The effects of ambient narrowband long-wavelength light on lens-induced myopia and form-deprivation myopia in tree shrews.

Here we examine the effects of ambient red light on lens-induced myopia and diffuser-induced myopia in tree shrews, small diurnal mammals closely related to primates. Starting at 24 days of visual experience (DVE), seventeen tree shrews were reared in red light (624 ± 10 or 634 ± 10 nm, 527-749 human lux) for 12-14 days wearing either a -5D lens (RL-5D, n = 5) or a diffuser (RLFD, n = 5) monocularly, or without visual restriction (RL-Control, n = 7). Refractive errors and ocular dimensions were compared to those obtained from tree shrews raised in broad-spectrum white light (WL-5D, n = 5; WLFD, n = 10; WL Control, n = 7). The RL-5D tree shrews developed less myopia in their lens-treated eyes than WL-5D tree shrews at the end of the experiment (-1.1 ± 0.9D vs. -3.8 ± 0.3D, p = 0.007). The diffuser-treated eyes of the RLFD tree shrews were near-emmetropic (-0.3 ± 0.6D, vs. -5.4 ± 0.7D in the WLFD group). Red light induced hyperopia in control animals (RL-vs. WL-Control, +3.0 ± 0.7 vs. +1.0 ± 0.2D, p = 0.02), the no-lens eyes of the RL-5D animals, and the no-diffuser eyes of the RLFD animals (+2.5 ± 0.5D and +2.3 ± 0.3D, respectively). The refractive alterations were consistent with the alterations in vitreous chamber depth. The lens-induced myopia developed in red light suggests that a non-chromatic cue could signal defocus to a less accurate extent, although it could also be a result of "form-deprivation" caused by defocus blur. As with previous studies in rhesus monkeys, the ability of red light to promote hyperopia appears to correlate with its ability to retard lens-induced myopia and form-deprivation myopia, the latter of which might be related to non-visual ocular mechanisms.

Fighting Myopia with Intermittent Nearwork Breaks: 20 Seconds Every 20 Minutes Might Not Be Enough Time.

SIGNIFICANCE: Practitioners commonly prescribe the 20/20/20 rule with hopes that, if patients follow it, they will reduce their myopic progression. This clinical perspective provides evidence that 20-second break from nearwork every 20 minutes are not enough time to impact ocular growth.The ongoing myopia epidemic is a major public health crisis. Although the correlation between nearwork tasks such as reading, computers, and smartphones and myopia development is controversial, multiple lines of research suggest that sustained nearwork contributes to myopia development. Clinicians have proposed that children should take short breaks from nearwork with a 20-second break every 20 minutes being a common suggestion. Animal model data do strongly support the idea that multiple short breaks across time can cancel out the effects of longer periods of myopia-promoting activities. However, the animal model data also suggest that repeated episodes of 20 seconds are ineffective at reducing myopia development and instead indicate that sustained breaks of 5 minutes or more every hour are needed to negate myopiagenic effects.

Repeated Low-level Red-light Therapy: The Next Wave in Myopia Management?

SIGNIFICANCE: Exposure to long-wavelength light has been proposed as a potential intervention to slow myopia progression in children. This article provides an evidence-based review of the safety and myopia control efficacy of red light and discusses the potential mechanisms by which red light may work to slow childhood myopia progression.The spectral composition of the ambient light in the visual environment has powerful effects on eye growth and refractive development. Studies in mammalian and primate animal models (macaque monkeys and tree shrews) have shown that daily exposure to long-wavelength (red or amber) light promotes slower eye growth and hyperopia development and inhibits myopia induced by form deprivation or minus lens wear. Consistent with these results, several recent randomized controlled clinical trials in Chinese children have demonstrated that exposure to red light for 3 minutes twice a day significantly reduces myopia progression and axial elongation. These findings have collectively provided strong evidence for the potential of using red light as a myopia control intervention in clinical practice. However, several questions remain unanswered. In this article, we review the current evidence on the safety and efficacy of red light as a myopia control intervention, describe potential mechanisms, and discuss some key unresolved issues that require consideration before red light can be broadly translated into myopia control in children.

