Emmetropization Mechanism Research Articles

Tree shrews do not maintain emmetropia in initially-focused narrow-band cyan light

We asked if emmetropia, achieved in broadband colony lighting, is maintained in narrow-band cyan light that is well focused in the emmetropic eye, but does not allow for guidance from longitudinal chromatic aberrations (LCA) and offers minimal perceptual color cues. In addition, we examined the response to a −5 D lens in this lighting. Seven tree shrews from different litters were initially housed in broad-spectrum colony lighting. At 24 ± 1 days after eye opening (Days of Visual Experience, DVE) they were housed for 11 days in ambient narrow-band cyan light (peak wavelength 505 ± 17 nm) selected because it is in focus in an emmetropic eye. Perceptually, monochromatic light at 505 nm cannot be distinguished from white by tree shrews. While in cyan light, each animal wore a monocular −5 D lens (Cyan −5 D eyes). The fellow eye was the Cyan no-lens eye. Daily awake non-cycloplegic measures were taken with an autorefractor (refractive state) and with optical low-coherence optical interferometry (axial component dimensions). These measures were compared with the values of animals raised in standard colony fluorescent lighting: an untreated group (n = 7), groups with monocular form deprivation (n = 7) or monocular −5 D lens treatment (n = 5), or that experienced 10 days in total darkness (n = 5). Refractive state at the onset of cyan light treatment was low hyperopia, (mean ± SEM) 1.4 ± 0.4 diopters. During treatment, the Cyan no-lens eyes became myopic (−2.9 ± 0.3 D) whereas colony lighting animals remained slightly hyperopic (1.0 ± 0.2 D). Initially, refractions of the Cyan −5 D eyes paralleled the Cyan no-lens eyes. After six days, they gradually became more myopic than the Cyan no-lens eyes; at the end of treatment, the refractions were −5.4 ± 0.3 D, a difference of −2.5 D from the Cyan no-lens eyes. When returned to colony lighting at 35 ± 1 DVE, the no-lens eye refractions rapidly recovered towards emmetropia but, as expected, the refraction of the −5 D eyes remained near −5 D. Vitreous chamber depth in both eyes was consistent with the refractive changes. In narrow-band cyan lighting the emmetropization mechanism did not maintain emmetropia even though the light initially was well focused. We suggest that, as the eyes diverged from emmetropia, there were insufficient LCA cues for the emmetropization mechanism to utilize the developing myopic refractive error in order to guide the eyes back to emmetropia. However, the increased myopia in the Cyan −5 D eyes in the narrow-band light indicates that the emmetropization mechanism nonetheless detected the presence of the lens-induced refractive error and responded with increased axial elongation that partly compensated for the negative-power lens. These data support the conclusion that the emmetropization mechanism cannot maintain emmetropia in narrow-band lighting. The additional myopia produced in eyes with the −5 D lens shows that the emmetropization mechanism responds to multiple defocus-related cues, even under conditions where it is unable to use them to maintain emmetropia.

Chick Eyes Can Recover from Lens Compensation without Visual Cues

This study shows that nonvisual mechanism(s) can guide chick eyes to recover from myopia or hyperopia bidirectionally to regain their age-matched length. Because eye growth control is phylogenetically conserved across many species, it is possible that, in general, emmetropization mechanisms are not exclusively based on a local visual feedback system. Across species, growing eyes compensate for imposed defocus by modifying their growth, showing the visual controls on eye growth and emmetropization. When the spectacle lens is removed, the eyes rapidly recover back to a normal size similar to that in the untreated eyes. We asked whether this recovery process was dependent on visual feedback or whether it might be guided by intrinsic nonvisual mechanisms. Chicks wore either a +7 (n = 16) or -7 D (n = 16) lens over one eye for 4 to 7 days; the fellow eye was left untreated. After lens removal, half were recovered in darkness and half in white light. Refractive error and ocular dimensions were measured before and after lens treatment and after recovery with a Hartinger refractometer and A-scan biometer, respectively. Whereas chick eyes completely recovered from prior lens treatment under normal light after 2 days, they also partially recovered from prior hyperopia (by 60%) and myopia (by 69%) after being kept in darkness for 3 days: a +7 and -7 D lens induced a difference between the eyes of +7.08 and -4.69 D, respectively. After recovery in darkness, the eyes recovered by 3.18 and 2.88 D, respectively. In the absence of visual cues, anisometropic eyes can modify and reverse their growth to regain a similar length to their fellow untreated eye. Because eye growth control is phylogenetically conserved across many species, it is possible that nonvisual mechanisms may contribute more generally to emmetropization and that recovery from anisometropic refractive errors may not be wholly visually controlled.

