Chromatic Light Therapy for Inhibiting Myopia Progression: Human Studies.

Myopia, a common refractive error, has been associated with various risk factors, but time outdoors has emerged as a significant protective factor against its onset. This association is believed to be mediated by the influence of sunlight on dopamine release, a neurotransmitter crucial for regulating eye growth. Recent research has explored the specific properties of light in order to identify potential interventions for myopia control in children. Low-level red light therapy has gained attention, and has shown promise in inhibiting myopia progression, although there are concerns about safety and rebound effects. Similarly, blue light stimulation aims to upregulate retinal dopamine activity, yet conclusive evidence supporting its efficacy is lacking. Moreover, researchers explored the use of the entire visible light spectrum by digitally imposing longitudinal chromatic aberration to adjust proper eye growth. Preliminary findings suggest that digitally simulated chromatic aberration could potentially serve as a myopia control strategy and highlights the need for further investigation into long-term effects. As research progresses, understanding the efficacy and safety of light-based interventions for myopia control remains crucial for informing clinical practice and optimizing patient outcomes.

Mechanisms of emmetropization and what might go wrong in myopia.

Studies in animal models and humans have shown that refractive state is optimized during postnatal development by a closed-loop negative feedback system that uses retinal image defocus as an error signal, a mechanism called emmetropization. The sensor to detect defocus and its sign resides in the retina itself. The retina and/or the retinal pigment epithelium (RPE) presumably releases biochemical messengers to change choroidal thickness and modulate the growth rates of the underlying sclera. A central question arises: if emmetropization operates as a closed-loop system, why does it not stop myopia development? Recent experiments in young human subjects have shown that (1) the emmetropic retina can perfectly distinguish between real positive defocus and simulated defocus, and trigger transient axial eye shortening or elongation, respectively. (2) Strikingly, the myopic retina has reduced ability to inhibit eye growth when positive defocus is imposed. (3) The bi-directional response of the emmetropic retina is elicited with low spatial frequency information below 8 cyc/deg, which makes it unlikely that optical higher-order aberrations play a role. (4) The retinal mechanism for the detection of the sign of defocus involves a comparison of defocus blur in the blue (S-cone) and red end of the spectrum (L + M-cones) but, again, the myopic retina is not responsive, at least not in short-term experiments. This suggests that it cannot fully trigger the inhibitory arm of the emmetropization feedback loop. As a result, with an open feedback loop, myopia development becomes "open-loop".

Effects of short-term exposure to red or near-infrared light on axial length in young human subjects.

PURPOSE: To determine whether visible light is needed to elicit axial eye shortening by exposure to long wavelength light. METHODS: Incoherent narrow-band red (620 ± 10 nm) or near-infrared (NIR, 875 ± 30 nm) light was generated by an array of light-emitting diodes (LEDs) and projected monocularly in 17 myopic and 13 non-myopic subjects for 10 min. The fellow eye was occluded. Light sources were positioned 50 cm from the eye in a dark room. Axial length (AL) was measured before and after the exposure using low-coherence interferometry. RESULTS: Non-myopic subjects responded to red light with significant eye shortening, while NIR light induced minor axial elongation (-13.3 ± 17.3 µm vs. +6.5 ± 11.6 µm, respectively, p = 0.005). Only 41% of the myopic subjects responded to red light exposure with a decrease in AL and changes were therefore, on average, not significantly different from those observed with NIR light (+0.2 ± 12.1 µm vs. +1.1 ± 11.2 µm, respectively, p = 0.83). Interestingly, there was a significant correlation between refractive error and induced changes in AL after exposure to NIR light in myopic eyes (r(15) = -0.52, p = 0.03) and induced changes in AL after exposure to red light in non-myopic eyes (r(11) = 0.62, p = 0.02), with more induced axial elongation with increasing refractive error. CONCLUSIONS: Incoherent narrow-band red light at 620 nm induced axial shortening in 77% of non-myopic and 41% of myopic eyes. NIR light did not induce any significant changes in AL in either refractive group, suggesting that the beneficial effect of red laser light therapy on myopia progression requires visible stimulation and not simply thermal energy.

Imposed positive defocus changes choroidal blood flow in young human subjects.

