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Peripheral defocus does not necessarily affect central refractive development
Vision Research 46 (2006) 3935–3940 www.elsevier.com/locate/visres
Peripheral defocus does not necessarily aVect central refractive development Ruth Schippert, Frank SchaeVel ¤ Section of Neurobiology of the Eye, University Eye Hospital Tuebingen, Calwerstrasse 7/1, 72076 Tuebingen, Germany Received 24 March 2006; received in revised form 11 May 2006
Abstract Purpose. Recent experiments in monkeys suggest that deprivation, imposed only in the periphery of the visual Weld, can induce foveal myopia. This raises the hypothesis that peripheral refractive errors imposed by the spectacle lens correction could inXuence foveal refractive development also in humans. We have tested this hypothesis in chicks. Methods. Chicks wore either full Weld spectacle lenses (+6.9 D/¡7 D), or lenses with central holes of 4, 6, or 8 mm diameter, for 4 days (n D 6 for each group). Refractions were measured in the central visual Weld, and at ¡45° (temporal) and +45° (nasal), and axial lengths were measured by A-scan ultrasonography. Results. As previously described, full Weld lenses were largely compensated within 4 days (refraction changes with positive lenses: +4.69 § 1.73 D, negative lenses: ¡5.98 § 1.78 D, both p < 0.001, Dunnett’s test, to untreated controls). With holes in the center of the lenses, the central refraction remained emmetropic and there was not even a trend of a shift in refraction (all groups: p > 0.5, Dunnetts test). At §45°, the lenses were partially compensated despite the 4/6/8 mm central holes; positive lenses: +2.63 / +1.44 / +0.43 D, negative lenses: ¡2.57 / ¡1.06 / +0.06 D. Conclusions. There is extensive local compensation of imposed refractive errors in chickens. For the tested hole sizes, peripherally imposed defocus did not inXuence central refractive development. To alter central refractive development, the unobstructed part in the central visual Weld may have to be quite small (hole sizes smaller than 4 mm, with the lenses at a vertex distance of 2–3 mm). © 2006 Elsevier Ltd. All rights reserved. Keywords: Myopia; Peripheral emmetropization; Chicken; Spectacles
1. Introduction The developmental matching of focal length and axial length of the eye is called emmetropization. It normally takes place during the Wrst years of life in human infants, and moves the generally more hyperopic refractions toward emmetropia (e.g. Gwiazda, Thorn, Bauer, & Held, 1993). Experiments in animal models have shown that emmetropization is largely visually guided: imposing deWned amounts of defocus with positive or negative spectacle lenses induces hyperopic or myopic refractive errors in chicks (SchaeVel, Glasser, & Howland, 1988; Irving, Sivak, & Callender,
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1992), guinea pigs (McFadden, Howlett, & Mertz, 2004), tree shrews (Shaikh, Siegwart, & Norton, 1999) and rhesus monkeys (Hung, Crawford, & Smith, 1995). Development of experimentally induced refractive errors is accompanied by changes in choroidal thickness, changes in vitreous chamber depth, and scleral remodeling which act together to move the photoreceptor layer in the direction of the focal plane (review: Wallman & Winawer, 2004). Detection of the sign of the imposed defocus occurs in the retina and, strikingly, it takes only a few minutes: “In a matter of minutes the eye knows which way to grow” (Zhu, Park, Winawer, & Wallman, 2005). However, the underlying retinal image processing is not yet understood. The signaling cascade that translates the output of the retinal image processing into biochemical signals to control changes in choroidal thickness and growth of the sclera is
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currently extensively studied. There is hope that the biochemical components of emmetropization can be modulated by drugs and that, one day, myopia development can be controlled by eye drops. However, no optimal candidate drug has yet been identiWed (review Wallman & Winawer, 2004). An alternative approach to interfere with myopia development is to use the natural feedback loops of emmetropization but trigger them with controlled patterns of defocus. It was recognized already long ago that refractive errors can be induced in chickens in local retinal areas if the retinal images were locally degraded (Wallman, Gottlieb, Rajaram, & Fugate-Wentzek, 1987). Later, it was found that refractive errors imposed by hemi-Weld spectacle lenses were compensated by local changes in the posterior part of the eye ball: only the defocused half of the globe adapted its growth whereas the other half remained normal (Diether & SchaeVel, 1997). Chickens have no fovea but rather an “area centralis”, a central part of the visual Weld with moderately enhanced visual acuity (Morris, 1982). Visual acuity, as judged by ganglion cell density, varies only by a factor of about two, if the center and the periphery are compared (Ehrlich, 1981). Accordingly, for a chicken eye, it pays oV to also emmetropize the periphery to ensure optimal visual acuity in all parts of the visual Weld. The situation is diVerent in foveate animals like primates. Due to the rapid decline in acuity toward the periphery (Osterberg, 1935), an optimized peripheral refractive state appears less important. In fact, it is well documented that the optical quality declines in the human eye towards the periphery, with large amount of astigmatismus (e.g. Atchison, Pritchard, & Schmid, 2006). On the other hand, the foveal position along the visual axis must be determined by scleral growth in the periphery, and not only by the growth of the sclera underlying the fovea itself (Seidemann, SchaeVel, Guirao, LopezGil, & Artal, 2002). Therefore, peripheral refractive errors, driving emmetropization in the periphery, may not be independent from foveal refractive errors. In fact, a recent study has shown that depriving monkey eyes of sharp vision only in the periphery while leaving foveal vision unobstructed causes development of foveal myopia (Smith, Kee, Ramamirtham, Qiao-Grider, & Hung, 2005a). This result may have important implications. Spectacle lenses could be redesigned to impose peripheral myopia to slow down the foveal myopia development (Smith et al., 2005b). Following a similar study in chickens, in which visual deprivation was conWned to the periphery of the visual Weld and complex patterns of refractions were obtained (Stone et al., 2006), we have applied spectacle lenses (powers either +6.9 D or ¡7 D) with central holes of variable diameters (4, 6, or 8 mm) to impose refractive errors only in the periphery of the visual Weld. Refractive development was studied onaxis and in the nasal and temporal visual Weld, and axial lengths were measured. Strikingly, in chickens, peripheral refractive errors did NOT aVect foveal refractive development for the hole sizes used in our study (4/6/8 mm), and vertex distances of 2–3 mm.
