurons was significantly higher and binocular suppression was lower in monkeys that had unrestricted vision. CONCLUSIONS: The decrease in ocular dominance imbalance in V2 was the neuronal change most closely associated with the observed reduction in the depth of amblyopia. The results suggest that the degree to which extrastriate neurons can maintain functional connections with the deprived eye (i.e., reducing undersampling for the affected eye) is the most significant factor associated with the beneficial effects of brief periods of unrestricted vision.

Brief daily periods of unrestricted vision preserve stereopsis in strabismus.

PURPOSE: This study examines whether brief periods of binocular vision could preserve stereopsis in monkeys reared with optical strabismus. METHODS: Starting at 4 weeks of age, six infant monkeys were reared with a total of 30 prism diopters base-in split between the eyes. Two of the six monkeys wore prisms continuously, one for 4 weeks and one for 6 weeks. Four of the six monkeys wore prisms but had 2 hours of binocular vision daily, one for 4, one for 6, and two for 16 weeks. Five normally reared monkeys provided control data. Behavioral methods were used to measure spatial contrast sensitivity, eye alignment, and stereopsis with Gabor and random dot targets. RESULTS: The same pattern of results was evident for both local and global stereopsis. For monkeys treated for 4 weeks, daily periods of binocular vision rescued stereopsis from the 10-fold reduction observed with continuous optical strabismus. Six weeks of continuous strabismus resulted in stereo blindness, whereas daily periods of binocular vision limited the reduction to a twofold loss from normal. Daily periods of binocular vision preserved stereopsis over 16 weeks of optical strabismus for one of the two monkeys. CONCLUSIONS: Two hours of daily binocular vision largely preserves local and global stereopsis in monkeys reared with optical strabismus. During early development, the effects of normal vision are weighed more heavily than those of abnormal vision. The manner in which the effects of visual experience are integrated over time reduces the likelihood that brief episodes of abnormal vision will cause abnormal binocular vision development.

Feasibility of using placebo vision therapy in a multicenter clinical trial.

PURPOSE: The Convergence Insufficiency Treatment Trial (CITT) Investigator Group conducted a preliminary study assessing the effectiveness of home-based push-up therapy and office-based vision therapy/orthoptics for the treatment of convergence insufficiency (CI). The CITT group developed a placebo therapy program that was designed to simulate real vision therapy/orthoptics. The purpose of this paper is to evaluate the effectiveness of this placebo therapy program in maintaining masking of subjects randomized to the office-based treatment arms (real or placebo). METHODS: Subjects (ages 9 to 30 years) were enrolled, stratified into two groups by age, and then randomly assigned to one of three treatment groups: pencil push-up therapy, office-based vision therapy/orthoptics, or office-based placebo vision therapy/orthoptics. At the end of treatment, subjects in the two office-based therapy groups (placebo and real) were asked: (1) which treatment do you think you received? and (2) how sure are you about your answer? RESULTS: Ninety-five percent of subjects assigned to real therapy and 83% assigned to placebo therapy thought they were in the real therapy group. Of the subjects who thought they received real therapy, 90% assigned to real therapy and 89% assigned to placebo therapy were "somewhat sure," "pretty sure," or "very sure" of their answer. Those assigned to real therapy had more responses in the "very sure" category. CONCLUSION: The CITT placebo therapy program was effective in maintaining subject masking in this multicenter clinical trial.

Brief daily periods of unrestricted vision can prevent form-deprivation amblyopia.

PURPOSE: To characterize how the mechanisms that produce unilateral form-deprivation amblyopia integrate the effects of normal and abnormal vision over time, the effects of brief daily periods of unrestricted vision on the spatial vision losses produced by monocular form deprivation were investigated in infant monkeys. METHODS: Beginning at 3 weeks of age, unilateral form deprivation was initiated 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. During the treatment period (18 weeks), three infants wore the diffusers continuously. For the other experimental infants, the diffusers were removed daily and replaced with clear, zero-powered lenses for 1 (n=5), 2 (n=6), or 4 (n=4) hours. Four infants reared with binocular zero-powered lenses and four normally reared monkeys provided control data. RESULTS: The degree of amblyopia varied significantly with the daily duration of unrestricted vision. Continuous form deprivation caused severe amblyopia. However, 1 hour of unrestricted vision reduced the degree of amblyopia by 65%, 2 hours reduced the deficits by 90%, and 4 hours preserved near-normal spatial contrast sensitivity. CONCLUSIONS: The severely amblyogenic effects of form deprivation in infant primates are substantially reduced by relatively short daily periods of unrestricted vision. The manner in which the mechanisms responsible for amblyopia integrate the effects of normal and abnormal vision over time promotes normal visual development and has important implications for the management of human infants with conditions that potentially cause amblyopia.