The effects of intensity, spectral purity and duty cycle on red light-induced hyperopia in tree shrews.

INTRODUCTION: There have recently been several clinical studies suggesting that brief periods of exposure to red light (repeated low-level red light, 'RLRL') may produce a dramatic anti-myopia effect, calling for further investigations into its therapeutic parameters. Unfortunately, many experimental species used in refractive studies develop myopia in response to this wavelength. Tree shrews are the only animal model other than rhesus monkeys that consistently exhibit hyperopic responses to ambient red light. Here, tree shrews were used to study the influence of the spectral purity, duty cycle and intensity of red light on its anti-myopic effect. METHODS: Juvenile tree shrews (Tupaia belangeri) were raised from 24 to 35 days after eye opening under ambient lighting that was: standard white colony fluorescent light; pure narrow band red light of either 600, 50-100 or 5 lux; red light that was diluted with 10% white light (by lux) or 50% white and 2 s of pure red light that alternated with 2 s of pure white light (50% duty cycle). Refractive measures were taken with a NIDEK ARK-700 autorefractor and axial dimensions with a LenStar LS-900 Axial Biometer. RESULTS: The pro-hyperopia effect of ambient red light was greatly reduced by even small amounts of concurrent white light 'contamination', but remained robust if 2-s periods of pure white light alternated with 2 s of red. Finally, the hyperopic effect of red light was maintained at reduced luminance levels in the 50-100 lux range and only failed at 5 lux. CONCLUSIONS: These results have implications for understanding the mechanisms by which ambient red light affects refractive development, and possibly also for clinical therapies using RLRL. Nevertheless, it remains to be determined if the mechanism of the current clinical RLRL therapy is the same as that operating on tree shrews in ambient red light.

Chromatically simulated myopic blur counteracts a myopiagenic environment.

There is a world-wide epidemic of myopia (nearsightedness), produced largely by human-made environmental visual cues that disrupt the emmetropization feedback mechanism that normally uses defocus cues to produce and maintain eyes in good focus. Previous studies have shown that the wavelength of light affects this process and that myopic defocus can slow the progression of myopia in children. We first asked if continuous exposure to a small cage with restricted viewing distance would produce an environmentally-induced myopia in tree shrews, small diurnal mammals closely related to primates. A group (n = 7) spent 11 days in a small cage with restricted viewing distance; one wall was a video display covered with Maltese crosses that included low-to-high spatial frequencies in the range visible to tree shrews. This group developed myopia (-1.2 ± 0.4 [stderr] D) that was significant relative to a colony group of seven animals (+1.0 ± 0.2 D) raised in mesh cages allowing more distant viewing. We then asked if chromatically-simulated myopic defocus, produced by blurring just the blue channel of the video display, would counteract this environmentally-induced myopia in a group of eight tree shrews. This group instead became significantly hyperopic (+4.0 ± 0.4 D) due to slowed axial elongation. These results demonstrate the high potency of chromatic cues in refractive regulation and may provide the basis for an anti-myopia treatment in humans.

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.

A multimodal neuroimaging study investigating resting-state connectivity, glutamate and GABA at 7 T in first-episode psychosis.

