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3.3 The Effects of Image Quality

3.3.1 Basic Results

Not too long ago (between 1977 and 1979) it was discovered that a lack of visual acuity on the retina leads to myopia in animals^{72, 208}.

This axial myopia can be artificially generated by^{88, 120, 209, 210}:

• Covering the eyes of animals with frosted glasses (form-deprivation myopia, FDM), or showing defocused pictures

Note:
Is there a connection between this effect and the residual tonic accommodation mentioned in section 1.4.1 (residual accommodation at low image contrast)? Permanent accommodation creates myopia (see point below), and with age this residual tonic accommodation was found to decrease. This corresponds to the fact that newly developed myopia also decreases with age.

• Applying strong minus glasses²¹¹ (lens-compensation myopia, called LCM; added plus glasses cause lens-compensation hyperopia, called LCH)

Note:
This matches the results shown in section 3.2, where information about the correlation of permanent accommodation with myopia was given, and where it was warned of overcorrection. Additionally it was reported before that near accommodation results in an immediate elongation of the eye.

• Forcing the eye into permanent near focus by restricting the distance of objects that can be seen (this effect is illumination dependent).

• Keeping a developing eye closed by suturing an eyelid (not by keeping the animal in a dark environment).

• Defects in the retina, which are caused by toxication²¹² or malformation lead to myopia, and nystagmus, an instable trembling of the eye, leads to high-grade myopia as well.

Some findings and facts for this artificial myopia are:

• At partly lens-covered eyes only the respective part of the sclera is changed.

• The worse the acuity of the image on the retina, the higher the myopia.

• The feedback mechanism between bad focus / elongated eye is taking place already in the retina.

• Applying glasses works both ways, i.e. applying plus glasses results in a shortening of the eye, resulting in hyperopia.

• Feldkaemper et al. stated²¹³: "… the eye becomes more sensitive to image degradation at low light, the human eye may also be more prone to develop myopia if the light levels are low during extended periods of near work."

• A defocused image and especially a reduced contrast have not only an impact (extension) on the vitreous body, but also on the length of the anterior chamber214. In the early stage of myopia for children it was found, however that the vitreous chamber was already elongating, but the anterior chamber depth was still unchanged²¹⁵.

Note:
This implies that the impact of image degradation affects not only the area of the eye which is close to the retina, i.e. the back of the eye, but also the rather distant front part of the eye. Conclusion: The growth adjustment of the eye appears to be an almost systemic process, which matches with some of the results given in section 3.3.2.

• Flickering light can stimulate the release of dopamine and reduce the degree of the artificially induced myopia^{216, 217}, and increase choroidal blood flow².

• Eyes grow in length only during the day; at deprivation by translucent glasses they grow during night and day³⁹.

• Ohngemach et al. stated²¹⁸: "Intermittent periods of normal vision inhibited deprivation myopia more if they occurred in the evening than in the morning" and relatively short periods (1 to 4 hours) were very efficient to reduce or to prevent form deprivation²¹⁹. Regular interrupting the deprivation can reduce the induced myopia, as Napper et al. stated²²⁰: "... several short periods of normal visual stimulation per day were more effective in preventing ... myopia ... than was one single period of the same total duration..."

Note:
These results give a scientific justification for the experience driven recommendations of the Bates-method (see section 3.2.2.1).

• After artificially introduced myopia the eye recovers to emmetropia after the cover is removed from the eye. If the myopia is corrected with glasses, no recovering to emmetropia took place^{221, 222}.

• Negative lenses, which cause myopic, elongated eyes, also cause a thinning of the choroid (the layer between the sclera and the retina). Vice versa, positive lenses, which are causing hyperopic, shortened eyes, also cause an also rapid increase in the thickness of the choroid ^{223, 224}.

• It takes only a short time like 10 minutes for the eye to detect whether the added lens is a plus lens or a minus lens, and to cause changes in the choroidal thickness and the corresponding vitreous chamber depth which persisted still some hours later²²⁵.

3.3.2 Connective Tissue Related Results

The results of deprivation and defocus as described so far sound like a normal and healthy growth of the eye, controlled by optical effects. The connective tissue of the modified sclera, however, is neither normal nor healthy (this is valid for the sclera of highly myopic humans as well)²²⁶.

Rada summarized²³⁸: "Scleral remodeling, as with any tissue, is a dynamic process that involves continual synthesis and degradation of extracellular matrix." Numerous enzymes, proteinases and cytokines are involved in this process.

The following list is a summary of some of the most significant research results. They demonstrate that there is a very strong correlation between higher grades of myopia and defects of the connective tissue.

