257 The Relevance of Studies in Chicks for Understanding Myopia in Humans
Both molecules seem to be involved in the visual control of eye-growth: day-time, but not night-time, levels of dopamine are reduced by formdeprivation,86 and apomorphine, a non-specific dopamine agonist, inhibits the development of myopia induced by wearing diffusers or negative lenses in both chicks86,90,91 and monkeys.89 Melatonin is a potent modulator of retinal dopamine release,122,123 but also has receptors in the cornea, lens, choroid, and sclera.124 Systemic administration of melatonin at night resulted in a significant increase in vitreous chamber depth in normal chick eyes and choroidal thinning in form-deprived eyes,124 and one of the three types of melatonin receptors is increased in the retina/ RPE/choroid in form-deprived eyes.
Second, in growing chick eyes, there are diurnal rhythms in choroidal thickness and in the rate of ocular elongation, the phases of which are nearly opposite, with the choroid being thickest at night and the eye longest during the day.118 Inhibition of ocular elongation by positive lenses shifts the two rhythms into near-synchrony, whereas acceleration of ocular elongation shifts the rhythms into anti-phase.125 The phase difference between the rhythms in axial length and choroid thickness predicts the rate of growth on the following day in individual animals when the sign of defocus is switched from myopic to hyperopic or vice versa.
Although equivalent studies have not been done on mammals, there are rhythms in axial length and choroidal thickness in humans126,127 and marmosets.128 When marmosets are young, with rapidly elongating eyes, the two rhythms are in approximate anti-phase, whereas in older adolescents, in whom growth has slowed, the rhythms are closer in phase, analogous to the patterns seen in chicks with different rates of ocular growth.
If choroidal thickness is correlated with the molecules that the choroid is releasing, as suggested in the previous section, perhaps these molecules stimulate ocular elongation more at one portion of the cycle than at another, or perhaps modulators of metalloproteinases involved in scleral remodeling, such as tPA, may be more effective at certain points in the daily cycle. Finally, the effect of bright light outdoors in preventing chicken129 and human130 myopia may act by stimulation of dopamine release.
Conclusions
The eyes of a wide variety of vertebrates adjust their growth using visual cues. The pervasive similarities in the mechanisms shown to operate in
258 J. Wallman and D.L. Nickla
chicks and primates suggest that the emmetropization machinery has been highly conserved in evolution. The bidirectional modulation of eye growth by hyperopic and myopic defocus in disparate species suggests that the same may occur in children. This possibility should not be ignored in considering what might make children myopic and what could be done to prevent it. Furthermore, the similar local effects in chicks and monkeys of defocus limited to one region of the retina implies that one must study the peripheral refractions in humans to understand the etiology of myopia. This, in turn, implies that one must consider the effects of alternating periods of myopic and hyperopic defocus, because all regions of the retina are continuously exposed to these alternations with the exception of the fovea, which is kept more-or-less in focus by ocular accommodation. From the animal work, it appears likely that understanding the spatial and temporal distribution of defocus will go a long way to understanding human myopia.
References
1.Sherman SM, Norton TT, Casagrande VA. (1977) Myopia in the lid-sutured tree shrew (Tupaia glis). Brain Res 124: 154–157.
2.Wiesel TN, Raviola E. (1977) Myopia and eye enlargement after neonatal lid fusion in monkeys. Nature 266: 66–68.
3.Wallman J, Turkel J, Trachtman J. (1978) Extreme myopia produced by modest changes in early visual experience. Science 201: 1249–1251.
4.O’Leary DJ, Millodot M. (1979) Eyelid closure causes myopia in humans.
Experientia 35: 1478–1479.
5.Barathi VA, Boopathi VG, Yap EP, Beuerman RW. (2008) Two models of experimental myopia in the mouse. Vision Res 48: 904–916.
6.Tkatchenko TV, Shen Y, Tkatchenko AV. (2010) Mouse Experimental Myopia Has Features of Primate Myopia. Invest Ophthalmol Vis Sci 51(3): 1297–1303.
7.Schaeffel F, Glasser A, Howland HC. (1988) Accommodation, refractive error and eye growth in chickens. Vision Res 28: 639–657.
8.Hung LF, Crawford ML, Smith EL. (1995) Spectacle lenses alter eye growth and the refractive status of young monkeys. Nature Med 1: 761–765.