Juvenile Tree Shrews Do Not Maintain Emmetropia in Narrow-band Blue Light.

In spectrally broad-band light, an emmetropization mechanism in post-natal eyes uses visual cues to modulate the growth of the eye to achieve and maintain near emmetropia. When we restricted available wavelengths to narrow-band blue light, juvenile tree shrews (diurnal dichromatic mammals closely related to primates) developed substantial refractive errors, suggesting that feedback from defocus-related changes in the relative activation of long- and short-wavelength-sensitive cones is essential to maintain emmetropia. The purpose of this study was to examine the effects of narrow-band ambient blue light on refractive state in juvenile tree shrews that had completed initial emmetropization (decrease from hyperopia toward emmetropia). Animals were raised in fluorescent colony lighting until they began blue-light treatment at 24 days of visual experience, at which age they had achieved age-normal low hyperopia (mean ± SEM refractive error, 1.2 ± 0.5 diopters). Arrays of light-emitting diodes placed atop the cage produced wavelengths of 457 (five animals) or 464 nm (five animals), flickered in a pseudo-random pattern (temporally broad band). A third group of five animals was exposed to steady 464-nm blue light. Illuminance on the floor of the cage was 300 to 500 human lux. Noncycloplegic autorefractor measures were made daily for a minimum of 11 days and up to 32 days. Seven age-matched animals were raised in colony light. The refractive state of all blue-treated animals moved outside the 95% confidence limits of the colony-light animals' refractions. Most refractions first moved toward hyperopia. Then the refractive state decreased monotonically and, in some animals, passed through emmetropia, becoming myopic. From the tree shrew cone absorbance spectra, the narrow-band blue light stimulated both long-wavelength-sensitive and short-wavelength-sensitive cones, but the relative activation would not change with the refractive state. This removed feedback from longitudinal chromatic aberration that may be essential to maintain emmetropia.

Spectrum of Darkness, Agent of Light: Myopia, Keratoconus, Ocular Surface Disease, and Evidence for a Profoundly Vitamin D-dependent Eye.

Serial observations obtained over more than eight years and 10,000 patient encounters in a general ophthalmology practice serving a population highly prone to chronic vitamin D (D3) deficiency, facilitated by the Oculus Pentacam Scheimpflug imaging system (Oculus Optikgeräte GmbH, Wetzlar, Germany), resulted in the recognition of consistent, predictable, and highly reproducible patterns of mechanical, optical, and physiologic change in the cornea and other ocular structures correlated to adequate vs. inadequate vitamin D availability. These patterns were identified from an analysis of more than 20,000 topographical and digital imaging studies, manifest refraction results, and other clinical ophthalmic exam findings recorded during patient visits. The main outcome measures included improved corneal and global optical quality and function, decreased ametropia, improved stability, and decreased subjective symptoms of compromised acuity and comfort. Adequate D3 replacement consistently yielded some degree of objective structural improvement in all subjects observed. The rate of improvement varied and synergistic interaction with cofactors was also suggested in particular topical steroids. A plausible explanation for the cause and mechanism of most myopia emerged and keratoconus, in particular, appears to be the extreme presentation of otherwise common corneal disturbances associated with inadequate vitamin D availability. Emmetropization mechanisms appear to awaken and reactivate with adequate D3. Intraocular pressure control likewise shows evidence of being vitamin D regulated and may play a significant interactive role in emmetropization and relief from ametropia. Ocular surface disease and inflammatory activity can be markedly alleviated in addition. As the findings are most readily appreciated via topographical map changes, a series of case reports are presented, selected from the mass of similar data, to illustrate specific aspects of these findings in the hope of inspiring controlled trials to better delineate their significance. Taken as a whole, these observations suggest the human eye may be profoundly dependent upon adequate vitamin D availability for many critical optical, structural, and physiologic properties. Myopia may represent the end result of adverse emmetropization feedback generated by low vitamin D-related irregular corneal astigmatism.

