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Intraocular pressure (IOP) is an important factor in numerous ocular conditions and research areas, including eye growth and myopia. In infant monkeys, IOP is typically measured under anesthesia. This study aimed to establish a method for awake IOP measurement in infant rhesus monkeys, determine diurnal variation, and assess the effects of dilation and sedation.Awake IOP (iCare TonoVet) was measured every 2 h from 7:30 am to 5:30 pm to assess potential diurnal variations in infant rhesus monkeys (age 3 weeks,At age 3 weeks, mean (±SEM) awake IOP was 15.4 ± 0.6 and 15.2 ± 0.7 mmHg for right and left eyes, respectively (Awake IOP measurement was feasible in young rhesus monkeys. No significant diurnal variations in IOP were observed between 7:30 am and 5:30 pm at age 3 weeks. In awake monkeys, IOP was slightly higher after mydriasis and considerably lower after sedation. Findings show that IOP under ketamine/acepromazine anesthesia is significantly different than awake IOP in young rhesus monkeys.

Although reduced ambient lighting (“dim” light) can cause myopia in emmetropizing chicks, it does not necessarily lead to myopic changes in emmetropizing rhesus monkeys. Because myopia is rarely spontaneous, a question remained whether dim light would hasten the progression of visually induced myopia. To determine the effects of dim light on the development of and recovery from form-deprivation myopia (FDM), seven 3-week-old infant rhesus monkeys were reared under dim light (mean ± SD = 55 ± 9 lx) with monocular diffuser spectacles until ~154 days of age, then maintained in dim light with unrestricted vision until ~337 days of age to allow for recovery. Refractive errors, corneal powers, ocular axial dimensions and sub-foveal choroidal thicknesses were measured longitudinally and compared to those obtained from form-deprived monkeys reared under typical laboratory lighting (504 ± 168 lx). Five of the seven subjects developed FDMs that were similar to those observed among their normal-light-reared counterparts. The average degree of form-deprivation-induced myopic anisometropia did not differ significantly between dim-light subjects (−3.88 ± 3.26D) and normal-light subjects (−4.45 ± 3.75D). However, three of the five dim-light subjects that developed obvious FDM failed to exhibit any signs of recovery and the two monkeys that were isometropic at the end of the treatment period manifest abnormal refractive errors during the recovery period. All refractive changes were associated with alterations in vitreous chamber elongation rates. It appears that dim light is not a strong myopiagenic stimulus by itself, but it can impair the optical regulation of refractive development in primates.

Purpose: Light affects a variety of non-image forming processes, such as circadian rhythm entrainment and the pupillary light reflex, which are mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). The purpose of this study was to assess the effects of long- and short-wavelength ambient lighting on activity patterns and pupil responses in rhesus monkeys.Methods: Infant rhesus monkeys were reared under either broadband “white” light (n = 14), long-wavelength “red” light (n = 20; 630 nm), or short-wavelength “blue” light (n = 21; 465 nm) on a 12-h light/dark cycle starting at 24.1 ± 2.6 days of age. Activity was measured for the first 4 months of the experimental period using a Fitbit activity tracking device and quantified as average step counts during the daytime (lights-on) and nighttime (lights-off) periods. Pupil responses to 1 s red (651 nm) and blue (456 nm) stimuli were measured after approximately 8 months. Pupil metrics included maximum constriction and the 6 s post-illumination pupil response (PIPR).Results: Activity during the lights-on period increased with age during the first 10 weeks (p < 0.001 for all) and was not significantly different for monkeys reared in white, red, or blue light (p = 0.07). Activity during the 12-h lights-off period was significantly greater for monkeys reared in blue light compared to those in white light (p = 0.02), but not compared to those in red light (p = 0.08). However, blue light reared monkeys exhibited significantly lower activity compared to both white and red light reared monkeys during the first hour of the lights-off period (p = 0.01 for both) and greater activity during the final hour of the lights-off period (p < 0.001 for both). Maximum pupil constriction and the 6 s PIPR to 1 s red and blue stimuli were not significantly different between groups (p > 0.05 for all).Conclusion: Findings suggest that long-term exposure to 12-h narrowband blue light results in greater disruption in nighttime behavioral patterns compared to narrowband red light. Normal pupil responses measured later in the rearing period suggest that ipRGCs adapt after long-term exposure to narrowband lighting.

Although reduced ambient lighting (~50 lx) does not increase the degree of form-deprivation myopia (FDM) in chickens or infant monkeys, it does reduce the probability that monkeys will recover from FDM and that the normal age-dependent reduction in hyperopia will occur in monkeys reared with unrestricted vision. These findings suggest that low ambient lighting levels affect the regulatory mechanism responsible for emmetropization. To study this issue, infant rhesus monkeys (age ~ 24 days) were reared under dim light (55 ± 9 lx) with monocular −3D (dim-light lens-induced myopia, DL-LIM, n = 8) or +3D spectacle lenses (dim-light lens-induced hyperopia, DL-LIH, n = 7) until approximately 150 days of age. Refractive errors, ocular parameters and sub-foveal choroidal thickness were measured periodically and compared with normal-light-reared, lens-control monkeys (NL-LIM, n = 16; NL-LIH, n = 7). Dim light rearing significantly attenuated the degree of compensatory anisometropias in both the DL-LIM (-0.63 ± 0.77D vs. −2.11 ± 1.10D in NL-LIM) and DL-LIH treatment groups (-0.18 ± 1.93D vs. +1.71 ± 0.39D in NL-LIH). These effects came about because the treated and fellow control eyes had a lower probability of responding appropriately to the eye’s effective refractive state. Vision-induced interocular differences in choroidal thickness were only observed in monkeys that exhibited compensating refractive changes, suggesting that failures in detecting the relative magnitude of optical errors underlay the abnormal refractive responses. Our findings suggest that low ambient lighting levels reduce the efficacy of the vision-dependent mechanisms that regulate refractive development.

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.

Oral administration of the adenosine receptor (ADOR) antagonist, 7-methylxanthine (7-MX), reduces both form-deprivation and lens-induced myopia in mammalian animal models. We investigated whether topically instilled caffeine, another non-selective ADOR antagonist, retards vision-induced axial elongation in monkeys. Beginning at 24 days of age, a 1.4% caffeine solution was instilled in both eyes of 14 rhesus monkeys twice each day until the age of 135 days. Concurrent with the caffeine regimen, the monkeys were fitted with helmets that held either −3 D (-3D/pl caffeine, n = 8) or +3 D spectacle lenses (+3D/pl caffeine, n = 6) in front of their lens-treated eyes and zero-powered lenses in front of their fellow-control eyes. Refractive errors and ocular dimensions were measured at baseline and periodically throughout the lens-rearing period. Control data were obtained from 8 vehicle-treated animals also reared with monocular −3 D spectacles (-3D/pl vehicle). In addition, historical comparison data were available for otherwise untreated lens-reared controls (-3D/pl controls, n = 20; +3D/pl controls, n = 9) and 41 normal monkeys. The vehicle controls and the untreated lens-reared controls consistently developed compensating axial anisometropias (-3D/pl vehicle = −1.44 ± 1.04 D; -3D/pl controls = −1.85 ± 1.20 D; +3D/pl controls = +1.92 ± 0.56 D). The caffeine regime did not interfere with hyperopic compensation in response to +3 D of anisometropia (+1.93 ± 0.82 D), however, it reduced the likelihood that animals would compensate for −3 D of anisometropia (+0.58 ± 1.82 D). The caffeine regimen also promoted hyperopic shifts in both the lens-treated and fellow-control eyes; 26 of the 28 caffeine-treated eyes became more hyperopic than the median normal monkey (mean (±SD) relative hyperopia = +2.27 ± 1.65 D; range = +0.31 to +6.37 D). The effects of topical caffeine on refractive development, which were qualitatively similar to those produced by oral administration of 7-MX, indicate that ADOR antagonists have potential in treatment strategies for preventing and/or reducing myopia progression.

