Optometry & Vision Science:
Bright Light Induces Choroidal Thickening in Chickens
Lan, Weizhong*; Feldkaemper, Marita†; Schaeffel, Frank†
Zhongshan Ophthalmic Center (WL), State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China; and Section of Neurobiology of the Eye (WL, MF, FS), Center for Ophthalmology, University of Tuebingen, Tuebingen, Germany.
Frank Schaeffel Section of Neurobiology of the Eye Center for Ophthalmology University of Tuebingen 72076 Tuebingen Germany e-mail: firstname.lastname@example.org
Bright light is a potent inhibitor of myopia development in animal models. Because development of refractive errors has been linked to changes in choroidal thickness, we have studied in chickens whether bright light may exert its effects on myopia also through changes in choroidal thickness.
Three-day-old chickens were exposed to “bright light” (15,000 lux; n = 14) from 10 AM to 4 PM but kept under “normal light” (500 lux) during the remaining time of the light phase for 5 days (total duration of light phase 8 AM to 6 PM). A control group (n = 14) was kept under normal light during the entire light phase. Choroidal thickness was measured in alert, hand-held animals with optical coherence tomography at 10 AM, 4 PM, and 8 PM every day.
Complete data sets were available for 12 chicks in bright light group and nine in normal light group. The striking inter-individual variability in choroidal thickness (coefficient of variance: 23%) made it necessary to normalize changes to the individual baseline thickness of the choroid. During the 6 hours of exposure to bright light, choroidal thickness decreased by −5.2 ± 4.0% (mean ± SEM). By contrast, in the group kept under normal light, choroidal thickness increased by +15.4 ± 4.7% (difference between both groups p = 0.003). After an additional 4 hours, choroidal thickness increased also in the “bright light group” by +17.8 ± 3.5%, while there was little further change (+0.6 ± 4.0%) in the “normal light group” (difference p = 0.004). Finally, the choroid was thicker in the “bright light group” (+7.6 ± 26.0%) than in the “normal light group” (day 5: −18.6 ± 26.9%; difference p = 0.036).
Bright light stimulates choroidal thickening in chickens, although the response is smaller than with experimentally imposed myopic defocus, and it occurs with some time delay. It nevertheless suggests that choroidal thickening is also involved in myopia inhibition by bright light.
Myopia is a common public health problem all over the world, with the prevalence ranging from around 30% in European-derived populations to nearly 80% in some Asian populations.1–4 In addition to the inconvenience that optical correction is necessary for daily activities, myopia significantly increases the risks of suffering from serious complications, such as chorioretinal degenerations, retinal detachment, glaucoma, and cataract. Myopia, especially in its extreme degrees, has been ranked among the leading causes of visual impairment and blindness.5 On the other hand, the causative factors and the underlying mechanisms responsible for myopia are still not fully understood. Consequently, no fully satisfactory therapies are available to prevent its onset or progression in children.6
Recent studies found that more outdoor activity in children was associated with lower incidence of myopia.7–9 Possible reasons could be the long viewing distances with relaxed accommodation, the more homogeneous focus over the visual field associated with long viewing distances, or the increased physical activity. Furthermore, growing evidence indicates that simply exposing the eye to bright light may be an effective intervention to reduce the incidence of myopia. The protective effect was found to rely on the duration of time spent outdoors, rather than on the engagement of physical sports.8,10 The assumption received further support by animal studies which have shown that bright light is a powerful inhibitor of myopia development: increasing the ambient illuminance from 500 to 15,000 lux reduced the progression of myopia induced by diffuser or negative lens wear in chickens11–13 and tree shrews.14 In rhesus monkeys, the effect was confined to deprivation myopia15 and was lacking in lens-induced myopia16—an unexpected result that calls for further studies. In a long-term study over 90 days, it was also shown that chickens become the more hyperopic the higher the ambient illuminance.17 Furthermore, it was suggested that the effect of light on deprivation myopia was mediated, at least in part, through the retinal dopamine system, as intravitreal injection of a dopamine antagonist abolished the protective effect of bright light.12
Several studies show that the choroid, a highly vascularized tissue layer between the retina and sclera, plays an important role in emmetropization. Prior to growth changes of the sclera, the choroid can optically compensate for refractive errors by increasing in thickness to correct for myopia and by thinning to correct for hyperopia.18–21 Choroidal thickening can also be induced by dopamine agonists, which inhibit myopia development.22 In emmetropic eyes, choroidal thickness remains at an intermediate level, ready to respond to drifts in refractive state that may occur during global eye growth.