Long-wavelength (red) light produces hyperopia in juvenile and adolescent tree shrews

In infant tree shrews, exposure to narrow-band long-wavelength (red) light, that stimulates long-wavelength sensitive cones almost exclusively, slows axial elongation and produces hyperopia. We asked if red light produces hyperopia in juvenile and adolescent animals, ages when plus lenses are ineffective. Animals were raised in fluorescent colony lighting (100–300 lux) until they began 13days of red-light treatment at 11 (n=5, “infant”), 35 (n=5, “juvenile”) or 95 (n=5, “adolescent”) days of visual experience (DVE). LEDs provided 527–749 lux on the cage floor. To control for the higher red illuminance, a fluorescent control group (n=5) of juvenile (35 DVE) animals was exposed to ∼975 lux. Refractions were measured daily; ocular component dimensions at the start and end of treatment and end of recovery in colony lighting. These groups were compared with normals (n=7). In red light, the refractive state of both juvenile and adolescent animals became significantly (P<0.05) hyperopic: juvenile 3.9±1.0 diopters (D, mean±SEM) vs. normal 0.8±0.1D; adolescent 1.6±0.2D vs. normal 0.4±0.1D. The fluorescent control group refractions (0.6±0.3D) were normal. In red-treated juveniles the vitreous chamber was significantly smaller than normal (P<0.05): juvenile 2.67±0.03mmvs. normal 2.75±0.02mm. The choroid was also significantly thicker: juvenile 77±4μmvs. normal 57±3μm (P<0.05). Although plus lenses do not restrain eye growth in juvenile tree shrews, the red light-induced slowed growth and hyperopia in juvenile and adolescent tree shrews demonstrates that the emmetropization mechanism is still capable of restraining eye growth at these ages.

The wavelength composition and temporal modulation of ambient lighting strongly affect refractive development in young tree shrews

Shortly after birth, the eyes of most animals (including humans) are hyperopic because the short axial length places the retina in front of the focal plane. During postnatal development, an emmetropization mechanism uses cues related to refractive error to modulate the growth of the eye, moving the retina toward the focal plane. One possible cue may be longitudinal chromatic aberration (LCA), to signal if eyes are getting too long (long [red] wavelengths in better focus than short [blue]) or too short (short wavelengths in better focus). It could be difficult for the short-wavelength sensitive (SWS, “blue”) cones, which are scarce and widely spaced across the retina, to detect and signal defocus of short wavelengths. We hypothesized that the SWS cone retinal pathway could instead utilize temporal (flicker) information. We thus tested if exposure solely to long-wavelength light would cause developing eyes to slow their axial growth and remain refractively hyperopic, and if flickering short-wavelength light would cause eyes to accelerate their axial growth and become myopic. Four groups of infant northern tree shrews (Tupaia glis belangeri, dichromatic mammals closely related to primates) began 13 days of wavelength treatment starting at 11 days of visual experience (DVE). Ambient lighting was provided by an array of either long-wavelength (red, 626 ± 10 nm) or short-wavelength (blue, 464 ± 10 nm) light-emitting diodes placed atop the cage. The lights were either steady, or flickering in a pseudo-random step pattern. The approximate mean illuminance (in human lux) on the cage floor was red (steady, 527 lux; flickering, 329 lux), and blue (steady, 601 lux; flickering, 252 lux). Refractive state and ocular component dimensions were measured and compared with a group of age-matched normal animals (n = 15 for refraction (first and last days); 7 for ocular components) raised in broad spectrum white fluorescent colony lighting (100–300 lux).During the 13 day period, the refraction of the normal animals decreased from (mean ± SEM) 5.8 ± 0.7 diopters (D) to 1.5 ± 0.2 D as their vitreous chamber depth increased from 2.77 ± 0.01 mm to 2.80 ± 0.03 mm. Animals exposed to red light (both steady and flickering) remained hyperopic throughout the treatment period so that the eyes at the end of wavelength treatment were significantly hyperopic (7.0 ± 0.7 D, steady; 4.7 ± 0.8 D, flickering) compared with the normal animals (p < 0.01). The vitreous chamber of the steady red group (2.65 ± 0.03 mm) was significantly shorter than normal (p < 0.01). On average, steady blue light had little effect; the refractions paralleled the normal refractive decrease. In contrast, animals housed in flickering blue light increased the rate of refractive decrease so that the eyes became significantly myopic (−2.9 ± 1.3 D) compared with the normal eyes and had longer vitreous chambers (2.93 ± 0.04 mm). Upon return to colony lighting, refractions in all groups gradually returned toward emmetropia. These data are consistent both with the hypothesis that LCA can be an important visual cue for postnatal refractive development, and that short-wavelength temporal flicker provides an important cue for assessing and signaling defocus.