BACKGROUND: The major excitatory and inhibitory neurometabolites in the brain, glutamate and γ-aminobutyric acid (GABA), respectively, are related to the functional MRI signal. Disruption of resting-state functional MRI signals has been reported in psychosis spectrum disorders, but few studies have investigated the role of these metabolites in this context. METHODS: We included 19 patients with first-episode psychosis and 21 healthy controls in this combined magnetic resonance spectroscopy (MRS) and resting-state functional connectivity study. All imaging was performed on a Siemens Magnetom 7 T MRI scanner. Both the MRS voxel and the seed for functional connectivity analysis were located in the dorsal anterior cingulate cortex (ACC). We used multiple regressions to test for an interaction between ACC brain connectivity, diagnosis and neurometabolites. RESULTS: ACC brain connectivity was altered in first-episode psychosis. The relationship between ACC glutamate and ACC functional connectivity differed between patients with first-episode psychosis and healthy controls in the precuneus, retrosplenial cortex, supramarginal gyrus and angular gyrus. As well, the relationship between ACC GABA and ACC functional connectivity differed between groups in the caudate, putamen and supramarginal gyrus. LIMITATIONS: We used a small sample size. As well, although they were not chronically medicated, all participants were medicated during the study. CONCLUSION: We demonstrated a link between the major excitatory and inhibitory brain metabolites and resting-state functional connectivity in healthy participants, as well as an alteration in this relationship in patients with first-episode psychosis. Combining data from different imaging modalities may help our mechanistic understanding of the relationship between major neurometabolites and brain network dynamics, and shed light on the pathophysiology of first-episode psychosis.

Amber light treatment produces hyperopia in tree shrews.

PURPOSE: Exposure to narrow-band red light, which stimulates only the long-wavelength sensitive (LWS) cones, slows axial eye growth and produces hyperopia in tree shrews and macaque monkeys. We asked whether exposure to amber light, which also stimulates only the LWS cones but with a greater effective illuminance than red light, has a similar hyperopia-inducing effect in tree shrews. METHODS: Starting at 24 ± 1 days of visual experience, 15 tree shrews (dichromatic mammals closely related to primates) received light treatment through amber filters (BPI 500/550 dyed acrylic) either atop the cage (Filter group, n = 8, 300-400 human lux) or fitted into goggles in front of both eyes (Goggle group, n = 7). Non-cycloplegic refractive error and axial ocular dimensions were measured daily. Treatment groups were compared with age-matched animals (Colony group, n = 7) raised in standard colony fluorescent lighting (100-300 lux). RESULTS: At the start of treatment, mean refractive errors were well-matched across the three groups (p = 0.35). During treatment, the Filter group became progressively more hyperopic with age (p < 0.001). By contrast, the Goggle and Colony groups showed continued normal emmetropization. When the treatment ended, the Filter group exhibited significantly greater hyperopia (mean [SE] = 3.5 [0.6] D) compared with the Goggle (0.2 [0.8] D, p = 0.01) and Colony groups (1.0 [0.2] D, p = 0.01). However, the refractive error in the Goggle group was not different from that in the Colony group (p = 0.35). Changes in the vitreous chamber were consistent with the refractive error changes. CONCLUSIONS: Exposure to ambient amber light produced substantial hyperopia in the Filter group but had no effect on refractive error in the Goggle group. The lack of effect in the Goggle group could be due to the simultaneous activation of the short-wavelength sensitive (SWS) and LWS cones caused by the scattering of the broad-band light from the periphery of the goggles.

How chromatic cues can guide human eye growth to achieve good focus.

The postnatal growing eye uses visual cues to actively control its own axial elongation to achieve and maintain sharp focus, a process termed emmetropization. The primary visual cue may be the difference in image sharpness as sensed by the arrays of short- and long-wavelength sensitive cone photoreceptors caused by longitudinal chromatic aberration: Shorter wavelengths focus in front of longer wavelengths. However, the sparse distribution of short-wavelength sensitive cones across the retina suggests that they do not have sufficient spatial sampling resolution for this task. Here, we show that the spacing of the short-wavelength sensitive cones in humans is sufficient for them, in conjunction with the longer wavelength cones, to use chromatic signals to detect defocus and guide emmetropization. We hypothesize that the retinal spacing of the short-wavelength sensitive cones in many mammalian species is an evolutionarily ancient adaption that allows the efficient use of chromatic cues in emmetropization.

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

SIGNIFICANCE: 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. PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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.

The responses of V1 cortical neurons to flashed presentations of orthogonal single lines and edges.