9.Whatham AR, Judge SJ. (2001) Compensatory changes in eye growth and refraction induced by daily wear of soft contact lenses in young marmosets.
Vision Res 41: 267–273.
10.Shen W, Sivak JG. (2007) Eyes of a lower vertebrate are susceptible to the visual environment. Invest Ophthalmol Vis Sci 48: 4829–4837.
259The Relevance of Studies in Chicks for Understanding Myopia in Humans
11.Metlapally S, McBrien NA. (2008) The effect of positive lens defocus on ocular growth and emmetropization in the tree shrew. J Vis 8(1): 1–12.
12.Howlett M, McFadden S. (2009) Spectacle lens compensation in the pigmented guinea pig. Vision Res 49: 219–227.
13.Gwiazda J, Hyman L, Hussein M, et al. (2003) A randomized clinical trial of progressive addition lenses versus single vision lenses on the progression of myopia in children. Invest Ophthal Vis Sci 44: 1492–1500.
14.Phillips JR. (2005) Monovision slows juvenile myopia progression unilaterally. Br J Ophthalmol 89: 1196–1200.
15.Field DJ, Brady N. (1997) Visual sensitivity, blur and the sources of variability in the amplitude spectra of natural scenes. Vision Res 37: 3367–3383.
16.Georgeson MA, May KA, Freeman TC, Hesse GS. (2007) From filters to features: scale-space analysis of edge and blur coding in human vision. J Vis 7(7): 1–21.
17.Schaeffel F, Diether S. (1999) The growing eye: an autofocus system that works on very poor images. Vision Res 39: 1585–1589.
18.Park T, Winawer J, Wallman J. (2003) Further evidence that chicks use the sign of blur in spectacle lens compensation. Vision Res 43: 1519–1531.
19.McLean RC, Wallman J. (2003) Severe astigmatic blur does not interfere with spectacle lens compensation. Invest Ophthal Vis Sci 44: 449–457.
20.Whatham AR, Judge SJ. (2001) Compensatory changes in eye growth and refraction induced by daily wear of soft contact lenses in young marmosets.
Vision Res 41: 267–273.
21.Troilo D, Totonelly K, Harb E. (2009) Imposed anisometropia, accommodation, and regulation of refractive state. Optom Vis Sci 86: E31–E39.
22.McFadden S, Wildsoet C. (2009) Mammalian eyes need an intact optic nerve to detect the sign of defocus during emmetropization. Invest Ophthalmol Vis Sci E-Abstract #1620. 50.
23.Norton TT, Siegwart JT, Jr., Amedo AO. (2006) Effectiveness of hyperopic defocus, minimal defocus, or myopic defocus in competition with a myopiagenic stimulus in tree shrew eyes. Invest Ophthalmol Vis Sci 47: 4687–4699.
24.Nickla DL, Sharda V, Troilo D. (2005) Temporal integration characteristics of the axial and choroidal responses to myopic defocus induced by prior form deprivation versus positive spectacle lens wear in chickens. Optom Vis Sci 82: 318–327.
25.Schaeffel F, Howland HC. (1991) Properties of the feedback loops controlling eye growth and refractive state in the chicken. Vision Res 31: 717–734.
26.Wildsoet CF, Schmid KL. (2000) Optical correction of form deprivation myopia inhibits refractive recovery in chick eyes with intact or sectioned optic nerves. Vision Res 40: 3273–3282.
260J. Wallman and D.L. Nickla
27.Norton TT, Amedo AO, Siegwart JT, Jr. (2006) Darkness causes myopia in visually experienced tree shrews. Invest Ophthalmol Vis Sci 47: 4700–4707.
28.Smith EL, 3rd, Hung LF. (1999) The role of optical defocus in regulating refractive development in infant monkeys. Vision Res 39: 1415–1435.
29.Tepelus TC, Schaeffel F. (2010) Individual set-point and gain of emmetropization in chickens. Vision Res 50(1): 57–64.
30.Jansonius NM, Kooijman AC. (1998) The effect of spherical and other aberrations upon the modulation transfer of the defocussed human eye.
Ophthalmic Physiol Opt 18: 504–513.
31.Tarrant J, Severson H, Wildsoet CF. (2008) Accommodation in emmetropic and myopic young adults wearing bifocal soft contact lenses. Ophthalmic Physiol Opt 28: 62–72.
