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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.

Purpose Loss of ganglion cell inner plexiform layer (GCIPL) and visual sensitivity in the macula region are known to occur at all stages of glaucoma. While both are dependent on the underlying retinal ganglion cells (RGCs), the relationship between structure and function is modest. We hypothesize that the imprecise relationship is due to a lack of direct correspondence between in vivo measures and RGC counts, as well as the relatively large stimulus size used by standard perimetry, which exceeds spatial summation. Methods The relationship between optical coherence tomography (OCT)-derived GCIPL thickness and corresponding inner cell density from retinal flat mounts was determined for four nonhuman primates with varying stages of neuropathy. Normative data for 10-2 threshold using Goldman size I to V stimuli were established for 10 animals, 4 of which were then followed longitudinally with OCT and perimetry. The relationship between GCIPL volume, which incorporated stimulus size after removal of residual thickness, and differential light sensitivity was determined for both experimental glaucoma and healthy eyes. Results Peak inner retinal cell density was 63,052 ± 9238 cells/mm2 in the healthy eye. Cell density was related to both GCIPL thickness and eccentricity (R2 = 0.74, P < .01). For all 10-2 eccentricities, size III stimuli were greater than the critical area (P < 0.01). Based on the structural and histologic relationship, the critical area corresponds to approximately 156 RGCs. Conclusions The relationship between cell density and GCIPL thickness is dependent on retinal eccentricity. For 10-2 perimetry, perimetric loss, especially at earlier stages of neuropathy, may best be detected using size II or smaller stimuli.

Optic nerve head (ONH) neuroretinal rim thickness, quantified as minimum rim width (BMO-MRW), is a sensitive measure for assessing early glaucomatous disease. The BMO-MRW is sensitive to transient fluctuations in intraocular pressure (IOP), but the time course over which BMO-MRW decreases and recovers with changes in IOP remains unknown. The goal of this study was to investigate the dynamics of BMO-MRW changes over 2-hour periods of mild or moderate IOP elevation, and subsequent recovery, in healthy non-human primate eyes. Eight non-human primates were included in the study. For each animal, in two different sessions separated by at least 2 weeks, the anterior chamber IOP of one eye was maintained at either 25 mmHg or 40 mmHg for 2 hours and, subsequently, at 10 mmHg for 2 hours. For the duration of anterior chamber cannulation, optical coherence tomography (OCT) radial scans centered on the ONH were acquired every 5 min and used to quantify BMO-MRW. An exponential decay or rise to maximum function was used to determine the extent and rate of structural change. Additionally, Bruch’s membrane opening (BMO) area, BMO height/displacement, and BMO-referenced anterior lamina cribrosa surface depth (BMO-ALCSD) were computed from radial scans. A circular scan was used to quantify retinal nerve fiber layer thickness (RNFLT) and circumpapillary choroid thickness. The primary results demonstrated that the BMO-MRW changed over an extended duration, while BMO displacement was rapid and remained stable with sustained IOP. The mean maximum predicted BMO-MRW thinning following 2 hours of IOP elevation was significantly related to pressure (34.2 ± 13.8 μm for an IOP of 25 mmHg vs 40.5 ± 12.6 μm for 40 mmHg, p = 0.03). The half-life for BMO-MRW thinning was 21.9 ± 9.2 min for 25 mmHg and 20.9 ± 4.2 min for 40 mmHg, not significantly different between IOP levels (p = 0.76). Subsequently, after 2 hours of IOP at 10 mmHg, all animals exhibited partial recovery of BMO-MRW with similar degrees of persistent residual thinning for the two IOP levels (21.5 ± 13.7 vs 21.0 ± 12.3 μm, p = 0.88). Similar to BMO-MRW, choroid thickness exhibited gradual thinning with IOP elevation and residual thinning following IOP reduction. However, there was no significant change in BMO area or BMO-ALCSD in either experimental session. The RNFLT gradually decreased over the duration of IOP elevation, with continued decreases following IOP reduction for the 40 mmHg session, resulting in total changes from baseline of −2.24 ± 0.81 and −2.45 ± 1.21 μm for 25 and 40 mmHg, respectively (p < 0.001). The sum of the results demonstrate that the ONH neural tissue is sensitive to changes in IOP, the effects of which are gradual over an extended time course and different for increased vs. decreased pressure. Understanding the duration over which IOP influences BMO-MRW has important implications for studies investigating the effects of IOP on the ONH. Additionally, individual variability in ONH response to IOP may improve our understanding of the risk and progression of disease.

Intraocular pressure (IOP) is an important risk factor for glaucoma, and the response of the ONH and surrounding tissues to elevated IOP are often investigated to better understand pathophysiology. In vivo structure including that of the optic nerve head (ONH) and surrounding tissue of the eye are often assessed using optical coherence tomography (OCT). With advances in OCT technology, both large vessels and capillaries can be imaged non-invasively (OCT Angiography). Because a significant portion of retinal thickness is comprised of vasculature, the purpose of the current study was to investigate OCT structural and vascular changes in healthy non-human primate eyes with systematic graded increases and decreases in IOP. Six healthy animals with no previous experimental intervention were used. The pressure in the anterior chamber was adjusted from 10 mmHg to 60 mmHg and back to 10 mmHg in 10 mmHg steps every 10 min. Using optical coherence tomography (OCT), retinal nerve fiber layer (RNFL) thickness, minimum rim width (MRW), Bruch's membrane opening (BMO) size and relative height, anterior lamina cribrosa surface (ALCS) depth, choroidal thickness, and angiography (OCTA) were quantified. With IOP challenge there were significant changes in all morphological measures quantified (p 0.01) other than BMO size (p = 0.30) and RNFL thickness (p = 0.29). Specifically, the position of the BMO was sensitive to both an increase and decease in IOP. The inner retinal capillary density gradually decreased with increasing IOP, reaching statistical significance when pressure exceeded 50 mmHg, but returned when IOP was reduced. The average choroidal thickness around the ONH decreased for elliptical annuli 500-1000 μm and 1000-1500 μm, from the BMO, with increasing IOP (p 0.01). For the 1000-1500 μm annulus, choroid thickness did not return to baseline with IOP reduction. Similarly, the MRW decreased with increase in IOP, but with pressure reduction did not return, and at the final 10 mmHg time point was thinner than at baseline (p 0.01). The results from this experiment illustrate differences in ONH neural rim tissue, RNFL and vessel density changes with acute IOP challenge. Overall, vessel collapse could not completely account for changes in RNFL or ONH MRW thickness. The study supports the hypothesis neural rim compression may be an important part of IOP-induced damage.

