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concentration,14 but the assumption that atropine acts via paralysis of accommodation is too simplistic.
Atropine is a non-specific muscarinic antagonist that has many functions within the eye. There are muscarinic receptors of various types in many ocular tissues, including the retina15 and the sclera,16 in addition to their presence in mammalian ciliary muscle. Atropine has been shown to have an inhibitory effect on scleral fibroblasts,17 preventing their proliferation and reducing their production of collagen, and this may explain the effect of atropine on reducing progressive scleral elongation associated with myopia.
Although atropine eye drops can prevent the development of experimental myopia in chicks,18 in this species atropine has no effect on accommodation for the ciliary muscle in chicks is striated muscle, and does not contain the M1 muscarinic receptor19,20 i.e. the receptor most closely related to myopia.21 In mammalian species, the ciliary muscle is non-striated and the ciliary body in mammals, e.g. the tree shrew, demonstrates the presence of all five types of muscarinic receptor, including the M1 receptor.22
Close work
Studies investigating the effect of close work in relation to the risk of childhood myopia have produced conflicting results. In some studies, there is a clear correlation between the amount of close work and the risk and severity of myopia development,23,24 while in other studies, the association is absent.25,26 Recently, it has been shown that rather than close work being an etiological factor for myopia, lack of outdoor activity may be the key, for outdoor activity is protective.27–29 Outdoor activity appears to be protective against myopia in its own right and not just as a reciprocal of indoor activity.30
Physical characteristics of the retinal image
Visual deprivation
As is well known, visual deprivation in early life leads to the development of myopia in many species including humans. Although the elongation of the eye leading to axial myopia appears to be driven by a retinal response to the physical characteristics of a blurred retinal image, the specific physical characteristics of a blurred image causing myopia remain to be identified.
365 Physical Factors in Myopia and Potential Therapies
Compensatory changes in refraction
In relation to experimental myopia it has been shown that young animals wearing negative lenses become myopic while those wearing positive lenses become hyperopic9,31 and this includes primates.32 It appears that the retina is able to differentiate between hyperopic blur and myopic blur even when the optic nerve has been sectioned.33 The ability of the retina to detect the sign of a defocused image allows a compensatory change in refraction to occur as a result of an alteration of eye growth in the appropriate direction but at present there is no satisfactory explanation for this.
The differing vergences of light in conditions of hyperopic or myopic defocus have been suggested as providing cues for the identification of the sign of defocus in these two conditions.34
Longitudinal chromatic aberration has also been suggested as allowing the eye to differentiate between hyperopic and myopic defocus.35–38 The characteristics of the retinal blur circle induced by defocus has also been advanced as an explanation for the ability of the retina to determine the sign of defocus39 but this has been disputed.40
Intensity and periodicity of light exposure
Light intensity and photoperiod are physical factors that appear to affect ocular and refractive development in a very complex fashion. As regards photoperiod, rearing chicks in continuous illumination leads to severe hyperopia, raised intraocular pressure, reduction of corneal curvature and of anterior chamber depth with an increase in axial and vitreous chamber lengths.41,42 The hyperopia that develops results from flattening of the cornea that overcomes the effect of increased length of the eye that would otherwise cause myopia. Continuous illumination also prevents visual deprivation myopia in the chick but not the compensatory myopia induced by negative lenses.43
In experimental animals it has been shown that the intensity of light in which animals are reared can have a significant effect upon ocular and refractive development. The effect of continuous illumination on the chick eye appears to be intensity dependent.44 Chicks exposed to higher intensities of light have longer vitreous chamber lengths but flatter corneas and are hyperopic. Chicks raised in low light conditions are less hyperopic than those raised in bright light.45 This situation of continuous illumination, however, is so abnormal that it has no obvious corollary with human refractive development.
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Spatial frequency
One possible feature of a blurred image as compared with a sharp image is a difference in spatial frequency composition. Judge (1990),46 however, was of the opinion that eye growth was unlikely to be influenced by the spatial frequency content of the retinal image as even slight defocus would eliminate all high frequency information. Additionally, it has been noted that young monkeys do not develop a high resolution visual system until around two years of age,47 so would be unaffected by high frequency spatial information in the visual image (or its absence) at the young age when visual deprivation myopia can be induced.
Lenses inducing myopia in chicks are those that block the transmission of midand high frequencies48 and it has been concluded that emmetropization is tuned to mid-frequency spatial frequencies.41 In another study in chicks, it was also concluded that mid-spatial frequency tuning was necessary for emmetropization although chromatic aberration might have a role as a clue to defocus.49
In some experiments no significant interaction between the spatial frequency characteristics and sign of defocus was demonstrated.38 Others have reported that the inclusion of mid to high spatial frequencies is necessary for refractive compensation to induced defocus.50
It has been suggested that it is not the edge structure of the spatial frequency alignments within the image but the spatial frequency composition itself that controls eye growth51 and the relative energy distribution across spatial distributions that is important. Because reduced luminance shifts contrast sensitivity to lower spatial frequencies, it has been suggested that reduced luminance acting through a reduction in spatial frequency, content of the retinal image may be a factor inducing a myopic shift in refraction.52
Contrast adaptation that is a spatial frequency dependent increase in contrast sensitivity after exposure to low contrast patterns may be another mechanism involved in refractive development for contrast adaptation correlates with various optical manipulations inducing myopia (frosted lenses, negative lens wear, and decreased retinal image sharpness).53
Light periodicity
Temporal modulation of light intensity using flickering light of low frequency (1–4 Hz) with luminance levels varying between 1.5 and 180 lux,
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during 12 hours of diurnal light exposure, had a marked myopia inducing effect on chicks wearing negative or positive lenses but not those with no defocus. The effect was greater in conditions of hyperopic blur than myopic blur.54 It is known that a flickering light of low frequency causes marked retinal vasodilatation55 thought to be due to nitric oxide release.56 Although a reduced release of dopamine occurs in visual deprivation myopia and in the myopia occurring in low light rearing conditions, in another study,57 flicker at a variety of frequencies from 2–20 Hz did not affect dopamine release from dopaminergic amacrine cells in the chick retina, suggesting that the cells in the retina thought to be involved in myopigenic signalling do not respond readily to short-term changes in retinal illumination.
In chicks, compensation to wearing plus or minus 10 D lenses was also affected by temporal and spatial characteristics of the retinal image. With temporal modulation having either a fast-on or a fast-off luminance gradient, compensation to +10 D lenses was reduced by a fast-on modulation and compensation to −10 D lenses similarly reduced by a fast-off modulation.58
Image clarity
In an attempt to see whether there were significant optical differences between out of focus images caused by negative lenses as compared with positive lenses, we carried out a series of experiments. Black and white checkerboard patterns were photographed in-focus and with varying degrees of defocus induced by negative or positive lenses placed in front of the camera lens. Not unexpectedly defocus reduced contrast, induced chromatic dispersion and had a significant effect on spatial frequency. The square-wave pattern of an in-focus checkerboard image was converted to a sign-wave pattern by 2–3 dioptres of defocus. All of these features of defocused images, however, were similar in degree whether the defocus simulated myopic or hyperopic blur and none offered an acceptable explanation for the apparent ability of the retina to differentiate between hyperopic and myopic blur, i.e. the sign of the defocus.
Another optical factor that might be a possible contributor to the etiology of myopia is the proportion of in-focus and out of focus information present in the visual image. It has been tacitly accepted that as a blurred retinal image in early life causes myopia, a sharp retinal image is required for emmetropia. In everyday life, however, a totally sharp image