In the present study, we have tested whether bright light, similar to dopamine agonists, can also induce choroidal thickening. If so, this could support the idea that bright light may inhibit myopia development in a similar way as dopamine. It would also deepen our understanding of the effects of outdoor exposure on myopia development.
MATERIALS AND METHODS
One-day-old male white leghorn chickens were obtained from a local hatchery in Kirchberg, Germany. The chickens were raised in a temperature-controlled room under a 10/14 hour light/dark cycle, under laboratory level illuminance of 500 lux during the light phase, with lights on at 8 AM and off at 6 PM. Chickens had free access to food and water. All experiments were completed in the University of Tuebingen. They adhered to the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research and were approved by the university committee for experiments involving animals.
From the third day post-hatching, the experimental group (n = 14 chicks) was exposed to illumination of 15,000 lux (below referred to as “bright light”) from 10 AM to 4 PM. The 6-hour bright-light exposure protocol was adopted from Ashby et al.11,12 In the remaining time of the light phase (total duration from 8 AM to 6 PM), they were kept under 500 lux (below referred to as “normal light”). Treatment was continued for five consecutive days. The control group (n = 14) was kept in normal light during the entire light phase. Details about the spectral energy distribution of the two light sources have been described previously.11 Air conditioners were applied to match the environmental temperature in the two groups (25–27°C).
At 10 AM, 4 PM, and 8 PM on each day, choroidal thickness in the posterior pole of the eye was measured in alert, hand-held chicks, using small animal optical coherence tomography (Spectralis OCT, Heidelberg Engineering, Germany, measuring at 1060 nm). Time points of measurement were chosen to make it possible to detect short-term effects of bright light, expecting right after the treatment, as well as middle-range effects after four more hours, and long-term effects, after a few days. During the measurements, the position of the chicken’s head was aligned with the camera lens by the operator so that the IR laser beam of the OCT entered the eye through the center of the pupil and OCT images of the posterior pole of the eye were captured. Continuous series of pictures were then taken of each eye. Those in which the pupil was properly centered and the borders of the individual fundal layers were clearly visible (Fig. 1, right) were accepted for further analysis. Proper centration was judged as follows. The OCT device provides a white horizontal line through the pupil (which appears brightly illuminated by the infrared light reflected from the fundus; see Fig. 1A, top left). The chicken head was moved until this line passed through the estimated center of the pupil. After storing the screen image, it was verified that the vertical distance between the pupil center and the horizontal line was in a narrow range of ±50 μm or less, using the scale bar provided by the device (inserted in Fig. 1, top left). Only those scans were further analyzed. Data on choroidal thickness were averaged from at least five eligible images for each eye.
Only in 24 of 28 chickens the choroidal-scleral interface was clearly visible. The remaining four were excluded. In another three, one data point was lacking due to poor cooperation of the animals during the measurements. Therefore, complete data sets were available only for 12 chickens raised in bright light and nine raised in normal light. OCT images were manually processed with ImageJ, a publicly available image processing software (ver. 1.46r; National Institutes of Health, USA). As recommended in a recent publication about the use of ultrahigh-resolution OCT,23 choroidal thickness was defined as the distance between the inner border of the sclera to the outer border of the RPE.