2. Methods All experiments were conducted in accordance with the ARVO statement for the use of Animals in Ophthalmic and Vision Research and approved by the University Commission for Animal Welfare. Male white leghorn chicks were obtained by a local hatchery and raised in groups under a 12-h light/12-h dark cycle in the animal facilities of the institute. Water and food were freely available. Chicks were unilaterally treated with plus or minus lenses (powers +6.9 D or ¡7 D) with central holes (4, 6 and 8 mm in diameter), or without holes for four days, starting at day 7 posthatching. The distances of the lenses from the corneal apex (referred to as vertex distances) ranged between 2 and 3 mm. Each group consisted of six animals. An untreated group served as control (n D 12, because both the left and the right eye were refracted over the horizontal visual Weld). In total, 54 chickens were used for this study. The holes left a part of the central visual Weld unobstructed. Projecting the lens hole apertures through the nodal point, visual angles of 38, 49, or 57° were obtained for a vertex distance of 2 mm, and 32, 44, or 52°, for a vertex distance of 3 mm (using the schematic eye for a 7 day old chicken; SchaeVel & Howland, 1991; Fig. 1). Refractive state was measured every other day in the central visual Weld (0°) and at ¡45° (nasal retina) and +45° (temporal retina) using automated infrared photoretinoscopy (calibrated for chickens of the same age; Seidemann & SchaeVel, 2002). To control the angular positions in the peripheral visual Welds, the Wrst Purkinje image of the photoretinoscope was placed at the margin of the entrance pupil, as previously described (Diether & SchaeVel, 1997). In this case, the refractor was located about 45° away from the pupillary axis of the chicken. Negative angular values refer to the nasal visual Weld and positive values to the temporal visual Weld (see also Table 1). Averages of Wve repeated measurements were taken. Axial length was determined by A-scan ultrasound as described earlier (SchaeVel & Howland, 1991) at the beginning and at the end of the lens treatment period. Axial length is referred to as the distance from corneal apex to the vitreoretinal interface. Averages of three repeated measurements were used for statistical analyses. To focus the analysis on refraction changes that were induced by the lens treatment, the following diVerences were computed. First, the diVerences in refraction and in axial length between the treated and the fellow control eye were calculated. Second, the changes in interocular diVerences over the four days treatment period were computed. The mean changes in interocular diVerences over the four days treatment period were statistically analyzed and are presented in Fig. 2a (positive lenses) and 2b (negative lenses). Statistical analysis (one-way ANOVA, Dunnett’s test, to untreated controls) was performed with the software package jmp (SAS Institute, Cary, USA). Asterisks denote signiWcance levels (¤p < 0.05, ¤¤ p < 0.01,¤¤¤p < 0.001).
3. Results 3.1. Refractive states No changes in refraction were observed over the lens treatment period in any of the untreated fellow eyes (data not shown). Average refractions (means § SD) of all groups at the beginning and at the end of the experiments are presented in Table 1. Full Weld lenses were largely compensated after four days, in all parts of the visual Weld (mean changes in interocular diVerences over the four days treatment period § standard deviations, with positive lenses: +4.61 § 1.40, with negative lenses: ¡5.96 § 1.45 D, all p < 0.001, Dunnett’s test, to untreated controls, Fig. 2a and b). No signiWcant diVerences were observed between the three angular
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Fig. 1. Estimation of the visual angle of the part of the visual Weld that remained unobstructed by the spectacle lenses, due to the central holes. PND posterior nodal distance, PNP posterior nodal point. Calculations are performed for a 2 mm vertex distance.
positions in the visual Weld, neither with the full Weld lenses, nor in the untreated eyes. With the holes drilled in the center of the spectacle lenses (4, 6 or 8 mm diameters), the refractions in the center of the visual Weld developed as in untreated chicks (Dunnett’s test: p > 0.05 in all groups). At the 45° positions, the lenses were partially compensated despite the 4, 6, or 8 mm central holes in the spectacle lenses. Refractions changed with positive lenses at +45° by +1.89, +1.01, and ¡0.26 D, and at ¡45° by 2.98¤¤, 2.30 and 0.51 D (Fig. 2a). With negative lenses, at +45°, the changes were: ¡2.93¤¤, ¡0.98, and ¡0.43 D, and at ¡45°: ¡2.56¤¤, ¡1.63¤, and 0.22 D (Fig. 2b).
3.2. Axial lengths Analysis of the biometric data occurred in the same fashion as the refraction data. Results are shown in Fig. 3. Eyes treated with full Weld positive lenses were signiWcantly shorter (¡0.30 mm¤¤) and eyes treated with full Weld negative lenses were signiWcantly longer (+0.57 mm¤¤¤) than their fellow eyes (Dunnett’s test to untreated control group). The central holes reduced the eVects of the lenses. In the other groups, treated with lenses with 4, 6, or 8 mm central holes, a signiWcant change in axial lengths was observed only in the case of a 4 mm hole in the negative lenses (positive lenses: 0.02,
Table 1 Refractions [diopters] of all groups at the beginning (day 0) and at the end (day 4) of the experiment at the three visual angles that were studied (¡45, 0 and +45°) Treatment
+6.9 D/0 mm +6.9 D/4 mm +6.9 D/6 mm +6.9 D/8 mm ¡7 D/0 mm ¡7 D/4 mm ¡7 D/6 mm ¡7 D/8 mm No lens
Day 0
Day 4
Nasal refraction (¡45°)
Central refraction (0 °)
Temporal refraction (+45°)
Nasal refraction (¡45 °)
Central refraction (0°)
Temporal refraction (+45°)
2.49 § 0.38 2.36 § 0.34 2.59 § 0.61 2.43 § 0.18 2.50 § 0.52 2.21 § 0.29 2.28 § 0.29 2.41 § 0.62 2.51 § 0.29
2.69 § 0.26 2.41 § 0.30 2.51 § 0.53 2.61 § 0.35 2.32 § 0.37 2.24 § 0.38 2.32 § 0.39 2.60 § 0.57 2.56 § 0.26
2.90 § 0.30 2.50 § 0.26 2.88 § 0.36 2.68 § 0.38 2.46 § 0.79 2.54 § 0.31 2.70 § 0.27 2.84 § 0.72 3.02 § 0.36
7.26 § 1.73 5.51 § 1.78 4.38 § 1.32 3.24 § 0.73 ¡3.73 § 1.68 ¡0.25 §1.01 0.93 § 1.21 2.67 § 0.86 2.74 § 0.41
7.38 § 1.84 2.73 § 0.34 2.86 § 0.97 2.91 § 0.27 ¡3.66 § 1.51 2.78 § 0.22 3.23 § 0.33 3.28 § 0.41 2.92 § 0.45
7.37 § 1.80 4.62 § 1.81 4.02 § 0.84 2.73 § 0.74 ¡2.78 § 1.02 ¡0.14 § 0.99 1.92 § 1.28 2.71 § 1.11 2.84 § 0.44
Data are presented as the means § SD. The untreated group consisted of 12 chicks (“no lens”).