PURPOSE: It has previously been found that imposing positive defocus changes axial length and choroidal thickness after only 30 min. In the present study, we investigated whether these changes may result from an altered choroidal blood flow. METHODS: Eighteen young adult subjects watched a movie from a large screen (65 in.) in a dark room at 2 m distance. A 15-min wash-out period was followed by 30 min of watching the movie with a monocular positive defocus (+ 2.5D). Changes in axial length and ocular blood flow were measured before and after the defocus, by using low-coherent interferometer (LS 900, Haag-Streit, Switzerland) and a laser speckle flowgraphy (LSFG) RetFlow unit (Nidek Co., LTD, Japan), respectively. Three regions were analyzed: (1) the macular area, where choroidal blood flow can be measured, (2) the optic nerve head (ONH), and (3) retinal vessel segments. RESULTS: Changes in choroidal blood flow were significantly and negatively correlated with changes in axial length that followed positive defocus in exposed eyes (R = - 0.67, p < 0.01). The absolute values of changes in choroidal blood flow in the defocused eyes were significantly larger than in the fellow control eyes (2.35 ± 2.16 AU vs. 1.37 ± 1.44 AU, respectively, p < 0.05). ONH and retinal blood flow were not associated with the induced changes in axial length. CONCLUSIONS: Positive defocus selectively alters choroidal, but not retinal or ONH blood flow in young human subjects after short-term visual exposure. The results suggest that blood flow modulation is involved in the mechanism of choroidal responses to optical defocus.

Myopia: why the retina stops inhibiting eye growth.

In myopia, the eye grows too long, and the image projected on the retina is poorly focused when subjects look at a distance. While the retina normally controls eye growth by visual processing, it seems to give up during myopia development. But what has changed? To determine whether the sharp image is in front or behind the retinal plane, a comparison of image sharpness in red and blue would provide a reliable cue because focal planes are about 1.3 D apart due to longitudinal chromatic aberration (LCA). However, up to now, it could not be demonstrated that the retina does, in fact, such a comparison. We used a new approach: movies were digitally filtered in real time to present either the blue channel of the RGB color format unfiltered while green and red were blurred ("blue in focus"), or the red channel was unfiltered while green and blue were blurred ("red in focus") accordingly to the human LCA function. Here we show that, even though filtered movies looked similar, eyes became significantly shorter when the movie was sharp in the red plane but became longer when it was presented sharp in the blue plane. Strikingly, the eyes of young subjects who were already myopic did not respond at all-showing that their retina could no longer decode the sign of defocus based on LCA. Our findings resolve a long-standing question as to how the human retina detects the sign of defocus. It also suggests a new non-invasive strategy to inhibit early myopia development: keeping the red image plane on a computer screen sharp but low pass filtering the blue.

Transient Eye Shortening During Reading Text With Inverted Contrast: Effects of Refractive Error and Letter Size.

Purpose: Myopes have a reduced ability to elicit transient axial eye shortening after imposed positive defocus, which may be due to changes in the biochemical signaling cascade controlling choroidal thickness. We have investigated whether reading with inverted text contrast can still elicit transient axial eye shortening in myopes, like it has been shown in emmetropes. Methods: Changes in axial length before and after reading were measured with the Lenstar LS-900. Text with inverted contrast was read from a large screen at 2 m distance (angular subtense 35.9°, screen luminance matched in all conditions to 86 ± 7 cd/m²) for 30 minutes. Moreover, we investigated the effects of letter sizes. Two text sizes were tested: "small" text (letter height 13.75 arcmin) and "large" text (letter height 34.39 arcmin). Results: Reading text with inverted contrast induced eye shortening (-10.2 ± 9.5 µm) in myopic eyes (n = 11; refraction -3.5 ± 1.9 diopters [D]), showing that an inhibitory signal was still generated by the retina as in emmetropes. In 15 subjects (refraction +1.7 to -4.2 D) we found that small text does not elicit significant differences in axial length (P = 0.09). However, with large text, changes in axial length were clearly different for the both contrast polarities (standard contrast, +1.7 ± 9.0 µm; inverted contrast, -9.7 ± 8.9 µm; P = 0.0017). Conclusions: Although positive defocus may not be an effective intervention to inhibit further eye growth in myopes, other visual stimuli can still trigger choroidal thickening and possibly generate signals to decrease myopia progression. Translational Relevance: Our results have shown the optimized text features, which may have a positive impact on myopia control.