32.Radhakrishnan H, Pardhan S, Calver RI, O’Leary DJ. (2004) Effect of positive and negative defocus on contrast sensitivity in myopes and nonmyopes. Vision Res 44: 1869–1878.
33.Wilson BJ, Decker KE, Roorda A. (2002) Monochromatic aberrations provide an odd-error cue to focus direction. J Opt Soc Am A Opt Image Sci Vis 19: 833–839.
34.Irving EL, Sivak JG, Callender MG. (1992) Refractive plasticity of the developing chick eye. Ophthalmic Physiol Opt 12: 448–456.
35.Rucker FJ, Wallman J. (2009) Chick eyes compensate for chromatic simulations of hyperopic and myopic defocus: evidence that the eye uses longitudinal chromatic aberration to guide eye-growth. Vision Res 49: 1775–1783.
36.Lee JH, Stark LR, Cohen S, Kruger PB. (1999) Accommodation to static chromatic simulations of blurred retinal images. Ophthalmic Physiol Opt 19: 223–235.
37.Fitzke FW, Hayes BP, Hodos W, et al. (1985) Refractive sectors in the visual field of the pigeon eye. J Physiol 369: 33–44.
38.Crewther SG, Crewther DP. (2003) Inhibition of retinal ON/OFF systems differentially affects refractive compensation to defocus. Neuroreport 14: 1233–1237.
39.Wallman J, Gottlieb MD, Rajaram V, Fugate-Wentzek LA. (1987) Local retinal regions control local eye growth and myopia. Science 237: 73–77.
40.Diether S, Schaeffel F. (1997) Local changes in eye growth induced by imposed local refractive error despite active accommodation. Vision Res 37: 659–668.
41.Smith EL, 3rd, Huang J, Hung LF, et al. (2009) Hemiretinal form deprivation: evidence for local control of eye growth and refractive development in infant monkeys. Invest Ophthal Vis Sci 50: 5057–5069.
42.Ferree GR, Rand G, Hardy C. (1931) Refraction for the peripheral field of vision. Arch Opthal 8: 717–731.
261The Relevance of Studies in Chicks for Understanding Myopia in Humans
43.Hoogerheide J, Rempt F, Hoogenboom WP. (1971) Acquired myopia in young pilots. Ophthalmologica 163: 209–215.
44.Mutti DO, Hayes JR, Mitchell GL, et al. (2007) Refractive error, axial length, and relative peripheral refractive error before and after the onset of myopia.
Invest Ophthal Vis Sci 48: 2510–2519.
45.Rose KA, Morgan IG, Ip J, et al. (2008) Outdoor activity reduces the prevalence of myopia in children. Ophthalmology 115: 1279–1285.
46.Winawer J, Wallman J. (2002) Temporal constraints on lens compensation in chicks. Vision Res 42: 2651–2668.
47.Zhu X, Winawer J, Wallman J. (2003) The potency of myopic defocus in lens-compensation. Invest Ophthalmol Vis Sci 44: 2818–2827.
48.Winawer J, Zhu X, Choi J, Wallman J. (2005) Ocular compensation for alternating myopic and hyperopic defocus. Vision Res 45: 1667–1677.
49.Zhu X, Wallman J. (2009) Temporal properties of compensation for positive and negative spectacle lenses in chicks. Invest Ophthalmol Vis Sci 50: 37–46.
50.Smith EL, 3rd, Hung LF, Kee CS, Qiao Y. (2002) Effects of brief periods of unrestricted vision on the development of form-deprivation myopia in monkeys. Invest Ophthalmol Vis Sci 43: 291–299.
51.Ciuffreda KJ, Wallis DM. (1998) Myopes show increased susceptibility to nearwork aftereffects. Invest Ophthal Vis Sci 39: 1797–1803.
52.Troilo D, Gottlieb MD, Wallman J. (1987) Visual deprivation causes myopia in chicks with optic nerve section. Curr Eye Res 6: 993–999.
53.Wildsoet CF, Pettigrew JD. (1988) Experimental myopia and anomalous eye growth patterns unaffected by optic nerve section in chickens: evidence for local control of eye growth. Clin Vis Sci 3: 99–107.
54.Poole AR, Pidoux I, Reiner A, et al. (1982) Mammalian eyes and associated tissues contain molecules that are immunologically related to cartilage proteoglycans and link protein. J Cell Biol 93: 910–920.