Dual-focus lenses that impose simultaneous competing myopic defocus over the entire visual field produce axial hyperopic shifts in refractive error. The purpose of this study was to characterize the effects of eccentricity on the ability of myopic defocus signals to influence central refractive development in infant monkeys. From 24 to 152 days of age, rhesus monkeys were reared with binocular, dual-focus lenses that had central, zero-powered zones surrounded by alternating concentric annular power zones of +3D and zero power. Between subject groups the diameter of the central, zero-powered zone was varied from 2 mm to 8 mm in 2 mm steps (+3D/pl 2 mm, n = 6; +3D/pl 4 mm, n = 6; +3D/pl 6 mm, n = 8, or + 3D/pl 8 mm, n = 6). For the treatment lens with 2, 4, 6 and 8 mm central zones, objects at eccentricities beyond 11°, 16°, 19° and 23°, respectively, were imaged exclusively through the dual-power peripheral zones. Refractive status (retinoscopy), corneal power (keratometry) and axial dimensions (ultrasonography) were measured at two-week intervals. Comparison data were obtained from monkeys reared with binocular, single-vision +3D full-field lenses (+3D FF, n = 6) and 41 normal control monkeys reared with unrestricted vision. At the end of the rearing period, with the exception of the +3D/pl 8 mm group (median = +3.64 D), the ametropias for the other lens-reared groups (medians: FF = +4.39 D, 2 mm = +5.19 D, 4 mm = +5.59 D, 6 mm = +3.50 D) were significantly more hyperopic than that for the normal monkeys (+2.50 D). These hyperopic errors were associated with shallower vitreous chambers. The key finding was that the extent and consistency of these hyperopic ametropias varied with the eccentricity of the dual-focus zones. The results confirm that myopic defocus in the near periphery can slow axial growth, but that imposed defocus beyond about 20° from the fovea does not consistently alter central refractive development.

Studies in chickens suggest low intensity ambient lighting causes myopia. The purpose of this experiment was to examine the effects of low intensity ambient lighting (dim light) on normal refractive development in macaque monkeys. Seven infant rhesus monkeys were reared under dim light (room illumination level: ~55 lx) from 24 to ~310 days of age with otherwise unrestricted vision. Refractive error, corneal power, ocular axial dimensions, and choroidal thickness were measured in anesthetized animals at the onset of the experiment and periodically throughout the dim-light-rearing period, and were compared with those of normal-light-reared monkeys. We found that dim light did not produce myopia; instead, dim-light monkeys were hyperopic relative to normal-light monkeys (median refractive errors at ~155 days, OD: +3.13 D vs. +2.31 D; OS: +3.31D vs. +2.44 D; at ~310 days, OD: +2.75D vs. +1.78D, OS: +3.00D vs. +1.75D). In addition, dim-light rearing caused sustained thickening in the choroid, but it did not alter corneal power development, nor did it change the axial nature of the refractive errors. These results showed that, for rhesus monkeys and possibly other primates, low ambient lighting by itself is not necessarily myopiagenic, but might compromise the efficiency of emmetropization.

We investigated a commercial low-coherence interferometer (LenStar LS 900 optical biometer) in measuring young rhesus monkey ocular dimensions. Ocular biometry data obtained using a LenStar and an A-scan ultrasound instrument (OPT-scan 1000) from 163 rhesus monkeys during 20-348 days of age were compared by means of coefficients of concordance and 95% limits of agreement. Linear regression was employed to examine and analyze the inter-instrument discrepancies. In young rhesus monkeys, the test-retest reliability of the LenStar was equal to or exceeded that of A-scan ultrasound (intraclass correlation = 0.86 to 0.93). The inter-instrument agreement was strong for vitreous chamber depth and axial length (coefficient of concordance = 0.95 and 0.86, respectively) and moderate for anterior chamber depth and lens thickness (coefficient of concordance = 0.74 and 0.63, respectively). The LenStar systematically underestimated ocular dimensions when compared to A-scan ultrasound (mean magnitude of difference = 0.11 to 0.57 mm). This difference could be minimized using linear calibration functions to equate LenStar data with ultrasound data. When this method was applied, the values between instruments were in excellent absolute agreement (mean magnitude of difference = 0.004 to 0.01 mm). In conclusion, the LenStar reliably measured ocular dimensions in young monkeys. When an appropriate calibration function is applied, the LenStar can be used as a substitute for A-scan ultrasonography.

Purpose: Intrinsically photosensitive retinal ganglion cells (ipRGCs) contain the photopigment melanopsin, and are primarily involved in non-image forming functions, such as the pupillary light reflex and circadian rhythm entrainment. The goal of this study was to develop and validate a targeted ipRGC immunotoxin to ultimately examine the role of ipRGCs in macaque monkeys. Methods: An immunotoxin for the macaque melanopsin gene (OPN4), consisting of a saporin-conjugated antibody directed at the N-terminus, was prepared in solutions of 0.316, 1, 3.16, 10, and 50 μg in vehicle, and delivered intravitreally to the right eye of six rhesus monkeys, respectively. Left eyes were injected with vehicle only. The pupillary light reflex (PLR), the ipRGC-driven post illumination pupil response (PIPR), and electroretinograms (ERGs) were recorded before and after injection. For pupil measurements, 1 and 5 s pulses of light were presented to the dilated right eye while the left pupil was imaged. Stimulation included 651 nm (133 cd/m2), and 4 intensities of 456 nm (16-500 cd/m2) light. Maximum pupil constriction and the 6 s PIPR were calculated. Retinal imaging was performed with optical coherence tomography (OCT), and eyes underwent OPN4 immunohistochemistry to evaluate immunotoxin specificity and ipRGC loss. Results: Before injection, animals showed robust pupil responses to 1 and 5 s blue light. After injection, baseline pupil size increased 12 ± 17%, maximum pupil constriction decreased, and the PIPR, a marker of ipRGC activity, was eliminated in all but the lowest immunotoxin concentration. For the highest concentrations, some inflammation and structural changes were observed with OCT, while eyes injected with lower concentrations appeared normal. ERG responses showed better preserved retinal function with lower concentrations. Immunohistochemistry showed 80-100% ipRGC elimination with the higher doses being more effective; however this could be partly due to inflammation that occurred at the higher concentrations. Conclusion: Findings demonstrated that the OPN4 macaque immunotoxin was specific for ipRGCs, and induced a graded reduction in the PLR, as well as, in ipRGC-driven pupil response with concentration. Further investigation of the effects of ipRGC ablation on ocular and systemic circadian rhythms and the pupil in rhesus monkeys will provide a better understanding of the role of ipRGCs in primates.

Adenosine receptor (ADOR) antagonists, such as 7-methylxanthine (7-MX), have been shown to slow myopia progression in humans and animal models. Adenosine receptors are found throughout the body, and regulate the release of neurotransmitters such as dopamine and glutamate. However, the role of adenosine in eye growth is unclear. Evidence suggests that 7-MX increases scleral collagen fibril diameter, hence preventing axial elongation. This study used immunohistochemistry (IHC) and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) to examine the distribution of the four ADORs in the normal monkey eye to help elucidate potential mechanisms of action. Eyes were enucleated from six Rhesus monkeys. Anterior segments and eyecups were separated into components and flash-frozen for RNA extraction or fixed in 4% paraformaldehyde and processed for immunohistochemistry against ADORA1, ADORA2a, ADORA2b, and ADORA3. RNA was reverse-transcribed, and qPCR was performed using custom primers. Relative gene expression was calculated using the ΔΔCt method normalizing to liver expression, and statistical analysis was performed using Relative Expression Software Tool. ADORA1 immunostaining was highest in the iris sphincter muscle, trabecular meshwork, ciliary epithelium, and retinal nerve fiber layer. ADORA2a immunostaining was highest in the corneal epithelium, trabecular meshwork, ciliary epithelium, retinal nerve fiber layer, and scleral fibroblasts. ADORA2b immunostaining was highest in corneal basal epithelium, limbal stem cells, iris sphincter, ciliary muscle, ciliary epithelium, choroid, isolated retinal ganglion cells and scattered scleral fibroblasts. ADORA3 immunostaining was highest in the iris sphincter, ciliary muscle, ciliary epithelium, choroid, isolated retinal ganglion cells, and scleral fibroblasts. Compared to liver mRNA, ADORA1 mRNA was significantly higher in the brain, retina and choroid, and significantly lower in the iris/ciliary body. ADORA2a expression was higher in brain and retina, ADORA2b expression was higher in retina, and ADORA3 was higher in the choroid. In conclusion, immunohistochemistry and RT-qPCR indicated differential patterns of expression of the four adenosine receptors in the ocular tissues of the normal non-human primate. The presence of ADORs in scleral fibroblasts and the choroid may support mechanisms by which ADOR antagonists may prevent myopia. The potential effects of ADOR inhibition on both anterior and posterior ocular structures warrant investigation.