What Do Animal Studies Tell Us about the Mechanism of Myopia-Protection by Light?

: Human studies have provided strong evidence that exposure to time outdoors is protective against the onset of myopia. A causal factor may be that the light levels outdoors (30,000-130,000 lux) are much higher than light levels indoors (typically less than 500 lux). Studies using animal models have found that normal animals exposed to low illuminance levels (50 lux) can develop myopia. The myopia and axial elongation, produced in animals by monocular form deprivation, is reduced by light levels in the 15,000 to 25,000 range. Myopia induced with a negative-power lens seems less affected, perhaps because the lens provides a powerful target for the emmetropization mechanism. Animal studies suggest that raising the light levels may have their effect by increasing retinal dopamine activity, probably via the D2 receptor pathway, altering gene expression in the retina and reducing the signals that produce axial elongation.

Opposing effects of atropine and timolol on the color and luminance emmetropization mechanisms in chicks

This study analyzed the luminance and color emmetropization response in chicks treated with the nonselective parasympathetic antagonist atropine and the sympathetic β-receptor blocker timolol.Chicks were binocularly exposed (8h/day) for 4days to one of three illumination conditions: 2Hz sinusoidal luminance flicker, 2Hz sinusoidal blue/yellow color flicker, or steady light (mean 680lux). Atropine experiments involved monocular daily injections of either 20μl of atropine (18nmol) or 20μl of phosphate-buffered saline. Timolol experiments involved monocular daily applications of 2 drops of 0.5% timolol or 2 drops of distilled H2O. Changes in the experimental eye were compared with those in the fellow eye after correction for the effects of saline/water treatments.Atropine caused a reduction in axial length with both luminance flicker (−0.078±0.021mm) and color flicker (−0.054±0.017mm), and a reduction in vitreous chamber depth with luminance flicker (−0.095±0.023mm), evoking a hyperopic shift in refraction (3.40±1.77D). Timolol produced an increase in axial length with luminance flicker (0.045±0.030mm) and a myopic shift in refraction (−4.07±0.92D), while color flicker caused a significant decrease in axial length (−0.046±0.017mm) that was associated with choroidal thinning (−0.046±0.015mm).The opposing effects on growth and refraction seen with atropine and timolol suggest a balancing mechanism between the parasympathetic and β-receptor mediated sympathetic system through stimulation of the retina with luminance and color contrast.