SIGNIFICANCE For glaucoma patients, high intraocular pressure (IOP) is a risk factor for progressive neuropathy. Similarly, animal models used to study the disease are based on an experimental elevation of IOP. Thus, accurate IOP measurements are important in characterizing experimental models and resulting effects. PURPOSE The purpose of the present study was to investigate IOP measurements in a non-human primate model of experimental glaucoma by comparing clinical tonometry (Tono-Pen and TonoVet) to the true IOP from intracameral manometry. METHODS A total of 17 rhesus macaque eyes from 12 animals were used for this study. Eleven eyes had no previous experimental intervention, whereas six eyes were at varying stages of laser-induced experimental glaucoma. IOPs were adjusted by inserting a needle in the anterior chamber that was attached to a pressure transducer and syringe pump system. The anterior chamber IOP was adjusted to values between 10 and 50 mmHg and corresponding measures with Tono-Pen and TonoVet were taken. RESULTS The IOPs by TonoVet and Tono-Pen were linearly related over the range of pressures tested (slope = 0.68 normal/healthy and 0.72 experimental glaucoma). For the most, TonoVet measures overestimated IOP at all anterior chamber pressure settings (mean difference of 3.17 mmHg, 95% CI 12.53 to -4.74 normal and 3.90 mmHg, 95% CI 12.90 to -6.53 experimental glaucoma). In contrast, Tono-Pen measures overestimated IOP at lower IOPs and underestimated at higher IOP (slope = -0.26 normal and -0.21 experimental glaucoma). CONCLUSIONS The TonoVet and Tono-Pen tonometers that are often used to assess IOP in both clinical and experimental settings generally reflect the status of IOP, but the results from this study suggest that the instruments need calibration with true anterior chamber pressure for accurate measures in experimental models of glaucoma.

Changes in the foveal anatomy during infancy are an important component in early development of spatial vision. The present longitudinal study in rhesus monkeys was undertaken to characterize the postnatal maturation of the fovea. Starting at four weeks after birth, the retinas of the left eyes of sixteen infant monkeys were imaged using spectral domain optical coherence tomography (SD OCT). Retinal scans were repeated every 30 days during the first year of life and every 60 days thereafter. Volume scans through the fovea were registered, scaled using a three surface schematic eye, and analyzed to measure foveal pit parameters. The individual layers of the retina were manually segmented and thicknesses were measured over a transverse distance of 1250 microns from the center of the foveal pit. Based on infrared scanning laser ophthalmoscope (IR SLO) images acquired with the SD OCT system, there were significant changes in the extent of the retina scanned as the eyes matured. Using a three-surface schematic eye, the length of each scan could be computed and was validated using image registration (R2 = 0.88, slope = 1.003, p < 0.05). Over the first 18 months of life, the mean retinal thickness at the pit center had increased by 21.4% with a corresponding 20.3% decrease in pit depth. The major changes occurred within the first 120 days, but did not stabilize until a year after birth. In Macaca mulatta infants, the primary anatomical maturation of the fovea occurs within the first few months of life, as determined by longitudinal data from SD OCT measurements. The timelines for maturation of the fovea correspond well with the normal development of the lateral geniculate nucleus, cortical neurophysiology, and spatial resolution in monkeys.

PURPOSE The purpose of this study was to determine the relationship between optical coherence tomography (OCT) measures of retinal nerve fiber layer (RNFL) and neuroretinal rim (NRR) in a nonhuman primate experimental glaucoma model, and in a population of clinical patients. METHODS For nonhuman primates, normative data were collected from 44 healthy monkeys, and nine animals with unilateral experimental glaucoma that were followed longitudinally. Cross-sectional human subjects data were collected from 89 healthy, 74 glaucoma suspects, and 104 glaucoma patients. Individualized transverse scaling for OCT scans was calculated using a schematic eye that incorporated optical ocular biometry. Custom algorithms were used to quantify RNFL thickness with and without vessels removed, scaled minimum rim width (sMRW), and neural rim volume (NRV). RESULTS For the experimental glaucoma group, NRR parameters showed the first changes with increased cumulative IOP. The data for both NRR and RNFL measures were best fit by an exponential rise model (NRV, R2=0.79, P

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.

An assessment of the retinal nerve fiber layer (RNFL) provides important information on the health of the optic nerve. There are several non-invasive technologies, including spectral domain optical coherence tomography (SD OCT), that can be used for in vivo imaging and quantification of the RNFL, but often there is disagreement in RNFL thickness between clinical instruments. The purpose of this study was to investigate the influence of scan centration, ocular magnification, and segmentation on the degree of agreement of RNFL thickness measures by two SD OCT instruments.RNFL scans were acquired from 45 normal eyes using two commercially available SD OCT systems. Agreement between RNFL thickness measures was determined using each instrument's algorithm for segmentation and a custom algorithm for segmentation. The custom algorithm included ocular biometry measures to compute the transverse scaling for each eye. Major retinal vessels were identified and removed from RNFL measures in 1:1 scaled images. Transverse scaling was also used to compute the RNFL area for each scan.Instrument-derived global RNFL thickness measured from the two instruments correlated well (R(2) = 0.70, p0.01) but with significant differences between instruments (mean of 6.7 μm; 95% limits of agreement of 16.0 μm to -2.5 μm, intraclass correlation coefficient = 0.62). For recentered scans with custom RNFL segmentation, the mean difference was reduced to 0.1 μm (95% limits of agreement 6.1 to -5.8 μm, intraclass correlation coefficient = 0.92). Global RNFL thickness was related to axial length (R = 0.24, p0.01), whereas global RNFL area measures were not (R(2) = 0.004, p = 0.66). Major retinal vasculature accounted for 11.3 ± 1.6% (Cirrus) or 11.8 ± 1.4% (Spectralis) of the RNFL thickness/area measures.Sources of disagreement in RNFL measures between SD-OCT instruments can be attributed to the location of the scan path and differences in their retinal layer segmentation algorithms. In normal eyes, the major retinal vasculature accounts for a significant percentage of the RNFL and is similar between instruments. With incorporation of an individual's ocular biometry, RNFL area measures are independent of axial length, with either instrument.

The glaucomas are a group of relatively common optic neuropathies, in which the pathological loss of retinal ganglion cells causes a progressive loss of sight and associated alterations in the retinal nerve fiber layer and optic nerve head. The diagnosis and management of glaucoma are often dependent on methods of clinical testing that either, 1) identify and quantify patterns of functional visual abnormality, or 2) quantify structural abnormality in the retinal nerve fiber layer, both of which are caused by loss of retinal ganglion cells. Although it is evident that the abnormalities in structure and function should be correlated, propositions to link losses in structure and function in glaucoma have been formulated only recently. The present report describes an attempt to build a model of these linking propositions using data from investigations of the relationships between losses of visual sensitivity and thinning of retinal nerve fiber layer over progressive stages of glaucoma severity. A foundation for the model was laid through the pointwise relationships between visual sensitivities (behavioral perimetry in monkeys with experimental glaucoma) and histological analyses of retinal ganglion cell densities in corresponding retinal locations. The subsequent blocks of the model were constructed from clinical studies of aging in normal human subjects and of clinical glaucoma in patients to provide a direct comparison of the results from standard clinical perimetry and optical coherence tomography. The final formulation is a nonlinear structure-function model that was evaluated by the accuracy and precision of translating visual sensitivities in a region of the visual field to produce a predicted thickness of the retinal nerve fiber layer in the peripapillary sector that corresponded to the region of reduced visual sensitivity. The model was tested on two independent patient populations, with results that confirmed the predictive relationship between the retinal nerve fiber layer thickness and visual sensitivities from clinical perimetry. Thus, the proposed model for linking structure and function in glaucoma has provided information that is important in understanding the results of standard clinical testing and the neuronal losses caused by glaucoma, which may have clinical application for inter-test comparisons of the stage of disease.