• Scleral samples of artificially myopic tree shrew eyes (an animal frequently used for these experiments) were significantly thinner and torn more easily.²²⁷ Similarly, highly myopic human eyes show scleral thinning at the posterior pole²²⁶.

• The structure of the fibers of the sclera was found to be different compared to normal eyes²²⁸.

• There is a reduction of the amount of collagen and of the synthesis of proteoglycans²²⁹ [proteins, which are a main component of connective tissue besides collagen]. • Any agent that blocks the cross linking of newly formed collagen dramatically increased myopia⁸⁸.

• Norton et al. stated²³⁰ "… deprived sclera contained less proteoglycan, or that the proteoglycans were less glycosylated or less sulfated." This led to his conclusion, "...that form deprivation slows or reverses the normal process of extracellular matrix accumulation in the sclera of this mammal."

• Rada et al. stated²³¹: "The turnover rate of … scleral proteoglycans is vision dependent and is accelerated in the posterior sclera of chick eyes during the development of experimental myopia. The loss of proteoglycans from the scleral matrix involves proteolytic cleavage …"

• Jones et al. stated²³²: "… eye growth induced by retinal-image degradation involves increases in the activities of multiple scleral proteinases [enzymes with the capability to dissolve proteins] that could modify the biomechanical properties of scleral structural components and contribute to tissue remodeling and growth."

• Funata et al. stated²²⁸: "… a gradual increase in the size of the collagen bundles and fibrils from the inner to the outer layer of the sclera was observed in the control eyes, but was not evident in the myopic eyes."

• Kusakari et al. stated²³³: "Collagen fibrillar diameters of the fibrous sclera in the posterior segment of myopic eyes were smaller than in control..." and "...collagen bundles of the fibrous sclera [of myopic eyes] spread into the cartilaginous sclera, whereas in control eyes the distinction was clear."

• McBrien stated²²¹: "… deprivation, which induced approximately 6 D of myopia, was accompanied by a three-fold increase in the active form of gelatinase A … an enzyme involved in collagen degradation." Rada et al. stated²³⁴: "... visual deprivation is associated with an increased amount of the 72-kd progelatinase and a decreased amount of TIMP [tissue inhibitors of metalloproteinases] within the posterior sclera." This means, there is an imbalance between tissue degrading agents and agents, which stop tissue degrading towards tissue degrading.

• Rada summarized²³⁸: "McBrien also found unaltered collagen fibrils after induced myopia of short duration. It was only when the animals remained myopic for many month that altered collagen fibrils were found."

• It was suggested by Siegwart et al.²³⁵ that the sclera in deprived eyes "... offered less resistance to vitreous-driven expansion of the eyes."

• Form-deprivation resulted in the building of hypertrophic cells (chondrocytes), i.e. in the enlargement of cells instead of the building of new additional cells²³⁶. In other words, there is no growth, but a stretching by a degradation of the quality of the tissue.

Note:
It appears plausible that these enlarged cells are showing a reduced stability, which would explain the stretching of the sclera in an extended myopic eyeball.

• Gentle et al. stated²³⁷: "Collagen type I expression was reduced in the sclera of myopic eyes, however, collagen III and V expression was unchanged relative to control..."

"...reduced scleral collagen accumulation in myopic eyes results from decreased collagen synthesis and accelerated collagen degradation." Collagen type I builds the main type of collagen in the sclera²³⁸.

• Rada et a. stated²³⁹: " Changes in the steady state levels of gelatinase A and TIMP-2 mRNA lead to changes in gelatinase activity within the fibrous sclera and mediate, at least in part, the process of visually regulated ocular growth and scleral remodeling."

Summary:

Obviously, the remodeling, which is a normal process during emmetropization, has also rather destructive and degrading features This makes it easy to understand that if a feedback mechanism is out of tune, it will lead to myopia. Some people may develop malignant myopia through such a mechanism. In other words, the process leading to myopia is not so much a passive one, which is determined by simple mechanical stretching of a healthy sclera, but an active one with significant biochemical alterations²²⁶, which includes that a biochemically degraded sclera is mechanically stretched.

It is still an open question whether the degradation of the sclera is completely biochemical. In this view, the reduced mechanical stability of the sclera is simply the effect of a changed biochemistry. The alternative is that mechanical forces initiate biochemical modifications (a process called mechanotransduction), which lead to the degradation²²⁶.

A real and detailed understanding of the causation of deprivation myopia or lens-induced myopia, is still missing. There are some arguments that the experiments with animals are not fully valid for humans²⁴⁰.

For general information about the connective tissue see section 4.2.1.

