The recently published Breher et al. [1] article examining psychophysical thresholds for nominally “on” and “off” stimuli in myopic eyes refers to earlier published work by our group about contrast theory [2,3]. They mistakenly state that Diffusion Optics Technology (DOT) myopia control lens design uses contrast reduction to down-regulate a hypothesized enhanced ON contrast sensitivity in myopes. This comment aims to rectify misunderstandings in that article.

The very unexpected discovery that a subset of haplotypes of the genes encoding long (L) and middle- (M) wavelength-sensitive cone opsins cause exon-skipping and are associated with myopia [4,5] is a challenge for classical theories of myopia. The original discovery of myopia-causing opsin gene haplotypes was in Bornholm eye disease, where affected individuals had both myopia and red-green color blindness [6]. However, the colorblindness was caused by an unrelated mutation, and myopia was caused by a gene splicing defect that reduced photopigment in a submosaic of cones. Thus, these myopes have cone mosaics made of normal cones intermixed with cones that are viable but inefficient at absorbing light.

Every cone in the human retina, even in the far periphery, forms the center of one midget ON-and one midget OFF-bipolar cell receptive field [7]. In individuals with a submosaic of cones that are inefficient at absorbing light, when the receptive field of a bipolar cell is sampling a region of the image with no contrast, if the central cone is normal, the surrounding cones will be a mixture of normal and absorption-deficient cones. Therefore, the center cone will absorb more photons than the average of its neighbors, and the ON-bipolar cell will be activated. At the same time, the receptive field of a bipolar cell with an inefficient cone center will absorb fewer photons than its neighbors, and the OFF-bipolar cell will be activated. Thus, a submosaic of cones that are inefficient at absorbing light will produce spurious activation of both ON- and OFF-bipolar cells–signaling contrast even when there is no contrast in the image. This is a major clue for understanding the mechanism of myopia since the haplotype of the opsin genes originally discovered in Bornholm eye disease produces, by far, the largest effect size (> 10 D) observed in non-syndromic myopia [5]. This indicates that constitutive spurious contrast signaling is a powerful driver of axial elongation. Moreover, there is tremendous haplotype diversity in the cone opsin genes in the normal population [4]. It has recently been shown that common opsin haplotypes that occur with high frequency in the population are associated with milder splicing defects and are risk factors for common myopia, making nucleotide polymorphisms in the opsin genes the most significant single-gene determinant of common myopia [4]. About 1/4th of the population has mutations in the opsin genes that increase the risk of myopia by >300%.

Breher et al. [1] argued that our contrast theory proposes that myopia associated with cone opsin gene splicing defects is caused by a differential involvement of ON- and OFF-retinal pathways. However, as explained above, we predict that in most individuals with opsin splicing defects, spurious activation would occur equally in both ON and OFF bipolar cells. While there is evidence for the involvement of ON pathways in myopia from the extremely high refractive errors often associated with stationary night blindness, which represents total ON-bipolar cell dysfunction, with unaltered OFF-function [8], this was not a consideration in the development of the DOT lenses [2]. They are designed to lower contrast on the retina more generally, reducing activity in both ON- and OFF-pathways. Second, Breher et al. [1] write that we have “hypothesized enhanced ON contrast sensitivity in myopes,” but we predict the opposite. We predict that spurious constitutive activation of ON and OFF bipolars in individuals with cone opsin gene splicing defects introduces noise that would lower contrast sensitivity in the affected individuals, including the large population with common myopia associated with milder opsin splicing defect haplotypes [4]. Moreover, the mechanism of action of the DOT lenses [2] doesn't require optical scattering to have an asymmetrical influence on ON/OFF pathway processing [1]. Thus, lower contrast sensitivities observed by Breher et al. [1] in myopes are consistent with the contrast hypothesis rather than contradicting it as they propose.