The glaucomas are a group of potentially blinding optic neuropathies that are characterized by progressive pathological losses of the retinal ganglion cells (RGCs) and their axons that form the optic nerve. The causes are unknown and, therefore, the diagnosis and assessment of progression of disease depends on ophthalmic testing to identify and quantify clinical characteristics of glaucomatous neuropathy, such as the pattern of visual field defects and/or thinning of the retinal nerve fiber layer. To relate these clinical measurements to the basic pathology of glaucoma, a neuron doctrine for glaucoma has been proposed to correlate data from standard tests (standard automated perimetry and optical coherence tomography) to the loss of RGCs. The doctrine was derived through initial laboratory studies of experimental glaucoma in macaque monkeys and, then, modified and refined though patient-based clinical investigations. The final formulation of the doctrine produced concordance between subjective and objective measurements when the results were translated to their common parameter of RGCs, for both normal vision and defective vision from glaucoma. Thus, it was concluded that for individual patients, alterations in structure-function relationships usually should be in agreement for the degree and location of visual field defects caused by glaucoma.

The effects of aging on retinal nerve fiber layer (RNFL) thickness should reflect the age-related losses in retinal ganglion cells (RGCs), but published data suggest that the relative rate of thinning of RNFL thickness with age is less than predicted by age-related losses of RGCs. Therefore, the present study was undertaken to reconcile the differences in age-dependency on measures of RGCs and axons that are incorporated in normative clinical data.Normative data for RNFL thickness and visual field sensitivities were obtained from the printouts of standard optical coherence tomography (OCT) and standard automated perimetry (SAP) for patients aged between 25 and 95 years, in decade steps. These data were used in models to estimate the number of RGCs underlying each measure.The age-related losses of RGCs derived from normative perimetry data agreed closely with published histologic data, without an age-dependent variable in the model. In contrast, the age-related losses of RGCs derived from normative total RNFL thickness data required an age-dependent decrease of 0.007 axons/microm(2)/year in axon density in the RNFL to account for the relatively slower rate of RNFL thinning than RGC loss.The analysis of normative data suggests a model of age-related thinning of RNFL in which the relationship between RNFL thickness and the density of RGC axons varies with the number of neurons that are lost through normal aging. This model posits that the OCT measurement of total RNFL thickness of a normal retina represents two components: 1) an age-dependent population of RNFL axons, and 2) a non-neural component that partially compensates for the age-related decrease in axons in the nerve fiber layer.

Perceptual learning is a training induced improvement in performance. Mechanisms underlying the perceptual learning of depth discrimination in dynamic random dot stereograms were examined by assessing stereothresholds as a function of decorrelation. The inflection point of the decorrelation function was defined as the level of decorrelation corresponding to 1.4 times the threshold when decorrelation is 0%. In general, stereothresholds increased with increasing decorrelation. Following training, stereothresholds and standard errors of measurement decreased systematically for all tested decorrelation values. Post training decorrelation functions were reduced by a multiplicative constant (approximately 5), exhibiting changes in stereothresholds without changes in the inflection points. Disparity energy model simulations indicate that a post-training reduction in neuronal noise can sufficiently account for the perceptual learning effects. In two subjects, learning effects were retained over a period of six months, which may have application for training stereo deficient subjects.

Visual performance improves with practice (perceptual learning). In this study, we sought to determine whether or not adult monkeys reared with early abnormal visual experience improve their stereoacuity by extensive psychophysical training and testing, and if so, whether alterations of neuronal responses in the primary visual cortex (V1) and/or visual area 2 (V2) are involved in such improvement. Strabismus was optically simulated in five macaque monkeys using a prism-rearing procedure between 4 and 14 wk of age. Around 2 yr of age, three of the prism-reared monkeys ("trained" monkeys) were tested for their spatial contrast sensitivity and stereoacuity. Two other prism-reared monkeys received no training or testing ("untrained" monkeys). Microelectrode experiments were conducted around 4 yr of age. All three prism-reared trained monkeys showed improvement in stereoacuity by a factor of 7 or better. However, final stereothresholds were still approximately 10-20 times worse than those in normal monkeys. In V1, disparity sensitivity was drastically reduced in both the trained and untrained prism-reared monkeys and behavioral training had no obvious effect. In V2, the disparity sensitivity in the trained monkeys was better by a factor of approximately 2.0 compared with that in the untrained monkeys. These data suggest that the observed improvement in stereoacuity of the trained prism-reared monkeys may have resulted from better retention of disparity sensitivity in V2 and/or from "learning" by upstream neurons to more efficiently attend to residual local disparity information in V1 and V2.

Experiencing daily brief periods of unrestricted vision during early monocular form deprivation prevents or reduces the degree of resulting amblyopia. To gain insight into the neural basis for these “protective” effects, we analyzed the monocular and binocular response properties of individual neurons in the primary visual cortex (V1) of macaque monkeys that received intermittent unrestricted vision. Microelectrode-recording experiments revealed significant decreases in the proportion of units that were dominated by the treated eyes, and the magnitude of this ocular dominance imbalance was correlated with the degree of amblyopia. The sensitivity of V1 neurons to interocular spatial phase disparity was significantly reduced in all treated monkeys compared with normal adults. With unrestricted vision, however, there was a small but significant increase in overall disparity sensitivity. Binocular suppression was prevalent in monkeys with constant form deprivation but significantly reduced by the daily periods of unrestricted vision. If neurons exhibited consistent responses to stimulation of the treated eye, monocular response properties obtained by stimulation of the two eyes were similar. These results suggest that the observed protective effects of brief periods of unrestricted vision are closely associated with the ability of V1 neurons to maintain their functional connections from the deprived eye and that interocular suppression in V1 may play an important role in regulating synaptic plasticity of these monkeys.

Purpose: The full ranges of glaucomatous visual field defects and retinal ganglion cell losses extend over several orders of magnitude and therefore an interpretation of the structure−function relationship for clinical perimetry requires scaling of both variables. However, the most appropriate scale has not been determined. The present study was undertaken to compare linear and logarithmic transformations, which have been proposed for correlating the perimetric defects and neural losses of glaucoma. Methods: Perimetry, by behavioural testing, and retinal histology data were obtained from rhesus monkeys with significant visual field defects caused by experimental glaucoma. Ganglion cell densities were measured in histologic sections of retina that corresponded to specific perimetry test locations for the treated and control eyes. The linear (percentage) and logarithmic (decibel) relationships for sensitivity loss as a function of ganglion cell loss were analysed. Results: With decibel scaling, visual sensitivity losses and ganglion cell densities were linearly correlated with high coefficients of determination (r2), although the parameters of the functions varied with eccentricity. The structure−function relationships expressed as linear percentage-loss functions were less systematic in two respects. Firstly, the relationship exhibited considerable scatter in the data for small losses in visual sensitivity and, secondly, visual sensitivity losses became saturated with larger losses in ganglion cell density. The parameters of the percentage-loss functions also varied with eccentricity, but the variation was less than for the decibel-loss functions. Conclusions: Linear scaling of perimetric defects and ganglion cell losses might potentially improve the structure−function relationship for visual defects associated with small amounts of cell loss, but the usefulness of the relationship is limited because of the high variability in that range. With log−log co-ordinates, the structure−function relationship for clinical perimetry is relatively more accurate and precise for cell losses greater than about 3 dB. The comparatively greater accuracy and precision of decibel loss functions are a likely consequence of the logarithmic scale of stimulus intensities for perimetry measurements and because the relationship between visual sensitivity and the number of neural detectors is a form of probability summation.