The relationship between anisometropia and amblyopia

This review aims to disentangle cause and effect in the relationship between anisometropia and amblyopia. Specifically, we examine the literature for evidence to support different possible developmental sequences that could ultimately lead to the presentation of both conditions. The prevalence of anisometropia is around 20% for an inter-ocular difference of 0.5D or greater in spherical equivalent refraction, falling to 2-3%, for an inter-ocular difference of 3D or above. Anisometropia prevalence is relatively high in the weeks following birth, in the teenage years coinciding with the onset of myopia and, most notably, in older adults starting after the onset of presbyopia. It has about one-third the prevalence of bilateral refractive errors of the same magnitude. Importantly, the prevalence of anisometropia is higher in highly ametropic groups, suggesting that emmetropization failures underlying ametropia and anisometropia may be similar. Amblyopia is present in 1-3% of humans and around one-half to two-thirds of amblyopes have anisometropia either alone or in combination with strabismus. The frequent co-existence of amblyopia and anisometropia at a child's first clinical examination promotes the belief that the anisometropia has caused the amblyopia, as has been demonstrated in animal models of the condition. In reviewing the human and monkey literature however it is clear that there are additional paths beyond this classic hypothesis to the co-occurrence of anisometropia and amblyopia. For example, after the emergence of amblyopia secondary to either deprivation or strabismus, anisometropia often follows. In cases of anisometropia with no apparent deprivation or strabismus, questions remain about the failure of the emmetropization mechanism that routinely eliminates infantile anisometropia. Also, the chronology of amblyopia development is poorly documented in cases of 'pure' anisometropic amblyopia. Although indirect, the therapeutic impact of refractive correction on anisometropic amblyopia provides strong support for the hypothesis that the anisometropia caused the amblyopia. Direct evidence for the aetiology of anisometropic amblyopia will require longitudinal tracking of at-risk infants, which poses numerous methodological and ethical challenges. However, if we are to prevent this condition, we must understand the factors that cause it to develop.

Visual guidance of recovery from lens-induced myopia in tree shrews (Tupaia glis belangeri).

To examine, in tree shrews, the visual guidance of recovery from negative lens-induced myopia by measuring the effect of wearing low-power negative or positive lenses during recovery. To learn if removing a negative lens for 2 h per day, after compensation has occurred, is sufficient to produce recovery. Starting 16 days after natural eye opening (days of visual experience), juvenile tree shrews wore a monocular -5 D lens for 11 days to produce compensation (age-appropriate refraction while wearing the lens). Recovery in four groups was started by discontinuing -5 D lens wear, which caused the treated eyes to be refractively myopic, and substituting: no lens (n = 7), a plano lens (n = 8), a -2 D lens (n = 6) or a +2 D lens (n = 10). In a fifth group (n = 6), the -5 D lens was removed for 2 h each day but worn the remainder of the time. Non-cycloplegic refractive measurements were made daily for the first 10 days and then less frequently. After 31-35 days, the lens-guided recovery period was ended for most animals; periodic measures were continued to assess post-lens recovery changes. All the eyes responded to the -5 D lens and were myopic (-4.8 ± 0.1 D, mean ± S.E.M.) compared to the untreated fellow control eye. In all groups except the -2 D lens group, some animals exhibited slow or incomplete recovery. During recovery, the treated eye of most animals recovered until its refraction, measured with the recovery-lens in place, was near to that of the control eye. Measured without the lens, the -2 D group was myopic and the +2 D group was hyperopic. With the lens in place, the plano-lens, -2 D lens, and +2 D lens groups remained slightly myopic (-1.0 ± 0.3 D, -0.6 ± 0.2 D and -1.3 ± 0.1 D, respectively). The rate of recovery during the first four days was unrelated to the amount of myopia initially experienced by the recovering eyes. Removal of the -5 D lens for 2 h each day produced recovery. During recovery, the emmetropization mechanism uses the presence of myopia, but perhaps not the magnitude, to guide eyes toward a refractive state similar to the control eye, regardless of whether the optically-recovered eye is longer or shorter than the fellow control eye. Wearing a goggle frame containing a lens of any power limits the recovery. The recovery signal can be intermittent, present for only 2 h per day, and still mediate recovery in competition with increasing amounts of hyperopia as recovery progresses.

Perspective: How Might Emmetropization and Genetic Factors Produce Myopia in Normal Eyes?