All analyses were performed with commercially available software (SPSS 16.0; SPSS, Chicago, IL, USA). The effect of bright light on choroidal thickness includes short- and long-term effects. Short-term effects, defined as the changes of choroidal thickness over the day, were statistically analyzed using paired t tests. Comparisons were done between choroidal thickness in the morning at 10 AM and in the afternoon, immediately after the bright light was switched off, at 4 PM, as well as at 8 PM. Furthermore, repeated-measures ANOVA was applied to analyze the averages of the short-term effects. After that, long-term effects were evaluated by comparing choroidal thickness between the first and the last day of the experiment (10 AM on day 1 and 10 AM on day 5). A chi-square test was applied to compare the percentages of chickens having thicker choroids. An unpaired t test was used to evaluate the magnitude of the changes in choroidal thickness between these two groups. All tests were two-tailed. Data are presented as the means ± one standard error of mean (SEM).
Validation and Repeatability of OCT Measurements of Choroidal Thickness in Alert Chickens
We found that OCT is a convenient and rapid technique to measure the choroidal thickness in alert chickens. After little practice, one could obtain sufficient numbers of OCT images for each eye within 10 seconds. To evaluate the variability of choroidal thickness in individual animals, we compared choroidal thickness in both eyes of six chickens at four different time points (8 AM, 12 PM, 4 PM, and 8 PM) on two consecutive days. Average choroidal thickness in these six chickens was 141.9 ± 25.1 μm. The average standard deviation for repeated measurements in the same animals was 6.87 μm (4.84%). Comparing choroidal thickness data collected at corresponding time points on two consecutive days, significant correlations were found (n = 48, R2 = 0.70, p < 0.001; a Bland-Altmann analysis24,25 is shown in Fig. 2). There were no significant differences between repeated measurements of choroidal thickness on the two consecutive days (0.48 ± 14.35 μm, p = 0.83). The mean difference in measurements between the two consecutive days was 0.45 ± 14.35 μm (95% CI: [−3.72, 4.61], p = 0.83). Choroidal thickness in both eyes was also correlated (n = 48, R2 = 0.67, p < 0.001, regression analysis not shown). Therefore, the effects of bright light on choroidal thickness were only measured in the right eyes of each animal.
Short-Term Effects of Bright Light
The average choroidal thickness in the 21 chickens that contributed to the main study, performed to evaluate the effects of bright light on choroidal thickness, was 175.7 ± 40.2 μm. Because the inter-subject variability was rather high (coefficient of variance: 23% in the present study, similar to 24% as reported previously26), we normalized the data to the individual baseline thickness of the choroid as measured at 10 AM on each day.
As shown in Fig. 3A, choroidal thickness remained either unchanged or even showed a trend to decrease during the 6 hours in bright light. On average, the everyday decrease in choroidal thickness in bright light was −5.2 ± 4.0% (Fig. 3B). By contrast, in animals that were kept under normal light, average choroidal thickness increased by +15.4 ± 4.7% (p = 0.07, 0.03, and 0.03 for days 2, 4, and 5, respectively). The changes in choroidal thickness in the two groups were significantly different from each other (repeated-measures ANOVA: p = 0.003; Fig. 3B). Surprisingly, the patterns of changes of choroidal thickness between these two groups reversed after an additional 4 hours by which the chicks had spent in normal light until 6 PM and two further hours in the dark, until 8 PM. At 8 PM, choroidal thickness had increased in the bright light group (p < 0.05 on each of the days) but remained unchanged in the control group (p > 0.05 on each of the days; Fig. 3C). On average, choroidal thickness increased by +17.8 ± 3.5% in the group that had been exposed to bright light while it changed by only +0.6 ± 4.0% in the group that was exposed to normal light during the entire light phase. The changes in choroidal thickness between these two groups were significantly different (repeated-measures ANOVA: p = 0.004; Fig. 3D).