55.Murphy C, Kern T, Howland H. (1992) Refractive state, corneal curvature, accommodative range and ocular anatomy of the Asian elephant (Elephas maximus). Vision Res 32: 2013–2021.
56.McBrien N, Gentle A. (2003) Role of the sclera in the development and pathological complications of myopia. Prog Retinal Eye Res 22: 307–338.
57.Norton T, Rada J. (1995) Reduced extracellular matrix in mammalian sclera with induced myopia. Vision Res 1271–1281.
58.Rada JA, Nickla DL, Troilo D. (2000) Decreased proteoglycan synthesis associated with form deprivation myopia in mature primate eyes. Invest
Ophthalmol Vis Sci 41: 2050–2058.
59.Gottlieb MD, Joshi HB, Nickla DL. (1990) Scleral changes in chicks with form-deprivation myopia. Curr Eye Res 9: 1157–1165.
262J. Wallman and D.L. Nickla
60.Marzani D, Wallman J. (1997) Growth of the two layers of the chick sclera is modulated reciprocally by visual conditions. Invest Ophthalmol Vis Sci 38: 1726–1739.
61.Rada JA, Thoft RA, Hassell JR. (1991) Increased aggrecan (cartilage proteoglycan) production in the sclera of myopic chicks. Developmental Biology 147: 303–312.
62.Rada JA, McFarland AL, Cornuet PK, Hassell JR. (1992) Proteoglycan synthesis by scleral chondrocytes is modulated by a vision dependent mechanism. Curr Eye Res 11: 767–782.
63.Rada JA, Matthews AL. (1994) Visual deprivation upregulates extracellular matrix synthesis by chick scleral chondrocytes. Invest Ophthalmol Vis Sci 35: 2436–2447.
64.Wallman J, Gottlieb MD, Rajaram V, Fugate-Wentzek LA. (1987) Local retinal regions control local eye growth and myopia. Science 237: 73–77.
65.Smith EL, Huang J, Hung LF, et al. (2009) Hemiretinal form deprivation: evidence for local control of eye growth and refractive development in infant monkeys. Invest Ophthalmol Vis Sci 50: 5057–5069.
66.Zhu X, Garzon A, Wallman J. (2009) FGF has opposite effects on the fibrous and cartilaginous layers of the chick sclera. Invest Ophthalmol Vis Sci
E-abstract #3842.
67.de longh R, McAvoy J. (1992) Distribution of acidic and basic fibroblast growth factor (FGF) in the foetal rat eye: Implications for lens development.
Growth Factors 6: 159–177.
68.Keithahn M, Aotaki-Keen A, Schneeberger S, et al. (1997) Expression of fibroblast growth factor-5 by bovine choroidal endothelial cells in vitro.
Invest Ophthalmol Vis Sci 38: 2073–2080.
69.Schweigerer L, Malerstein B, Neufeld G, Gospodarowicz D. (1987) Basic fibroblast growth factor is synthesized in cultured retinal pigment epithelial cells. Biochem Biophys Res Commun 143: 934–940.
70.Fischer A, McGuire J, Schaeffel F, Stell W. (1999) Light and defocus-dependent expression of the transcription factor ZENK in the chick retina. Nat Neurosci 2: 706–712.
71.Simon P, Feldkaemper M, Bitzer M, et al. (2004) Early transcriptional changes of retinal and choroidal TGFB-2, RALD-2, and ZENK following imposed positive and negative defocus in chickens. Mol Vis 10: 588–597.
72.Bitzer M, Schaeffel F. (2002) Defocus-induced changes in ZENK expression in the chicken retina. Invest Ophthalmol Vis Sci 43: 246–252.
73.Zhu X, Wallman J. (2009) Opposite effects of glucagon and insulin on competition for spectacle lenses in chicks. Invest Ophthalmol Vis Sci 50:
24–36.
74.Vessey KA, Lencses KA, Rushforth DA, et al. (2005) Glucagon receptor agonists and antagonists affect the growth of the chick eye: a role for
263 The Relevance of Studies in Chicks for Understanding Myopia in Humans
glucagonergic regulation of emmetropization. Invest Ophthalmol Vis Sci 46: 3922–3931.
75.Feldkaemper M, Neacsu I, Schaeffel F. (2009) Insulin acts as a powerful stimulator of axial myopia in chicks. Invest Ophthalmol Vis Sci 50: 13–23.