Substantial evidence has emerged over the past decades for a role of genetics in the development of human refractive error. There is also an emmetropization mechanism that uses visual signals to match the axial length to the focal plane. There has been little discussion of how these two important factors might interact. We explore here ways in which genetic factors driving axial growth may interact with the emmetropization mechanism, mostly to produce emmetropic eyes but often to produce myopia. An important factor may be a normal, yet reduced ability of juvenile eyes to use myopia to restrain genetically driven axial elongation. Reduced ability to respond to myopia by slowing axial elongation may contribute to the development of myopia in cases where genetics alone would make the axial length longer than the focal plane.

The effect of age on compensation for a negative lens and recovery from lens-induced myopia in tree shrews ( Tupaia glis belangeri)

We examined in tree shrews the effect of age on the development of, and recovery from, myopia induced with a negative lens. Starting at 11, 16, 24, 35 or 48 days after natural eye-opening (days of visual experience [VE]), juvenile tree shrews ( n = 5 per group) wore a monocular −5 D lens for 11 days. A long-term lens-wear group ( n = 6) began treatment at 16 days of VE and wore the lens for 30 days. A young adult group ( n = 5) began to wear a −5 D lens between 93 and 107 days of VE (mean ± SD, 100 ± 6 days of VE) and wore the lens for 29–54 days (mean ± SD, 41.8 ± 9.8 days). The recovery phase in all groups was started by discontinuing −5 D lens wear. Contralateral control eyes in the three youngest groups were compared with a group of age-matched normal eyes and showed a small (<1 D), transient myopic shift. The amount of myopia that developed during lens wear was measured as the difference between the treated and control eye refractions. After 11 days of lens wear, the induced myopia was similar for the four younger groups (near full compensation: 11 days, −5.1 ± 0.4 D; 16 days, −4.7 ± 0.3 D; 24 days, −4.9 ± 0.4 D; 35 days, −4.0 ± 0.02) and slightly less in the oldest juvenile group (48 days, −3.3 ± 0.5 D). The young adult animals developed −4.8 ± 0.3 D of myopia after a longer lens-wear period. The rate of compensation (D/day) was high in the 4 youngest groups and decreased in the 48-day and young adult groups. The refractions of the long-term lens-wear juvenile group remained stable after compensating for the −5 D lens. During recovery, all animals in the youngest group recovered fully (<1 D residual myopia) within 7 days. Examples of both rapid (<10 days) and slow recovery (>12 days) occurred in all age groups except the youngest. Every animal showed more rapid recovery (higher recovery slope) in the first 4 days than afterward. One animal showed extremely slow recovery. Based on the time-course of myopia development observed in the youngest age groups, the start of the susceptible period for negative-lens wear is around 11–15 days after eye opening; the rate of compensation remains high until approximately 35 days of VE and then gradually declines. Compensation is stable with continued lens wear. The emmetropization mechanism, both for lens compensation and recovery, remains active into young adulthood. The time-course of recovery is more variable than that of compensation and seems to vary with age, with the amount of myopia (weakly) and with the individual animal.

Homeomorphic Matlab Model of Myopia Development

A homeomorphic biomechanical model of the eye based on the Incremental Retinal-Defocus Theory (IRDT) was developed to simulate myopic and hyperopic growth under different optical defocus conditions. The IRDT states that the time-integrated reduction in retinal-image defocus magnitude decreases the rate of retinal neuromodulator release, which in turn decreases the rate of proteoglycan synthesis and reduces scleral structural integrity, thus resulting in axial elongation and myopia development. A homeomorphic biomechanical model of the eye was constructed to test the IRDT based only on optical defocus and its resultant contribution to mechanical forces acting on the components of the eye. The Matlab simulation results showed a more fl attened oblate shape for myopic defocus, and a more elongated prolate shape with hyperopic defocus. Thus, the homeomorphic biomechanical model of the eye was able to simulate the emmetropization mechanism using only the forces acting on the masses at the nodes. In addition, neurochemicals injected at local retinal regions modifi ed the spring constants to result in predicted changes in ocular deformation. The fi ndings have clinical implications with respect to basic theories of myopia development, as well as future therapeutic use of direct ocular drug delivery to control human myopia.

Development of refractive errors into old age.

