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(Investigative Ophthalmology and Visual Science. 2002;43:291-299.)
© 2002 by The Association for Research in Vision and Ophthalmology, Inc.

Effects of Brief Periods of Unrestricted Vision on the Development of Form-Deprivation Myopia in Monkeys

Earl L. Smith, III, Li-Fang Hung, Chea-su Kee and Ying Qiao

From the College of Optometry, University of Houston, Houston, Texas.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To characterize the temporal integration properties of the mechanisms responsible for form-deprivation myopia (FDM), the effects of brief daily periods of unrestricted vision on the degree of FDM were investigated in infant monkeys.

METHODS. Starting at approximately 3 weeks of age, unilateral form deprivation was produced in 24 infant rhesus monkeys by securing a diffuser spectacle lens in front of one eye and a clear, zero-powered lens in front of the fellow eye. During the treatment period (17 ± 2 weeks), six infants wore the diffuser lenses continuously. In the other experimental infants, the diffuser lenses were removed each day and replaced with clear, zero-powered lenses for 1 (n = 7), 2 (n = 7), or 4 hours (n = 4). Refractive development was assessed by retinoscopy and A-scan ultrasonography. Control data were obtained from 11 normal infants and 3 infants reared with zero-powered lenses over both eyes.

RESULTS. The degree of FDM varied significantly with the duration of unrestricted vision. Continuous form deprivation produced -5.2 ± 3.6 D of relative axial myopia. However, 1 hour of unrestricted vision was sufficient to reduce the degree of axial FDM by more than 50% (-1.7 ± 3.2 D). The infants that were allowed 4 hours of unrestricted vision exhibited only -0.4 ± 0.5 D of FDM.

CONCLUSIONS. As observed in chickens and tree shrews, relatively long periods of form deprivation can be counterbalanced by quite short periods of unrestricted vision. These results indicate that the processes or signals that promote axial elongation in monkeys are comparatively weak or easily overridden by factors that slow ocular growth.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Visual experience plays an important role in both normal and abnormal refractive development. Evidence from a wide range of animal species, including higher primates, has demonstrated that visual feedback associated with the eye’s effective refractive state modulates normal axial growth in a manner that eliminates refractive errors—that is, emmetropization is a visually regulated process (chickens,1 2 3 4 5 tree shrews,6 7 marmosets,8 and rhesus monkeys.9 10 ). However, viewing conditions that prevent clear vision and degrade the retinal image typically accelerate axial growth, resulting in myopic refractive errors, a phenomenon known as form-deprivation myopia (FDM).11 12 13 14 15

The relationship between normal refractive development and FDM is not well understood in primates. Although the mechanisms that mediate FDM could play a beneficial role in emmetropization9 13 16 17 and it is possible that FDM is the result of the normal emmetropization process gone awry,4 a number of observations in chickens suggest that FDM and emmetropization are not mediated by identical mechanisms.5 18 19 20 21 22 Defining the viewing conditions that support normal emmetropization and those that produce FDM is necessary to understand the functional significance of FDM mechanisms and the relationship between FDM and primate emmetropization. Moreover, because FDM mechanisms are still active at ages that correspond to the typical onset age for juvenile myopia in humans,23 24 25 knowledge of the visual conditions that trigger FDM is needed to assess the potential role of FDM in the genesis of common refractive errors.

Studies in both chickens and monkeys have shown that FDM is a graded phenomenon.17 26 Although the degree of FDM decreases with the degree of image degradation, even modest reductions in image contrast, which are equivalent to the defocus effects encountered in normal viewing environments, are capable of producing significant amounts of FDM. Consequently, the mechanisms that mediate FDM appear to be sensitive enough to variations in image quality to influence normal refractive development. However, the temporal integration characteristics of FDM mechanisms could limit their contribution to normal refractive development. In young chicks, very brief daily periods of unrestricted vision are sufficient to greatly reduce FDM, even when the retinal image is severely degraded for most of the daily lighting cycle.27 28 29 Although little is known about the temporal integration characteristics in primates, observations from a small number of marmosets suggest that form deprivation may also have to be maintained for a very large fraction of the day to have an impact on primate refractive development.8 However, it is difficult to generalize these results from marmosets to FDM in all primates, because the occluder-rearing procedures that were used in the marmoset study produced axial hyperopia in the form-deprived eyes rather than axial myopia. Thus, the purpose of this investigation was to characterize the temporal integration properties of FDM mechanisms in primates by determining how brief daily periods of unrestricted vision influence the development of FDM in infant macaque monkeys. This information would also help to define the nature of visual experience required for normal emmetropization. Some of these results have been presented briefly elsewhere.30


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Data are presented for 38 infant rhesus monkeys (Macaca mulatta). All the infants were obtained at 1 to 3 weeks of age and reared in our primate nursery, which was maintained on a 12-hour light–12-hour dark lighting cycle. All the rearing and experimental procedures were approved by The University of Houston’s Institutional Animal Care and Use Committee and were in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Monocular form deprivation was produced in 24 infant monkeys by securing a diffuser spectacle lens in front of one eye and a clear plano lens in front of the fellow eye. The diffuser lenses, which consisted of a plano carrier lens that was covered with a commercially available occlusion foil, were the strongest diffuser lenses that we used in our previous studies of FDM.26 Measurements of spatial contrast sensitivity revealed that these diffuser lenses reduced the contrast sensitivity of normal adult humans by more than 1 log unit for grating spatial frequencies of 0.125 cyc/deg, with a resultant cutoff spatial frequency near 1 cyc/deg. The lens-rearing period, which extended from approximately 3 weeks (24.3 ± 2.8 days) to 4 to 5 months of age (144 ± 17 days), encompassed the bulk of the rapid phase of emmetropization in rhesus monkeys.10 31 During the treatment period, six infants wore the diffusers continuously. The refractive data for five of these subjects have been previously reported.26 In the other form-deprived monkeys, the diffuser lenses were removed each day and replaced with clear plano lenses for unitary periods of 1 (n = 7), 2 (n = 7), or 4 hours (n = 4). These periods of unrestricted vision were centered near the midpoint of the normal 12-hour lights-on cycle. Additional details concerning the general rearing procedures can be found in Smith and Hung.10