We propose that activity in the contrast pathways is the signal that drives eye growth and that separate “start” and “stop” signals are not required to explain the etiology of myopia [9]. Moreover, we hypothesize that contrast signaling is the final common pathway for both genetic and environmental contributions to myopia. Accordingly, the spurious signaling in the contrast pathway caused by various genetic mutations plus the abnormal exposure to high contrast images on the peripheral retina produced by printed materials and video displays of all types are combined to determine a person's refractive error. Breher et al. [1] state that over-stimulation caused by the spurious activity resulting from having an opsin-skipping haplotype is “suggested to be attenuated when optical scattering is applied.” However, the DOT lenses [2] cannot attenuate the spurious activity caused by having a subset of cones that absorb fewer photons. Rather, the scattering attenuates the overall contrast in actual retinal images, thereby reducing the total final contrast signaling burden and reducing myopia progression both in those children who are predisposed because of their genetics and in those whose myopia is being driven because of excessive exposure to myopiagenic stimuli.

Breher et al. [1] say that “the proposal that scattering should inhibit myopia, rather than stimulating it, contrasts with the classical concept of deprivation myopia.” This is true. However, recent findings require us to modify our hypotheses about contrast and myopia. Smith et al. [10] showed that when nonhuman primates wore strong diffusers under conditions where auxiliary lighting raised the light levels to ∼25,000 lux during the middle of the day, most animals tested developed form-deprivation hyperopia. This result signals a paradigm shift away from the classical concept of deprivation myopia. Since our evolutionary ancestors were outdoor dwellers, the high-light-level results, which are consistent with the contrast hypothesis, may be more relevant than those obtained under the unnatural low-light laboratory conditions. The reason why diffusers worn at low light levels are associated with myopia remains to be clarified. However, we agree with Breher et al. [1] that contrast adaptation in response to altered image quality may be a major regulator of eye growth. There are contrast adaptation mechanisms in the retina that increase the gain of contrast detectors when the contrast on the retina is reduced [11]. It is also true that cone photoreceptors are noisy [12], and under the very low contrast conditions produced by strong diffusers, the gain may be increased such that cone noise drives spurious contrast signals. Thus, very low contrast may paradoxically drive contrast signaling. Cone noise is reduced at high light levels, possibly explaining why diffusers worn at high light levels are associated with hyperopia, as predicted by the contrast theory.

Contrary to the idea that lowering contrast stimulates eye growth, peripheral visual signals dominate refractive development [13], and in animal studies, imposing myopic defocus in the periphery (thus lowering contrast on the retina) can slow axial growth [14]. Moreover, increasing the amount of positive power in myopia control lenses, in excess of what might compensate for any peripheral hyperopia, e.g., + 3 diopters [15], has been shown to be more effective in controlling axial growth. Thus, there can be little doubt that lowering contrast by myopic defocus reduces eye growth. However, a remaining sticking point is that hyperopic defocus in young children can be argued to also lower contrast, requiring a mechanism in the eye to distinguish between hyperopic defocus and myopic defocus. The final clarification of contrast theory relies on three facts: 1) peripheral visual signals dominate refractive development, 2) in the natural environment in which emmetropization mechanisms evolved, images of distant scenery often fill the peripheral retina, and 3) young eyes are “far-sighted” meaning that they can typically bring images of distant scenery into clear focus via accommodation. Thus, we claim that accommodation can compensate for hyperopic blur in young children, bringing distant scenery into sharp, high-contrast focus. Therefore, because the accommodation mechanism can distinguish between hyperopic and myopic defocus and compensate for hyperopia in young children, the retinal emmetropization mechanism doesn't need to. The difference between hyperopic and myopic defocus is that accommodation reduces hyperopic defocus and increases contrast on the retina, while accommodation increases myopic defocus, lowering contrast. Eyes are accommodated to some degree most of the time. As the eye grows from hyperopia through emmetropia to myopia, accommodation will progressively reduce the amount of time clear images from distant scenery are well focused on the peripheral retina. According to contrast theory, the time-averaged reduction of peripheral contrast in the natural world will result in slowing eye growth as emmetropia is reached.

We acknowledge the efforts of Breher et al. [1] to investigate the relationship between Diffusion Optics Technology and receptive field processing. By clarifying our theory's principles, we hope to foster a dialogue within the scientific community regarding Diffusion Optics Technology (DOT), contrast theory, and myopia control, and we look forward to further discussions that may arise from this exchange.