To determine the effects of stimulus spatial frequency and retinal eccentricity on the perception of depth magnitude derived from disparity cues alone, subjects were asked to estimate the magnitude of depth of a stereoscopically viewed Gabor patch presented to the central or peripheral field with either crossed or uncrossed absolute disparity. Disparity vergence responses to the same Gabor stimuli were separately estimated subjectively by determining the offset required for dichoptic nonius alignment following presentation of the stimulus. The normalized stereoscopic magnitude estimation data generally showed that crossed disparities were perceived with greater depth than uncrossed disparities of the same magnitude, whether presented to the central or peripheral field. Asymmetries in magnitude of depth perception ranged from mild differences between depth directions to complete lack of depth perception for one direction. Disparity vergence response functions varied from (1) appropriate initiation of vergence to both directions of disparity, (2) initiation of vergence to only one direction of disparity, or (3) an attenuated initiation of vergence response to either direction of disparity. Within subjects, their asymmetries in magnitude of depth perception did not correlate with their asymmetries in vergence initiation. The similarity of the asymmetric depth magnitude estimation for a given individual at both stimulus locations tested suggests that common neural mechanisms are responsible for central and peripheral depth magnitude estimation. The lack of correlation between the perceptual and motor responses to the same stimuli suggests that the neural pathways for these responses diverge shortly after the detection of disparity in primary visual cortex.

Stereothresholds are elevated by vergence constant error (fixation disparity), vergence noise, or both. This study investigated the separate and combined effects of simulated vergence constant error and variability on stereothresholds in four normal observers. Targets were 30 arc min bright vertical lines presented separately to the two eyes for 150 ms in darkness. Vergence constant error, simulated as a pedestal disparity, was induced by altering the screen positions of the stereo half-images relative to a previously visible binocular fixation point. Vergence variability was simulated simultaneously by disconjugate motion (amplitude=0–0.5 deg per eye; frequency=2 or 4 Hz) of a pair of scanning mirrors in a Wheatstone stereoscope that was used to present the images to each eye. Various combinations of pedestal disparity and simulated vergence variability produce equivalent stereothresholds whenever the calculated mean deviation ( ∑| instantaneous vergence errors |/N ) of the stimulus from the fixation plane is the same. In particular, stereothresholds are optimal for mean deviations up to approximately 1.4 arc min and then increase according to a power function with an exponent of 0.61. The results imply that vergence constant errors and vergence variability impair stereothresholds because of the resulting mean deviation from the horopter.

We investigated relations between macular retinal ganglion cell plus inner plexiform layer (RGC+IPL) thickness and macular retinal function revealed by multifocal electroretinonography (mfERG) in a nonhuman primate model of experimental glaucoma.Retinal ganglion cell (RGC) structure and function were followed with spectral-domain optical coherence tomography (SD-OCT) and ERGs in five macaques with unilateral experimental glaucoma. Linear regression was used to study correlations in control (Con) and experimental (Exp) eyes between peripapillary retinal nerve fiber layer (RNFL) thickness, macular RGC+IPL thickness, multifocal photopic negative response (mfPhNR) and high-frequency multifocal oscillatory potentials (mfOP) in slow-sequence mfERG, and low-frequency component (mfLFC) in global-flash mfERG. We used ANOVA and paired t-tests to compare glaucoma-related mfERG changes between superior and inferior hemifields, foveal hexagon, inner three rings, and four quadrants of macula.Average macular RGC+IPL and temporal RNFL thickness were strongly correlated (r(2) = 0.90, P0.001). In hexagon-by-hexagon analysis, all three mfERG measures were correlated (P0.001) with RGC+IPL thickness for Con (r(2), 0.33-0.51) and Exp eyes (r(2), 0.17-0.35). The RGC structural and functional metrics decreased as eccentricity increased. The reduction in amplitude of mfERG measures in Exp eyes relative to Con eyes was proportionally greater, in general, than the relative thinning of RGC+IPL at the same location for eyes in which structural loss was not evident, or mild to moderate. Although not statistically significant, percent amplitude reduction of mfERG measures was greatest in the inferior temporal quadrant.Macular RGC+IPL thickness and mfERG measures of RGC function can be complementary tools in assessing glaucomatous neuropathy.

Multifocal ERGs (MERGs) of 5 adult monkeys (Macaca mulatta) with inner retinal defects caused by laser-induced glaucoma were compared to MERGs from 3 monkeys with inner retinal activity suppressed pharmacologically. MERGs were recorded with DTL fiber electrodes from anesthetized monkeys. Stimuli consisted of 103 equal size hexagons within 17 degrees of the fovea. Stimuli at each location passed through a typical VERIS m-sequence of white (200 cd/m2) and black (12 cd/m2) presentations. In animals with laser-induced glaucoma, visual field sensitivity was assessed by static perimetry using the Humphrey C24-2 full-threshold program modified for animal behavior. Inner retinal (amacrine and ganglion cell) activity was suppressed by intravitreal injection of TTX (4.7-7.6 microM) and NMDA (1.6-5 mM). In normal eyes the first order response (1st order kernel) was larger and more complex, with more distinct oscillations (>60 Hz) in central than in peripheral locations. The 2nd order kernel also was dominated by oscillatory activity. There were naso-temporal variations in both kernels. Pharmacological suppression of inner retinal activity reduced or eliminated the oscillatory behavior, and naso-temporal variations. The 1st order kernel amplitude was increased most and was largest at the fovea. Removed inner retinal responses also were largest at the fovea. The 2nd order kernel was greatly reduced at all locations. In eyes with advanced glaucoma, the effects were similar to those produced by suppressing inner retinal activity, but the later portion of the 1st order kernel waveform was different, lacking a dip after the large positive wave. Visual sensitivity losses and MERG changes both increased over the timecourse of glaucoma, with changes in the MERG being more diffusely distributed across the visual field. We conclude that 1st and 2nd order responses of the primate MERG can be identified that originate from inner retina and are sensitive indicators of glaucomatous neuropathy.