The purpose of this investigation was to determine the effects of narrow band, long-wavelength lighting on normal refractive development and the phenomena of lens compensation and form-deprivation myopia (FDM) in infant rhesus monkeys. Starting at 24 and continuing until 151 days of age, 27 infant rhesus monkeys were reared under long-wavelength LED lighting (630 nm; illuminance = 274 ± 64 lux) with unrestricted vision (Red Light (RL) controls, n = 7) or a +3 D (+3D-RL, n = 7), −3 D (−3D-RL, n = 6) or diffuser lens (From Deprivation (FD-RL), n = 7) in front of one eye and a plano lens in front of the fellow eye. Refractive development, corneal power, and vitreous chamber depth were measured by retinoscopy, keratometry, and ultrasonography, respectively. Comparison data were obtained from normal monkeys (Normal Light (NL) controls, n = 39) and lens- (+3D-NL, n = 9; −3D-NL, n = 18) and diffuser-reared controls (FD-NL, n = 16) housed under white fluorescent lighting. At the end of the treatment period, median refractive errors for both eyes of all RL groups were significantly more hyperopic than that for NL groups (P = 0.0001 to 0.016). In contrast to fluorescent lighting, red ambient lighting greatly reduced the likelihood that infant monkeys would develop either FDM or compensating myopia in response to imposed hyperopic defocus. However, as in the +3D-NL monkeys, the treated eyes of the +3D-RL monkeys exhibited relative hyperopic shifts resulting in significant anisometropias that compensated for the monocular lens-imposed defocus (P = 0.001). The red-light-induced alterations in refractive development were associated with reduced vitreous chamber elongation and increases in choroidal thickness. The results suggest that chromatic cues play a role in vision-dependent emmetropization in primates. Narrow-band, long-wavelength lighting prevents the axial elongation typically produced by either form deprivation or hyperopic defocus, possibly by creating direction signals normally associated with myopic defocus.

Purpose Previous studies suggest that the adenosine receptor antagonist, 7-methylxanthine (7-MX), retards myopia progression. Our aim was to determine whether 7-MX alters the compensating refractive changes produced by defocus in rhesus monkeys. Methods Starting at age 3 weeks, monkeys were reared with -3 diopter (D; n = 10; 7-MX -3D/pl) or +3D (n = 6; 7-MX +3D/pl) spectacles over their treated eyes and zero-powered lenses over their fellow eyes. In addition, they were given 100 mg/kg of 7-MX orally twice daily throughout the lens-rearing period (age 147 ± 4 days). Comparison data were obtained from lens-reared controls (-3D/pl, n = 17; +3D/pl, n = 9) and normal monkeys (n = 37) maintained on a standard diet. Refractive status, corneal power, and axial dimensions were assessed biweekly. Results The -3D/pl and +3D/pl lens-reared controls developed compensating myopic (-2.10 ± 1.07 D) and hyperopic anisometropias (+1.86 ± 0.54 D), respectively. While the 7-MX +3D/pl monkeys developed hyperopic anisometropias (+1.79 ± 1.11 D) that were similar to those observed in +3D/pl controls, the 7-MX -3D/pl animals did not consistently exhibit compensating myopia in their treated eyes and were on average isometropic (+0.35 ± 1.96 D). The median refractive errors for both eyes of the 7-MX -3D/pl (+5.47 D and +4.38 D) and 7-MX +3D/pl (+5.28 and +3.84 D) monkeys were significantly more hyperopic than that for normal monkeys (+2.47 D). These 7-MX-induced hyperopic ametropias were associated with shorter vitreous chambers and thicker choroids. Conclusions In primates, 7-MX reduced the axial myopia produced by hyperopic defocus, augmented hyperopic shifts in response to myopic defocus, and induced hyperopia in control eyes. The results suggest that 7-MX has therapeutic potential in efforts to slow myopia progression.

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.

Visual signals that produce myopia are mediated by local, regionally selective mechanisms. However, little is known about spatial integration for signals that slow eye growth. The purpose of this study was to determine whether the effects of myopic defocus are integrated in a local manner in primates.Beginning at 24 ± 2 days of age, seven rhesus monkeys were reared with monocular spectacles that produced 3 diopters (D) of relative myopic defocus in the nasal visual field of the treated eye but allowed unrestricted vision in the temporal field (NF monkeys). Seven monkeys were reared with monocular +3 D lenses that produced relative myopic defocus across the entire field of view (FF monkeys). Comparison data from previous studies were available for 11 control monkeys, 8 monkeys that experienced 3 D of hyperopic defocus in the nasal field, and 6 monkeys exposed to 3 D of hyperopic defocus across the entire field. Refractive development, corneal power, and axial dimensions were assessed at 2- to 4-week intervals using retinoscopy, keratometry, and ultrasonography, respectively. Eye shape was assessed using magnetic resonance imaging.In response to full-field myopic defocus, the FF monkeys developed compensating hyperopic anisometropia, the degree of which was relatively constant across the horizontal meridian. In contrast, the NF monkeys exhibited compensating hyperopic changes in refractive error that were greatest in the nasal visual field. The changes in the pattern of peripheral refractions in the NF monkeys reflected interocular differences in vitreous chamber shape.As with form deprivation and hyperopic defocus, the effects of myopic defocus are mediated by mechanisms that integrate visual signals in a local, regionally selective manner in primates. These results are in agreement with the hypothesis that peripheral vision can influence eye shape and potentially central refractive error in a manner that is independent of central visual experience.

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.

Purpose We investigated how the relative surface area devoted to the more positive-powered component in dual-focus lenses influences emmetropization in rhesus monkeys. Methods From 3 to 21 weeks of age, macaques were reared with binocular dual-focus spectacles. The treatment lenses had central 2-mm zones of zero-power and concentric annular zones that had alternating powers of either +3.0 diopters (D) and 0 D (+3 D/pL) or -3.0 D and 0 D (-3 D/pL). The relative widths of the powered and plano zones varied from 50:50 to 18:82 between treatment groups. Refractive status, corneal curvature, and axial dimensions were assessed biweekly throughout the lens-rearing period. Comparison data were obtained from monkeys reared with binocular full-field single-vision lenses (FF+3D, n = 6; FF-3D, n = 10) and from 35 normal controls. Results The median refractive errors for all of the +3 D/pL lens groups were similar to that for the FF+3D group (+4.63 D versus +4.31 D to +5.25 D; P = 0.18-0.96), but significantly more hyperopic than that for controls (+2.44 D; P = 0.0002-0.003). In the -3 D/pL monkeys, refractive development was dominated by the zero-powered portions of the treatment lenses; the -3 D/pL animals (+2.94 D to +3.13 D) were more hyperopic than the FF-3D monkeys (-0.78 D; P = 0.004-0.006), but similar to controls (+2.44 D; P = 0.14-0.22). Conclusions The results demonstrate that even when the more positive-powered zones make up only one-fifth of a dual-focus lens' surface area, refractive development is still dominated by relative myopic defocus. Overall, the results emphasize that myopic defocus distributed across the visual field evokes strong signals to slow eye growth in primates.

We analyzed the contribution of individual ocular components to vision-induced ametropias in 210 rhesus monkeys. The primary contribution to refractive-error development came from vitreous chamber depth; a minor contribution from corneal power was also detected. However, there was no systematic relationship between refractive error and anterior chamber depth or between refractive error and any crystalline lens parameter. Our results are in good agreement with previous studies in humans, suggesting that the refractive errors commonly observed in humans are created by vision-dependent mechanisms that are similar to those operating in monkeys. This concordance emphasizes the applicability of rhesus monkeys in refractive-error studies.