The measures of refractive development in our form-deprived subjects were compared with similar measures that were reported previously in 14 control animals.10 26 Eleven of the control subjects were normally reared infants. As a control for any potential effects associated with our lens-rearing procedures, three of these control monkeys were reared with clear plano lenses in front of both eyes for the duration of the treatment period (plano-control monkeys).

Optical and Biometric Measurements
The subjects’ spherical equivalent, spectacle plane refractive corrections for each eye were measured independently by two observers using a streak retinoscope. The eye’s axial dimensions, represented by the mean of 10 individual measurements, were determined by A-scan ultrasonography. An instrument with a 7-MHz transducer was used at each measurement session. Additional measurements were obtained from some animals, by using a 30-MHz A-scan system. To make these measurements, cycloplegia was induced with multiple drops of topically applied 1% tropicamide, and the animals were anesthetized with an intramuscular injection of ketamine hydrochloride (20 mg/kg) and acepromazine maleate (0.2 mg/kg) and the topical instillation of 0.5% tetracaine hydrochloride. The infant monkeys were first examined at ages corresponding to the beginning of the lens-rearing period and typically at approximately 2-week intervals thereafter. See Smith and Hung10 and Hung et al.32 for more details.

Statistical Tests
A one-way analysis of variance (ANOVA) that used the Tukey method for multiple pair-wise comparisons was used to test for differences between the control and treatment groups in interocular differences in refractive error and vitreous chamber depth. Primarily because refractive errors are not normally distributed in normal monkeys, the nonparametric Mann-Whitney test was used to test for significant differences between the refractive errors for normal control monkeys and the nontreated eyes of the experimental monkeys.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The main outcome measures for the effects of monocular form deprivation were the direction and magnitude of the interocular differences in refractive error and vitreous chamber depth. Interocular comparison are a very sensitive treatment measure, because for normal and plano-control monkeys the refractive errors and axial dimensions for the two eyes are typically very well matched throughout early development. At ages corresponding to the end of the lens-rearing period for the diffuser monkeys (between 121 and 176 days of age), significant degrees of anisometropia were rare in both normal and plano-control infants. During this age period, the largest anisometropia observed was 0.75 D, and only one other control animal exhibited an interocular difference in refractive error as large as 0.50 D. The mean anisometropia obtained for the control animals at ages corresponding to the end of the lens-rearing period was 0.19 ± 0.16 D. Similarly, vitreous chamber depth was generally well matched in both eyes of both normal and plano-control monkeys. Between 121 and 176 days of age, the largest interocular difference in vitreous chamber depth observed in the control animals was 0.21 mm, and the mean interocular difference was 0.10 ± 0.06 mm.

Continuous unilateral form deprivation consistently disrupted the normal balance between the two eyes. Five of the six infants that wore the diffuser lenses continuously showed development of myopic anisometropia that fell outside the range of the interocular differences observed in the control animals. Although, as previously reported,4 15 26 33 the degree of FDM varied considerably between animals (possibly reflecting genetic differences between individual animals4 ) the effects of continuous form deprivation were generally quite robust, as illustrated by the refractive data from the representative monkeys in Figure 1 . At the end of the lens-rearing period, the degree of relative myopia observed in the treated eyes of the continuously deprived monkeys varied from -0.25 to -9.5 D, with a mean interocular refractive error difference of -5.2 ± 3.6 D (treated eye minus fellow eye). The relative myopic errors found in the deprived eyes could largely be accounted for by interocular differences in vitreous chamber depth (Fig. 1 , lower plots). For each animal in which myopic anisometropia developed that fell outside the control range, the deprived eye exhibited a relatively longer vitreous chamber than its fellow nontreated eye.



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  		Figure 1. Spherical equivalent refractive corrections (top) and relative vitreous chamber depths (bottom) plotted as a function of age in four representative monkeys that wore the diffuser lenses continuously throughout the treatment period. These monkeys were selected to illustrate the range of myopia produced by continuous form deprivation. Top: Ametropia in the form-deprived (•) and nontreated ({circ}) fellow eyes. Thin lines represent the ametropia in the right eyes of the 14 normal-control monkeys. Bottom: (•) interocular differences in vitreous chamber depth in the experimental subjects (treated eye minus fellow eye). Thin lines show the interocular differences in vitreous chamber depth in individual control monkeys (right eye minus left eye). Vitreous chamber depth was defined as the distance between the posterior lens surface and vitreal–retinal interface. In all plots, the first and last data points of each function indicate, respectively, the start and end of the treatment period in the form-deprived monkeys.

