Clinical observations provide support for the idea that visual signals from the peripheral retina can have a significant impact on emmetropization at the fovea and possibly the genesis of common refractive errors. For example, patients who have natural or treatment-induced peripheral retinal abnormalities frequently exhibit larger than normal ranges of central refractive errors and, on average, larger central refractive errors (Connolly, Ng, McNamara, Regillo, Vander & Tasman, 2002; Knight-Nanan & O’Keefe, 1996; Nathan, Kiely, Crewther & Crewther, 1985; Nissenkorn, Yassur, Mashkowski, Sherf & Ben-Sira, 1983; Sieving & Fishman, 1978). It is possible that these central refractive errors come about because the treatment and/or disease processes interfere with the mechanisms responsible for emmetropization. In this respect, children who have conditions or diseases that primarily affect the peripheral retina usually exhibit larger central refractive errors than children with eye diseases that primarily affect central vision (Nathan et al., 1985).

The most direct evidence that peripheral vision can influence central refractive development come from animal experiments in which the visual signals from the fovea were eliminated or from experiments in which peripheral vision was selectively manipulated. For example, laser photoablation of the fovea in infant monkeys does not 1) interfere with emmetropization in animals reared with unrestricted vision, 2) prevent form-deprivation from producing central axial myopia, or 3) alter the recovery from experimentally induced refractive errors (Smith III, Kee, Ramamirtham, Qiao-Grider & Hung, 2005; Smith III, Ramamirtham, Qiao-Grider, Hung, Huang, Kee, Coats & Paysee, 2007). These results demonstrate that visual signals from the fovea are not essential for many vision-dependent changes in refractive development and that visual signals from the periphery, in isolation, can be used to determine the direction of axial growth required to eliminate central refractive errors and to determine when ocular growth has eliminated that refractive error, i.e., when emmetropia has been established. Moreover, when experimental manipulations impose conflicting visual signals between the central and peripheral retina, peripheral vision can dominate overall ocular growth. For example, chicks and monkeys that were reared with diffuser lenses that selectively deprived the peripheral retina of form vision, but allowed unrestricted central vision, typically developed central axial myopia (Smith III et al., 2005; Stone, Pendrak, Sugimoto, Lin, Gill, Capehart & Liu, 2006). Overall, these results indicate that peripheral vision can have a substantial influence on foveal refractive development in macaques.

However, Schippert and Schaeffel (Schippert & Schaeffel, 2006) recently reported that optically imposed peripheral hyperopic defocus does not affect central refractive development in chicks. They found that although lenses that defocused the entire retina consistently produced central myopic compensation in chicks, lenses with central apertures that allowed unrestricted central vision did not. This apparent discrepancy between the effects of peripheral form deprivation and peripheral defocus could reflect differences in the mechanisms that mediate the effects of defocus and form deprivation. In this respect, several observations suggest that the effects of defocus and form deprivation are mediated by different, but overlapping, vision-dependent processes (Bartmann, Schaeffel, Hagel & Zrenner, 1994; Kee, Marzani & Wallman, 2001; Schaeffel, Hagel, Bartmann, Kohler & Zrenner, 1994).

The treatment lenses produced obvious alterations in the course of emmetropization in many of the animals in the -3D-aperture group. Figure 2A shows the spherical-equivalent refractive corrections plotted as a function of age for the right eyes of the control (thin lines) and the -3D-aperture animals (filled symbols). Four of the monkeys in the -3D-aperture group developed myopic refractive errors that were outside the control range throughout most of the lens-rearing period and, by the end of the treatment period, 2 other experimental monkeys showed refractive errors that were less hyperopic/more myopic than 94% of the age-matched control animals.

The refractive corrections obtained at ages corresponding to the end of the lens-rearing period are shown for the right eyes of individual control (open diamonds) and treated monkeys (filled diamonds) in Figure 2B. For comparison purposes, the refractive errors obtained at the end of the lens-rearing period for monkeys that wore binocular, full-field, −3.0 D treatment lenses are also shown (half-filled diamonds). At the end of the treatment period, there were no systematic interocular differences in the refractive errors (paired t-test, P = 0.32) or vitreous chamber depths (paired t-test, P = 0.12) for the monkeys in the -3D-aperture group. However, the median refractive errors for the right and left eyes of the monkeys in the -3D-aperture group were significantly more myopic than those for the control animals (Mann-Whitney test; right eyes, +0.38 D vs +2.50 D, P = 0.01; left eyes, +1.28 D vs +2.56 D, P = 0.008). The range of refractive errors exhibited by the monkeys in the -3D-aperture group compared favorable to the range of end-of-treatment refractive errors found in monkeys reared with full-field -3D lenses (−2.69 to +5.63 D vs −2.61 to +3.93 D). Although the average (+0.36 ± 2.69 D vs +0.46 ± 2.49 D; two-sample t-test, P = 0.94) and median refractive errors (−0.25 D vs +0.38 D; Mann-Whitney test, P = 0.87) for the monkeys in the -3D-aperture group were slightly less myopic/more hyperopic than those for the monkeys reared with full-field, -3D lenses, these differences were not statistically significant.