Understanding the role of peripheral defocus on central refractive development is critical because refractive errors can vary significantly with eccentricity and peripheral refractions have been implicated in the genesis of central refractive errors in humans. Two rearing strategies were used to determine whether peripheral hyperopia alters central refractive development in rhesus monkeys. In intact eyes, lens-induced relative peripheral hyperopia produced central axial myopia. Moreover, eliminating the fovea by laser photoablation did not prevent compensating myopic changes in response to optically imposed hyperopia. These results show that peripheral refractive errors can have a substantial impact on central refractive development in primates.

PurposeDifferent subspecies of rhesus monkeys (Macaca mulatta) that are derived from different geographical locations, primarily Indian and China, are commonly employed in vision research. Substantial morphological and behavioral differences have been reported between Chinese- and Indian-derived subspecies. The purpose of this study was to compare refractive development in Chinese- and Indian-derived rhesus monkeys.MethodsThe subjects were 216 Indian-derived and 78 Chinese-derived normal infant rhesus monkeys. Cross-sectional data were obtained at 3 weeks of age for all subjects. In addition, longitudinal data were obtained from 10 Indian-derived (male=5, female=5) and 5 Chinese-derived monkeys (male=3, female=2) that were reared with unrestricted vision. Ocular and refractive development was assessed by retinoscopy, keratometry, video-based ophthalmophakometry, and A-scan ultrasonography.ResultsAlthough the course of emmetropization was very similar in these two groups of rhesus monkeys, there were consistent and significant inter-group differences in ocular dimensions and refractive error. Throughout the observation period, the Chinese-derived monkeys were on average about 0.4D less hyperopic than the Indian-derived monkeys and the Chinese-derived monkeys had longer overall axial lengths, deeper anterior and vitreous chamber depths, thicker crystalline lenses, flatter corneas and lower powered crystalline lenses.ConclusionsThe ocular differences observed in this study presumably reflect genetic differences between subspecies but could reflect the differences in the genetic pool between isolated colonies rather than true subspecies differences. Nonetheless, the substantial ocular differences that we observed emphasize that caution must be exercised when comparing and/or pooling data from rhesus monkeys obtained from different colonies. These inter-subspecies differences might be analogous to the ethnic differences in ocular parameters that have been observed in humans.

Visual feedback associated with the eye's effective refractive state actively regulates refractive development and ocular growth, in particular vitreous chamber depth. In essence, error signals that encode the sign of optical defocus (i.e., whether the eye is myopic or hyperopic) can increase or decrease the rate of axial elongation in order to minimize the eye's refractive error.1,2 From an operational perspective, signals encoding the sign of defocus are ideal for driving the process of emmetropization; and although signals associated with defocus appear to dominate emmetropization, there is growing evidence that several aspects of ambient lighting can also influence the course of refractive development. In laboratory animals, the intensity of ambient lighting has been shown to influence the normal course of emmetropization. For example, chickens reared with unrestricted vision under dim lighting develop myopic refractive errors and exhibit higher than normal intersubject variability in refractions.3 On the other hand, elevated lighting levels promote the development of low degrees of hyperopia. Elevated lighting levels have also been shown to reduce the eye's response to some myopiagenic stimuli. Specifically, elevated lighting levels significantly reduce the degree of axial myopia normally produced by form deprivation in chickens,4,5 tree shrews,6 and macaques.7 These results support the hypothesis that the protective effects that time outdoors has against myopia in children are due, at least in part, to the higher ambient light levels typically encountered outdoors.4,8,9 However, elevated lighting levels do not alter the final degree of myopia produced by optically imposed hyperopic defocus,6,10,11 which indicates that defocus growth signals can override the effects of elevated lighting levels. The spectral composition of ambient lighting can also influence refractive development. As a consequence of longitudinal chromatic aberration (LCA), the total refracting power of the eye varies inversely with the wavelength of light so that the eye is relatively more hyperopic/less myopic for long- versus short-wavelength light. It is well established that signals associated with LCA provide directional cues for accommodation.12–14 The results from a recent series of experiments have demonstrated that the eye can also use chromatic signals from LCA in several different ways to encode the sign of defocus for the emmetropization process.15–19 In particular, Rucker and her colleagues15–19 have shown that color stimuli that mimic the color contrast differences produced by myopic and hyperopic defocus can produce predictable changes in refractive development. For example, with myopic defocus the relative contrast for long-wavelength image components is higher than that for short-wavelength components; and when chickens are reared viewing chromatic simulations of myopic defocus, the chicken eye exhibits alterations associated with reduced growth.16 However, the fact that the compensation to optically imposed defocus20,21 and the recovery from form deprivation22 can still take place when animals are reared in quasimonochromatic environments indicates that signals associated with luminance contrast signals can guide refractive development and that chromatic signals associated with LCA are not always essential for emmetropization. Because both luminance and color signals can influence emmetropization, alterations in the spectral composition of ambient lighting could influence refractive development in multiple ways. For example, if the target for emmetropization is the focal plane that maximizes luminance contrast and chromatic cues are assumed not to be available, then manipulations of the wavelength composition of the ambient lighting should produce changes in the set point or target refractive error that are related to the magnitude of the eye's LCA. In this respect, the eyes of fish,23 chickens,14,19 and guinea pigs24–27 exposed to quasimonochromatic long-wavelength light develop longer ocular diameters and become more myopic/less hyperopic than eyes exposed to relatively shorter wavelengths. In some of these experiments, particularly those that involved relatively short treatment durations, the magnitude of the light-induced differences in ocular parameters matched the shift in the eye's focal length predicted on the basis of LCA.14,19 This pattern of results suggested that luminance-based cues alone were responsible for the changes in refractive development produced by exposure to quasimonochromatic light. However, with longer treatment durations, the magnitude of the ocular and refractive changes, at least in guinea pigs27 and chickens,28 continued to increase well beyond predictions based on LCA, indicating that luminance contrast cues are not always sufficient to control refractive development, and that either the absence of chromatic cues and/or the presence of anomalous sign-of-defocus cues produced by changes in the spectral composition of the ambient lighting interfered with emmetropization. It is important to determine how and the extent to which the wavelength composition of ambient lighting influences emmetropization, especially in primates, because it may be possible to manipulate the spectral characteristics of ambient lighting in ways that could have therapeutic benefit. For example, based primarily on the wavelength-dependent shifts in the focal plane that has the maximum luminance contrast, it has been hypothesized that environments dominated by long-wavelength light, and the relative hyperopic defocus associated with long wavelengths, may promote the development of myopia. On the other hand, environments dominated by relatively short-wavelength light may be protective against myopia. In this respect, because outdoor scenes and artificially lighted indoor scenes tend to be dominated by relatively short- and long-wavelength light, respectively, it has been hypothesized that differences in the spectral composition of indoor and outdoor scenes may contribute to the protective effects that time outdoors has on myopia in children.28 To date we know relatively little about how variations in the wavelength composition of ambient lighting affect emmetropization in primates. Liu et al.29 reported that refractive development in macaques reared in relatively short-wavelength light (455 nm) was not different from that observed in monkeys housed in white light (5000 K). Similarly seven of the nine monkeys that they reared in quasimonochromatic red light (610 nm) exhibited refractive errors that were similar to those of control animals reared in white light. However, two of the monkeys exposed to the red light developed myopic errors, suggesting that there may be individual differences in the susceptibility to long-wavelength stimulation. The purpose of this study was to test the hypothesis that environments dominated by long-wavelength light promote the development of myopia in monkeys.

High-order monochromatic aberrations could potentially influence vision-dependent refractive development in a variety of ways. As a first step in understanding the effects of wave aberration on refractive development, we characterized the maturational changes that take place in the high-order aberrations of infant rhesus monkey eyes. Specifically, we compared the monochromatic wave aberrations of infant and adolescent animals and measured the longitudinal changes in the high-order aberrations of infant monkeys during the early period when emmetropization takes place. Our main findings were that (1) adolescent monkey eyes have excellent optical quality, exhibiting total RMS errors that were slightly better than those for adult human eyes that have the same numerical aperture and (2) shortly after birth, infant rhesus monkeys exhibited relatively larger magnitudes of high-order aberrations predominately spherical aberration, coma, and trefoil, which decreased rapidly to assume adolescent values by about 200 days of age. The results demonstrate that rhesus monkey eyes are a good model for studying the contribution of individual ocular components to the eye's overall aberration structure, the mechanisms responsible for the improvements in optical quality that occur during early ocular development, and the effects of high-order aberrations on ocular growth and emmetropization.