 
The axial myopic anisometropia produced by monocular form deprivation was dramatically reduced by short, daily periods of unrestricted vision. Figure 2 illustrates the refractive errors and interocular differences in vitreous chamber depth for four representative infants that were selected to illustrate the range of effects observed in the 1-hour unrestricted-vision group. Although one of the seven monkeys in this experimental group (MKY XEN, far right panels) showed substantial FDM, the other six infants that were allowed 1 hour of unrestricted vision showed either no relative axial myopia (e.g., MKY NAN) or only small amounts of FDM in the treated eye (e.g., MKY TIA and MKY BER). In comparison to the monkeys that experienced continuous form deprivation, the dramatically lower amounts of FDM observed in these animals were not simply due to a reduction in the total number of hours of form deprivation that the animals experienced over the course of the lens-rearing period. The average length of the lens-rearing period was 20 days longer in this treatment group than that in the group that wore the diffusers continuously. Moreover, observations in individual animals suggested that extending the length of the lens-rearing period would not have substantially increased the amount of FDM. For example, small degrees of FDM developed in monkeys TIA and BER after only 6 to 8 weeks of lens treatment (Fig. 2 , middle 2 columns). However, the degree of FDM exhibited by these two animals was relatively stable for the remainder of the treatment period.



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  		Figure 2. Spherical equivalent refractive corrections (top) and relative vitreous chamber depths (bottom) plotted as a function of age in four representative form-deprived monkeys that were allowed 1 hour of unrestricted vision each day. Symbols and details as in Figure 1 .

 
The refractive development in representative form-deprived monkeys that were allowed 2 and 4 hours of unrestricted vision each day are shown in Figures 3 and 4 , respectively. (Note that in Figs. 3 and 4 the vertical scales have been expanded in comparison to those in Figs. 1 and 2 .) Five of the seven monkeys in the 2-hour unrestricted group showed development of relative axial myopia in the treated eye. However, the magnitude of these refractive anomalies were typically only 1 to 2 D in magnitude and as illustrated by MKY GIL (Fig. 3 , left), two of the seven infants in this group did not show development of relative myopia. Four hours of unrestricted vision almost completely eliminated the effects of 8 hours of form deprivation. However, there were indications that the rearing strategy had an influence on refractive development. First, during the course of the lens-rearing regimen, monkeys NIN and DEL (Fig. 4 , second and fourth columns from the left) exhibited transient myopic anisometropia that fell outside the range of anisometropia observed after 30 days of age in our control monkeys. Second, at some points during the lens-rearing period, the absolute refractive errors in three of the monkeys in the 4-hour unrestricted group fell outside the range of ametropia for age-matched control monkeys. An interesting finding was that both the deprived and nondeprived eyes showed ametropia that fell outside the control range (e.g., MKY TAY).



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  		Figure 3. Spherical equivalent refractive corrections (top) and relative vitreous chamber depths (bottom) plotted as a function of age in four representative form-deprived monkeys that were allowed 2 hours of unrestricted vision each day. Symbols and details as in Figure 1 .

 


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  		Figure 4. Spherical equivalent refractive corrections (top) and relative vitreous chamber depths (bottom) plotted as a function of age in the four form-deprived monkeys that were allowed 4 hours of unrestricted vision each day. Symbols and details as in Figure 1 .

 
Figure 5 summarizes the results in all the experimental animals at 4 months of age—that is, an age that was at or very near the end of the treatment period. The magnitude of FDM, as represented by the interocular differences in refractive error, decreased significantly as the duration of unrestricted vision was increased (Fig. 5A) . Under our rearing conditions, continuous form deprivation produced on average -5.2 D of relative myopia, which was significantly higher than that in all the other subject groups (ANOVA, F = 6.8, P < 0.0001; Tukey’s pair-wise comparisons, family error rate, 0.05). The average amount of FDM decreased systematically with increases in the duration of unrestricted vision to -0.4 D in the animals that were allowed 4 hours of unrestricted vision each day. Only 1 hour of unrestricted vision was sufficient to reduce the amount of FDM to less than half the amount produced by continuous form deprivation. The pattern of results was very similar for the average interocular differences in vitreous chamber depth (Fig. 5B ; ANOVA, F = 4.5, P < 0.005; Tukey pair-wise comparisons, family error rate, 0.05). One hour of unrestricted vision reduced the degree of relative axial elongation by more than 50% and after 4 hours of unrestricted vision, the average vitreous chamber depth in the deprived eyes was only 0.04 mm longer than that in the fellow nondeprived eyes.



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  		Figure 5. The mean (±SE) interocular differences in refractive error (A) and vitreous chamber depth (B) plotted as a function of the duration of the daily period of unrestricted vision. The filled and open symbols represent the form deprived and normal-control subjects, respectively. The number of subjects in each group is noted by each symbol. Positive values indicate that the treated eye (right eye for normal-control subjects) was more myopic and exhibited a longer vitreous chamber depth than the fellow nontreated eye. Solid lines: the best-fitting exponential functions; the resultant time constants were 65.4 minutes and 59.1 minutes for the degree of relative myopia and vitreous chamber elongation, respectively.