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Fig. 2. (a) The mean changes of refractive state in interocular diVerences over the four days treatment period that developed after wearing positive spectacle lenses with central holes of 0 (no hole), 4, 6, and 8 mm diameter, relative to the initial value in all treatment groups. Error bars denote standard errors of the means (SEM), from n D 6 animals in each group. Refractions are plotted against the visual Weld angles. Asterisks denote signiWcance levels (*p < 0.05; **p < 0.01; ***p < 0.001). Note that the refraction in the central visual Weld was not aVected by the peripheral defocus, but that the defocus imposed by the lenses in the periphery was partially compensated. As expected, the smaller the central hole, the more extensive was the compensation of the peripherally imposed refractive errors. (b) The mean changes of refractive state in interocular diVerences over the four days treatment period that developed after wearing positive spectacle lenses with central holes of 0 (no hole), 4, 6, and 8 mm diameter, relative to the initial value in all treatment groups. Error bars denote standard errors of the means (SEM), from n D 6 animals in each group. Refractions are plotted against the visual Weld angles. Asterisks denote signiWcance levels as in Fig. 2a.
Fig. 3. The mean changes of axial length in interocular diVerences, after four days of treatment with positive and negative spectacle lenses (means § SEM, n D 6 in each group), and for diVerent diameters of the central holes in the lenses. SigniWcance levels are denoted by asterisks, as in Fig. 2a and b. ¤
¡0.03 and 0.10 mm, negative lenses: 0.18 , ¡0.06 and 0.01 mm, Fig. 3). Unfortunately, A-scan ultrasonography did not permit to detect changes in eye dimensions in the periphery. 4. Discussion DiVerent from recent experiments in rhesus monkeys (Smith et al., 2005a), the most striking result of this study was that chickens can emmetropize in the periphery without
changing their central refraction. This would imply that the strategy to interfere with foveal refractive development, as proposed by Smith et al. (2005b), may not be as eVective in chickens. On the other hand, it is clear that the diVerences in eVects of full Weld lenses and lenses with a central hole must disappear if the hole sizes are made smaller and smaller. In fact, Morgan and Ambadeniya (2006), have recently reported that +10D lenses with a plano zone in their center of only 3 mm diameter induced general hyperopia, similar to full Weld +10 D lenses. In their study, and similar to the observations in the present study, the lenses had no eVect when the central plano zone was 5 mm in diameter. Apparently, the critical size of the plano or hole zone is between 3 and 4 mm in diameter. Further diVerences in their and our study were treatment duration (7 days vs. 4 days) and lens power (+10 D vs. +6.9 D) but these diVerences should not change the conclusion that the critical hole size must be 3 mm or less. 4.1. Comparison of the calculated angular extent of the open visual Weld sizes Smith et al. (2005a) used a diVerent calculation to estimate the angular extent of the unobstructed Weld size due to the holes in the eye covers. Their calculation took the eVect of pupil size into account, and was developed by Carkeet (1998). Applying their algorithm to our biometric parameters in the chickens, the calculated angular extent of the open visual Weld were much larger (99, 113, and 123°)-
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deWnitely also much larger than in the monkey experiments by Smith et al. (2005a; 24 and 36°). The reason was mainly that the vertex distances of the occluders were much larger (14 mm) than in the chick experiments (2–3 mm). In the experiments by Morgan and Ambadeniya (2006), the unobstructed visual Weld size would have between 70 and 90° with the 3 mm aperture, assuming the same vertex distances. We believe that the simple way of estimating the extent of the open part of the visual Weld using the nodal point may also have some merits: why should the experiment by Morgan and Ambadeniya (2006) have worked? We observed independent emmetropization already at 45° away from the center with the 4 mm holes—not expected if the unobstructed visual Weld size would be 99°. There are also diVerences between primates and chickens, both with respect to the ganglion cell density across the visual Weld and, accordingly, peripheral visual acuity. It may not make sense to present a chicken with a 4 mm hole at 14 mm vertex distance, as in the study by Smith et al. (2005a). Due to the lack of a fovea, there may be no clear Wxation pattern and the position of the open Weld area may move over the retina. Using a custom-made video gaze tracker, we tried to track eye movements in alert chickens. While the eye tracking was basically possible and conWrmed lateral eye movements of about 10–20°, a more detailed quantiWcation was not possible because the chickens often closed their eyes when their head was Wxated in a holder. Fixation of the head, on the other hand, was necessary because eye and head movements could not be separated when the camera of the video gaze tracker was at a stationary position at some distance. 4.2. Scleral growth pattern necessary to generate the observed patterns in refractions To generate a refraction gradient across the visual Weld that compensates for lenses with central holes is a most impressive accomplishment. One has to consider that the sclera can change its position relative to the principle plane only by growing in the tangential direction. It cannot move its position by growing straight towards the new focal plane. The required growth patterns are, therefore, quite sophisticated. In addition, the focus error signals that are generated in the retina when a lens is worn with a central hole, are complex. In the peripheral parts of the visual Weld, vision occurs primarily through the spectacle lenses. In the center, vision is largely unobstructed. In a ring-shaped region between these two areas, both focal planes are superimposed. The extension of this region is modulated by eye movements. The relative weighting of the contrast in the two focal planes is proportional to the cross sectional area of two circles, one the pupil and the other the hole in the lens. 4.3. Asymmetries in emmetropization across the visual Weld in the chicken As in previous studies (SchaeVel, Troilo, Wallman, & Howland, 1990), there was also an asymmetry in the