76.Fischer A, Omar G, Walton N, et al. (2005) Glucagon-expressing neurons within the retina regulate the proliferation of neural progenitors in the circumferential marginal zone of the avian eye. J Neurosci 25: 10157–10166.
77.Buck L, Schaeffel F, Simon P, Feldkaemker M. (2004) Effects of positive and negative lens treatment on retinal and choroidal glucagon and glucagon recepter mRNA levels in the chicken. Invest Ophthamol 45(2): 402–409.
78.Fischer A, Ritchey E, Scott M, Wynne A. (2008) Bullwhip neurons in the retina regulate the size and shape of the eye. Dev Biol 317: 196–212.
79.Waldbillig R, Arnold D, Fletcher R, Chader G. (1990) Insulin and IGF-1 binding in chick sclera. Invest Ophthalmol Vis Sci 31: 1015–1022.
80.Waldbillig R, Arnold D, Fletcher R, Chader G. (1991) Insulin and IGF-1 binding in developing chick neural retina and pigment epithelium: a characterization of binding and structural differences. Exp Eye Res 53: 13–22.
81.Zhong X, Ge J, Smith EL, Stell W. (2004) Image defocus modulates activity of bipolar and amacrine cells in macaque retina. Invest Ophthalmol Vis Sci 45: 2065–2074.
82.Seko Y, Shimizu M, Tokoro T. (1998) Retinoic acid increases in the retina of the chick with form deprivation myopia. Ophthalmic Res 30: 361–367.
83.McFadden SA, Howlett MH, Mertz JR. (2004) Retinoic acid signals the direction of ocular elongation in the guinea pig eye. Vision Res 44: 643–653.
84.Bitzer M, Feldkaemper M, Schaeffel F. (2000) Visually induced changes in components of the retinoic acid system in fundal layers of the chick. Exp Eye Res 70: 97–106.
85.Mertz JR, Wallman J. (2000) Choroidal retinoic acid synthesis: a possible mediator between refractive error and compensatory eye growth. Exp Eye Res 70: 519–527.
86.Stone RA, Lin T, Laties AM, Iuvone PM. (1989) Retinal dopamine and formdeprivation myopia. Proc Nat Acad Sci 86: 704–706.
87.Guo SS, Sivak JG, Callender MG, Diehljones B. (1995) Retinal dopamine and lens-induced refractive errors in chicks. Curr Eye Res 14: 385–389.
88.Pendrak K, Nguyen T, Lin T, et al. (1997) Retinal dopamine in the recovery from experimental myopia. Curr Eye Res 16: 152–157.
89.Luvone PM, Tigges M, Stone RA, et al. (1991) Effects of apomorphine, a dopamine receptor agonist, on ocular refraction and axial elongation in a primate model of myopia. Invest Ophthalmol Vis Sci 32: 1674–1677.
90.Rohrer B, Spira AW, Stell WK. (1993) Apomorphine blocks form-depriva- tion myopia in chickens by a dopamine D2-receptor mechanism acting in retina or pigmented epithelium. Vis Neurosci 10: 447–453.
264J. Wallman and D.L. Nickla
91.Schmid KL, Wildsoet C. (2004) Inhibitory effects of apomorphine and atropine and their combination on myopia in chicks. Optometry Vis Sci 81: 137–147.
92.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.
93.Bedrossian RH. (1971) The effect of atropine on myopia. Ann Ophthalmol 3: 891–897.
94.Shih YF, Chen CH, Chou AC, et al. (1999) Effects of different concentrations of atropine on controlling myopia in myopic children. J Ocular Pharm Therapeut 15: 85–90.
95.Kennedy RH, Dyer JA, Kennedy MA, et al. (2000) Reducing the progression of myopia with atropine: a long term cohort study of Olmsted County students. Binocul Vis Strabismus Q 15: 281–304.
96.Stone RA, Lin T, Laties AM. (1991) Muscarinic antagonist effects on experimental chick myopia. Exp Eye Res 52: 755–7588.
97.McBrien NA, Moghaddam HO, Reeder AP. (1993) Atropine reduces experimental myopia and eye enlargement via a nonaccommodative mechanism.
Invest Ophthalmol Vis Sci 34: 205–215.
98.Schwahn HN, Schaeffel F. (1994) Chick eyes under cycloplegia compensate for spectacle lenses despite six-hydroxy dopamine treatment. Invest Ophthalmol Vis Sci 35: 3516–3524.