 
Although the most dramatic effects of monocular form deprivation occurred in the treated eyes, refractive development in the fellow nondeprived eyes was also affected. Figure 6 shows the ametropia (left) and vitreous chamber depth (right) at 4 months of age in treated and nontreated eyes of individual monkeys. In contrast to their fellow deprived eyes, many of the nondeprived eyes were more hyperopic than normal (Mann-Whitney test, P = 0.02). The refractive errors in the nontreated eyes of 8 of the 24 diffuser-reared monkeys exceeded the largest hyperopic error found in the age-matched normal-control monkeys. The vitreous chamber depths for the nontreated eyes of five of the diffuser-reared monkeys were also shorter than the shortest vitreous chamber found in the normal control monkeys. In comparison, only one nontreated eye exhibited a longer vitreous chamber depth and a more myopic refractive error than eyes in the control animals. Inspection of the refractive error plot for the nontreated eyes (Fig. 6 , left) suggests that as in the treated eyes, the effects of form deprivation varied with the duration of the daily period of unrestricted vision. However, due primarily to the variability in the continuous form-deprivation group, this trend was not significant (ANOVA, F = 1.25, P = 0.31; Tukey pair-wise comparisons, family error rate, 0.05).



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  		Figure 6. Refractive error (left) and vitreous chamber depth (right) plotted for the treated and nontreated eyes of individual form-deprived monkeys. The treated and nontreated eye data for a given monkey are represented by same-shaped symbols. The data are arranged on the abscissa according to the duration of the daily period of unrestricted vision. For reference purposes, the refractive errors for the right and left eyes of the normal-control monkeys;7> are represented by the filled and open symbols, respectively.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results show that the dramatic effects of relatively long daily periods of form deprivation on refractive development in primates are largely counterbalanced by relatively short daily periods of unrestricted vision. It is evident that the vision-dependent mechanisms that mediate emmetropization in infant monkeys can function effectively with only short periods of unrestricted vision, despite being subjected to form deprivation for most of the daily light cycle. The close similarities in the time constants of the protective effects provided by brief daily periods of unrestricted vision for refractive error and vitreous chamber depth emphasize that these effects are mediated by mechanisms that influence axial growth.

Because we used a 12-hour light–12-hour dark lighting cycle for all our subject groups, it is not possible from our data alone to determine whether the critical factor in preventing FDM was the length of the period of unrestricted vision, the reduced duration of the period of form deprivation, or some combination of the two. However, related observations from previous studies suggest that the duration of unrestricted vision is probably the key factor. First, a period of unrestricted vision produces strong protective effects against FDM and/or myopic compensation for minus lenses regardless of whether the unrestricted vision is provided in the middle of the daily lighting cycle28 29 or at either the start6 21 or end of the lighted period.21 Thus, breaking the period of form deprivation into two shorter periods by having the period of unrestricted vision in the middle of the light cycle is not a necessary condition for the observed protective effects. Second, the dramatic protective effects produced by a 1-hour period of unrestricted vision are probably not due to a simple reduction in the period of form deprivation from 12 to 11 hours. Bradley et al.34 used a much shorter daily lighting cycle (8.5 hours of light per day; Bradley D, personal communication, 2001) than we used in this study, yet both studies found that continuous form deprivation produced comparable degrees of FDM in infant monkeys.

Comparison between Species
Our results in infant monkeys are qualitatively very similar to those previously observed in young chicks.27 28 29 Specifically, in both species very brief daily periods of unrestricted vision greatly reduce the degree of axial myopia produced by form deprivation. Similarly, in both chicks21 and tree shrews6 interrupting minus-lens wear with brief daily periods of normal vision dramatically reduces the myopic compensation evoked by hyperopic defocus. In many respects, the qualitative agreement observed between these studies is not surprising. Each of these species demonstrates FDM12 13 14 15 and myopic compensation for minus lenses.2 3 6 9 10 Moreover, even if the mechanisms responsible for FDM and lens-induced myopic compensation are not identical,5 18 19 20 22 35 it is likely that these processes share common components. However, the degree of quantitative agreement between these studies is quite remarkable.

Figure 7 compares the protective effects of daily periods of unrestricted vision on experimentally induced myopia in infant monkeys, chicks, and tree shrews. The relative degree of myopia produced by either monocular form deprivation or minus-lens wear is plotted as a function of the number of hours of unrestricted vision allowed each day. Despite dramatic differences in the normal rates of ocular development between chicks,25 36 tree shrews,37 and rhesus monkeys,31 the effects of briefs periods of unrestricted vision are quantitatively very similar. For example, the eyes of tree shrews, chicks, and rhesus monkeys reach 90% of their adult axial length after approximately 1, 2.5, and 12 months of visual experience, respectively. However, in both infant monkeys and chicks,28 29 the effects of 12 hours of form deprivation are decreased by more than 50% by only 1 hour of unrestricted vision. Similarly, in tree shrews only 1 hour of unrestricted vision reduced the myopic compensation produced by a 14-hour period of minus-lens wear by 50%.6 In chicks, 3 hours of unrestricted vision, the shortest period that was investigated, completely eliminated the myopic compensation produced by 12 hours of negative lens wear.21 Moreover, inspection of Figure 7 reveals that all the chick and tree shrew data are adequately described by the exponential function that was fit to the monkey data (Fig. 7 , solid line). The time constant for the monkey data was 65.4 minutes (time required to reduce the treatment effect to 1/e of the maximum value) compared with a value of 60.6 minutes for the combined data from tree shrews and chicks.



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  		Figure 7. Comparison of the effects of brief periods of unrestricted vision on the degree of relative myopia produced by monocular form deprivation and/or negative spectacle lenses in monkeys (large open circles; current study), tree shrews (diamonds6 ), and chicks (triangles28 and squares21 ). The solid line is the best-fitting exponential function calculated for the monkeys from this study. The duration of the daily period of unrestricted vision is indicated on the abscissa. In each case, the degree of myopia, which was defined as the interocular difference in refractive error between treated and nontreated eyes, was normalized with respect to the amount of myopia produced by uninterrupted form deprivation or lens wear.