A randomized clinical trial of vision therapy/orthoptics versus pencil pushups for the treatment of convergence insufficiency in young adults.

PURPOSE: : The purpose of this article is to compare vision therapy/orthoptics, pencil pushups, and placebo vision therapy/orthoptics as treatments for symptomatic convergence insufficiency in adults 19 to 30 years of age. METHODS: : In a randomized, multicenter clinical trial, 46 adults 19 to 30 years of age with symptomatic convergence insufficiency were randomly assigned to receive 12 weeks of office-based vision therapy/orthoptics, office-based placebo vision therapy/orthoptics, or home-based pencil pushups. The primary outcome measure was the symptom score on the Convergence Insufficiency Symptom Survey. Secondary outcome measures were the near point of convergence and positive fusional vergence at near. RESULTS: : Only patients in the vision therapy/orthoptics group demonstrated statistically and clinically significant changes in the near point of convergence (12.8 cm to 5.3 cm, p = 0.002) and positive fusional vergence at near (11.3Delta to 29.7Delta, p = 0.001). Patients in all three treatment arms demonstrated statistically significant improvement in symptoms with 42% in office-based vision therapy/orthoptics, 31% in office-based placebo vision therapy/orthoptics, and 20% in home-based pencil pushups achieving a score <21 (our predetermined criteria for elimination of symptoms) at the 12-week visit. DISCUSSION: : In this study, vision therapy/orthoptics was the only treatment that produced clinically significant improvements in the near point of convergence and positive fusional vergence. However, over half of the patients in this group (58%) were still symptomatic at the end of treatment, although their symptoms were significantly reduced. All three groups demonstrated statistically significant changes in symptoms with 42% in office-based vision therapy/orthoptics, 31% in office-based placebo vision therapy/orthoptics, and 20% in home-based pencil push-ups meeting our criteria for elimination of symptoms.

A randomized clinical trial of treatments for convergence insufficiency in children.

OBJECTIVE: To compare vision therapy/orthoptics, pencil push-ups, and placebo vision therapy/orthoptics as treatments for symptomatic convergence insufficiency in children 9 to 18 years of age. METHODS: In a randomized, multicenter clinical trial, 47 children 9 to 18 years of age with symptomatic convergence insufficiency were randomly assigned to receive 12 weeks of office-based vision therapy/orthoptics, office-based placebo vision therapy/orthoptics, or home-based pencil push-ups therapy. MAIN OUTCOME MEASURES: The primary outcome measure was the symptom score on the Convergence Insufficiency Symptom Survey. Secondary outcome measures were the near point of convergence and positive fusional vergence at near. RESULTS: Symptoms, which were similar in all groups at baseline, were significantly reduced in the vision therapy/orthoptics group (mean symptom score decreased from 32.1 to 9.5) but not in the pencil push-ups (mean symptom score decreased from 29.3 to 25.9) or placebo vision therapy/orthoptics groups (mean symptom score decreased from 30.7 to 24.2). Only patients in the vision therapy/orthoptics group demonstrated both statistically and clinically significant changes in the clinical measures of near point of convergence (from 13.7 cm to 4.5 cm; P < .001) and positive fusional vergence at near (from 12.5 prism diopters to 31.8 prism diopters; P < .001). CONCLUSIONS: In this pilot study, vision therapy/orthoptics was more effective than pencil push-ups or placebo vision therapy/orthoptics in reducing symptoms and improving signs of convergence insufficiency in children 9 to 18 years of age. Neither pencil push-ups nor placebo vision therapy/orthoptics was effective in improving either symptoms or signs associated with convergence insufficiency.