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responsiveness of emmetropization in the nasal and temporal visual Weld. The compensation of imposed refractive errors was more complete in the nasal visual Weld. This could be due to convergent eye movements during foraging which produce an asymmetry in the areas that are defocused. In this case, a larger proportion of the temporal retina would be defocused and this could cause better compensation. Previous experiments with full Weld lenses (SchaeVel et al., 1990), however, already showed a similar asymmetry, so that eye movements can be ruled out as an explanation. Apparently, in chicks, the mechanism for the compensation of imposed refractive errors is more responsive in the temporal than in the nasal retina. 4.4. Extrapolations to human refractive development The experiments performed by Smith et al. (2005a) suggest that peripheral image quality can modulate foveal refractive development in primates. In these experiments the peripheral retina was deprived of sharp vision by having the monkeys wear diVusers with central holes of 24 or 36° angular extension. Although the optical condition that was imposed in the study by Smith et al. (2005a) was “deprivation”, rather than optical defocus, it is likely that the results would have been similar with negative lenses. Similar experiments with positive lenses, which should make the fovea more hyperopic, need still to be done. There are some hints already that peripheral refractive errors could aVect refractive development also in humans: the pattern of peripheral refractions in myopes and hyperopes is what would be expected if peripheral refractive state aVected central refractive state: relatively more peripheral hyperopia in myopes and more myopia in hyperopes (Millodot, 1981; Mutti, Mitchell, Moeschberger, Jones, & Zadnik, 2002; Seidemann & SchaeVel, 2002). Whether the peripheral refractions are a consequence of or a reason for the foveal refractions, remains unresolved. Furthermore, there is anecdotal evidence that hard RGP contact lenses may reduce myopia development. It is clear that these temporarily reduce corneal refractive power mechanically but there is also some minor eVect on vitreous chamber depth. A possible mechanism is that contact lenses cause less hyperopic refractions in the periphery than spectacles (Seidemann, Guirao, Artal, & SchaeVel, 1999). It could equally well be that some of the positive eVect of hard contact lenses on myopia progression is visually mediated. Finally, two major recent studies, in which myopic children were treated with progressive addition lenses (PAL), showed some inhibition of myopia development (Gwiazda et al., 2004; Edwards, Li, Lam, Lew, & Yu, 2002). The underlying hypothesis was that the reading glasses would reduce the lag of accommodation (Seidemann & SchaeVel, 2003; Shapiro, Kelly, & Howland, 2005) which is assumed to promote myopia development (Gwiazda et al., 1993). However, it could equally well be that the inhibitory eVect on myopia was due to the continuous myopic defocus that these lenses impose in the
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lower visual Weld. As has been shown in animal experiments (review: Wallman & Winawer, 2004), such a condition inhibits eye growth in the respective retinal areas, including the fovea. The eVects of PAL reading glasses on myopia would then neither be related to reduced or reversed lags of accommodation, nor to near work. If this is true, spectacles lenses that would represent “reading glasses in all directions in the peripheral visual Weld” would be much more eVective than regular PALs—an important hypothesis that will probably be tested in the future. 5. Conclusion The afoveate chicken displays extensive local compensation of imposed refractive errors. Therefore, peripheral defocus aVects refractive development in the center of the visual Weld only if the unobstructed part in the central visual Weld remains very narrow. These results do not rule out that, in primates with foveal vision, imposition of myopic refractive errors in the periphery may be a useful way to modulate foveal myopia progression. Acknowledgments This study was supported by a grant from the German Research Council (Scha 518/11-1 to FS). We thank Dr. Marita Feldkaemper for reading and improving an earlier version of the manuscript, and Prof. Earl Smith for helpful comments and his Excel spreadsheet to apply his calculations on the angular extent of the open central Weld to our chicken data. References Atchison, D. A., Pritchard, N., & Schmid, K. L. (2006). Peripheral refraction along the horizontal and vertical visual Welds in myopia. Vision Research, 46, 1450–1458. Diether, S., & SchaeVel, F. (1997). Local changes in eye growth induced by imposed local refractive error despite active accommodation. Vision Research, 37, 659–668. Carkeet, A. (1998). Field restriction and vignetting in contact lenses with opaque peripheries. Clinical and Experimental Optometry, 81, 151–158. Edwards, M. H., Li, R. W., Lam, C. S., Lew, J. K., & Yu, B. S. (2002). The Hong Kong progressive lens myopia control study: study design and main Wndings. Investigative Ophthalmology and Visual Science, 43, 2852–2858. Ehrlich, D. (1981). Regional specialization of the chick retina as revealed by the size and density of neurons in the ganglion cell layer. Journal of Comparative Neurology, 195, 643–657. Gwiazda, J.E., Hyman, L., Norton, T.T., Hussein, M.E., Marsh-Tootle, W., Manny, R., Wang, Y., Everett, D.; COMET Group. (2004). Accommodation and related risk factors associated with myopia progression and their interaction with treatment in COMET children. Investigative Ophthalmology and Visual Science 45, 2143–2151. Gwiazda, J., Thorn, F., Bauer, J., & Held, R. (1993). Myopic children show insuYcient accommodative response to blur. Investigative Ophthalmology and Visual Science, 34, 690–694.