To evaluate refractive errors in older adults. The distribution of refractive error components was evaluated in a sample of 569 older adults including 171 participants over the age of 80 years. The mean age was 75.2 years with a range from 59 to 106 years. Emphasis was placed on modern methods of analyzing astigmatic refractive errors, which convert cylindrical refractive errors into primary and oblique components. The known increase in hyperopia after maturity continues into old age. The primary negative astigmatic component increases dramatically in prevalence and amount after age 70 years, whereas the oblique component remains unchanged. Significant anisometropia is common in the oldest old, suggesting failure of emmetropization mechanisms with age. Substantial gender differences exist in refractive changes with age. The continuing changes in all components of refractive error into old age and the surprisingly high prevalence of large amounts of astigmatism and anisometropia emphasize the importance of regular refractive evaluations among the oldest old.

Animal Models of Myopia: Learning How Vision Controls the Size of the Eye.

As they grow up, approximately 25% of children in the United States become myopic (nearsighted). A much smaller fraction become significantly hyperopic (farsighted), while the majority develop little or no refractive error and are emmetropic. The causes of refractive error, especially myopia, have been the subject of debate for more than a century. Some have held that myopia is primarily an inherited disorder, and others, that myopia is caused by protracted near work and, especially, by accommodation during protracted near work. It has not been possible, based solely on clinical observations, to resolve the relative roles of heredity versus environment in the development of refractive error. In the mid-1970s, several animal models were developed to study the mechanisms underlying refractive error. Using animal models, it was found that the visual environment exerts a powerful influence on refractive state by controlling the axial length of the eye during the postnatal developmental period. Although several species have been examined, three have emerged as primary models and have played complementary roles: tree shrews (mammals closely related to primates), chicks, and monkeys. Each has advantages and disadvantages. Collectively, research on animal models has provided evidence on three issues, namely that (1) the visual environment can produce refractive error; (2) an emmetropization mechanism normally guides eyes to low refractive error; and (3) under-accommodation, rather than excessive accommodation, may cause myopia. Two decades of research on animal models have provided criteria that may be used to evaluate the usefulness of additional species as models of emmetropization.

Regulation of the mechanical properties of tree shrew sclera by the visual environment

Experiments in several species have shown that the axial elongation rate of the developing eye can be increased or decreased by manipulating the visual environment, indicating that a visually guided emmetropization mechanism controls the enlargement of the vertebrate eye during postnatal development. Previous studies in tree shrews (Tupaia glis belangeri) suggest that regulation of the mechanical properties of the sclera may be an important part of the mechanism that controls the axial elongation rate in this mammal. To learn whether the mechanical properties of the sclera change when the axial elongation rate is increased or decreased under visual control, uniaxial mechanical tests were performed on 3-mm wide strips of tree shrew sclera. The creep rate was measured under 1, 3, and 5 g of tension, maintained for 30 min at each level. The modulus of elasticity was calculated from the elastic extension that occurred when the force was increased from 0 to 1 g, l to 3 g, and 3 to 5 g. Both were measured in the sclera of both eyes from animals exposed to four experimental conditions: (1) Normal development, at intervals from the day of natural eyelid opening (day 1 of visual experience [VE]) to greater than 5 years of age; (2) Monocular form deprivation (MD), for varying lengths of time; (3) Recovery from MD; (4) Monocular −5 D lens treatment. The creep rate was low in normal animals (1–2% elongation/h), did not change significantly between day 1 and day 75 of VE, and was not significantly different between the two eyes. Four days of MD produced a 200–300% increase in creep rate in the sclera from deprived eyes. Creep rate remained similarly elevated after 11 and 21 days of MD. After 2 days of recovery, which followed 11 days of MD, the creep rate of sclera from the recovering eyes was below normal levels. In animals that wore a monocular −5 D lens for up to 21 days, creep rate increased, and then decreased, in concert with the increase, and decrease, in axial elongation rate as the eyes compensated for the lens. The modulus of elasticity of the sclera was not significantly affected by any manipulation. The temporal correspondence between changes in axial elongation rate and changes in creep rate support the hypothesis that regulation of the time-dependent mechanical properties of fibrous mammalian sclera plays a role in controlling axial elongation rate during both normal emmetropization and the development of refractive errors.