 
The striking quantitative similarities between such diverse species provides strong support for the idea that many of the vision-dependent mechanisms that influence ocular growth have been conserved across vertebrate species. In monkeys, tree shrews, and chicks, it appears that the processes or signals that promote axial elongation are comparatively weak or easily overridden by other factors that influence ocular development—in particular, factors that slow ocular growth. As previously suggested,6 21 a system with these integration characteristics would be beneficial in the sense that it would reduce the likelihood for myopia.

Interocular Effects
In addition to the expected axial myopia observed in the form-deprived eyes, the nontreated eyes were on average significantly more hyperopic than the eyes of normal and plano-control monkeys. Continuous unilateral form deprivation and optical defocus have previously been shown to influence the refractive development of the fellow nontreated eyes in both infant monkeys9 15 26 34 38 and chicks.5 21 39 In this study, the nontreated eye effects appeared to be graduated, with the animals that experienced longer daily periods of form deprivation generally showing the larger ametropia in the nontreated eye. Thus, the consistency over time of form deprivation in the treated eye influences the nontreated eye effect.

How can altered visual experience in one eye influence the normally regulated growth of the fellow nontreated eyes? Several possible mechanisms have been suggested. It has been speculated that interocular effects could reflect a humoral growth influence from one eye to the other.5 For example, in chicks, in which the medial walls of the two orbits are essentially juxtaposed, growth factors could easily cross from one orbit to the other. However, the inconsistencies in the direction of the refractive alterations observed in the nontreated eyes of chicks argue against this idea.5 21 Moreover, in monkeys, in which the orbital separation is more substantial, it seems less likely that such a mechanism could explain interocular effects. Alternatively, the nontreated eye effects could come about as a result of some central influence on the regulation of early eye growth.5 26 34 40 For example, in chicks, tree shrews, and monkeys, changes in choroidal thickness appear to precede vision-dependent changes in ocular growth.5 24 32 41 42 It is possible that the innervation of the choroid or some other critical ocular structure has a binocular component that is somehow altered by monocular form deprivation and that these innervational changes somehow modulate the normal growth of the fellow eye in monocularly treated animals. However, the nature of this input and exactly how it could influence growth is unknown. In monkeys, in which accommodation in the two eyes is closely yoked, interocular effects have been associated with alterations in the fixation behavior of the nontreated eye. For example, infant monkeys reared with low-powered positive lenses in front of one eye, but zero-powered lenses in front of the fellow eye, posture their accommodation for the eye viewing through the positive lens. Consequently, the fellow nontreated eye experiences hyperopic defocus and relative axial myopia develops.9 10 On the one hand, given the degree of image degradation produced by our diffuser lenses and the likelihood that the treated eyes were amblyopic,43 it is very unlikely that our monkeys, particularly the animals that wore the diffuser lenses continuously, attempted to fixate through the treated eyes. On the other hand, it is reasonable to suppose that the relative hyperopic errors found in the nontreated eyes represent a vision-dependent alteration in ocular growth.

It has been argued that optical defocus associated with underaccommodation or errors of accommodation promotes the normal reduction in hyperopia that occurs during emmetropization.16 44 As the degree of hyperopia is reduced and the eye approaches emmetropia, there is a time-averaged improvement in the clarity of the retinal image that slows down ocular growth, resulting in the maintenance of near emmetropic refractive errors. If this scenario is correct, it is possible that the hyperopic errors in the nontreated eyes came about because monocular form deprivation actually increased the accuracy of accommodation in the nontreated fellow eyes in a time-averaged manner. For example, it has been hypothesized that the presence of high accommodative convergence–accommodation ratios in children results in an accommodative lag at near working distances, which would result in a chronic reduction in retinal image quality.45 It could be argued that occluding one eye prevents convergence issues from influencing accommodative tone. As a result, in comparison with normal infant monkeys, the nontreated eyes of monocularly form-deprived monkeys would experience better overall image quality and/or longer periods of clear vision. In essence, the hyperopia in the nontreated eye could have resulted from a premature cessation of the normal emmetropization process.

Implications for Human Refractive Development
In many respects, FDM is a ubiquitous phenomenon. First, FDM is not restricted to neonates. Although the most dramatic alterations in axial growth and refractive error occur when form deprivation is imposed early in life, evidence from chickens,25 wallabies,46 and primates23 47 demonstrates that the eye probably maintains at least some degree of sensitivity to FDM well into early adult life. Second, although rather severe measures are frequently used to impose form deprivation, the mechanisms that mediate FDM are very sensitive to reductions in retinal image quality. In both chickens17 and monkeys,26 diffuser lenses that produce relatively small reductions in image quality, reductions that are comparable to the defocus effects that can be experienced in everyday viewing conditions, are capable of producing exaggerated axial growth and myopia. Third, the mechanisms responsible for FDM appear to be present and active in virtually every species that has been studied in a systematic fashion. Experimentally induced form deprivation has been shown to consistently produce axial myopia in a great variety of animal species, ranging from birds to primates.48 More important, at least from a species-centric point of view, many pathologic conditions that prevent the formation of a clear retinal image in human children are also associated with axial myopia.49 50 51 52 53 54 55 56