"Emmetropic, but not myopic human eyes distinguish positive defocus from calculated defocus in monochromatic red light".

Studies in animal models have provided evidence that broadband light and chromatic cues are necessary for successful emmetropization. We have studied this question in young human subjects by measuring short-term changes in axial length when they watched movies with calculated defocus (2.5D) or optically defocused movies (+2.5D) with red interference filters (620 ± 10 nm). Since filters cut luminance down by a factor of 10, a control experiment with neutral density filters (ND 1.0) was done. Ten myopes and 10 emmetropes were studied. Four experimental conditions were tested on two separate days. On the first day, movies with calculated defocus, and defocused by positive lenses were watched with ND filters. On the second day, movies with the same defocus patterns were watched with the red filters. Movies were presented on a large TV screen (LG OLED65C9, 65″) in a dark room at 2 m distance for 30 min. Changes in axial length before and after each stimulation were measured with the Lenstar (LS 900, with autopositioning system; Haag-Streit). Interestingly, the effects of calculated defocus or optical positive defocus on axial length were suppressed by 1.0 ND filters in myopes and emmetropes, with no clear trend. In contrast, narrow-band red light suppressed eye elongation with calculated defocus but not eye shortening with positive defocus in emmetropes. In myopes, as previously found in white light, there was a trend of axial eye elongation with positive lenses. In conclusion, the effect of positive lenses on eye growth did not require chromatic cues.

Emmetropic, But Not Myopic Human Eyes Distinguish Positive Defocus From Calculated Blur.

Purpose: Defocus blur imposed by positive lenses can induce hyperopia, whereas blur imposed by diffusers induces deprivation myopia. It is unclear whether the retina can distinguish between both conditions when the magnitude of blur is matched. Methods: Ten emmetropic (average 0.0 ± 0.3 diopters [D]) and 10 subjects with myopia (-2.7 ± 0.9 D; 24 ± 4 years) watched a movie on a large screen (65 inches at 2 meters (m) distance. The movie was presented either unfiltered ("control"), with calculated low-pass filtering equivalent to a defocus of 2.5 D, or with binocular real optical defocus of +2.5 D. Spatial filtering was done in real-time by software written in Visual C++. Axial length was followed with the Lenstar LS-900 with autopositioning system. Results: Watching unfiltered movies ("control") caused no changes in axial length. In emmetropes, watching movies with calculated defocus caused axial eye elongation (+9.8 ± 7.6 µm) while watching movies with real positive defocus caused shorter eyes (-8.8 ± 9.2 µm; difference between both P < 0.0001). In addition, in myopes, calculated defocus caused longer eyes (+8.4 ± 9.0 µm, P = 0.001). Strikingly, myopic eyes became also longer with positive defocus (+9.1 ± 11.2 µm, P = 0.02). The difference between emmetropic and myopic eyes was highly significant (-8.8 ± 9.2 µm vs. +9.1 ± 11.2 µm, respectively, P = 0.001). Conclusions: (1) In emmetropic human subjects, the retina is able to distinguish between real positive defocus and calculated defocus even when the modulation transfer function was matched, (2) in myopic eyes, the retina no longer distinguishes between both conditions because the eyes became longer in both cases. Results suggest that the retina in a myopic eye has reduced ability to detect positive defocus.

Demyelination and shrinkage of axons in the retinal nerve fiber layer in chickens developing deprivation myopia.