Purpose: Human infants exhibit a high prevalence of astigmatism. Although macaque monkeys are commonly used as animal models in experiments on early ocular growth and emmetropization, the prevalence of astigmatism in infant monkeys is unexplored. In this study we examine the prevalence and nature of astigmatism in infant monkeys.Methods: Refractive and corneal astigmatism were measured in 132, 2–5-week-old rhesus monkeys (Macaca mulatta) using cycloplegic retinoscopy and keratometry, respectively. Longitudinal measures of refractive development were obtained from 16 normal infants over the first 6 months of life.Results: Infant monkeys exhibited a low prevalence of astigmatism. Approximately 90% of the 2–5-week-old infants had 1.00 D (n=20), it was predominantly against-the-rule in nature (70.0%). The infant monkeys that were followed longitudinally rarely showed significant astigmatic errors at any time during the observation period. When these infant monkeys exhibited significant astigmatism, it was usually transient and not present on subsequent measurements.Conclusions: Unlike human infants, infant monkeys exhibit relatively little astigmatism. The low prevalence of astigmatism during early development suggests that astigmatism does not provide an essential cue for vision-dependent eye growth in infant primates.

Purpose We investigated the effects of two simultaneously imposed, competing focal planes on refractive development in monkeys. Methods Starting at 3 weeks of age and continuing until 150 ± 4 days of age, rhesus monkeys were reared with binocular dual-focus spectacle lenses. The treatment lenses had central 2-mm zones of zero power and concentric annular zones with alternating powers of +3.0 diopter [D] and plano (pL or 0 D) (n = 7; +3D/pL) or -3.0 D and plano (n = 7; -3D/pL). Retinoscopy, keratometry, and A-scan ultrasonography were performed every 2 weeks throughout the treatment period. For comparison purposes data were obtained from monkeys reared with full field (FF) +3.0 (n = 4) or -3.0 D (n = 5) lenses over both eyes and 33 control animals reared with unrestricted vision. Results The +3 D/pL lenses slowed eye growth resulting in hyperopic refractive errors that were similar to those produced by FF+3 D lenses (+3 D/pL = +5.25 D, FF +3 D = +4.63 D; P = 0.32), but significantly more hyperopic than those observed in control monkeys (+2.50 D, P = 0.0001). One -3 D/pL monkey developed compensating axial myopia; however, in the other -3 D/pL monkeys refractive development was dominated by the zero-powered portions of the treatment lenses. The refractive errors for the -3 D/pL monkeys were more hyperopic than those in the FF -3 D monkeys (-3 D/pL = +3.13 D, FF -3D = -1.69 D; P = 0.01), but similar to those in control animals (P = 0.15). Conclusions In the monkeys treated with dual-focus lenses, refractive development was dominated by the more anterior (i.e., relatively myopic) image plane. The results indicate that imposing relative myopic defocus over a large proportion of the retina is an effective means for slowing ocular growth.

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.

To determine whether high light levels, which have a protective effect against form-deprivation myopia, also retard the development of lens-induced myopia in primates.Hyperopic defocus was imposed on 27 monkeys by securing -3 diopter (D) lenses in front of one eye. The lens-rearing procedures were initiated at 24 days of age and continued for periods ranging from 50 to 123 days. Fifteen of the treated monkeys were exposed to normal laboratory light levels (∼350 lux). For the other 12 lens-reared monkeys, auxiliary lighting increased the illuminance to 25,000 lux for 6 hours during the middle of the daily 12 hour light cycle. Refractive development, corneal power, and axial dimensions were assessed by retinoscopy, keratometry, and ultrasonography, respectively. Data were also obtained from 37 control monkeys, four of which were exposed to high ambient lighting.in normal- and high-light-reared monkeys, hyperopic defocus accelerated vitreous chamber elongation and produced myopic shifts in refractive error. the high light regimen did not alter the degree of myopia (high light: -1.69 ± 0.84 D versus normal light: -2.08 ± 1.12 D; P = 0.40) or the rate at which the treated eyes compensated for the imposed defocus. Following lens removal, the high light monkeys recovered from the induced myopia. The recovery process was not affected by the high lighting regimen.In contrast to the protective effects that high ambient lighting has against form-deprivation myopia, high artificial lighting did not alter the course of compensation to imposed defocus. These results indicate that the mechanisms responsible for form-deprivation myopia and lens-induced myopia are not identical.

To investigate the effects of experimentally induced defocus on eye growth and refractive development, one eye of four infant rhesus monkeys was fit with either a +3.0 D (N = 2) or -3.0 D (N = 2) extended-wear, soft, contact lens, and the other eye was fit with a zero-powered, control lens. The lens rearing regimen was started between 12 and 22 days of age and continued for 24 to 64 days. Hyperopic shifts in refractive error were found in all eyes, including the eyes treated with plano lenses. In addition to these absolute hyperopic shifts, 1.5 to 3.25 D of axial anisometropia were produced in all four monkeys, with the eyes wearing the powered lenses becoming relatively more hyperopic than the control eyes wearing the plano lenses. The induced hyperopia and anisometropia decreased rapidly after lens removal. The reapplication of the lenses at later ages in two animals produced smaller, but similar, changes. It appears that in very young primates extended-wear, soft, contact lenses can alter eye growth and refractive development through both visual and nonvisual mechanisms.

The influence of visual experience on ocular development in higher primates is not well understood. To investigate the possible role of defocus in regulating ocular growth, spectacle lenses were used to optically simulate refractive anomalies in young monkeys (for example, myopia or nearsightedness). Both positive and negative lenses produced compensating ocular growth that reduced the lens-induced refractive errors and, at least for low lens powers, minimized any refractive-error differences between the two eyes. These results indicate that the developing primate visual system can detect the presence of refractive anomalies and alter each eye's growth to eliminate these refractive errors. Moreover, these results support the hypothesis that spectacle lenses can alter eye development in young children.

This study aimed to investigate the changes in ocular shape and relative peripheral refraction during the recovery from myopia produced by form deprivation (FD) and hyperopic defocus. FD was imposed in six monkeys by securing a diffuser lens over one eye; hyperopic defocus was produced in another six monkeys by fitting one eye with −3D spectacle. When unrestricted vision was re-established, the treated eyes recovered from the vision-induced central and peripheral refractive errors. The recovery of peripheral refractive errors was associated with corresponding changes in the shape of the posterior globe. The results suggest that vision can actively regulate ocular shape and the development of central and peripheral refractions in infant primates.