Because FDM occurs in humans and the phenomenon could contribute to the development of common refractive errors, it is important to understand the visual conditions that support normal development and those that produce FDM in humans. In this respect, the results of this study and those summarized in Figure 7 have potential clinical implications for human infants who have conditions that potentially prevent the formation of a clear retinal image. Given that brief daily periods of unrestricted vision have been shown to prevent axial myopia in primates and several other species, it is possible that the effects of form deprivation on refractive development in humans can also be counterbalanced by brief daily periods of unrestricted vision. Because only a few weeks of continuous form deprivation can promote axial myopia in monkeys,12 15 57 amelioration of the conditions that produce form deprivation as quickly as possible is undoubtedly the best option for ensuring normal refractive development in human infants. However, if it is not possible to permanently eliminate the cause of form deprivation immediately, temporary manipulations that provide short daily periods of clear vision, such has elevating a drooping eyelid, may be sufficient to maintain normal emmetropization. Based on their studies in tree shrews, Shaikh et al.6 have similarly proposed that brief periods of clear vision may reduce progression of juvenile myopia in humans. The key point is that a beneficial effect on refractive development could result from what may appear to be minimal effort.

That brief daily periods of unrestricted vision counterbalance the effects of much longer periods of form deprivation also provides a potential explanation for some of the apparent inconsistencies between humans and animals concerning the effects of visual experience on refractive development. For example, although the degree of FDM varies from one monkey to the next (or one chicken to the next58 ) and for unknown reasons axial myopia does not develop in some individual form-deprived monkeys, the great majority of infant monkeys that experience form deprivation show development of substantial axial myopia.15 26 33 34 38 59 60 Similarly, substantial axial myopia has been consistently observed in human infants who have anomalous conditions that are likely to produce continuous form deprivation. For instance, infants with significant corneal opacity early in life exhibit a very high prevalence of axial myopia that is comparable to that in monkeys.50 54 However, there have been a number of reports of children in whom FDM failed to develop, even though they had ocular conditions that can produce form deprivation.52 53

Although these observations could be taken as evidence that visual experience may not have comparable effects on refractive development in humans and animals, the absence of effect could reflect inconsistencies in the abnormal visual experience. Assuming that the temporal integration characteristics of FDM mechanisms are similar in humans and monkeys, it seems reasonable to speculate that myopia may fail to develop in many infants with, for example, blepharoptosis, because the anomalous visual experience may occasionally be interrupted by episodes of unrestricted vision. In essence, some of the apparent inconsistency between humans and monkeys may occur because treatment compliance can be rigorously enforced in monkeys, but the nature of visual experience associated with many anomalous ocular conditions in human infants is likely to be comparatively inconsistent. In this light, these inconsistencies observed in humans may be taken as an indication that the effects of visual experience on refractive development in humans and many animal species are quite similar.


   Footnotes
 
Supported by Grants EY03611 and EY07551 from the National Eye Institute and funds from the Greeman-Petty Professorship, University of Houston Foundation.

Submitted for publication April 26, 2001; revised September 17, 2001; accepted October 2, 2001.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Earl L. Smith III, College of Optometry, University of Houston, 505 J. Davis Armistead Building, Houston, TX 77204-2020; esmith{at}uh.edu