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Peripheral defocus does not necessarily aVect central refractive development Ruth Schippert, Frank SchaeVel ¤ Section of Neurobiology of the Eye, University Eye Hospital Tuebingen, Calwerstrasse 7/1, 72076 Tuebingen, Germany Received 24 March 2006; received in revised form 11 May 2006
Abstract Purpose. Recent experiments in monkeys suggest that deprivation, imposed only in the periphery of the visual Weld, can induce foveal myopia. This raises the hypothesis that peripheral refractive errors imposed by the spectacle lens correction could inXuence foveal refractive development also in humans. We have tested this hypothesis in chicks. Methods. Chicks wore either full Weld spectacle lenses (+6.9 D/¡7 D), or lenses with central holes of 4, 6, or 8 mm diameter, for 4 days (n D 6 for each group). Refractions were measured in the central visual Weld, and at ¡45° (temporal) and +45° (nasal), and axial lengths were measured by A-scan ultrasonography. Results. As previously described, full Weld lenses were largely compensated within 4 days (refraction changes with positive lenses: +4.69 § 1.73 D, negative lenses: ¡5.98 § 1.78 D, both p < 0.001, Dunnett’s test, to untreated controls). With holes in the center of the lenses, the central refraction remained emmetropic and there was not even a trend of a shift in refraction (all groups: p > 0.5, Dunnetts test). At §45°, the lenses were partially compensated despite the 4/6/8 mm central holes; positive lenses: +2.63 / +1.44 / +0.43 D, negative lenses: ¡2.57 / ¡1.06 / +0.06 D. Conclusions. There is extensive local compensation of imposed refractive errors in chickens. For the tested hole sizes, peripherally imposed defocus did not inXuence central refractive development. To alter central refractive development, the unobstructed part in the central visual Weld may have to be quite small (hole sizes smaller than 4 mm, with the lenses at a vertex distance of 2–3 mm). © 2006 Elsevier Ltd. All rights reserved. Keywords: Myopia; Peripheral emmetropization; Chicken; Spectacles
1. Introduction The developmental matching of focal length and axial length of the eye is called emmetropization. It normally takes place during the Wrst years of life in human infants, and moves the generally more hyperopic refractions toward emmetropia (e.g. Gwiazda, Thorn, Bauer, & Held, 1993). Experiments in animal models have shown that emmetropization is largely visually guided: imposing deWned amounts of defocus with positive or negative spectacle lenses induces hyperopic or myopic refractive errors in chicks (SchaeVel, Glasser, & Howland, 1988; Irving, Sivak, & Callender,
*
Corresponding author. Fax: +49 7071 5196. E-mail address: [email protected] (F. SchaeVel).
0042-6989/$ - see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.visres.2006.05.008
1992), guinea pigs (McFadden, Howlett, & Mertz, 2004), tree shrews (Shaikh, Siegwart, & Norton, 1999) and rhesus monkeys (Hung, Crawford, & Smith, 1995). Development of experimentally induced refractive errors is accompanied by changes in choroidal thickness, changes in vitreous chamber depth, and scleral remodeling which act together to move the photoreceptor layer in the direction of the focal plane (review: Wallman & Winawer, 2004). Detection of the sign of the imposed defocus occurs in the retina and, strikingly, it takes only a few minutes: “In a matter of minutes the eye knows which way to grow” (Zhu, Park, Winawer, & Wallman, 2005). However, the underlying retinal image processing is not yet understood. The signaling cascade that translates the output of the retinal image processing into biochemical signals to control changes in choroidal thickness and growth of the sclera is
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currently extensively studied. There is hope that the biochemical components of emmetropization can be modulated by drugs and that, one day, myopia development can be controlled by eye drops. However, no optimal candidate drug has yet been identiWed (review Wallman & Winawer, 2004). An alternative approach to interfere with myopia development is to use the natural feedback loops of emmetropization but trigger them with controlled patterns of defocus. It was recognized already long ago that refractive errors can be induced in chickens in local retinal areas if the retinal images were locally degraded (Wallman, Gottlieb, Rajaram, & Fugate-Wentzek, 1987). Later, it was found that refractive errors imposed by hemi-Weld spectacle lenses were compensated by local changes in the posterior part of the eye ball: only the defocused half of the globe adapted its growth whereas the other half remained normal (Diether & SchaeVel, 1997). Chickens have no fovea but rather an “area centralis”, a central part of the visual Weld with moderately enhanced visual acuity (Morris, 1982). Visual acuity, as judged by ganglion cell density, varies only by a factor of about two, if the center and the periphery are compared (Ehrlich, 1981). Accordingly, for a chicken eye, it pays oV to also emmetropize the periphery to ensure optimal visual acuity in all parts of the visual Weld. The situation is diVerent in foveate animals like primates. Due to the rapid decline in acuity toward the periphery (Osterberg, 1935), an optimized peripheral refractive state appears less important. In fact, it is well documented that the optical quality declines in the human eye towards the periphery, with large amount of astigmatismus (e.g. Atchison, Pritchard, & Schmid, 2006). On the other hand, the foveal position along the visual axis must be determined by scleral growth in the periphery, and not only by the growth of the sclera underlying the fovea itself (Seidemann, SchaeVel, Guirao, LopezGil, & Artal, 2002). Therefore, peripheral refractive errors, driving emmetropization in the periphery, may not be independent from foveal refractive errors. In fact, a recent study has shown that depriving monkey eyes of sharp vision only in the periphery while leaving foveal vision unobstructed causes development of foveal myopia (Smith, Kee, Ramamirtham, Qiao-Grider, & Hung, 2005a). This result may have important implications. Spectacle lenses could be redesigned to impose peripheral myopia to slow down the foveal myopia development (Smith et al., 2005b). Following a similar study in chickens, in which visual deprivation was conWned to the periphery of the visual Weld and complex patterns of refractions were obtained (Stone et al., 2006), we have applied spectacle lenses (powers either +6.9 D or ¡7 D) with central holes of variable diameters (4, 6, or 8 mm) to impose refractive errors only in the periphery of the visual Weld. Refractive development was studied onaxis and in the nasal and temporal visual Weld, and axial lengths were measured. Strikingly, in chickens, peripheral refractive errors did NOT aVect foveal refractive development for the hole sizes used in our study (4/6/8 mm), and vertex distances of 2–3 mm.