Soon after birth, the eyes of most infants normally grow in a highly coordinated manner toward the ideal optical state that is then maintained throughout childhood and into early adult life, a process called emmetropization. Evidence from many different species indicates that this process is actively regulated by visual feedback associated with the eye's refractive state—in essence, optical defocus.1–3 For example, making the eyes of young animals artificially myopic with positive lenses or hyperopic with negative lenses produces compensating ocular growth that can, within certain operational limits, eliminate the imposed refractive error.4–10 However, for reasons not currently understood, a substantial and increasing proportion of the human population develop myopia during early adolescence.11–13 It is possible that myopia onset and progression in children are triggered by visual experience, acting through the vision-dependent biochemical cascade that normally promotes the development of the optimal refractive state or possibly the failure of this focus-dependent process to stop axial growth. In this respect, most optical treatment strategies that have been designed to prevent or reduce myopia in children are based on manipulating accommodative effort and/or the effective focus of the retinal image. The fact that some recent optical treatment strategies that impose relative myopic defocus over a large portion of the retina have been shown to produce clinically meaningful reductions in myopia progression14–20 has reinforced the predominant view that visual factors other than defocus do not influence refractive development. However, the local mechanisms that mediate the effects of optical defocus on ocular growth are complex, involving many different retinal, choroidal, and scleral components.21–23 Although optical defocus appears to be the primary stimulus, some individual components in this signal cascade (e.g., dopaminergic amacrine cells) have been shown to be influenced by other stimulus attributes (e.g., light levels).1 As a consequence, the operational efficiency of this defocus-driven feedback loop is potentially influenced by a variety of external factors, including other visual factors. Specifically, recent observations in humans and laboratory animals suggest that ambient light levels may also influence this vision-dependent loop and consequently refractive development. For example, individuals who spend more time outdoors have more hyperopic refractive errors and a lower prevalence of juvenile-onset myopia.24–27 The protective effect of time outdoors is not associated with sporting activities nor is it a substitution effect for time spent in activities that are linked to myopia (e.g., near work).26,28 Instead, it is the total amount of time outdoors that appears to be important. In this respect, the absolute differences in the amount of outdoor activities between myopic and nonmyopic children are relatively small; however, these behavioral differences are present up to 3 years before the onset of myopia,24 which suggests that lower amounts of outdoor activities may contribute to myopia onset. Although the mechanisms underlying this protective effect are not well understood, it has been proposed that these protective effects are due to the relatively flat dioptric topographies of outdoor scenes23 and/or to the high ambient lighting levels typically encountered outdoors,29 which are often 100 times higher than indoor levels. In this respect, it may be significant that most human studies that have reported the protective effects of outdoor activities have been conducted in climates with substantial amounts of sunlight (e.g., Singapore and Sydney).26–28 Research in chickens has provided direct evidence that high lighting levels can have a protective effect against myopigenic visual stimuli. For example, exposing young chicks to high illuminances, either from sunlight or intense laboratory lights, reduces the degree of axial myopia produced by form deprivation by 65% over a 4-day treatment period, accelerates the hyperopic compensation to positive lenses, and slows myopic compensation to negative lenses, although full compensation is still achieved by the end of a 6-day treatment period.29,30 In addition, the ability of a brief period of unrestricted vision to prevent form-deprivation myopia increases with increasing ambient lighting levels,29 and in chicks reared with unrestricted vision, emmetropization is slowed by high light levels, leading to more hyperopic refractive errors.31 It is not reasonable to extrapolate the results from chickens to humans, because light levels and lighting cycles can have qualitatively different effects in primates and birds. Although there are many similarities in the vision-dependent mechanisms that regulate refractive development in birds and primates,1–3 there are qualitative differences. In particular, although lighting cycles can affect refractive development in monkeys,32,33 lighting levels and light cycles can influence refractive development in chickens via mechanisms that do not appear to operate in primates (e.g., direct pineal stimulation)34 and to alter ocular growth in chickens in ways that do not occur in primates. For example, exposure to continuous light produces dramatic changes in corneal curvature in chickens,35,36 but it does not affect the anterior segment in monkeys.32,33 Therefore, the purpose of this study was to evaluate the potential protective effects of high ambient lighting on vision-induced myopia in primates by comparing refractive development in monocularly form-deprived infant rhesus monkeys reared under normal laboratory lighting with that of those exposed to high levels of artificial light.

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.

PURPOSE. The purpose of this study was to determine whether visual signals from the fovea contribute to the changes in the pattern of peripheral refractions associated with form deprivation myopia in monkeys. METHODS. Monocular form-deprivation was produced in 18 rhesus monkeys by securing diffusers in front of their treated eyes between 22 ± 2 and 155 ± 17 days of age. In eight of these form-deprived monkeys, the fovea and most of the perifovea of the treated eye were ablated by laser photocoagulation at the start of the diffuser-rearing period. Each eye's refractive status was measured by retinoscopy along the pupillary axis and at 15° intervals along the horizontal meridian to eccentricities of 45°. Control data were obtained from 12 normal monkeys and five monkeys that had monocular foveal ablations and were subsequently reared with unrestricted vision. RESULTS. Foveal ablation, by itself, did not produce systematic alterations in either the central or peripheral refractive errors of the treated eyes. In addition, foveal ablation did not alter the patterns of peripheral refractions in monkeys with form-deprivation myopia. The patterns of peripheral refractive errors in the two groups of form-deprived monkeys, either with or without foveal ablation, were qualitatively similar (treated eyes: F = 0.31, P = 0.74; anisometropia: F = 0.61, P = 0.59), but significantly different from those found in the normal monkeys (F = 8.46 and 9.38 respectively, P < 0.05). CONCLUSIONS. Central retinal signals do not contribute in an essential way to the alterations in eye shape that occur during the development of vision-induced axial myopia.

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.

Many aspects of ocular growth and refractive development are regulated by visual feedback associated with the eye’s refractive state (see refs 1 and 2 for reviews). Knowledge of the operational properties of the vision-dependent mechanisms that influence refractive development is critical for understanding the role of vision in the genesis of common refractive errors and for developing the optimal treatment regimens for refractive error. In this respect, one of the most important discoveries arising from animal research is that in some species many of the effects of vision on ocular growth and refractive development appear to be mediated by mechanisms that are located entirely within the eye (see refs 2 and 3 for reviews). The primary evidence for these retinal mechanisms has come from reduction-strategy experiments that have examined the effects of a visual stimulus on refractive development when the obvious neural inputs and/or outputs from the eye have been eliminated. For example, in chicks and tree shrews pharmacological blockade and/or surgical section of the optic nerve do not interfere with the phenomenon of form-deprivation myopia (FDM)4–6 or the recovery from FDM7 and although the set point for emmetropization is altered by optic nerve section, compensation for positive and negative lenses still occurs.8,9 Similarly, surgical interruption of the primary parasympathetic inputs to the eye does not prevent FDM or lens induced changes in refractive error in chicks.9 These experiments show that the visual signals that alter eye growth do not have to leave the eye and that the most obvious neural input to the eye is not essential for many aspects of vision-dependent ocular growth. In addition, it has been shown that these retinal mechanisms exert their influence in a spatially restricted, local manner. The most direct evidence for the local nature of these retinal mechanisms come from experiments in which the nature of visual experience has been varied across the visual field. For example, in chicks, tree shrews and guinea pigs that are reared with diffusers or negative lenses that only cover part of the visual field, the axial elongation and myopia are restricted to the affected part of the retina (McFadden, IOVS, 2002, 43, E-Abstract 189).10–14 Similarly, in chicks positive lenses that only affect the image over half the retina slow vitreous chamber elongation and produce hyperopia only in the treated portion of the retina.10 These results demonstrate that the ocular mechanisms that regulate eye growth pool visual signals from restricted spatial regions and exert their influence locally. It is thought that the actions of these local retinal mechanisms alter the shape of the eye in response to variations in the environment in order to enhance the optimum focus across the retina.1,13,15,16 It is not known if local retinal mechanisms are involved in emmetropizing responses in primates. In a study involving a small number of monkeys, Raviola and Wiesel17 found that optic nerve section prevented FDM in stumptail macaques, but not in rhesus monkeys. In addition, surgically eliminating the parasympathetic and sympathetic inputs to the eye did not prevent FDM in rhesus monkeys.17 These results suggest that there are vision-dependent retinal mechanisms in rhesus monkeys that influence eye growth, but not in stumptail monkeys. This discrepancy between two closely related species is puzzling and may have come about as a result of the variability associated with the phenomenon of form-deprivation myopia in monkeys,18–21 possible hyperopic shifts produced by optic nerve section,9 and/or the small number of animals studied. Regardless, it has not been clearly established that refractive development is mediated by retinal mechanisms in primates and there have not been any previous attempts to characterize the spatial summation properties of any potential retinal mechanisms in primates. Because of the significance of local retinal mechanisms to our understanding of the effects of vision on refractive development, it is critical to determine if they exist in primates and if they can produce predictable changes in eye shape. The great majority of what we know about local retinal mechanisms comes from studies in chicks. However, because of differences in the structure of the sclera in chicks and primates,3 it is not reasonable to expect that similar visual manipulations will produce comparable shape changes in chicks and primates. For example, the cartilaginous portion of the chick sclera is comparatively rigid and depriving half of the retina of a chick produces a prominent bulge on the deprived side of the eye.5,13 Because primates have a less rigid fibrous sclera, it is possible that providing half of the retina with a stimulus for growth would produce a more symmetrical, prolate axial elongation in primates. In this study, we employed a rearing strategy that has provided strong evidence for the existence of local retinal mechanisms in chicks, guinea pigs, and tree shrews. Specifically, we examined the effects of hemi-retinal form deprivation on ocular growth and the pattern of peripheral refraction in infant monkeys. Some of these results have been presented in abstract form.22