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Irving, EL, Callender, MG, Sivak, JG (1991) Inducing myopia, hyperopia, and astigmatism in chicks Optom Vis Sci 68,364-368[Medline][Order article via Infotrieve]
  2. Irving, EL, Sivak, JG, Callender, MG (1992) Refractive plasticity of the developing chick eye Ophthalmic Physiol Optics 12,448-456[Medline][Order article via Infotrieve]
  3. Schaeffel, F, Glasser, A, Howland, HC (1988) Accommodation, refractive error and eye growth in chickens Vision Res 28,639-657[Medline][Order article via Infotrieve]
  4. Schaeffel, F, Howland, H. (1991) Properties of the feedback loops controlling eye growth and refractive state in the chicken Vision Res 31,717-734[Medline][Order article via Infotrieve]
  5. Wildsoet, C, Wallman, J. (1995) Choroidal and scleral mechanisms of compensation for spectacle lenses in chicks Vision Res 35,1175-1194[Medline][Order article via Infotrieve]
  6. Shaikh, AW, Siegwart, JT, Norton, TT (1999) Effect of interrupted lens wear on compensation for a minus lens in tree shrews Optom Vis Sci 76,308-315[Medline][Order article via Infotrieve]
  7. Siegwart, JT, Norton, TT (1999) Regulation of the mechanical properties of tree shrew sclera by the visual environment Vision Res 39,387-407[Medline][Order article via Infotrieve]
  8. Graham, B, Judge, SJ (1999) The effects of spectacle wear in infancy on eye growth and refractive error in the marmoset (Callithrix jacchus) Vision Res 39,189-206[Medline][Order article via Infotrieve]
  9. Hung, L-F, Crawford, MLJ, Smith, EL, III (1995) Spectacle lenses alter eye growth and the refractive status of young monkeys Nat Med 1,761-765[Medline][Order article via Infotrieve]
  10. Smith, EL, III, Hung, L-F. (1999) The role of optical defocus in regulating refractive development in infant monkeys Vision Res 39,1415-1435[Medline][Order article via Infotrieve]
  11. Troilo, D, Judge, SJ (1993) Ocular development and visual deprivation myopia in the common marmoset (Callithrix jacchus) Vision Res 33,1311-1324[Medline][Order article via Infotrieve]
  12. Wiesel, TN, Raviola, E. (1977) Myopia and eye enlargement after neonatal lid fusion in monkeys Nature 266,66-68[Medline][Order article via Infotrieve]
  13. Wallman, J, Adams, JI (1987) Developmental aspects of experimental myopia in chicks: susceptibility, recovery and relation to emmetropization Vision Res 27,1139-1163[Medline][Order article via Infotrieve]
  14. McBrien, NA, Norton, TT (1992) The development of experimental myopia and ocular component dimensions in monocularly lid-sutured tree shrews (Tupaia belangeri) Vision Res 32,843-852[Medline][Order article via Infotrieve]
  15. Smith, EL, III, Harwerth, RS, Crawford, MLJ, von Noorden, GK (1987) Observations on the effects of form deprivation on the refractive status of the monkey Invest Ophthalmol Vis Sci 28,1236-1245[Abstract/Free Full Text]
  16. Norton, TT, Siegwart, JT (1995) Animal models of emmetropization: matching axial length to the focal plane J Am Optom Assoc 66,405-414[Medline][Order article via Infotrieve]
  17. Bartmann, M, Schaeffel, F. (1994) A simple mechanism for emmetropization without cues from accommodation or colour Vision Res 34,873-876[Medline][Order article via Infotrieve]
  18. Bartmann, M, Schaeffel, F, Hagel, G, Zrenner, E. (1994) Constant light affects retinal dopamine levels and blocks deprivation myopia but not lens-induced refractive errors in chickens Vis Neurosci 11,199-208[Medline][Order article via Infotrieve]
  19. Schaeffel, F, Hagel, G, Bartmann, M, Kohler, K, Zrenner, E. (1994) 6-Hydroxydopamine does not affect lens-induced refractive errors but suppresses deprivation myopia Vision Res 34,143-149[Medline][Order article via Infotrieve]
  20. Schaeffel, F, Bartmann, M, Hagel, G, Zrenner, E. (1995) Studies on the role of the retinal dopamine/melatonin system in experimental refractive errors in chickens Vision Res 35,1247-1264[Medline][Order article via Infotrieve]
  21. Schmid, KL, Wildsoet, CF (1996) Effects on the compensatory responses to positive and negative lenses of intermittent lens wear and ciliary nerve section in chicks Vision Res 36,1023-1036[Medline][Order article via Infotrieve]
  22. Troilo, D, Wallman, J. (1991) The regulation of eye growth and refractive state: an experimental study of emmetropization Vision Res 31,1237-1250[Medline][Order article via Infotrieve]
  23. Smith, EL, III, Bradley, DV, Fernandes, A, Boothe, RG (1999) Form deprivation myopia in adolescent monkeys Optom Vis Sci 76,428-432[Medline][Order article via Infotrieve]
  24. Siegwart, JT, Norton, TT (1998) The susceptible period for deprivation-induced myopia in tree shrew Vision Res 38,3505-3515[Medline][Order article via Infotrieve]
  25. Papastergiou, GI, Schmid, GF, Laties, AM, Pendrak, K, Lin, T, Stone, RA (1998) Induction of axial elongation and myopic refractive shift in one year old chickens Vision Res 38,1883-1888[Medline][Order article via Infotrieve]
  26. Smith, EL, III, Hung, L-F. (2000) Form-deprivation myopia in monkeys is a graded phenomenon Vision Res 40,371-381[Medline][Order article via Infotrieve]
  27. Nickla, DL, Panos, SN, Fugate-Wentzek, LA, Gottlieb, MD, Wallman, J. (1989) What attributes of visual stimulation determine whether chick eyes develop deprivation myopia? [ARVO Abstract] Invest Ophthalmol Vis Sci 30,31
  28. Napper, GA, Brennan, NA, Barrington, M, Squires, M, Vessey, GA, Vingrys, AJ (1995) The duration of normal visual exposure necessary to prevent form deprivation myopia in chicks Vision Res 35,1337-1344[Medline][Order article via Infotrieve]
  29. Napper, GA, Brennan, NA, Barrington, M, Squires, MA, Vessey, GA, Vingrys, A. (1997) The effect of an interrupted daily period of normal visual stimulation on form deprivation myopia in chicks Vision Res 37,1557-1564[Medline][Order article via Infotrieve]