Validity and reliability of the revised convergence insufficiency symptom survey in adults.

PURPOSE: To assess the validity and reliability of the revised Convergence Insufficiency Symptom Survey (CISS) in adults aged 19-30 years. The CISS was developed to be the primary outcome measure for studies evaluating various treatments for convergence insufficiency (CI). METHODS: CISS mean scores from adults with symptomatic CI and adults with normal binocular vision (NBV) were compared to assess the survey's validity. Adults with symptomatic CI were given the CISS twice to evaluate reliability, which was assessed using intraclass correlation coefficient (ICC) and 95% limits of agreement. RESULTS: Forty-six adults with CI and 46 adults with NBV participated in the study. The mean CISS score for the CI group was 37.3 (S.D. = 9.3) and 11.0 (S.D. = 8.2) for the NBV group. These mean values were significantly different (p < 0.0001). Good discrimination (sensitivity = 97.8%, specificity = 87%) was obtained using a score of 21 or higher. For the CI group the ICC was 0.885 (95% CI of 0.798, 0.936) and the 95% limits of agreement were -9.0 to 7.6. CONCLUSIONS: Adults with symptomatic CI had a significantly higher CISS score than adults with NBV. The results of the study demonstrate that the CISS is a valid and reliable instrument that can be used clinically or as an outcome measure for research studies of adults with CI.

Binocular deficits associated with early alternating monocular defocus. I. Behavioral observations.

To study the binocular vision deficits associated with anisometropia, monkeys were reared with alternating monocular defocus, which allowed monocular mechanisms to develop normally while binocular mechanisms were selectively compromised. A defocusing contact lens of -1.5 D, -3 D, or -6 D was worn on alternate eyes on successive days (n = 3 per lens power) from 3 wk to 9 mo of age. The control subjects were two normally reared monkeys and two human observers. Functional binocular vision was assessed through behavioral measurements of stereoscopic depth discrimination thresholds as a function of spatial frequency. To characterize the extent of the deficits in disparity processing at a given spatial frequency, the contrast required to support stereopsis was determined for a range of disparities that exceeded the subjects' measured stereoacuity. The lens-reared monkeys showed spatial-frequency-selective deficits in stereopsis that depended on the magnitude of the simulated anisometropia experienced during the rearing period. For a given spatial frequency, the treated monkeys generally required higher than normal contrasts to support stereopsis even for large disparities. Moreover, a given increase in contrast produced smaller than normal improvements in stereo discrimination in our treated subjects, which suggests that in addition to deficits in contrast sensitivity, disparity-sensitive mechanisms exhibited low contrast gains. The spatial-frequency selective nature of the binocular deficits produced by the imposed anisometropia indicate that disparity processing mechanisms are normally spatial-frequency selective and that mechanisms tuned to different spatial frequencies can be differentially affected by abnormal binocular visual experience.

Binocular deficits associated with early alternating monocular defocus. II. Neurophysiological observations.

Experiencing binocularly conflicting signals early in life dramatically alters the binocular responses of cortical neurons. Because visual cortex is highly plastic during a critical period of development, cortical deficits resulting from early abnormal visual experience often mirror the nature of interocular decorrelation of neural signals from the two eyes. In the preceding paper, we demonstrated that monkeys that experienced early alternating monocular defocus (-1.5, -3.0, or -6.0 D) show deficits in stereopsis that generally reflected the magnitude of imposed monocular defocus. Because these results indicated that alternating monocular defocus affected the higher spatial frequency components of visual scenes more severely, we employed microelectrode recording methods to investigate whether V1 neurons in these lens-reared monkeys exhibited spatial-frequency-dependent alterations in their binocular response properties. We found that a neuron's sensitivity to interocular spatial phase disparity was reduced in the treated monkeys and that this reduction was generally more severe for units tuned to higher spatial frequencies. In the majority of the affected units, the disparity-sensitivity loss was associated with interocular differences in monocular receptive field properties. The present results suggest that the behavioral deficits in stereopsis produced by abnormal visual experience reflect at least in part the constraints imposed by alterations at the earliest stages of binocular cortical processing and support the hypothesis that the local disparity processing mechanisms in primates are spatially tuned and can be independently compromised by early abnormal visual experience.