3.3.3 Some More Biochemical Results

Some results about the impact of the imaging process on the biochemistry of the eye are:

• A drop in the level of the neurotransmitter dopamine (released by specific retina cells) in the vitreous body accompanies experimental myopia, and agonists for dopamine (i.e. agents that are supporting the action of dopamine) can at least slow down this deprivation myopia^{209, 241}. Correspondingly, dopamine antagonists (i.e. agents which are blocking the action of dopamine) can enforce myopia²⁴².

• About Amacrine cells (types of neurons), Whikehart stated²⁴³: "...evidence indicates that amacrine cells (some of which use dopamine) serve as intermediate cells for the lateral transfer of signals across the retina", i.e. between the ganglion cells. Junqueira et al., however, stated⁶⁴⁷: "...their function is also obscure". Stone stated²⁴⁴: "... results ... suggest that dopaminergic amacrine cells may well be involved more generally in physiologic modifications of eye growth, not just in the form-deprivation myopia". This result, however, is disputed²⁴⁵. Colchicine, which destroys amacrine cells, promotes eye growth substantially ²⁴⁶.

• Devadas et al. stated²⁴⁷ that the level of dopamine is (among others) controlled by "a retinal dark-light switch … in the light-state it secretes dopamine, while in the dark state it secretes melatonin …". Dopamine and melatonin are blocking each other²⁴².

• After induced form-deprivation myopia the electrolyte balance in the vitreous was disturbed: potassium and phosphate decreased, while chloride concentration increased. It was hypothesized that this change is caused by a reduction in the metabolic activity of the retina.²⁴⁸.

• Mertz et al. stated²⁴⁹: "...visual conditions that cause increased rates of eye elongation (diffusers or negative lens wear) produce a sharp decrease in all-trans-retinoic acid synthesis [from retinol, i.e. vitamin A] to levels barely detectable ... visual conditions which result in decreased rates of ocular elongation (recovery from diffusers of positive lens wear) produce a four- to fivefold increase in the formation of all-trans-retinoic acid". Correspondingly, Morgan stated⁷⁴ "synthesis [of retinoid acid] is increased under conditions that suppress eye growth..."

Supplementation of retinoic acid appears not to be helpful, because McFadden found²⁵⁰: "... retinal-retinoic-acid increased in myopic eyes with accelerated elongation and was lower in eyes with inhibited elongation. Retinoic acid levels in the choroid/sclera combined mirrored these directional changes. Feeding retinoic acid RA (25 mg/kg) repeatedly to guinea pigs, also resulted in rapid eye elongation (up to 5 times normal)."

Note:
It was shown that retinoic acid administered in the dark mimics the effect of light for some proteins expressed in the eye²⁵¹; this offers a link to the results about the level of illumination, which will be presented in section 3.7.2.

The feeding with 25 mg/kg retinoic acid, however, has no relevance to any normal supplementation, this dose is extremely high.

• The peptide glucagon, and the gene ZENK play a role in experimental myopia of chicks⁷⁴.

This remodeling is typical for the adjustment process during growth, when the normally growing eye is optimized for best image resolution. Myopia occurs only when this feedback mechanism is disturbed.

3.3.4 Remarks on the Image Quality Model

Some critical remarks against too simplifying conclusions drawn from image quality experiments are:

• Most of the tests with experimental myopia were done with chicks; the chick, however, does not possess retinal blood supply²⁵², and also the sclera of chicks and mammals are very different⁷⁴. For monkeys, at some species excessive accommodation is involved in experimental myopia, at other species it is not²⁵².

Moreover, Schaeffel et al. stated⁶⁶ that "there are also striking differences in the development of deprivation myopia in different populations of chickens." The result of experiments with mice was summarized by Schaeffel et al²⁵³: "Prolonged occlusion produces a significant myopic shift in B6 mice, but not in D2 mice [B6 and D2 are two different strains of mice]."

Note:
These results by Schaeffel underline the thesis that myopia is not caused by genetic heritage or by environment, but by the interworking of both (see section 3.21.7).

• With all those experiments, myopia can be initiated to a predictable degree. People, however, don't react obviously not uniformly, i.e. when exposed to the same environment, the same tasks and the same nutrition, some people become myopic and some will not. In other words, for people there are ways to counterbalance the impact of myopia initiating events, which seem not to exist for the tested animals. The target of myopia prevention should be, to promote and enforce these counterbalancing mechanisms.

• No explanation of the delay / lag of accommodation at myopes was given so far by the image quality model.

• For a potential impact of the vergence issue on the results of experimental myopia see section 3.4.

• These experiments can induce stress on the animals; stress, however, was found to be able to promote myopia as well (see section 3.13). Moreover, some of the experiments are increasing the temperature in the chick eye²⁵⁴; for the impact of the temperature on myopia see section 3.10. The stress model and the temperature model, however, cannot explain the different effects of positive and negative lenses (sign detection).

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