2. Methods All experiments were conducted in accordance with the ARVO statement for the use of Animals in Ophthalmic and Vision Research and approved by the University Commission for Animal Welfare. Male white leghorn chicks were obtained by a local hatchery and raised in groups under a 12-h light/12-h dark cycle in the animal facilities of the institute. Water and food were freely available. Chicks were unilaterally treated with plus or minus lenses (powers +6.9 D or ¡7 D) with central holes (4, 6 and 8 mm in diameter), or without holes for four days, starting at day 7 posthatching. The distances of the lenses from the corneal apex (referred to as vertex distances) ranged between 2 and 3 mm. Each group consisted of six animals. An untreated group served as control (n D 12, because both the left and the right eye were refracted over the horizontal visual Weld). In total, 54 chickens were used for this study. The holes left a part of the central visual Weld unobstructed. Projecting the lens hole apertures through the nodal point, visual angles of 38, 49, or 57° were obtained for a vertex distance of 2 mm, and 32, 44, or 52°, for a vertex distance of 3 mm (using the schematic eye for a 7 day old chicken; SchaeVel & Howland, 1991; Fig. 1). Refractive state was measured every other day in the central visual Weld (0°) and at ¡45° (nasal retina) and +45° (temporal retina) using automated infrared photoretinoscopy (calibrated for chickens of the same age; Seidemann & SchaeVel, 2002). To control the angular positions in the peripheral visual Welds, the Wrst Purkinje image of the photoretinoscope was placed at the margin of the entrance pupil, as previously described (Diether & SchaeVel, 1997). In this case, the refractor was located about 45° away from the pupillary axis of the chicken. Negative angular values refer to the nasal visual Weld and positive values to the temporal visual Weld (see also Table 1). Averages of Wve repeated measurements were taken. Axial length was determined by A-scan ultrasound as described earlier (SchaeVel & Howland, 1991) at the beginning and at the end of the lens treatment period. Axial length is referred to as the distance from corneal apex to the vitreoretinal interface. Averages of three repeated measurements were used for statistical analyses. To focus the analysis on refraction changes that were induced by the lens treatment, the following diVerences were computed. First, the diVerences in refraction and in axial length between the treated and the fellow control eye were calculated. Second, the changes in interocular diVerences over the four days treatment period were computed. The mean changes in interocular diVerences over the four days treatment period were statistically analyzed and are presented in Fig. 2a (positive lenses) and 2b (negative lenses). Statistical analysis (one-way ANOVA, Dunnett’s test, to untreated controls) was performed with the software package jmp (SAS Institute, Cary, USA). Asterisks denote signiWcance levels (¤p < 0.05, ¤¤ p < 0.01,¤¤¤p < 0.001).
3. Results 3.1. Refractive states No changes in refraction were observed over the lens treatment period in any of the untreated fellow eyes (data not shown). Average refractions (means § SD) of all groups at the beginning and at the end of the experiments are presented in Table 1. Full Weld lenses were largely compensated after four days, in all parts of the visual Weld (mean changes in interocular diVerences over the four days treatment period § standard deviations, with positive lenses: +4.61 § 1.40, with negative lenses: ¡5.96 § 1.45 D, all p < 0.001, Dunnett’s test, to untreated controls, Fig. 2a and b). No signiWcant diVerences were observed between the three angular
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Fig. 1. Estimation of the visual angle of the part of the visual Weld that remained unobstructed by the spectacle lenses, due to the central holes. PND posterior nodal distance, PNP posterior nodal point. Calculations are performed for a 2 mm vertex distance.
positions in the visual Weld, neither with the full Weld lenses, nor in the untreated eyes. With the holes drilled in the center of the spectacle lenses (4, 6 or 8 mm diameters), the refractions in the center of the visual Weld developed as in untreated chicks (Dunnett’s test: p > 0.05 in all groups). At the 45° positions, the lenses were partially compensated despite the 4, 6, or 8 mm central holes in the spectacle lenses. Refractions changed with positive lenses at +45° by +1.89, +1.01, and ¡0.26 D, and at ¡45° by 2.98¤¤, 2.30 and 0.51 D (Fig. 2a). With negative lenses, at +45°, the changes were: ¡2.93¤¤, ¡0.98, and ¡0.43 D, and at ¡45°: ¡2.56¤¤, ¡1.63¤, and 0.22 D (Fig. 2b).
3.2. Axial lengths Analysis of the biometric data occurred in the same fashion as the refraction data. Results are shown in Fig. 3. Eyes treated with full Weld positive lenses were signiWcantly shorter (¡0.30 mm¤¤) and eyes treated with full Weld negative lenses were signiWcantly longer (+0.57 mm¤¤¤) than their fellow eyes (Dunnett’s test to untreated control group). The central holes reduced the eVects of the lenses. In the other groups, treated with lenses with 4, 6, or 8 mm central holes, a signiWcant change in axial lengths was observed only in the case of a 4 mm hole in the negative lenses (positive lenses: 0.02,
Table 1 Refractions [diopters] of all groups at the beginning (day 0) and at the end (day 4) of the experiment at the three visual angles that were studied (¡45, 0 and +45°) Treatment
+6.9 D/0 mm +6.9 D/4 mm +6.9 D/6 mm +6.9 D/8 mm ¡7 D/0 mm ¡7 D/4 mm ¡7 D/6 mm ¡7 D/8 mm No lens
Day 0
Day 4
Nasal refraction (¡45°)
Central refraction (0 °)
Temporal refraction (+45°)
Nasal refraction (¡45 °)
Central refraction (0°)
Temporal refraction (+45°)
2.49 § 0.38 2.36 § 0.34 2.59 § 0.61 2.43 § 0.18 2.50 § 0.52 2.21 § 0.29 2.28 § 0.29 2.41 § 0.62 2.51 § 0.29
2.69 § 0.26 2.41 § 0.30 2.51 § 0.53 2.61 § 0.35 2.32 § 0.37 2.24 § 0.38 2.32 § 0.39 2.60 § 0.57 2.56 § 0.26
2.90 § 0.30 2.50 § 0.26 2.88 § 0.36 2.68 § 0.38 2.46 § 0.79 2.54 § 0.31 2.70 § 0.27 2.84 § 0.72 3.02 § 0.36
7.26 § 1.73 5.51 § 1.78 4.38 § 1.32 3.24 § 0.73 ¡3.73 § 1.68 ¡0.25 §1.01 0.93 § 1.21 2.67 § 0.86 2.74 § 0.41
7.38 § 1.84 2.73 § 0.34 2.86 § 0.97 2.91 § 0.27 ¡3.66 § 1.51 2.78 § 0.22 3.23 § 0.33 3.28 § 0.41 2.92 § 0.45
7.37 § 1.80 4.62 § 1.81 4.02 § 0.84 2.73 § 0.74 ¡2.78 § 1.02 ¡0.14 § 0.99 1.92 § 1.28 2.71 § 1.11 2.84 § 0.44
Data are presented as the means § SD. The untreated group consisted of 12 chicks (“no lens”).