Laser photoablation of the fovea did not prevent the monkeys in the -3D-laser group from becoming myopic. As illustrated in Figure 3A, which shows the spherical-equivalent refractive corrections plotted as a function of age for the right eyes of the control animals and the laser-treated eyes of the monkeys in the -3D-laser group, 5 of the 6 experimental monkeys developed myopic errors that were outside the control range. The relative myopic changes were apparent in all five of these animals by about 100 days of age.

Figure 3B shows the refractive errors obtained at ages corresponding to the end of the lens-rearing period for the laser-treated eyes of the animals in the -3D-laser group (filled diamonds) and the right eyes of the control monkeys (open diamonds). For reference, the open circles show the refractive corrections obtained at equivalent ages for the laser-treated eyes of monkeys that were reared with unrestricted vision; the top-filled diamonds show the refractive corrections obtained at the end of the lens-rearing period for the right eyes of monkeys reared with full-field -3 D lenses. At the end of the lens-rearing period, there was a tendency for the laser-treated eyes of the monkeys in the -3D-laser group to be more myopic than their fellow intact eyes that were also treated with -3D lenses (bottom-filled diamonds), however, these differences were not statistically significant (paired t-test, P = 0.09). The median refractive errors for the fellow and laser-treated eyes of the monkeys in the -3D-laser group were also comparable to those for the left and right eyes, respectively, of the monkeys with intact retinas and reared with full-field -3 D lenses (Mann-Whitney test, P = 0.85 and 1.00). On the other hand, the median refractive errors for the laser-treated eyes of the monkeys in the -3D-laser group were significantly more myopic than the right eyes of the control animals (+0.13 D vs +2.50 D, Mann-Whitney test, P = 0.001) and the laser-treated eyes of the laser-control monkeys that were reared with unrestricted vision (+0.13 D vs +2.50 D, Mann-Whitney Test, P = 0.02).

The range of refractive errors exhibited by the laser-treated eyes of the monkeys in the -3D-laser group was larger than that for the monkeys reared with full-field, -3D lenses primarily because one of the monkeys in the -3D-laser group developed relatively high levels of myopia in its treated (−8.87 D) and fellow eyes (−4.06 D).

Selective peripheral form deprivation has been shown to cause central axial myopia in infant monkeys (Smith III et al., 2005) and chickens (Stone et al., 2006). Although several observations suggest that the mechanisms that mediate the effects of form deprivation and optical defocus are not identical (Wallman & Winawer, 2004), the results from our monkeys in the -3D-aperture group appear to be qualitatively similar to those produced by peripheral form deprivation. This similarity indicates that the spatial distribution across the retina and relative effectiveness of the mechanisms that mediate the effects of form deprivation and defocus are also similar.