How cortical neurons process multiple inputs is a fundamental issue in modern neuroscience. Neurons in visual cortical area V1 have been shown to exhibit cross-orientation suppression, where the response to an optimally oriented visual stimulus is reduced by the simultaneous presence of an orthogonally oriented stimulus. This is consistent with the view that cortical neurons respond to multiple inputs with a weighted average (or normalization) of the responses to the inputs presented separately. However, most of these studies have used drifting or counterphase-modulated grating stimuli, potentially confounding orientation effects with non-orientation-specific gain control mechanisms. Additionally, primate vision depends to a great extent on transient stimulus presentations during fixations between saccades. Therefore this study examined the responses of primate V1 neurons to orthogonal flashed-onset single edges and lines, and to their combinations. Single edges or lines do not typically cause strong suppression of the responses to an orthogonal stimulus, even though a grating does. This appears to hold true regardless of the relative contrasts of the orthogonal single lines or edges. This is consistent with response suppression from an orthogonal grating being due to non-orientation-specific contrast gain control (Koeling M, Shapley R, Shelley M. J Comp Neurosci 25: 390-400, 2008; Priebe NJ, Ferster D. Nat Neurosci 9: 552-561, 2006; Walker GA, Ohzawa I, Freeman RD. J.Neurophysiol 79: 227-239, 1998). While normalization mechanisms are clearly important for the cerebral cortex, under many conditions the responses of V1 cortical neurons to an optimally oriented stimulus can be unaffected by the presence of orthogonal stimuli, which may be important to avoid confounding the interpretation of a neural response.

The Role of Chromatic Aberration in Vision.

The study of biological optics would be complicated enough if light only came in a single wavelength. However, altering the wavelength (or distribution of wavelengths) of light has multiple effects on optics, including on diffraction, scattering (of various sorts), transmission through and reflection by various media, fluorescence, and waveguiding properties, among others. In this review, we consider just one wavelength-dependent optical effect: longitudinal chromatic aberration (LCA). All vertebrate eyes that have been tested have significant LCA, with shorter (bluer) wavelengths of light focusing closer to the front of the eye than longer (redder) wavelengths. We consider the role of LCA in the visual system in terms of both how it could degrade visual acuity and how biological systems make use of it.

The Parameters Governing the Anti-Myopia Efficacy of Chromatically Simulated Myopic Defocus in Tree Shrews.

Purpose: We previously showed that exposing tree shrews (Tupaia belangeri, small diurnal mammals closely related to primates) to chromatically simulated myopic defocus (CSMD) counteracted small-cage myopia and instead induced hyperopia (approximately +4 diopters [D]). Here, we explored the parameters of this effect. Methods: Tree shrews were exposed to the following interventions for 11 days: (1) rearing in closed (n = 7) or open (n = 6) small cages; (2) exposed to a video display of Maltese cross images with CSMD combined with overhead lighting (n = 4); (3) exposed to a video display of Maltese cross images with zero blue contrast ("flat blue," n = 8); and (4) exposed to a video display of black and white grayscale tree images with different spatial filtering (blue pixels lowpass <1 and <2 cycles per degree [CPD]) for the CSMD. Results: (1) Tree shrews kept in closed cages, but not open cages, developed myopia. (2) Overhead illumination reduced the hyperopia induced by CSMD. (3) Zero-blue contrast produced hyperopia but slightly less than the CSMD. (4) Both of the CSMD tree images counteracted small cage myopia, but the one low pass filtering blue <1 CPD was more effective at inducing hyperopia. Conclusions: Any pattern with reduced blue contrast at and below approximately 1 CPD counteracts myopia/promotes hyperopia, but maximal effectiveness may require that the video display be the brightest object in the environment. Translational Relevance: Chromatically simulated myopic blur might be a powerful anti-myopia therapy in children, but the parameter selection could be critical. Issues for translation to humans are discussed.

Attention influences single unit and local field potential response latencies in visual cortical area V4.