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Fig. 2. (a) The mean changes of refractive state in interocular diVerences over the four days treatment period that developed after wearing positive spectacle lenses with central holes of 0 (no hole), 4, 6, and 8 mm diameter, relative to the initial value in all treatment groups. Error bars denote standard errors of the means (SEM), from n D 6 animals in each group. Refractions are plotted against the visual Weld angles. Asterisks denote signiWcance levels (*p < 0.05; **p < 0.01; ***p < 0.001). Note that the refraction in the central visual Weld was not aVected by the peripheral defocus, but that the defocus imposed by the lenses in the periphery was partially compensated. As expected, the smaller the central hole, the more extensive was the compensation of the peripherally imposed refractive errors. (b) The mean changes of refractive state in interocular diVerences over the four days treatment period that developed after wearing positive spectacle lenses with central holes of 0 (no hole), 4, 6, and 8 mm diameter, relative to the initial value in all treatment groups. Error bars denote standard errors of the means (SEM), from n D 6 animals in each group. Refractions are plotted against the visual Weld angles. Asterisks denote signiWcance levels as in Fig. 2a.
Fig. 3. The mean changes of axial length in interocular diVerences, after four days of treatment with positive and negative spectacle lenses (means § SEM, n D 6 in each group), and for diVerent diameters of the central holes in the lenses. SigniWcance levels are denoted by asterisks, as in Fig. 2a and b. ¤
¡0.03 and 0.10 mm, negative lenses: 0.18 , ¡0.06 and 0.01 mm, Fig. 3). Unfortunately, A-scan ultrasonography did not permit to detect changes in eye dimensions in the periphery. 4. Discussion DiVerent from recent experiments in rhesus monkeys (Smith et al., 2005a), the most striking result of this study was that chickens can emmetropize in the periphery without
changing their central refraction. This would imply that the strategy to interfere with foveal refractive development, as proposed by Smith et al. (2005b), may not be as eVective in chickens. On the other hand, it is clear that the diVerences in eVects of full Weld lenses and lenses with a central hole must disappear if the hole sizes are made smaller and smaller. In fact, Morgan and Ambadeniya (2006), have recently reported that +10D lenses with a plano zone in their center of only 3 mm diameter induced general hyperopia, similar to full Weld +10 D lenses. In their study, and similar to the observations in the present study, the lenses had no eVect when the central plano zone was 5 mm in diameter. Apparently, the critical size of the plano or hole zone is between 3 and 4 mm in diameter. Further diVerences in their and our study were treatment duration (7 days vs. 4 days) and lens power (+10 D vs. +6.9 D) but these diVerences should not change the conclusion that the critical hole size must be 3 mm or less. 4.1. Comparison of the calculated angular extent of the open visual Weld sizes Smith et al. (2005a) used a diVerent calculation to estimate the angular extent of the unobstructed Weld size due to the holes in the eye covers. Their calculation took the eVect of pupil size into account, and was developed by Carkeet (1998). Applying their algorithm to our biometric parameters in the chickens, the calculated angular extent of the open visual Weld were much larger (99, 113, and 123°)-
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deWnitely also much larger than in the monkey experiments by Smith et al. (2005a; 24 and 36°). The reason was mainly that the vertex distances of the occluders were much larger (14 mm) than in the chick experiments (2–3 mm). In the experiments by Morgan and Ambadeniya (2006), the unobstructed visual Weld size would have between 70 and 90° with the 3 mm aperture, assuming the same vertex distances. We believe that the simple way of estimating the extent of the open part of the visual Weld using the nodal point may also have some merits: why should the experiment by Morgan and Ambadeniya (2006) have worked? We observed independent emmetropization already at 45° away from the center with the 4 mm holes—not expected if the unobstructed visual Weld size would be 99°. There are also diVerences between primates and chickens, both with respect to the ganglion cell density across the visual Weld and, accordingly, peripheral visual acuity. It may not make sense to present a chicken with a 4 mm hole at 14 mm vertex distance, as in the study by Smith et al. (2005a). Due to the lack of a fovea, there may be no clear Wxation pattern and the position of the open Weld area may move over the retina. Using a custom-made video gaze tracker, we tried to track eye movements in alert chickens. While the eye tracking was basically possible and conWrmed lateral eye movements of about 10–20°, a more detailed quantiWcation was not possible because the chickens often closed their eyes when their head was Wxated in a holder. Fixation of the head, on the other hand, was necessary because eye and head movements could not be separated when the camera of the video gaze tracker was at a stationary position at some distance. 4.2. Scleral growth pattern necessary to generate the observed patterns in refractions To generate a refraction gradient across the visual Weld that compensates for lenses with central holes is a most impressive accomplishment. One has to consider that the sclera can change its position relative to the principle plane only by growing in the tangential direction. It cannot move its position by growing straight towards the new focal plane. The required growth patterns are, therefore, quite sophisticated. In addition, the focus error signals that are generated in the retina when a lens is worn with a central hole, are complex. In the peripheral parts of the visual Weld, vision occurs primarily through the spectacle lenses. In the center, vision is largely unobstructed. In a ring-shaped region between these two areas, both focal planes are superimposed. The extension of this region is modulated by eye movements. The relative weighting of the contrast in the two focal planes is proportional to the cross sectional area of two circles, one the pupil and the other the hole in the lens. 4.3. Asymmetries in emmetropization across the visual Weld in the chicken As in previous studies (SchaeVel, Troilo, Wallman, & Howland, 1990), there was also an asymmetry in the