99.Luft W, Ming Y, Stell W. (2003) Variable effects of previously untested muscarinic receptor antagonists on experimental myopia. Invest Ophthalmol Vis Sci 44: 1330–1338.
100.Fischer A, Miethke P, Morgan I, Stell W. (1998) Cholinergic amacrine cells are not required for the progression and atropine-mediated suppression of form deprivation myopia. Brain Res 794: 48–60.
101.Wallman J, Wildsoet C, Xu A, et al. (1995) Moving the retina: choroidal modulation of refractive state. Vision Res 35: 37–50.
102.Wildsoet C, Wallman J. (1995) Choroidal and scleral mechanisms of compensation for spectacle lenses in chicks. Vision Res 35: 1175–1194.
103.Hung L-F, Wallman J, Smith EI. (2000) Vision-dependent changes in the choroidal thickness of Macaque monkeys. Invest Ophthalmol Vis Sci 41: 1259–1269.
104.Troilo D, Nickla D, Wildsoet C. (2000) Choroidal thickness changes during altered eye growth and refractive state in a primate. Invest Ophthalmol Vis Sci 41: 1249–1258.
105.Rada J, Palmer L. (2007) Choroidal regulation of scleral glycosaminoglycan synthesis during recovery from induced myopia. Invest Ophthalmol Vis Sci
48: 2957–2966.
265The Relevance of Studies in Chicks for Understanding Myopia in Humans
106.Wang Y, Gilliles C, Cone RE, O’Rourke J. (1995) Extravascular secretion of t-PA by the intact superfused choroid. Invest Ophthalmol Vis Sci 36: 1625–1632.
107.Troilo D, Nickla D, Mertz J, Summers Rada J. (2006) Change in the synthesis rates of ocular retinoic acid and scleral glycosaminoglycan during experimentally altered eye growth in marmosets. Invest Ophthalmol Vis Sci 47: 1768–1777.
108.McFadden S, Howlett M, Mertz J. (2004) Retinoic acid signals the direction of ocular elongation in the guinea pig eye. Vision Res 44: 643–653.
109.Rada J, Huang Y, Rada K. (2001) Identification of choroidal ovotransferrin as a potential ocular growth regulator. Curr Eye Res 22: 121–132.
110.Jobling AI, Wan R, Gentle A, Bui BV, McBrien N. (2009) Retinal and choroidal TGF-B in the tree shrew model of myopia: Isoform expression, activation and effects on function. Exp Eye Res 88: 458–466.
111.Lutty GA, Merges C, Threlkeld AB, Crone S, McLeod DS. (1993) Heterogeneity in localization of isoforms of TGF-beta in human retina, vitreous, and choroid. Invest Ophthalmol Vis Sci 34: 477–487.
112.Seko Y, Shimokawa H, Tokoro T. (1995) Expression of bFGF and TGF-B2 in experimental myopia in chicks. Invest Ophthalmol Vis Sci 36: 1183–1187.
113.Rohrer B, Stell WK. (1994) Basic Fibroblast Growth-Factor (Bfgf) and Transforming Growth-Factor-Beta (TGF-Beta) Act as Stop and Go signals to modulate postnatal ocular growth in the chick. Exp Eye Res 58: 553–561.
114.Liang H, Crewther S, Crewther D, Junghans B. (2004) Structural and elemental evidence for edema in the retina, retinal pigment epithelium, and choroid during recovery from experimentally induced myopia. Invest Ophthalmol Vis Sci 45: 2463–2474.
115.Nickla D. (2007) Transient increases in choroidal thickness are consistently associated with brief daily visual stimuli that inhibit ocular growth in chicks.
Exp Eye Res 84: 951–959.
116.Nickla D, Wilken E, Lytle G, et al. (2006) Inhibiting the transient choroidal thickening response using the nitric oxide synthase inhibitor L-NAME prevents the ameliorative effects of visual experience on ocular growth in two different visual paradigms. Exp Eye Res 83: 456–464.
117.Weiss S, Schaeffel F. (1993) Diurnal growth rhythms in the chicken eye: Relation to myopia development and retinal dopamine levels. J Comp Physiol A 172: 263–270.
118.Nickla DL, Wildsoet C, Wallman J. (1998) Visual influences on diurnal rhythms in ocular length and choroidal thickness in chick eyes. Exp Eye Res 66: 163–181.