Placing diffusers in front of the eyes induces deprivation myopia in a variety of animal models. As a result of the low pass filtering of the retinal images, less spatial information is available to the retina which should reduce neural activity. Since it has been found that myelination of axons in the central nervous system is modulated by neuronal activity, we have studied whether ganglion cell axons may shrink in response to the restricted visual input. Young chickens were treated for 5 h or 7 days with frosted diffusers to induce deprivation myopia. Nerve fiber layer thickness was measured in vivo, using B-scan OCT. Refractive states were tracked by IR photoretinoscopy, and UV fundus reflectivity by a custom-built device which flashed an LED centered in the camera aperture and recorded pupil brightness after refractive errors were corrected by trial lenses. Moreover, structure and histology of the retinal nerve fibers layer (RNFL) were analyzed ex vivo using transmission electron microscopy and immunohistochemistry. Since chicks have both non-myelinated and myelinated fibers in their RNFL, the thickness of myelin sheaths (G ratio) was measured, as well as the percentage of myelinated axons and the diameters of unmyelinated axons. Short-term deprivation caused an increase in UV fundus reflectivity already after 5 h (measured as pixel grey levels in the pupil: 28 ±â€¯5 vs. 36 ±â€¯10, p < 0.05) and thinning of the myelin sheaths (higher G ratio), compared to untreated control eyes (0.74 ±â€¯0.01 vs. 0.79 ±â€¯0.03, p < 0.05). Neither axon diameters (0.81 ±â€¯0.05 µm vs. 0.82 ±â€¯0.15 µm) nor thickness of the RNFL had changed after only 5 h (42.9 ±â€¯1.3 µm vs. 42.3 ±â€¯2.5 µm). However, after 7 days of diffuser wear, axons had become thinner (0.56 ±â€¯0.14 µm vs. 0.78 ±â€¯0.09 µm vs, p < 0.05), which could explain the thinning of the RNFL (36.3 ±â€¯2.7 µm vs. 42.1 ±â€¯2.4 µm, p < 0.01). Furthermore, myopic eyes had 38% less myelinated axons than untreated eyes as determined by immunohistochemical labelling against myelin basic protein (immunopositive areas in the central retina 1406 ±â€¯341 µm2 vs. 2185 ±â€¯290 µm2 in controls, p < 0.001). Myelin sheaths in the remaining axons remained unchanged (G ratio 0.76 ±â€¯0.02 vs. 0.76 ±â€¯0.03). Our study shows that deprivation myopia is associated with a significant loss of myelinated axons and shrinkage of the axon diameters of certain fibers in the RNFL. Early changes were already detected after 5 h and were accompanied by an increased fundus reflectivity in UV light. These parameters could therefore serve as the biomarkers for myopia development, at least in the chicken.

Changes in fundus reflectivity during myopia development in chickens.

Previous studies have shown that changes in functional activity in the retina can be visualized as changes in fundus reflectivity. When the image projected on the retina is low pass filtered or defocused by covering the eye with a frosted diffuser or a negative lens, it starts growing longer and develops myopia. We have tested the hypothesis that the resulting altered retinal activity may show up as changes in fundus reflectivity. Fundus reflectivity was measured in chickens in vivo, both in visible (400-800 nm, white) and near ultraviolet (UV) light (315-380 nm). Two CCD cameras were used; a RGB camera and a camera sensitive in near UV light (peak sensitivity at 360 nm). White and UV LEDs, respectively, placed in the center of the camera lens aperture, served as light sources. Software was written to flash the LEDs and record the average brightness of the pupil that was illuminated by light reflected from the fundus. The average pixel grey level (px) in the pupil was taken as a measure of the amount of reflected light while refractive errors were corrected by trial lenses after pupil brightness was corrected for pupil size. It was found that myopic eyes had brighter pupils in UV light, compared to eyes with normal vision, no matter whether myopia was induced by diffusers or negative lenses (48 ± 9 vs. 28 ± 3, p<0.001 and 47 ± 7 vs. 27 ± 2, respectively). Using SD-OCT in alert chickens it was found that the retinal nerve fiber layer (RNFL) and the retinal ganglion cell layer (RGCL) in the central retina became thinner already at early stages of myopia development, compared to controls (31.2 ± 5.8 µm vs. 43.9 ± 2.6 µm, p<0.001 and 36.9 ± 1.2 µm vs. 44 ± 0.5 µm, respectively). While the decrease in RNFL thickness occurred concomitantly with the increase in UV reflectivity, it remains unclear whether these changes were causally linked. Thinning of the RNFL could be due to reduced neural activity in retinal ganglion cells but also due to metabolic changes in the retina during myopia development.