The effects on duck hepatitis B virus (DHBV) replication of specific analogues of two classes of chemical compounds not previously tested against hepadnaviruses are described. One is erythromycin A-9-methyloxime (EMO) and other oxime derivatives of erythromycin A, and the other is purine nucleoside analogues (cyclobut A and cyclobut G)with cyclobutane rings. Viral replication was assessed by measuring serum levels of DHBV DNA in infected ducklings and DHBV DNA in infected primary duck hepatocyte cultures. Administration of EM0 15 mg/kg of body weight IM to infected ducklings resulted in a rapid fall in DHBV DNA levels during therapy and a return to pretreatment levels after EM0 administration was stopped. There was local toxicity at injection sites with muscle necrosis in some animals. When 100 mg/kg EM0 was administered by gastric tube no such viral response was observed. The difference in virus response to EM0 15mgikg IM and 100 mgikg by gastric tube was not due to failure to achieve comparable blood and tissue levels of EM0 administered by the different routes. The results suggest an indirect effect dependent on IM injection of EM0 rather than a direct antiviral effect of the compound. Administration of cyclobut G or cyclobut A at 70 mg/kg IM led to a rapid reduction of DHBV DNA to undetectable levels in serum, and in only 1 of 4 animals did DHBV DNA became detectable again within 10 days after stopping the drug. lntragastric administration of cyclobut G at 180 mg/kg per day was also associated with rapid reduction of serum DHBV DNA with onset of treatment in all animals, undetectable levels in 4 of 5 animals during therapy, and return to pretreatment levels in all animals after the drug was stopped. There were no apparent toxic effects. In cell culture 1 μM cyclobut A or cyclobut G inhibited virus production by more than twentyfold without apparent toxic effects. The results indicate that cyclobut A and cyclobut G are more active on a molar basis than other compounds tested against DHBV in these models, and they appear to be effective byu the oral route. Cyclobut G was much less active than AZT in inhibiting HIV-1 in cell culture.

Purpose To characterize peripheral refractions in infant monkeys. Methods Cross-sectional data for horizontal refractions were obtained from 58 normal rhesus monkeys at 3 weeks of age. Longitudinal data were obtained for both the vertical and horizontal meridians from 17 monkeys. Refractive errors were measured by retinoscopy along the pupillary axis and at eccentricities of 15 degrees , 30 degrees , and 45 degrees . Axial dimensions and corneal power were measured by ultrasonography and keratometry, respectively. Results In infant monkeys, the degree of radial astigmatism increased symmetrically with eccentricity in all meridians. There were, however, initial nasal-temporal and superior-inferior asymmetries in the spherical equivalent refractive errors. Specifically, the refractions in the temporal and superior fields were similar to the central ametropia, but the refractions in the nasal and inferior fields were more myopic than the central ametropia, and the relative nasal field myopia increased with the degree of central hyperopia. With age, the degree of radial astigmatism decreased in all meridians, and the refractions became more symmetrical along both the horizontal and vertical meridians. Small degrees of relative myopia were evident in all fields. Conclusions As in adult humans, refractive error varied as a function of eccentricity in infant monkeys and the pattern of peripheral refraction varied with the central refractive error. With age, emmetropization occurred for both central and peripheral refractive errors, resulting in similar refractions across the central 45 degrees of the visual field, which may reflect the actions of vision-dependent, growth-control mechanisms operating over a wide area of the posterior globe.

Because of the prominence of central vision in primates, it has generally been assumed that signals from the fovea dominate refractive development. To test this assumption, the authors determined whether an intact fovea was essential for either normal emmetropization or the vision-induced myopic errors produced by form deprivation.In 13 rhesus monkeys at 3 weeks of age, the fovea and most of the perifovea in one eye were ablated by laser photocoagulation. Five of these animals were subsequently allowed unrestricted vision. For the other eight monkeys with foveal ablations, a diffuser lens was secured in front of the treated eyes to produce form deprivation. Refractive development was assessed along the pupillary axis by retinoscopy, keratometry, and A-scan ultrasonography. Control data were obtained from 21 normal monkeys and three infants reared with plano lenses in front of both eyes.Foveal ablations had no apparent effect on emmetropization. Refractive errors for both eyes of the treated infants allowed unrestricted vision were within the control range throughout the observation period, and there were no systematic interocular differences in refractive error or axial length. In addition, foveal ablation did not prevent form deprivation myopia; six of the eight infants that experienced monocular form deprivation developed myopic axial anisometropias outside the control range.Visual signals from the fovea are not essential for normal refractive development or the vision-induced alterations in ocular growth produced by form deprivation. Conversely, the peripheral retina, in isolation, can regulate emmetropizing responses and produce anomalous refractive errors in response to abnormal visual experience. These results indicate that peripheral vision should be considered when assessing the effects of visual experience on refractive development.

The purpose of this study was to investigate the relationship between refractive errors and high-order aberrations in infant rhesus monkeys. Specifically, we compared the monochromatic wave aberrations measured with a Shack-Hartman wavefront sensor between normal monkeys and monkeys with vision-induced refractive errors. Shortly after birth, both normal monkeys and treated monkeys reared with optically induced defocus or form deprivation showed a decrease in the magnitude of high-order aberrations with age. However, the decrease in aberrations was typically smaller in the treated animals. Thus, at the end of the lens-rearing period, higher than normal amounts of aberrations were observed in treated eyes, both hyperopic and myopic eyes and treated eyes that developed astigmatism, but not spherical ametropias. The total RMS wavefront error increased with the degree of spherical refractive error, but was not correlated with the degree of astigmatism. Both myopic and hyperopic treated eyes showed elevated amounts of coma and trefoil and the degree of trefoil increased with the degree of spherical ametropia. Myopic eyes also exhibited a much higher prevalence of positive spherical aberration than normal or treated hyperopic eyes. Following the onset of unrestricted vision, the amount of high-order aberrations decreased in the treated monkeys that also recovered from the experimentally induced refractive errors. Our results demonstrate that high-order aberrations are influenced by visual experience in young primates and that the increase in high-order aberrations in our treated monkeys appears to be an optical byproduct of the vision-induced alterations in ocular growth that underlie changes in refractive error. The results from our study suggest that the higher amounts of wave aberrations observed in ametropic humans are likely to be a consequence, rather than a cause, of abnormal refractive development.

Purpose—To characterize the temporal integration properties of the emmetropization process, the authors investigated the effects of brief daily interruptions of lens wear on the ocular compensation for negative lenses in infant rhesus monkeys. Methods—Eighteen monkeys wore −3 D lenses binocularly starting from approximately 3 weeks of age. Six of these monkeys wore the lenses continuously. For the other animals, the −3 D lenses were removed for four 15-minute periods each day. During these periods, the monkeys viewed through either zero-power lenses (n = 6) or +4.5 D lenses (n = 6). Three monkeys reared with binocular plano lenses and 16 monkeys reared normally served as controls. Refractive development was assessed by cycloplegic retinoscopy and A-scan ultrasonography. Results—As expected, the group of animals that wore the −3 D lenses continuously exhibited clear evidence of compensating axial myopia. These predictable myopic changes were mostly eliminated by the brief, daily periods of viewing through plano lenses. Interestingly, brief periods of viewing through +4.5 D lenses produced weaker protective effects. Conclusions—Brief periods of unrestricted vision can prevent the axial myopia normally produced by long daily periods of imposed hyperopic defocus. Thus, the temporal integration properties of the emmetropization process normally reduce the likelihood that transient periods of hyperopic defocus will cause myopia. Evidence from a wide range of animal species has demonstrated that emmetropization is an active process that is regulated by visual feedback associated with the eye's effective refractive state. 1–3 In particular, it has consistently been shown that early in life optically imposed alterations in the eye's refractive state can produce predictable compensating changes in axial growth. For example, negative lenses that displace the eye's secondary focal point beyond the retina (imposing hyperopic defocus) can increase axial growth rates, resulting in a reduction in the optical error that exists when viewing through the negative lens. Conversely, positive lenses that impose myopic defocus (shifting the focal point in front of the retina) can slow axial

