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Visual Neuroscience  |   January 2013
The Effect of Temporal and Spatial Stimuli on the Refractive Status of Guinea Pigs Following Natural Emmetropization
Author Affiliations & Notes
  • Zhina Zhi
    From the School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China; and
  • Miaozhen Pan
    From the School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China; and
  • Ruozhong Xie
    From the School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China; and
    State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of the People's Republic of China, and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
  • Shibo Xiong
    From the School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China; and
    State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of the People's Republic of China, and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
  • Xiangtian Zhou
    From the School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China; and
    State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of the People's Republic of China, and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
  • Jia Qu
    From the School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China; and
    State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of the People's Republic of China, and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
  • Each of the following is a corresponding author: Jia Qu, School of Optometry and Ophthalmology, Wenzhou Medical College, 270 Xueyuan Road, Wenzhou, Zhejiang, China, 325027; jqu@wz.zj.cn
  • Xiangtian Zhou, School of Optometry and Ophthalmology, Wenzhou Medical College, 270 Xueyuan Road, Wenzhou, Zhejiang, China, 325027; zxt-dr@wz.zj.cn
Investigative Ophthalmology & Visual Science January 2013, Vol.54, 890-897. doi:10.1167/iovs.11-8064
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      Zhina Zhi, Miaozhen Pan, Ruozhong Xie, Shibo Xiong, Xiangtian Zhou, Jia Qu; The Effect of Temporal and Spatial Stimuli on the Refractive Status of Guinea Pigs Following Natural Emmetropization. Invest. Ophthalmol. Vis. Sci. 2013;54(1):890-897. doi: 10.1167/iovs.11-8064.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To understand the visual information essential for maintaining stable refraction after emmetropization, we investigated the effects of spatial and temporal stimuli on the refractive status of guinea pigs.

Methods.: Eighty-eight guinea pigs (4 weeks old) were randomly divided into 10 groups. Thirty animals were raised in backgrounds of gray (n = 13), square-wave (n = 9), or sine-wave grating (n = 8). Thirty-one animals were raised in gray backgrounds with three frequencies of flicker: gray-1-Hz (n = 10), gray-6-Hz (n = 12), and gray-20-Hz (n = 9). Eighteen animals were raised in regular cages with different frequencies of flicker (n = 6 respectively in 1-Hz-, 6-Hz-, and 20-Hz-flicker groups). Nine animals were raised in regular cages with no additional stimuli and used as normal controls. Ocular biometry was measured before and after 3 weeks of exposure to the test environments.

Results.: Guinea pigs raised in the gray background for 3 weeks developed myopia, −6.1 ± 2.1 diopters (D), whereas those exposed to either sine-wave or square-wave gratings, or raised in regular cages, retained stable refractions. Animals in the gray-6-Hz group developed lower myopia, −2.7 ± 2.7 D, than the gray group not exposed to flicker. Animals stimulated with a range of flickering frequencies in regular cages also developed myopia but to a lower degree, −3.1 to 0.2 D, than those in gray backgrounds, −5.0 to −2.7 D.

Conclusions.: Guinea pigs require both spatial and temporal stimuli to maintain stable refractions. The influence of temporal stimuli on refraction varies with the type and amount of spatial information available in the visual environment.