Many previous studies have demonstrated that changes in selective attention can alter the response magnitude of visual cortical neurons, but there has been little evidence for attention affecting response latency. Small latency differences, though hard to detect, can potentially be of functional importance, and may also give insight into the mechanisms of neuronal computation. We therefore reexamined the effect of attention on the response latency of both single units and the local field potential (LFP) in primate visual cortical area V4. We find that attention does produce small (1-2 ms) but significant reductions in the latency of both the spiking and LFP responses. Though attention, like contrast elevation, reduces response latencies, we find that the two have different effects on the magnitude of the LFP. Contrast elevations increase and attention decreases the magnitude of the initial deflection of the stimulus-evoked LFP. Both contrast elevation and attention increase the magnitude of the spiking response. We speculate that latencies may be reduced at higher contrast because stronger stimulus inputs drive neurons more rapidly to spiking threshold, while attention may reduce latencies by placing neurons in a more depolarized state closer to threshold before stimulus onset.

Limited bandwidth short-wavelength light produces slowly-developing myopia in tree shrews similar to human juvenile-onset myopia.

During postnatal development, an emmetropization feedback mechanism uses visual cues to modulate the axial growth of eyes so that, with maturation, images of distant objects are in focus on the retina. If the visual cues indicate that the eye has become too long, it generates STOP signals that slow eye elongation. Myopia is a failure of this process where the eye becomes too long. The existing animal models of myopia have been essential in understanding the mechanics of emmetropization but use visual cues that lead to rapidly progressing myopia and don't match the stimuli that lead to human myopia. Form deprivation removes esssentially all spatial contrast. Minus lens wear accurately guides axial elongation to restore sharp focus: technically it is not a model of myopia! In contrast, childhood myopia involves a slow drift into myopia, even with the presence of clear images. We hypothesize that, in the modern visual environment, STOP signals are present but often are not quite strong enough to prevent myopic progression. Using tree shrews, small diurnal mammals closely related to primates, we have developed an animal model that we propose better represents this situation. We used limited bandwidth light to provide limited chromatic cues for emmetropization that are not quite enough to produce fully effective STOP signaling, resulting in a slow drift into myopia as seen in children. We hypothesize that this animal model of myopia may prove useful in evaluating anti-myopia therapies where form deprivation and minus lens wear would be too powerful.

IMI 2023 Digest.

Myopia is a dynamic and rapidly moving field, with ongoing research providing a better understanding of the etiology leading to novel myopia control strategies. In 2019, the International Myopia Institute (IMI) assembled and published a series of white papers across relevant topics and updated the evidence with a digest in 2021. Here, we summarize findings across key topics from the previous 2 years. Studies in animal models have continued to explore how wavelength and intensity of light influence eye growth and have examined new pharmacologic agents and scleral cross-linking as potential strategies for slowing myopia. In children, the term premyopia is gaining interest with increased attention to early implementation of myopia control. Most studies use the IMI definitions of ≤-0.5 diopters (D) for myopia and ≤-6.0 D for high myopia, although categorization and definitions for structural consequences of high myopia remain an issue. Clinical trials have demonstrated that newer spectacle lens designs incorporating multiple segments, lenslets, or diffusion optics exhibit good efficacy. Clinical considerations and factors influencing efficacy for soft multifocal contact lenses and orthokeratology are discussed. Topical atropine remains the only widely accessible pharmacologic treatment. Rebound observed with higher concentration of atropine is not evident with lower concentrations or optical interventions. Overall, myopia control treatments show little adverse effect on visual function and appear generally safe, with longer wear times and combination therapies maximizing outcomes. An emerging category of light-based therapies for children requires comprehensive safety data to enable risk versus benefit analysis. Given the success of myopia control strategies, the ethics of including a control arm in clinical trials is heavily debated. IMI recommendations for clinical trial protocols are discussed.

Separability of stimulus parameter encoding by on-off directionally selective rabbit retinal ganglion cells.