Long-Term Effects of Bright Light
Long-term effects of bright light on choroidal thickness were determined by comparing choroidal thickness as measured at 10 AM on day 1 to choroidal thickness at 10 AM on day 5. Eight out of 12 chickens (66.7%) in the group exposed to bright light exhibited thicker choroids, while only two out of nine chickens (22.2%) in the control group had thicker choroids (chi-square test: p = 0.044). The change in choroidal thickness in the group exposed to bright light over 5 days was +7.6 ± 26.0%, while the choroid became actually thinner in the group exposed to normal light by −18.6 ± 26.9% (unpaired t test: p = 0.036, Fig. 4).
It should be realized, however, that there was no summation of the effects of bright light on choroidal thickness over the 5-day treatment period. The difference in choroidal thickness between both groups was present already after the first day and was preserved over time (average increase in choroidal thickness at day 1: +23%; at day 5: +25%).
We found that the thickness of the choroid increased in a group of chickens that was exposed daily from 10 AM to 4 PM to bright light of 15,000 lux, compared to a group that was exposed to normal light of 500 lux during the same time period. The difference was significant mainly because the choroid became actually thinner over the 5-day time period in the group exposed to normal light. This finding is consistent with previous reports that choroid thins significantly with increasing age in humans.27,28 Furthermore, studying the short-term effects of bright light on each day, we found that the increase in choroidal thickness did not occur during exposure but rather with a time delay after the animals had been returned to normal light, and then into the dark, in the late afternoon. In general, the effects of bright light on choroidal thickness were small (range +10 to +20%), comparable to those that can be induced by dopamine agonists in chicks22 or by atropine in humans29 and definitely much smaller than those induced by positive defocus or during recovery from induced deprivation myopia (up to +300% in chicks).18,20
OCT Measurements of Choroidal Thickness in Alert Chickens
Different from previous studies, where choroidal thickness was determined by A-scan ultrasonography, we used optical coherence tomography (OCT). This technique was found to be very convenient to measure alert chickens and showed good repeatability and resolution. Because it is a non-contact technique and does not require anesthesia, it is especially valuable for multiple measurements necessary to determine time courses. Also, in comparison with optical low-coherence interferometry (the Lenstar LS 900, Haag-Streit, Switzerland), OCT offers significant advantages. It produces a two-dimensional, cross-sectional view of the fundus which facilitates the detection of landmarks like the root of the pecten or the optic disc. Owing to the long-wavelength light, the penetration depth is enhanced which facilitates the detection of the borders of the choroid. In the present study, we found that the reproducibility of the application of OCT in measuring choroidal thickness was high (average SD 6.87 μm) and the inter-visit repeatability was good. It was noted that the resolution was less than in human eyes where it can reach 1–2 μm,24–26 but, given that the changes in choroidal thickness were larger than the variability of repeated measurements (coefficient of variance: 4.84%), the resolution of OCT in chicks was still satisfactory.
A complicating factor is that the definition of the borders of the choroid is not trivial. For instance, Guggenheim et al26 used a different criterion when they used OCT to match the boundaries of the tissue layers to those detected by A-scan ultrasonography. It is possible that the border between the cartilaginous sclera and the fibrous sclera was inadvertently taken as the outer boundary of the choroid. This could at least explain why an apparently thicker choroid was measured (the average thickness of choroid in our data would increase from 175.71 to 236.19 μm which is close to their data). However, because the major interest of this study was in changes in choroidal thickness, the absolute values were less important.