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responsiveness of emmetropization in the nasal and temporal visual Weld. The compensation of imposed refractive errors was more complete in the nasal visual Weld. This could be due to convergent eye movements during foraging which produce an asymmetry in the areas that are defocused. In this case, a larger proportion of the temporal retina would be defocused and this could cause better compensation. Previous experiments with full Weld lenses (SchaeVel et al., 1990), however, already showed a similar asymmetry, so that eye movements can be ruled out as an explanation. Apparently, in chicks, the mechanism for the compensation of imposed refractive errors is more responsive in the temporal than in the nasal retina. 4.4. Extrapolations to human refractive development The experiments performed by Smith et al. (2005a) suggest that peripheral image quality can modulate foveal refractive development in primates. In these experiments the peripheral retina was deprived of sharp vision by having the monkeys wear diVusers with central holes of 24 or 36° angular extension. Although the optical condition that was imposed in the study by Smith et al. (2005a) was “deprivation”, rather than optical defocus, it is likely that the results would have been similar with negative lenses. Similar experiments with positive lenses, which should make the fovea more hyperopic, need still to be done. There are some hints already that peripheral refractive errors could aVect refractive development also in humans: the pattern of peripheral refractions in myopes and hyperopes is what would be expected if peripheral refractive state aVected central refractive state: relatively more peripheral hyperopia in myopes and more myopia in hyperopes (Millodot, 1981; Mutti, Mitchell, Moeschberger, Jones, & Zadnik, 2002; Seidemann & SchaeVel, 2002). Whether the peripheral refractions are a consequence of or a reason for the foveal refractions, remains unresolved. Furthermore, there is anecdotal evidence that hard RGP contact lenses may reduce myopia development. It is clear that these temporarily reduce corneal refractive power mechanically but there is also some minor eVect on vitreous chamber depth. A possible mechanism is that contact lenses cause less hyperopic refractions in the periphery than spectacles (Seidemann, Guirao, Artal, & SchaeVel, 1999). It could equally well be that some of the positive eVect of hard contact lenses on myopia progression is visually mediated. Finally, two major recent studies, in which myopic children were treated with progressive addition lenses (PAL), showed some inhibition of myopia development (Gwiazda et al., 2004; Edwards, Li, Lam, Lew, & Yu, 2002). The underlying hypothesis was that the reading glasses would reduce the lag of accommodation (Seidemann & SchaeVel, 2003; Shapiro, Kelly, & Howland, 2005) which is assumed to promote myopia development (Gwiazda et al., 1993). However, it could equally well be that the inhibitory eVect on myopia was due to the continuous myopic defocus that these lenses impose in the
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lower visual Weld. As has been shown in animal experiments (review: Wallman & Winawer, 2004), such a condition inhibits eye growth in the respective retinal areas, including the fovea. The eVects of PAL reading glasses on myopia would then neither be related to reduced or reversed lags of accommodation, nor to near work. If this is true, spectacles lenses that would represent “reading glasses in all directions in the peripheral visual Weld” would be much more eVective than regular PALs—an important hypothesis that will probably be tested in the future. 5. Conclusion The afoveate chicken displays extensive local compensation of imposed refractive errors. Therefore, peripheral defocus aVects refractive development in the center of the visual Weld only if the unobstructed part in the central visual Weld remains very narrow. These results do not rule out that, in primates with foveal vision, imposition of myopic refractive errors in the periphery may be a useful way to modulate foveal myopia progression. Acknowledgments This study was supported by a grant from the German Research Council (Scha 518/11-1 to FS). We thank Dr. Marita Feldkaemper for reading and improving an earlier version of the manuscript, and Prof. Earl Smith for helpful comments and his Excel spreadsheet to apply his calculations on the angular extent of the open central Weld to our chicken data. References Atchison, D. A., Pritchard, N., & Schmid, K. L. (2006). Peripheral refraction along the horizontal and vertical visual Welds in myopia. Vision Research, 46, 1450–1458. Diether, S., & SchaeVel, F. (1997). Local changes in eye growth induced by imposed local refractive error despite active accommodation. Vision Research, 37, 659–668. Carkeet, A. (1998). Field restriction and vignetting in contact lenses with opaque peripheries. Clinical and Experimental Optometry, 81, 151–158. Edwards, M. H., Li, R. W., Lam, C. S., Lew, J. K., & Yu, B. S. (2002). The Hong Kong progressive lens myopia control study: study design and main Wndings. Investigative Ophthalmology and Visual Science, 43, 2852–2858. Ehrlich, D. (1981). Regional specialization of the chick retina as revealed by the size and density of neurons in the ganglion cell layer. Journal of Comparative Neurology, 195, 643–657. Gwiazda, J.E., Hyman, L., Norton, T.T., Hussein, M.E., Marsh-Tootle, W., Manny, R., Wang, Y., Everett, D.; COMET Group. (2004). Accommodation and related risk factors associated with myopia progression and their interaction with treatment in COMET children. Investigative Ophthalmology and Visual Science 45, 2143–2151. Gwiazda, J., Thorn, F., Bauer, J., & Held, R. (1993). Myopic children show insuYcient accommodative response to blur. Investigative Ophthalmology and Visual Science, 34, 690–694.
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