In contrast to the results from our monkeys in the -3D-aperture group and the effects of peripheral form deprivation in chicks, Schippert and Schaeffel (2006) have reported that peripheral defocus does not necessarily affect central refractive development in chicks. Although it is possible that the effects of peripheral vision are more localized in chicks, and that any changes are restricted to the periphery of the chick eye, it is also likely that this apparent discrepancy reflects methodological differences in rearing strategies rather than an interspecies difference in sensitivity to peripheral defocus or a difference between the effects of defocus and form deprivation in chicks. In this study, as in our previous study of peripheral form deprivation (Smith III et al., 2005), our helmet system held the treatment lenses at a vertex distance of 14 mm. In contrast, the treatment lenses employed by Schippert and Schaeffel (2006) were held at a vertex distance of only 2 mm. Even though the nominal aperture sizes (4, 6, and 8 mm diameter apertures) used by Schippert and Schaeffel (2006) were similar to those that we have employed in monkeys, the greater vertex distance of our lenses would reduce the amount of retina viewing through the aperture, as Schippert and Schaeffel note. The effect of an aperture in a diffuser or a lens can be expressed either as a field stop, which limits the part of the visual field visible to the animal, or as the fraction of the retina illuminated, ascertained by calculating the effect of the eye’s peripheral optics on light rays entering the eye at the edge of the aperture. We used the former method because it is not affected significantly by eye growth and does not require modeling the peripheral optics, which would require estimating the peripheral corneal and lens curvatures and the refractive index distribution of the lens, parameters that are changing in growing eyes. Using this method, we estimate that in our monkeys all objects outside the central 31 deg were defocused relative to the central retina, whereas in Schippert and Schaeffel’s chicks wearing lenses with 4 mm apertures, a central field of about 95 deg included at least some rays that passed through the aperture, i.e., more than 3 times larger than with the aperture that we employed. It is likely that Schippert and Schaeffel (2006) failed to observe any effects of peripheral defocus on central refractive development because only the extreme retinal periphery was consistently defocused. In agreement with this argument, Stone et al. (2006) were able to produce central axial myopia by rearing chicks with diffuser lenses that had 5 mm diameter apertures that were held a vertex distance of about 8.5 mm. With this greater vertex distance, all images outside about the central 43 deg were consistently degraded by their diffusers. Thus, it appears that when comparable eccentricities are manipulated, peripheral optical effects have similar effects on central refraction in chicks and monkeys.

The results from the monkeys in our -3D-laser group provide additional insights into the contribution of foveal signals to vision-dependent eye growth. Four basic observations have provided the foundation for the idea that refractive development is regulated by visual feedback associated with the eye’s refractive status. Specifically, the observations that emmetropization requires vision, that chronic image degradation interferes with emmetropization typically resulting in axial myopia (i.e., form deprivation myopia), that the eyes of young animals can recover from experimentally induced refractive errors, and that optically imposed defocus can predictably alter the course of emmetropization (i.e., “lens compensation phenomenon) provide strong evidence for the vision-dependent nature of refractive development (Smith III, 1998; Wallman & Winawer, 2004). We have previously shown that laser ablation of the fovea in infant monkeys does not interfere with emmetropization in animals reared in unrestricted vision, does not prevent central axial myopia in response to form deprivation, and does not alter the recovery from experimentally induced refractive errors (Smith III et al., 2005; Smith III et al., 2007). The findings from the monkeys in the -3D-laser group demonstrate that visual signals from the fovea are also not required to produce compensating axial myopia in response to optically imposed hyperopia. Thus, visual signals from the fovea are not essential for any of the basic phenomena that support the idea that refractive development is a vision-dependent process. On the other hand, the results from all of these studies indicate that visual signals from the periphery are sufficient to mediate these basic phenomena. Given the dominance of the fovea in primate vision, these results may seem counterintuitive. However, it is important to keep in mind that the mechanisms that regulate eye growth appear to have evolved from fish, to have been largely conserved across species, and to operate very effectively in species without foveas. So it is unlikely that signals from the fovea contribute to vision-dependent refractive development in a qualitatively unique manner. It is very likely that visual signals from the fovea do contribute to the overall growth process and to refractive development. It is reasonable to suppose that the contribution of the fovea reflects its absolute area and/or the absolute number of neurons in the fovea (exactly which neurons are critical is not known) (Wallman & Winawer, 2004). Regardless, in both respects the fovea represents a relatively small portion of the retina. The periphery dominates primarily as a consequence of its relative size and issues related to spatial summation. However, because accommodation is controlled mostly by visual signals from the central retina, the fovea plays a key role in determining the overall quality of the retinal image.

The findings from both of our experimental animal groups support the idea that peripheral refractive errors, in particular relative peripheral hyperopia, can influence central refractive development. Several observations in humans suggest that relative peripheral hyperopia is a risk factor for myopia. Specifically, adults and children who exhibit relative peripheral hyperopia are more likely to develop central myopia than individuals who exhibit relative peripheral myopia (Hoogerheide et al., 1971; Mutti et al., 2007). However, from the available human data, it is not possible to determine whether the relationship between peripheral hyperopia and central myopia is causal in nature. Observations in form-deprived infant monkeys suggest that in some cases peripheral hyperopia may reflect changes in eye shape that are associated with the process of axial elongation (Huang, Hung, Ramamirtham, Blasdel, Humbird, Bockhorst & Smith III, 2009). However, regardless of whether peripheral hyperopia is a concomitant change that occurs during axial elongation or if peripheral hyperopia develops independently, because selective peripheral hyperopic defocus can produce axial myopia in infant monkeys, it is reasonable to hypothesize that the presence of peripheral hyperopia in children will promote myopic progression and increase the severity of myopia.