  30. Smith, EL, III, Hung, L-F, Qiao, Y, Kee, C-s (2000) Brief periods of unrestricted vision prevent form-deprivation myopia in monkeys Thorn, F Troilo, D Gwiazda, J eds. Myopia 2000: Proceedings of the VIII International Conference on Myopia ,143-146 Boston.
  31. Bradley, DV, Fernandes, A, Lynn, M, Tigges, M, Boothe, RG (1999) Emmetropization in the rhesus monkey (Macaca mulatta): birth to young adulthood Invest Ophthalmol Vis Sci 40,214-229[Abstract/Free Full Text]
  32. Hung, L-F, Wallman, J, Smith, EL, III (2000) Vision dependent changes in the choroidal thickness of macaque monkeys Invest Ophthalmol Vis Sci 41,1259-1269[Abstract/Free Full Text]
  33. Tigges, M, Tigges, J, Fernandes, A, Eggers, HM, Gammon, JA (1990) Postnatal axial eye elongation in normal and visually deprived rhesus monkeys Invest Ophthalmol Vis Sci 31,1035-1046[Abstract/Free Full Text]
  34. Bradley, DV, Fernandes, A, Boothe, RG (1999) The refractive development of untreated eyes of rhesus monkeys varies according to the treatment received by their fellow eyes Vision Res 39,1749-1757[Medline][Order article via Infotrieve]
  35. Kee, C-s, Marzani, D, Wallman, J (2001) Differences in time course and visual requirements of ocular responses to lenses and diffusers Invest Ophthalmol Vis Sci 42,575-583[Abstract/Free Full Text]
  36. Li, T, Troilo, D, Glasser, A, Howland, H. (1995) Constant light produces severe corneal flattening and hyperopia in chickens Vision Res 35,1203-1209[Medline][Order article via Infotrieve]
  37. Norton, TT, McBrien, NA (1992) Normal development of refractive state and ocular component dimensions in the tree shrew Vision Res 32,833-842[Medline][Order article via Infotrieve]
  38. Raviola, E, Wiesel, TN (1985) An animal model of myopia N Engl J Med 312,1609-1615[Abstract]
  39. Sivak, JG, Barrie, DL, Weerheim, JA (1989) Bilateral experimental myopia in chicks Optom Vis Sci 66,854-858[Medline][Order article via Infotrieve]
  40. Kiorpes, L, Wallman, J. (1995) Does experimentally-induced amblyopia cause hyperopia in monkeys? Vision Res 35,1289-1297[Medline][Order article via Infotrieve]
  41. Troilo, D, Nickla, D, Wildsoet, C. (2000) Choroid thickness changes during altered eye growth and refractive state in the common marmoset (Callithrix jacchus) Invest Ophthalmol Vis Sci 41,1249-1258[Abstract/Free Full Text]
  42. Wallman, J, Wildsoet, C, Xu, A, et al (1995) Moving the retina: choroidal modulation of refractive state Vision Res 35,37-50[Medline][Order article via Infotrieve]
  43. Smith, EL, III, Hung, L-F, Harwerth, R. (2000) The degree of image degradation and the depth of amblyopia Invest Ophthalmol Vis Sci 41,3775-3781[Abstract/Free Full Text]
  44. Wallman, J. (1993) Retinal control of eye growth and refraction Prog Retinal Res 12,134-153
  45. Gwiazda, J, Grice, K, Thorn, F. (1999) Response AC/A ratios are elevated in myopic children Ophthalmic Physiol Opt 19,173-179[Medline][Order article via Infotrieve]
  46. Harman, AM, Hoskins, R, Beazley, LD (1999) Experimental eye enlargement in mature animals changes the retinal pigment epithelium Vis Neurosci 16,619-628[Medline][Order article via Infotrieve]
  47. Troilo, D, Nickla, DL, Wildsoet, CF (2000) Form deprivation myopia in mature common marmosets (Callithrix jacchus) Invest Ophthalmol Vis Sci 41,2043-2049[Abstract/Free Full Text]
  48. Smith, EL, III (1998) Environmentally induced refractive errors in animals Rosenfield, M Gilmartin, B eds. Myopia and Nearwork ,57-90 Butterworth-Heinemann Oxford, UK.
  49. Hoyt, CS, Stone, RD, Fromer, C, Billdon, FA (1981) Monocular axial myopia associated with neonatal eyelid closure in human infants Am J Ophthalmol 91,197-200[Medline][Order article via Infotrieve]
  50. Meyer, C, Mueller, MF, Duncker, GIW, Meter, H-J. (1999) Experimental animal myopia models are applicable to human juvenile-onset myopia Surv Ophthalmol 44,S93-S102
  51. Rob, RM (1977) Refractive errors associated with hemangiomas of the eyelids and orbit in infancy Am J Ophthalmol 83,52-58[Medline][Order article via Infotrieve]
  52. von Noorden, GK, Lewis, RA (1987) Ocular axial length in unilateral congenital cataracts and blepharoptosis Invest Ophthalmol Vis Sci 28,750-752[Abstract/Free Full Text]
  53. Gair, EJ, Adams, GGW (1999) Normal visual development after unilateral complete ptosis at birth J Am Assoc Pediatr Ophthalmol Strabismus 3,58-59
  54. Gee, SS, Tabbara, KF (1988) Increase in ocular axial length in patients with corneal opacification Ophthalmology 95,1276-1278[Medline][Order article via Infotrieve]
  55. Twomey, JM, Givlarry, A, Restori, M, Kirkness, CM, Moore, AT, Holden, AL (1990) Ocular enlargement following infantile corneal opacification Eye 4,497-503
  56. O’Leary, DJ, Millodot, M. (1979) Eyelid closure causes myopia in humans Experientia 35,1478-1479[Medline][Order article via Infotrieve]
  57. Smith, EL, III, Harwerth, RS, Crawford, MLJ, von Noorden, GK (1988) The influence of the period of deprivation on experimental refractive errors Lennerstrand, G von Noorden, GK Campos, E eds. Strabismus and Amblyopia ,197-206 Macmillan Press London.
  58. Schaeffel, F, Howland, HC (1988) Mathematical model of emmetropization in the chicken J Opt Soc Am A 5,2080-2086[Medline][Order article via Infotrieve]
  59. Thorn, F, Doty, RW, Gramiak, R. (1982) Effect of eyelid suture on the development of ocular dimensions in macaques Curr Eye Res 1,727-733
  60. Greene, PR, Guyton, DL (1986) Time course of rhesus lid-suture myopia Exp Eye Res 42,529-534[Medline][Order article via Infotrieve]



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