119.Papastergiou GI, Schmid GF, Riva CE, et al. (1998) Ocular axial length and choroidal thickness in newly hatched chicks and one-year-old chickens
266 J. Wallman and D.L. Nickla
fluctuate in a diurnal pattern that is influenced by visual experience and intraocular pressure changes. Exp Eye Res 66: 195–205.
120.Nickla DL, Rada JA, Wallman J. (1999) Isolated chick sclera shows a circadian rhythm in proteoglycan synthesis perhaps associated with the rhythm in ocular elongation. J Comp Physiol [A] 185: 81–90.
121.Besharse JC, Iuvone PM, Pierce ME. (1988) Regulation of rhythmic photoreceptor metabolism: a role for post-receptoral neurons. Prog Retinal Res 7: 21–61.
122.Ribelayga C, Wang Y, Mangel SC. (2004) A circadian clock in the fish retina regulates dopamine release via activation of melatonin receptors. J Physiol 554: 467–482.
123.Lorenc-Duda A, Berezinska M, Urbanska A, et al. (2009) Dopamine in the turkey retina — an impact of environmental light, circadian clock, and melatonin. J Mol Neurosci 38: 12–18.
124.Summers Rada J, Wiechmann A. (2006) Melatonin receptors in chick ocular tissues: implications for a role of melatonin in ocular growth regulation.
Invest Ophthalmol Vis Sci 47: 25–33.
125.Nickla D. (2006) The phase relationships between the diurnal rhythm in axial length and choroidal thickness and the association with ocular growth rate in chicks. J Comp Physiol A 192: 399–407.
126.Stone RD, Quinn GE, Francis EL, et al. (2004) Diurnal axial length fluctuations in human eyes. Invest Ophthalmol Vis Sci 45: 63–70.
127.Brown JS, Flitcroft DI, Ying G, et al. (2009) In vivo human choroidal thickness measurements: Evidence for diurnal fluctuations. Invest Ophthalmol Vis Sci 50: 5–12.
128.Nickla D, Wildsoet C, Troilo D. (2002) Diurnal rhythms in intraocular pressure, axial length, and choroidal thickness in a primate model of eye growth, the common marmoset. Invest Ophthalmol Vis Sci 43: 2519–2528.
129.Ashby R, Ohlendorf A, Schaeffel F. (2009) The effect of ambient illuminance on the development of deprivation myopia in chicks. Invest Ophthalmol Vis Sci 50: 5348–5354.
130.Rose K, Morgan I, Ip J, et al. (2008) Outdoor activity reduces the prevalence of myopia in children. Ophthalmology 116: 1229–1230.
4.2
The Mechanisms Regulating Scleral
Change in Myopia
Neville A. McBrien*
Myopia is one of the most prevalent ocular conditions and is the result of a mismatch between the power and axial length of the eye. As a result, images of distant objects are brought to a focus in front of the retina, resulting in blurred vision. In the vast majority of cases, the structural cause of myopia is an excessive axial length of the eye, or more specifically, the vitreous chamber depth. In about 3% of the general population in Europe, USA and Austraila, the degree of myopia is above 6 dioptres and is termed high myopia. In South East Asia the figure is closer to 20% of the general population with high myopia. The prevalence of sight-threatening ocular pathology is markedly increased in eyes with high degrees of myopia (> –6D). This results from the excessive axial elongation of the eye, which, by necessity, must involve the outer coat of the eye, the sclera. Consequently, high myopia is reported as a leading cause of registered blindness and partial sight. Current theories of refractive development acknowledge the pivotal role of the sclera in the control of eye size and the development of myopia. This chapter considers the major structural, biochemical, and biomechanical mechanisms that underlie abnormal development of the mammalian sclera in myopia. This chapter will characterize the aberrant mechanisms of scleral remodelling that underlie the development of myopia. In describing these mechanisms, certain critical events in both the early and later stages of myopia development that lead to scleral thinning, the loss of scleral tissue, the weakening of the scleral mechanical properties and, ultimately, to the development of posterior staphyloma will be reviewed. In conclusion, it will be proposed that the prevention of aberrant scleral remodelling must be the
*Corresponding author. Department of Optometry and Vision Sciences, The University of Melbourne, Victoria 3010, Australia. E-mail: n.mcbrien@unimelb.edu.au.
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