The ganglion cell output of the retina constitutes a bottleneck in sensory processing in that ganglion cells must encode multiple stimulus parameters in their responses. Here we investigate encoding strategies of On-Off directionally selective retinal ganglion cells (On-Off DS RGCs) in rabbits, a class of cells dedicated to representing motion. The exquisite axial discrimination of these cells to preferred vs. null direction motion is well documented: it is invariant with respect to speed, contrast, spatial configuration, spatial frequency, and motion extent. However, these cells have broad direction tuning curves and their responses also vary as a function of other parameters such as speed and contrast. In this study, we examined whether the variation in responses across multiple stimulus parameters is systematic, that is the same for all cells, and separable, such that the response to a stimulus is a product of the effects of each stimulus parameter alone. We extracellularly recorded single On-Off DS RGCs in a superfused eyecup preparation while stimulating them with moving bars. We found that spike count responses of these cells scaled as independent functions of direction, speed, and luminance. Moreover, the speed and luminance functions were common across the whole sample of cells. Based on these findings, we developed a model that accurately predicted responses of On-Off DS RGCs as products of separable functions of direction, speed, and luminance (r = 0.98; P < 0.0001). Such a multiplicatively separable encoding strategy may simplify the decoding of these cells' outputs by the higher visual centers.

Effect of Scleral Crosslinking Using Multiple Doses of Genipin on Experimental Progressive Myopia in Tree Shrews.

Purpose: To evaluate the effect of scleral crosslinking (SXL) on slowing experimental progressive myopia in tree shrew eyes using sub-Tenon's injections of genipin (GEN) at different concentrations and number of injections. Methods: Three or five sub-Tenon's injections of GEN at 0 mM (sham), 10 mM, or 20 mM were performed in one eye every other day starting at 18 days of visual experience. Form deprivation (FD) myopia was induced in the injected eye between 24 and 35 days of visual experience; the fellow eye served as control. Tree shrews were randomly assigned to five experimental groups: FD (n = 8); FD + 5 × sham injections (n = 6); FD + 3 × GEN injections at 10 mM (n = 6) and 20 mM (n = 6); and FD + 5 × GEN injections at 20 mM (n = 6). Refractive state and ocular dimensions were measured daily. Results: Compared with the FD group, the sham-injected group showed a transient effect on slowing vitreous chamber elongation. With increasing GEN dose, SXL had an increasing treatment effect on slowing vitreous chamber elongation and myopia progression. In addition, SXL led to a dose-dependent shortening of the aqueous chamber depth and corneal thickening. Lens thickening was observed in the group with the highest concentration. Conclusions: We have shown that SXL using GEN can slow axial elongation and myopia progression in tree shrews. The extent of this treatment effect was dose dependent. Several unexpected effects were observed (corneal thickening, decrease of the anterior chamber depth, and lens thickening), which require further optimization of the GEN delivery approach before clinical consideration. Translational Relevance: The results of this preclinical study suggest that scleral crosslinking using genipin can slow myopia progression.

The local and non-local components of the local field potential in awake primate visual cortex.

The Local Field Potential (LFP) is the analog signal recorded from a microelectrode inserted into cortex, typically in the frequency band of approximately 1 to 200 Hz. Here visual stimuli were flashed on in the receptive fields of primary visual cortical neurons in awake behaving macaques, and both isolated single units (neurons) and the LFP signal were recorded from the same unipolar microelectrode. The fall-off of single unit activity as a visual stimulus was moved from near the center to near the edge of the receptive field paralleled the fall-off of the stimulus-locked (evoked) LFP response. This suggests that the evoked LFP strongly reflects local neuronal activity. However, the evoked LFP could be significant even when the visual stimulus was completely outside the receptive field and the single unit response had fallen to zero, although this phenomenon was variable. Some of the non-local components of the LFP may be related to the slow distributed, or non-retinotopic, LFP signal previously observed in anesthetized animals. The induced (not time-locked to stimulus onset) component of the LFP showed significant increases only for stimuli within the receptive field of the single units. While the LFP primarily reflects local neuronal activity, it can also reflect neuronal activity at more distant sites, although these non-local components are typically more variable, slower, and weaker than the local components.