It is generally recognized that the vertical horopter has a backwards tilt such that it passes through the fixation point and a point near the feet of the observer. The basis of the tilt has been attributed to either a shear in binocular retinal correspondence along the vertical meridian or the presence of cyclovergence eye movements. In an attempt to determine empirically the mechanisms underlying the tilt of the vertical horopter, retinal correspondence along the vertical meridian was investigated as a function of viewing distance. In addition, binocular measurements of torsional eye position were made in the same observers under similar viewing conditions. The vertical horopter was determined using two criteria. In the first instance, increment depth discrimination thresholds for both crossed and uncrossed disparities were measured as a function of retinal eccentricity along the vertical meridian, up to 5 degrees superiorly and inferiorly, and the horopter was defined by the region in space which had the lowest stereo-threshold. Secondly, subjective alignment of dichoptically presented nonius lines defined the horopter by identical visual directions. Both criteria were used to determine the horopter at 2 m while only the criterion of identical visual direction was used at the nearer distance of 50 cm. The vertical horopter showed a backwards tilt that decreased from an average of about 12 degrees at 2 m to 3 degrees at 50 cm, with some variability between observers. Torsional eye position did not change significantly between fixation distances. These results confirmed the geometric relation between the backwards tilt in the vertical horopter and fixation distance and support Helmholtz's original contention that the tilt is a consequence of a shear in retinal correspondence in the vertical meridian.

Optical defocus can within certain limits predictably alter ocular growth and refractive development in infant monkeys. However defocus, particularly unilateral defocus associated with anisometropia, can also promote abnormal sensory and motor development. We investigated the relationship between the effective operating range for emmetropization in infant monkeys and the refractive errors that produced amblyopia. Specifically, we examined the refractive-error histories of monkeys that did not demonstrate compensating ocular growth for imposed refractive errors and used operant psychophysical methods to measure contrast sensitivity functions for 17 infant monkeys that were reared with varying degrees of optically imposed anisometropia. Imposed anisometropias that were within the operating range of the monkey's emmetropization process were eliminated by differential interocular growth and did not produce amblyopia. On the other hand imposed anisometropias that failed to initiate compensating growth consistently produced amblyopia; the depth of the amblyopia varied directly with the magnitude of the imposed anisometropia. These results indicate that amblyopia and anisometropia are frequently associated because persistent anisometropia causes amblyopia. However, the failure of emmetropization in infants with refractive conditions that are known to promote sensory and motor anomalies indicates that factors other than optical defocus, presumably factors associated with the development of amblyopia and/or strabismus, can also influence early refractive development and in some cases cause anisometropia.

Purpose. In normal vision, stereoscopic cues are combined with perspective cues to provide veridical depth perception. The relative strengths of these depth cues, however, may be dependent upon context effects. We investigated the role of stimulus context on the interactions of binocular disparity, contrast, and size. Methods. The subjects, four observers with normal stereoacuity and one stereo-amblyope, discriminated far vs. near perceived depth of Gabor patches; feedback was based on the sign of binocular disparity. Depth discrimination functions were measured under conditions in which depth cues were consonant or in conflict. Three stimulus contexts were used: (1) variable disparity with fixed spatial frequency and contrast; (2) variable contrast with fixed spatial frequency and disparity; and (3) variable spatial frequency with fixed contrast and disparity. The effects of stimulus context were derived from comparisons of discrimination rates for identical stimuli across the three sets of conditions. Results. In subjects with normal stereopsis, for disparities less than 2 arcmin, depth perception was dominated by contrast in contrast-varying sessions, or by size in spatial frequency-varying sessions. With larger disparities, depth perception became dependent on disparity, regardless of the contrast or spatial frequency of the test stimulus. The results for the stereo-amblyope showed much greater dependence on perspective cues and, in most cases, the transition from perspective- to disparity-based depth perception did not occur. Conclusions. These investigations demonstrate strong stimulus context effects and have important implications for the combination rules of stereoscopic and perspective cues in depth perception of normal and stereo-deficient subjects.

Prismatic binocular dissociation was used during infancy to mimic conditions of strabismus in macaque infants. Prisms worn continuously produce a diplopia unfavorable for the maintenance and development of the binocular visual system. Prism-reared monkeys were tested as young adults and found to be permanently stereoblind for dynamic random dot stereograms. Control monkeys did comparably to humans on such tests. It is concluded that short periods of diplopia attendant with strabismus are sufficient to produce permanent stereoblindness.

Motor and sensory fusion, the basic processes of binocularity, must be present for bifoveal fixation with true fusion and stereopsis during ordinary viewing. The characteristics of motor and sensory fusion have been established for patients with normal and subnormal binocular vision; the present report describes our psychophysical studies of these processes in the macaque monkey. Three recent investigations of motor and sensory fusion in monkeys are described. The studies involved: (1) the comparability of motor and sensory fusion in monkeys and humans with normal binocular vision, (2) the effects of an early period of abnormal binocular vision on motor and sensory fusion in monkeys, and (3) the contrast sensitivity for binocular disparity in monkeys with stereo-deficiencies. The results of these studies demonstrated an excellent homology between the normal binocular vision of monkeys and humans. We also found that a period of esotropia during infancy caused deficiencies in sensory fusion, but not motor fusion. In some monkeys, the sensory deficiency persisted over the entire range of binocular disparities that were compatible with stereopsis, while other subjects demonstrated normal stereo-sensitivity for the largest fusible binocular disparities. The stereo-deficiencies of these monkeys, along with other visual attributes, suggest that their binocular vision is a viable model for the binocularity of patients with subnormal binocular vision or the monofixation syndrome.

Stereoscopic depth discrimination thresholds increase with retinal eccentricity and distance from the horopter. However, in contrast to spatial resolution, the effects of spatial frequency on stereothresholds in the periphery are unknown. For spatial vision, it is generally assumed that the retina is comprised of a series of overlapping spatial filter mechanisms and that there is a commensurate increase in spatial scale as a function of retinal eccentricity. If the same holds true for mechanisms sensitive to stereoscopic depth, then stereo-thresholds for low spatial frequency stereoscopic stimuli may remain relatively invariant across the visual field, while rhresholds for relatively high spatial frequency stimuli would increase. To further understand the role of the disparity sensitive mechanisms involved in depth discrimination, increment depth discrimination thresholds for both crossed and uncrossed disparities were measured as a function of eccentricity for retinal locations up to 10.0 deg along the horizontal meridian. We found that stereoscopic depth discrimination thresholds, as a function of distance from the horopter, increased in an exponential manner irrespective of spatial frequency. Stereo-thresholds also increased as a function of retinal eccentricity, however, the rate of increase depended on the spatial frequency composition of the stimuli. Best stereo-thresholds for stimuli composed of low spatial frequencies remained relatively invariant for retinal eccentricities up to 10.0 deg, while thresholds for the high spatial frequency stimuli increased with eccentricity.