Active emmetropization ? evidence for its existence and ramifications for clinical practice

There is increasing evidence from animal studies in support of the concept of an active emmetropization mechanism which has potentially important clinical ramifications for the management of refractive errors. Recent research into refractive development and emmetropization is reviewed, with emphasis given to work involving the chick, tree shrew and monkey, which represent the three most widely used animal models in this field. The findings of this research are reviewed in a clinical context. Compensatory eye growth responses to focusing errors imposed by lenses represent the most compelling evidence for active emmetropization. These observations are complemented by other evidence showing recovery from induced refractive errors such as form-deprivation myopia. Of the animals listed above, chicks show the most impressive emmetropization, being able to compensate fully (using choroidal and scleral mechanisms) to lens powers ranging from +15 D to -10 D. The range of lens powers eliciting appropriate compensatory responses is narrower in the tree shrew and monkey, and the response patterns generally are also more complex to interpret. These data relate to young animals and together indicate refractive plasticity during development. Extrapolation of these findings to humans predicts that natural emmetropization will be inhibited in neonates by early intervention with prescription lenses, and that refractive correction of myopia will lead to accelerated progression. This convincing evidence for active emmetropization warrants due consideration in developing clinical management strategies for refractive errors.

Active emmetropization — evidence for its existence and ramifications for clinical practice

SummaryThere is increasing evidence from animal studies in support of the concept of an active emmetropization mechanism which has potentially important clinical ramifications for the management of refractive errors.Recent research into retractive development and emmetropization is reviewed, with emphasis given to work involving the chick, tree shrew and monkey, which represent the three most widely used animal models in this field. The findings of this research are reviewed in a clinical context.Compensatory eye growth responses to focusing errors imposed by lenses represent the most compelling evidence for active emmetropization. These observations are complemented by other evidence showing recovery from induced refractive errors such as form‐deprivation myopia. Of the animals listed above, chicks show the most impressive emmetropization, being able to compensate fully (using choroidal and scleral mechanisms) to lens powers ranging from +15 D to ‐10 D. The range of lens powers eliciting appropriate compensatory responses is narrower in the tree shrew and monkey, and the response patterns generally are also more complex to interpret. These data relate to young animals and together indicate refractive plasticity during development. Extrapolation of these findings to humans predicts that natural emmetropization will be inhibited in neonates by early intervention with prescription lenses, and that refractive correction of myopia will lead to accelerated progression.This convincing evidence for active emmetropization warrants due consideration in developing clinical management strategies for refractive errors.

Effects of optically induced blur on the refractive status of young monkeys

In each of eight rhesus monkeys, one eye was defocused with a —9 D contact lens beginning before 1 month of age for periods of 2–3 months. At the end of the rearing period, interocular comparisons showed that one subject had developed a relative axial myopia (3.0 D), however, five monkeys had developed a relative axial hyperopia (2.0–3.5 D). After discontinuing the contact-lens rearing procedure, the induced refractive errors diminished over time in all subjects. These results indicate that the defocus threshold for form-deprivation myopia is relatively high and that substantial levels of optical defocus which do not exceed this threshold typically produce axial hyperopia. The recovery data suggests that monkeys have an emmetropization mechanism which is sensitive to optical defocus, but the failure of this mechanism to compensate for the refractive errors simulated during the lens-rearing procedures suggests that this mechanism has a limited operating range.

Emmetropization as a first-order feedback system

The existence of a regulatory mechanism that controls the growth of the eye toward emmetropia is generally agreed upon, but such an emmetropization mechanism has never been verified experimentally. This report supports the hypothesis that emmetropization can be described as a feedback process with a first-order equation and establishes a theoretical framework for future study, experimentation, and manipulation of this elusive mechanism. The feedback hypothesis has been tested by comparing two models. The first is a first-order feedback system, the second a non-feedback model with an almost identical equation. The feedback model fits data from human subjects significantly better.