Variability of Choroidal Thickness in Young Chickens
In the current study, a large inter-individual variability was observed in choroidal thickness with a coefficient of variance of 23%, very similar to a recent study in chickens of similar age (24%).26 It is interesting that the coefficients of variance for retina and sclera are much smaller (3 and 6%, respectively). The authors speculated that the high variability of choroidal thickness may be due to the fact that it continuously responds to fluctuations in refractive errors during emmetropization.26 The inter-individual high variability in choroidal thickness could relate to the high inter-individual variability in the set point of emmetropization in chicks.30 It was found that choroidal thickness in young chicks has a heritability of at least 50%.26
Possible Mechanisms Underlying the Transient Changes of Choroidal Thickness that are Induced by Bright Light
The mechanism by which the choroid can thicken or become thinner is not fully understood, but several hypotheses have been proposed.18,21 They include enhanced permeability of choroidal capillaries, increased synthesis of proteoglycans, upregulated aqueous humor flow through uveoscleral routes into the choroid, and decreased tonus of the non-vascular smooth muscle in the choroid. Scenarios as to how bright light could affect choroidal thickness could be (1) increased permeability of choroidal capillaries or increased choroid blood flow because it has been shown that choroidal perfusion is higher in the light than in the dark31,32; however, the obvious time delay between light exposure and choroidal thickening still needs to be explained. (2) Thickening of the choroid may also occur because of local synthesis of extracellular matrix molecules, like proteoglycans,33–35 which takes time. It is clear that the time course of upregulation of proteoglycans under bright light must be directly measured to confirm this hypothesis.
How the retinal signals reach the choroid is another question. Among others, possible pathways include dopamine and nitric oxide. Both the synthesis and the release of dopamine are light-regulated,36–42 and there is a dose-response relationship between the synthesis and release of retinal dopamine and the intensity of ambient light in mammals43 and chickens.13 The protective effect of bright light against deprivation myopia appears to be mediated, at least in part, by the retinal dopamine system12 because spiperone, a dopamine antagonist, could antagonize the inhibitory effect of bright light on myopia. Dopamine agonists that inhibit axial eye growth also elicit a transient increase in choroidal thickness in chicks,22 although dopamine is unlikely to be the molecule that acts directly on the choroid. Dopamine is mainly synthesized by a subpopulation of retinal amacrine cell and does not seem to pass through the RPE.44 Synthesis and release of dopamine change rapidly in response to a light stimulus.43 Assuming that dopamine is involved, it is possible that it acts upstream to the choroidal response. Downstream from dopamine signaling could involve nitric oxide. Sekaran et al45 found that steady or flicker light stimulation enhances retinal nitric oxide (NO) release. A similar effect was observed after application of exogenous dopamine to retinas in darkness, while inhibition of endogenous dopaminergic activity completely suppressed the light-evoked increase in NO release. Nickla et al showed that inhibiting NO synthase prevented the choroidal thickening response to myopic defocus and disinhibited ocular growth.46,47 NO is a gaseous neuroactive substance which has a diffusional radius of at least 100 μm48 and is capable of diffusing across biological membranes freely. We speculate that dopamine released from dopaminergic amacrine cells in response to exposure to bright light might trigger the release of NO which diffuses across the RPE and induces choroidal thickening, but it is clear that this needs to be measured directly.
Bright light induces choroidal thickening in chickens, but the effects after 5 days of bright-light exposure remained relatively small (range: +10 to +20%) compared to the effects that are induced by positive lenses or occur during recovery from deprivation myopia (range: +300%, reported by Wallman et al18). In previous studies (reviewed by Winawer and Wallman49), thicker choroids were linked to inhibition of axial eye growth. Also, the inhibitory effects of bright light on axial eye growth are smaller than those of positive lenses, which is in line with the smaller effects of bright light on the choroid. The fact that an increase in choroidal thickness is generally followed by an inhibition of axial eye growth may make it possible to predict the potency of bright light treatment regimens to inhibit myopia.
Section of Neurobiology of the Eye
Center for Ophthalmology
University of Tuebingen
This study was supported by the National Natural Science Foundation of China, Beijing, China (grant nos. 81170871 and 81200714); the Foundation for Distinguished Young Talents in Higher Education of Guangdong, Guangdong Province, China (grant no. LYM 11009); and a scholarship from the German Academic Exchange Service (DAAD) to W.L.
The authors have no proprietary or commercial interest in any materials discussed in this article. Part of the material was presented at the annual ARVO meeting in Seattle, Washington, May 2013.
Received April 5, 2013; accepted August 19, 2013.
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light; myopia; choroid; OCT; chicken
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