Studies of refractive error and emmetropization involving laboratory animals typically use objective methods, such as retinoscopy and autorefraction, to determine the eye’s refractive error. These techniques can provide a quick, precise, and reliable way to measure refractive error when performed by an experienced examiner. However, these measures are frequently obtained when the animals are anesthetized and accommodation has been pharmacologically paralyzed. For a variety of reasons, the objective refractive-error measurements made under these conditions may not match the refractive status manifest by an animal when it is awake and alert. In order to properly interpret the refractive errors measured with these objective measures and to fully understand the functional significance of objectively measured refractive errors, it is important to understand the relationship between these objective measures of refraction and an animal’s functional refractive error, in essence its subjective refractive error. In humans, many studies have found systematic differences in the refractive errors determined by retinoscopy and subjective refraction. While most of these studies have reported that refractive errors measured by retinoscopy are slightly more hyperopic than subjectively determined refractive errors, the differences between the two measurement methods are generally small, on the order of about +0.25 D or less,1, 2 and decrease with age.3 On the other hand, objectively measured refractive errors in laboratory animals, particularly those obtained via retinoscopy, are often reported to be much more hyperopic than their presumed subjective refractions, especially in animals with small eyes.4 However, in this respect, the relationship between objective and subjective refractions in animals is largely unknown primarily because there is very little subjectively determined refractive error data available from animals. Because of the difficulties associated with behaviorally measuring refractive errors in alert animals, investigators have typically used objective, electrophysiological methods to obtain an estimate of an animal’s subjective refraction. The most common procedures involve determining the lens power (in essence the refractive correction) required to optimize the responses or receptive field profiles of individual retinal ganglion cells5–7 or to produce the most robust pattern-evoked electroretinogram8, 9 or pattern-evoked cortical potential.10–12 Although these measures are valid in humans (i.e., yield refractions that are similar to subjectively determined errors) and these electrical measures reflect the initial focus-dependent photoreceptor responses, there are still substantial differences in the state of the animal during these measures versus the normal wake/alert state (for example, these measures are almost always obtained when the animals are anesthetized and cyclopleged). The overall goal of this study was to examine the relationship between objective, optical measures of refractions and the optimal behavioral refraction (in this case, the refractive correction that optimized the contrast detection thresholds for high spatial frequencies). The specific aim of this study was to compare the refractive errors measured in adolescent rhesus monkeys by retinoscopy and autorefraction with those obtained using operant psychophysical methods.

Glaucoma is a multifaceted group of eye diseases that results in the degeneration of retinal ganglion cell axons and the death of retinal ganglion cells (RGCs). The mechanisms of glaucomatous damage (e.g., mechanical, vascular, and glial) are not fully understood. Although several of these factors likely contribute to RGC death, substantial evidence suggests that the initial site of axonal injury likely occurs at the level of the lamina cribrosa in the optic nerve head (ONH).1–11 In humans and nonhuman primates, the lamina cribrosa is a three-dimensional porous structure consisting of flexible beams of collagenous tissue that support and nourish the RGC axons passing through it from the retina to the brain.12 Increases in intraocular pressure (IOP) impart stress and strain on the lamina,13–15 resulting in a posterior bowing and stretching of the load-bearing laminar beams12,16 and potential increases in laminar pore area and elongation (or more elliptically shaped pores). Stretching and deformation of the laminar beams (and associated pores) could sheer or damage encompassed axons and laminar capillaries, thereby hampering axonal transport, blood flow and the diffusion of nutrients,17 and/or the neurotrophic support provided to the axons by alterations in glial cells.18 ONH tissues have been examined in human glaucomatous eyes and nonhuman primate models of experimental glaucoma. Postmortem histologic studies have shown significant changes in prelaminar and laminar tissues within the ONH in early experimental glaucoma.16,19,20 Additional ex vivo studies in glaucomatous human and nonhuman primate eyes have described early changes in laminar morphology and position,16,21 laminar pore geometry,22 and the composition and architecture of laminar connective tissues.20,23 In light of this work, there is a growing consensus that in vivo studies are necessary to validate ex vivo results and examine longitudinal changes during glaucoma.24,25 The lamina cribrosa has been examined in vivo. Fontana et al.26 imaged anterior laminar pores in living human glaucomatous eyes using a modified confocal scanning laser ophthalmoscope (SLO) and showed that pore area and elongation were larger in eyes with more severe glaucoma. However, images were taken using a wide field of view (20°) and were not of high resolution because of the presence of ocular aberrations. Therefore, the size and total number of pores that could be resolved and the number of subjects in which laminar pores could be successfully imaged were limited. Vilupuru et al.27 used a confocal adaptive optics scanning laser ophthalmoscope (AOSLO), an instrument that noninvasively provides cellular-level images through a correction of the eye's aberrations, to improve the resolution and contrast of laminar images in vivo in nonhuman primates with experimental glaucoma. This study quantified laminar pore geometries in three diseased monkey eyes, each at a single time point. However, changes in pore geometry with disease were not investigated. Recent studies have combined adaptive optics with optical coherence tomography (OCT) to image the human lamina cribrosa in three spatial dimensions,28,29 but a quantitative analysis of laminar geometry and pore structure has not been reported. We have assessed the repeatability of imaging and quantifying laminar pores in vivo in two normal macaque and three normal human eyes using an AOSLO at different time points. Statistical tests were performed to investigate whether significant differences were present in any analyzed laminar pore parameters within and across imaging sessions. This study provides an important first step in understanding the feasibility of using in vivo AOSLO imaging to assess laminar structure in normal eyes, human glaucomatous eyes, and nonhuman primate eyes with experimentally induced glaucoma.

An evaluation of the retinal nerve fiber layer (RNFL) provides important information on the health of the optic nerve. Standard measurements of the RNFL consider only thickness, but an accurate assessment should also consider axial length, size of the optic nerve head (ONH), blood vessel contribution, and distance of the scan from the ONH margin. In addition, although most primate ONHs are elliptical, the circular scan centered on the ONH is the mainstay in both clinical and research analyses. The purpose of this study was to evaluate thickness and area measures of RNFL cross sections when axial length and ONH shape are included.Circular, raster, and radial scans of left eye optic nerves were acquired from 40 normal rhesus monkeys (Macaca mulatta) using spectral domain optical coherence tomography. The disc margin was identified by manually selecting the RPE/Bruch's membrane opening and ONH border tissue. With a pixel-to-micrometer conversion computed from a three-surface schematic eye, RNFL scans were interpolated at 300 to 600 μm (50-μm increments) from the edge of the ONH. The thickness and area of the RNFL at each distance were obtained by custom programs. Blood vessels in the RNFL were selected and removed from the overall RNFL measures.The average RNFL thickness decreased systematically from 149 ± 12.0 μm for scans 300 μm from the disc margin to 113 ± 7.2 μm at an eccentricity of 600 μm (P0.05). In contrast, the cross-sectional areas of the RNFL did not vary with scan location from the disc margin (0.85 ± 0.07 mm(2) at 300 μm compared with 0.86 ± 0.06 mm(2) at 600 μm). Blood vessels accounted for 9.3% of total RNFL thickness or area, but varied with retinal location. On average, 17.6% of the superior and 14.2% of the inferior RNFL was vascular, whereas blood vessels accounted for only 2.3% of areas of the temporal and nasal RNFL regions.In nonhuman primates, with appropriate transverse scaling and ONH shape analysis, the cross-sectional area of the RNFL is independent of scan distance, up to 600 μm from the rim margin, indicating that the axonal composition changes little over this range. The results suggest that, with incorporation of transverse scaling, the RNFL cross-sectional area, rather than RNFL thickness, provides an accurate assessment of the retinal ganglion cell axonal content within the eye.

This study examines whether brief periods of binocular vision could preserve stereopsis in monkeys reared with optical strabismus.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.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.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.