Purpose The purpose of this study was to characterize normal ocular development in infant monkeys and to establish both qualitative and quantitative relationships between human and monkey refractive development. Methods The subjects were 214 normal rhesus monkeys. Cross-sectional data were obtained from 204 monkeys at about 3 weeks of age and longitudinal data were obtained from 10 representative animals beginning at about 3 weeks of age for a period of up to 5 years. Ocular development was characterized via refractive status, corneal power, crystalline lens parameters, and the eye’s axial dimensions, which were determined by retinoscopy, keratometry, phakometry and A-scan ultrasonography, respectively. Results From birth to about 5 years of age, the growth curves for refractive error and most ocular components (excluding lens thickness and equivalent lens index) followed exponential trajectories and were highly coordinated between the two eyes. However, overall ocular growth was not a simple process of increasing the scale of each ocular component in a proportional manner. Instead the rates and relative amounts of change varied within and between ocular structures. Conclusion The configuration and contribution of the major ocular components in infant and adolescent monkey eyes are qualitatively and quantitatively very comparable to those in human eyes and their development proceeds in a similar manner in both species. As a consequence, in both species the adolescent eye is not simply a scaled version of the infant eye.

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.

Astigmatism is the most common refractive error, occurring frequently in both healthy (for a review, see reference 1) and diseased eyes.2–4 For instance, in a recent multicentered, school-based study (ages 5–17 years), significant amounts of astigmatism were more prevalent (≥1.0 D, 28.4%) than myopia (≥−0.75 D, 9.2%) or hyperopia (≥+1.25 D, 12.8%).5 However, astigmatic errors, particularly large astigmatic errors, are frequently associated with significant spherical ametropias. Although emmetropes or subjects who have low degrees of spherical ametropia usually also exhibit small amounts of astigmatism, subjects who have high amounts of myopia or hyperopia frequently exhibit high amounts of astigmatism.6–11 In fact, it has been reported that the magnitudes of astigmatism and myopia are linearly correlated in children12 and young adults.7, 13 Why is astigmatism associated with spherical ametropias? Although mechanical factors such as eyelid tension2, 3, 14 and ocular rigidity15 have been implicated in the genesis of astigmatism, little is known about the etiology of astigmatism or the mechanism(s) underlying the association between astigmatism and spherical ametropia. However, our recent studies in monkeys16, 17 indicate that visual experience can alter corneal shape resulting in astigmatism. Specifically, when we reared infant monkeys with cylinder lenses in front of their eyes, we found that the optically imposed astigmatism not only altered emmetropization resulting in axial ametropias,17 but it also promoted the development of significant amounts of astigmatism.16 However, the fact that the axis of the ocular astigmatism was not in the appropriate direction to neutralize the astigmatic errors imposed by the treatment lenses suggested that the eye does not have an active vision-dependent “sphericalization” process analogous to emmetropization.18 Instead, the ocular astigmatism found in the cylinder lens-reared monkeys, which was associated with both axial myopia and hyperopia,17 seemed to be a byproduct of the vision-dependent mechanisms that regulate axial elongation and the emmetropization process. If this is true, then eyes that experienced altered refractive-error development as a result of other visual manipulations should also show a high frequency of astigmatism. A variety of rearing strategies have been shown to predictably alter refractive development. For example, in many different animal species, including humans, form deprivation consistently produces axial myopia (e.g., humans,19 rhesus monkeys,20 marmosets,21 tree shrews,22 and chickens23). Moreover, optically imposing either myopia or hyperopia in young animals with spherical lenses results in compensating axial ametropias that are dependent on the sign and power of the treatment lenses (e.g., rhesus monkeys,24 marmosets,25 tree shrews,26 and chickens27). However, in part because experimentally induced refractive errors have traditionally been expressed in a spherical-equivalent format (i.e., the averaged correction for the two principal astigmatic meridians), only a few studies in chickens have previously noted an association between astigmatism and either axial hyperopia or myopia.28, 29 The purpose of this study was to determine if vision-dependent alterations in axial growth also lead to the development of astigmatism in primates. Specifically, we examined the frequency and characteristics of astigmatism in infant monkeys that developed axial ametropias in response to a variety of different types of altered visual experience.

Purpose Although many aspects of vision-dependent eye growth are qualitatively similar in many species, the failure to observe recovery from form-deprivation myopia (FDM) in higher primates represents a significant potential departure. The purpose of this investigation was to re-examine the ability of rhesus monkeys (Macaca mulatta) to recover from FDM. Methods Monocular form deprivation was produced either with diffuser spectacle lenses (n = 30) or by surgical eyelid closure (n = 14). The diffuser-rearing strategies were initiated at 24 +/- 3 days of age and continued for an average of 115 +/- 20 days. Surgical eyelid closure was initiated between 33 and 761 days of age and maintained for14 to 689 days. After the period of form deprivation, the animals were allowed unrestricted vision. The ability of the animals to recover from treatment-induced refractive errors was assessed periodically by retinoscopy, keratometry, and A-scan ultrasonography. Control data were obtained from 35 normal monkeys. Results At the onset of unrestricted vision, the deprived eyes of 18 of the diffuser-reared monkeys and 12 of the lid-sutured monkeys were at least 1.0 D less hyperopic or more myopic than their fellow eyes. The mean (diffuser = -4.06 D, lid-suture = -4.50 D) and range (diffuser = -1.0 to -10.19 D, lid-suture = -1.0 to -10.25 D) of myopic anisometropia were comparable in both treatment groups. All 18 of these diffuser-reared monkeys demonstrated recovery, with 12 animals exhibiting complete recovery. The rate of recovery, which was mediated primarily by alterations in vitreous chamber growth rate, declined with age. None of the lid-sutured monkeys exhibited clear evidence of recovery. Instead, 8 of the 12 lid-sutured monkeys exhibited progression of myopia. Conclusions Like many other species, young monkeys are capable of recovering from FDM. However, the potential for recovery appears to depend on when unrestricted vision is restored, the severity of the deprivation-induced axial elongation, and possibly the method used to produce FDM.

Protracted daily lighting cycles do not promote abnormal ocular enlargement in infant monkeys as they do in a variety of avian species. However, observations in humans suggest that ambient lighting at night may reduce the efficiency of the emmetropization process in primates. To test this idea, we investigated the ability of infant monkeys reared with continuous light to compensate for optically imposed changes in refractive error.Beginning at about 3 weeks of age, a hyperopic or myopic anisometropia was imposed on 12 infant rhesus monkeys by securing either a -3 D or +3 D lenses in front of one eye and a zero-powered lens in front of the fellow eye. Six of these monkeys were reared with the normal vivarium lights on continuously, whereas the other six lens-reared monkeys were maintained on a 12-h-light/12-h-dark lighting cycle. The ocular effects of the lens-rearing procedures were assessed periodically during the treatment period by cycloplegic retinoscopy, keratometry, and A-scan ultrasonography.Five of six animals in each of the lighting groups demonstrated clear evidence for compensating anisometropic growth. In both lighting groups, eyes that experienced optically imposed hyperopic defocus (-3 D lenses) exhibited faster axial growth rates and became more myopic than their fellow eyes. In contrast, eyes treated with +3 D lenses showed relatively slower axial growth rates and developed more hyperopic refractive errors. The average amount of compensating anisometropia (continuous light, 1.6 +/- 0.5 D vs. control, 2.3 +/- 0.5 D), the structural basis for the refractive errors, and the ability to recover from the induced refractive errors were also not altered by continuous light exposure.Ambient lighting at night does not appear to overtly compromise the functional integrity of the vision-dependent mechanisms that regulate emmetropization in higher primates.