Amblyopia, a developmental disorder of spatial vision, is thought to result from a cascade of cortical deficits over several processing stages beginning at the primary visual cortex (V1). However, beyond V1, little is known about how cortical development limits the visual performance of amblyopic primates. We quantitatively analyzed the monocular and binocular responses of V1 and V2 neurons in a group of strabismic monkeys exhibiting varying depths of amblyopia. Unlike in V1, the relative effectiveness of the affected eye to drive V2 neurons was drastically reduced in the amblyopic monkeys. The spatial resolution and the orientation bias of V2, but not V1, neurons were subnormal for the affected eyes. Binocular suppression was robust in both cortical areas, and the magnitude of suppression in individual monkeys was correlated with the depth of their amblyopia. These results suggest that the reduced functional connections beyond V1 and the subnormal spatial filter properties of V2 neurons might have substantially limited the sensitivity of the amblyopic eyes and that interocular suppression was likely to have played a key role in the observed alterations of V2 responses and the emergence of amblyopia.

The increment depth discrimination function was originally described by Ogle [(1953) Journal of the Optical Society of America, 43, 906-913] as a single exponential function. In contrast, recent studies have suggested that a two-component function better describes increment depth discrimination. To determine the relative effects of stereoscopic and non-stereoscopic width cues on the form of the function, we measured increment depth discrimination under conditions where both stereoscopic and dichoptic width cues were available. We found that increment depth discrimination data were well described by two-segment functions if both stereoscopic and dichoptic width cues were available. However, when dichoptic width cues were eliminated, by randomizing the pedestal disparity (crossed or uncrossed disparity) between trials, the increment depth discrimination function was better described by a single exponential function. This result has important implications for models of stereoscopic depth processing because it shows that stereoscopic depth discrimination thresholds progressively increase as a function of distance from the horopter.

The effects of prolonged exposure to intense, short-wavelength light were studied in monkeys through the measurement of increment-threshold spectral sensitivity (ITSS) and threshold-versus-intensity (TVI) functions using a behavioural method. The long-term effect of intense blue-light exposure was to induce a short-wavelength (SW) sensitivity loss which did not depend on the intensity or chromatic composition of the adapting field. The TVI curves for short wavelength stimuli revealed an increase in test threshold without changes in field sensitivity. Since this SW sensitivity loss may generalize to characteristic colour vision defects found in many outer retinal diseases, models of acquired alterations of colour vision mechanisms are considered. These models describe probable changes in ITSS functions and TVI curves in diseases affecting the inner or outer retina as well as changes in dark adaptation.

The quality of visual experience during infancy determines the functional sensitivity and precision of the mature primate visual system. Infant monkeys subjected to monocular form deprivation show a period of critical visual development that, though decreasing in sensitivity, lasts throughout the first 2 years of life. Photopic threshold spectral sensitivity appears to have a briefer critical period, which is essentially complete by 6 months old, whereas scotopic visual functions appear well developed by 3 months old. Binocular visual functions seem to have the longest period of sensitivity to abnormal visual experience because periods of monocular form deprivation initiated during the first 2 years affect visual functions. Viewing the world through prisms, which mimics the condition of strabismus, causes a permanent loss of cortical binocular cells and stereopsis in monkeys. This result explains stereoblindness in children having equivalent clinical histories.

A stable form of interocular suppression, referred to as "permanent suppression," can be produced by presenting a contoured field to one eye and a spatially homogenous field to the fellow eye, a viewing condition analogous to the classic "hole-in-the-hand" illusion. We examined the relation between permanent suppression and binocular rivalry suppression by comparing the changes in the increment-threshold spectral sensitivity function produced by these two forms of suppression. Permanent suppression produced a reduction in spectral sensitivity; however, in contrast to binocular rivalry suppression, the sensitivity alterations associated with permanent suppression were independent of the test-probe wavelength. The different patterns of sensitivity loss observed during binocular rivalry and permanent suppression indicate that different neural mechanisms mediate these two forms of interocular suppression.

Purpose Age-related losses in retinal nerve fiber layer (RNFL) thickness have been assumed to be the result of an age-dependent reduction of retinal ganglion cells (RGCs), but the published rates differ: age-related losses of RGCs of approximately 0.6%/year compared to 0.2%/year for thinning of the RNFL. An analysis of normative data for standard automated perimetry (SAP) sensitivities and optical coherence tomography (OCT) measures of RNFL thickness showed that the apparent disagreement in age-dependent losses of RGCs and axons in the RNFL can be reconciled by an age-dependent decrease in the proportion of the RNFL thickness that is composed of axons. The purpose of the present study was to determine whether the mechanisms of age-related losses that were suggested by the normative data can be confirmed with data from healthy, normal eyes. Methods Data were obtained from visual fields (normal results in a Glaucoma Hemifield Test [GHT] on standard automated perimetry [SAP] 24-2 fields) and RNFL thickness measurements (standard OCT scan) of 55 patients (age range, 18-80 years; mean, 44.5 +/- 17.3). The SAP measures of visual sensitivity and OCT measures of RNFL thickness for one eye of each patient were used to estimate neuron counts by each procedure. Results The age-related thinning of RNFL was 0.27%/year when a constant axon density was used to derive axon counts from RNFL thickness, compared with 0.50%/year for the age-related loss of RGCs from SAP. In agreement with the model developed with normative clinical data, concordance between losses of axons and soma was achieved by an age-dependent reduction of 0.46%/year in the density of axons in the RNFL. Conclusions The results suggest that the proportion of RNFL that is composed of RGC axons is not constant with age; rather, the proportion of the total thickness from non-neuronal tissue increases with age. If a similar compensation occurs in the RNFL thickness with axon loss from glaucoma, then a stage-dependent correction to translate OCT measurements to neuronal components is needed, in addition to the age-dependent correction.

PURPOSE Decreasing the interocular correlation in random dot stereograms elevates disparity detection thresholds. Whether decorrelation also affects perceived depth from suprathreshold disparity magnitudes is unknown. The present study investigated the effects of interocular correlation and contrast on the magnitude of perceived depth in suprathreshold random dot stereograms. METHODS Stereoscopic depth magnitude estimation as a function of percent interocular correlation of dynamic random dot stimuli was measured for five human subjects with clinically normal binocular vision. Each trial's stimulus was randomly assigned one of two magnitudes of either crossed or uncrossed relative disparity. Subjects verbally reported the direction and magnitude of perceived relative depth for each trial using a modulus-free scale. Normalized depth magnitude estimations as a function of the percent interocular correlation demonstrated the relationship between perceived depth, interocular correlation and contrast within subjects. Inter-subject variability was examined with comparisons of data across subjects. RESULTS The depth magnitude perceived for a given magnitude of disparity declined as the percent of correlation of elements between the eyes decreased for both crossed and uncrossed directions. The effect generally was greater for uncrossed disparities and lower contrast. Some subjects demonstrated asymmetries in perceived depth for crossed vs. uncrossed disparities of the same magnitude. CONCLUSIONS Magnitude estimation of suprathreshold stimuli provided a method of studying performance characteristics of stereoscopic depth perception across the range of functional disparities. Differences found in depth magnitude estimation as a function of the sign of disparity suggest that the neural mechanisms underlying depth perception from uncrossed disparity are more sensitive to image decorrelation, particularly at low contrast, than the mechanisms underlying depth estimation from crossed disparity. These results could occur from differences in near and far disparity-sensitive neurons, from the geometrical relationship between disparity and physical distance in normal viewing, or from the response measure independent of perception.

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.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.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.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.

The full ranges of glaucomatous visual field defects and retinal ganglion cell losses extend over several orders of magnitude and therefore an interpretation of the structure-function relationship for clinical perimetry requires scaling of both variables. However, the most appropriate scale has not been determined. The present study was undertaken to compare linear and logarithmic transformations, which have been proposed for correlating the perimetric defects and neural losses of glaucoma.Perimetry, by behavioural testing, and retinal histology data were obtained from rhesus monkeys with significant visual field defects caused by experimental glaucoma. Ganglion cell densities were measured in histologic sections of retina that corresponded to specific perimetry test locations for the treated and control eyes. The linear (percentage) and logarithmic (decibel) relationships for sensitivity loss as a function of ganglion cell loss were analysed.With decibel scaling, visual sensitivity losses and ganglion cell densities were linearly correlated with high coefficients of determination (r(2)), although the parameters of the functions varied with eccentricity. The structure-function relationships expressed as linear percentage-loss functions were less systematic in two respects. Firstly, the relationship exhibited considerable scatter in the data for small losses in visual sensitivity and, secondly, visual sensitivity losses became saturated with larger losses in ganglion cell density. The parameters of the percentage-loss functions also varied with eccentricity, but the variation was less than for the decibel-loss functions.Linear scaling of perimetric defects and ganglion cell losses might potentially improve the structure-function relationship for visual defects associated with small amounts of cell loss, but the usefulness of the relationship is limited because of the high variability in that range. With log--log co-ordinates, the structure--function relationship for clinical perimetry is relatively more accurate and precise for cell losses greater than about 3 dB. The comparatively greater accuracy and precision of decibel loss functions are a likely consequence of the logarithmic scale of stimulus intensities for perimetry measurements and because the relationship between visual sensitivity and the number of neural detectors is a form of probability summation.

PURPOSE. To study the relationship between the width of ocular dominance columns in primary visual cortex and spatial contrast sensitivity functions in monkeys with strabismus or anisometropia during infancy. METHODS. Adult monkeys having had monocular visual abnormalities induced in infancy were tested behaviorally for spatial contrast sensitivity and then subjected to functional enucleation of one eye to reveal the ocular dominance columns (ODCs) of the primary visual cortex by cytochrome oxidase (CO) staining. The relative widths of the left and right eyes’ ODCs were measured and related to the contrast sensitivity functions. RESULTS. The relative widths of the ODCs having input from eyes with strabismic or anisometropic amblyopia were reduced in proportion to the age of onset and the duration of the early visual abnormality. The relative losses in contrast sensitivity were in ordinal agreement with the losses in relative width of the ODCs. CONCLUSIONS. Amblyopia induced by the early monocular abnormalities of strabismus or anisometropia is proportional to the loss in cortical afference as reflected in the reduction in width of the respective ODCs in the primary visual cortex. (Invest Ophthalmol Vis Sci. 2004;45:3036 –3042) DOI: 10.1167/iovs.04-0029

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.

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.

Extracellular levels of glutamate are thought to be increased in glaucoma and thus contribute to retinal damage. An increase in glutamate concentration or duration in the extracellular retinal space is expected to impact glutathione content in Muller cells since glutamate is the rate-limiting constituent in glutathione synthesis. We have investigated whether glutathione content is changed in retinal Muller cells of monkeys with experimental glaucoma using immunocytochemistry and image analysis. Muller cells in glaucomatous retinas showed significantly greater immunoreactivity (27-57%) for glutathione than those in fellow control retinas, increasing with the duration of elevated intraocular pressure (IOP). This pattern of labeling was prominent in all four monkeys studied. The presence of more glutathione in Muller cells of glaucomatous retinas is consistent with an increase in extracellular glutamate and an increase in transport and metabolism of glutamate.

PURPOSE. Patients with primary microstrabismus have a high degree of binocularity, which suggests that their ocular misalignment may have a sensory rather than an oculomotor origin, as in large-angle strabismus. The purpose of these experiments was to determine whether microstrabismic subjects have sensory abnormalities that could give rise to a small angle of strabismus. METHODS. The binocular disparity response functions for sensory and motor processes were compared in seven orthotropic subjects and six strabismic subjects (four with primary microstrabismus and two with infantile esotropia). Binocularity was assessed by disparity vergence (central and peripheral stimuli) and depth discrimination (relative and absolute disparities) measures. Motor and sensory disparity response functions were both determined by psychophysical methods: vergence responses by dichoptic nonius alignment and sensory responses by forced-choice depth discrimination. RESULTS. All the strabismic subjects demonstrated normal retinal correspondence with peripheral binocular stimuli and anomalous retinal correspondence with central fusion stimuli. The microstrabismic subjects' disparity vergence responses with peripheral fusion stimuli were centered on disparities relative to their angle of strabismus. However, with central fusion stimuli, the disparity vergence responses were relative to the subjective angle of strabismus. The microstrabismic subjects' stereoacuities were substantially reduced, but their discrimination responses did not show an asymmetry indicative of an unrepresented population of disparity-selective mechanisms. CONCLUSIONS. The data do not support a sensory abnormality as the primary cause of microstrabismus. The results are not compatible with an oculomotor adaptation to an inherent anomalous correspondence or with a strabismus caused by an absence of a class of disparity-selective mechanisms. Thus, just as in large-angle strabismus, the anomalous retinal correspondence and defective stereopsis of microstrabismus appear to be consequences of abnormal visual experience caused by an interocular deviation.

To investigate the hypothesis that the pathophysiology for the death of retinal ganglion cells in glaucoma involves excitotoxic effects from elevated concentrations of vitreal glutamate.Experimental glaucoma was induced in the right eyes of 18 rhesus monkeys by argon laser treatments to the trabecular meshwork. After significant visual field defects and/or typical clinical glaucomatous changes had developed (1.5-13 months), the eyes were removed, and a sample (0.1-0.2 mL) of posterior vitreous was collected. Similar vitreous samples also were collected from eight untreated monkeys. The vitreous samples were analyzed in a masked fashion by high-pressure liquid chromatography in two independent laboratories. Mean levels of vitreal glutamate were determined for the treated and control eyes and differences between groups of eyes were evaluated by Student's t-test.The mean level (+/- SD) of vitreal glutamate in the eight untreated monkeys was 5.0 +/- 2.0 microM. A similar level of 5.7 +/- 1.8 microM was measured in the untreated eyes of monkeys with experimental glaucoma. In the glaucomatous eyes, the mean concentration of vitreal glutamate was 5.7 +/- 2.6 microM, which was not significantly different from the concentrations in the control eyes.Vitreal glutamate concentrations were not elevated in eyes with anatomic and functional damage from experimental glaucoma. This finding is in contradiction to previous reports that vitreal glutamate increases to toxic levels and probably contributes to glaucomatous damage of retinal ganglion cells.