Introduction
Humans and some other animals, such as chickens, guinea pigs, tree shrews, and marmosets, are usually hyperopic at birth. 14 Therefore, these species undergo an emmetropization process of normal refractive development after birth to establish a match between the axial growth and optical development of the eye. Emmetropization requires an environment to provide favorable spatial details, chromatic information, motion, and flicker to the eye. 510 The visual information from this environment is managed by a variety of signal-processing channels, including ON and OFF channels, which have been widely studied in relation to their role in refractive development in chickens. 1116 Factors affecting the function of ON or OFF channels in the visual pathway can change the direction of refractive development of the eye. 11,15,16 In general, all of the visual information provided by the natural environment can be classified as spatial and temporal stimuli, which may vary in chromaticity and intensity. These two types of stimuli are processed by midget and parasol ganglion cells in the ON and OFF pathways within the retina before they reach the visual cortex. 12 Furthermore, the speed of response in signal processing by these two types of ganglion cells varies with the spatial frequency and contrast of the visual stimuli. 
Both hyperopic and myopic defocus alter refractive development of the eye due to the attenuation of medium and high spatial frequency information in images of distant objects. In neonatal chickens and monkeys, the development of form deprivation myopia is most consistent with a lack of medium spatial information from the visual environment. 1719 Optical defocus alters eye growth in a variety of young animals, including chickens, 7,20,21 tree shrews, 4,22 monkeys, 23 and fish. 24 In humans, axial myopia has been reported in infants and young children with corneal opacities, 25 cataracts, 26 and ptosis, 27 all of which may attenuate medium to high spatial frequencies. 
These results suggest that spatial visual stimuli with medium frequency components are necessary for refractive development in neonatal animals. Furthermore, in chickens, exposure to light flickering at frequencies higher than 6 Hz inhibits myopia induced by either form deprivation or hyperopic defocus, whereas a lower-frequency flicker, 1 to 4 Hz, enhances experimental myopia. 6,28 Together, these results point to critical requirements for emmetropia and prevention of myopia with respect to both spatial and temporal visual stimuli. 
Across species, refractive status and axial length of the eye generally remain stable after emmetropization 3,29,30 ; however, myopia can still occur at this stage in young humans under natural visual environments, 31,32 probably due to changes in certain environmental factors. Therefore, it is important to know if the visual stimuli required for emmetropization still play a critical role in maintaining emmetropia or if the maintenance of a stable refraction of the eye has different visual requirements. Such information may guide strategies to prevent or inhibit myopic progression in young adults through manipulations of their visual environment. Therefore, we investigated manipulations of the available spatial information, flickering stimuli alone, and the available spatial information in presence of flickering stimuli on refractive development of 4-week-old guinea pigs that had already completed natural emmetropization. 3  
Materials and Methods
Experimental Design
The animal research in this study was approved by the Animal Care and Ethics Committee at Wenzhou Medical College, Wenzhou, China. Treatment and care of the animals were conducted according to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Eighty-eight pigmented guinea pigs (4 weeks old) were obtained from the Animal Breeding Unit at Wenzhou Medical College. All of the animals were raised on a cycle of 12-hour illumination (50 lux) and 12-hour darkness during the experimental period. Food and water were supplied during the dark hours from 8 PM to 8 AM to avoid exposing the animals to unexpected visual backgrounds. The animals were randomly assigned to three experiments using 10 different groups as follows. 
Experiment 1: Effects of Different Spatial Visual Backgrounds.
Three groups were tested under a visual background of gray (n = 13), square-wave grating (n = 9), and sine-wave grating (n = 8), respectively. The gray background, which was made by printing gray ink onto transparent plastic films, provided no spatial signals (Fig. 1). The square-wave and sine-wave gratings were formed by black-and-white bands (0.8-cm width), and the contrast varied according to the square- or sine-wave function. The gratings for square- and sine-wave backgrounds were at the same contrast (75%) with 0.6 cpd as the grating frequency. The grating frequency perceived by the animal was from 0.07 to 0.7 cpd based on a range of distances from 7 to 70 cm between the animal and the visual background. Physically, the sine-wave target contained frequency components between 0.07 and 0.7 cpd, while the square-wave target was formed by a series of harmonic frequency components of sine waves between 0.07 and 4.9 cpd according to a Fourier analysis. 
Figure 1. 
 
Visual backgrounds used in different groups.
Figure 1. 
 
Visual backgrounds used in different groups.
Experiment 2: Effects of Flickering Frequencies under a Gray Background.
Three groups, gray-1-Hz (n = 10), gray-6-Hz (n = 12), and gray-20-Hz (n = 9), were tested under a visual background of gray with the light flickering at 1, 6, and 20 Hz, respectively. 
The animals in experiments 1 and 2 were housed in 115 × 70 × 25-cm cages (Fig. 2). The visual background designed for each experiment was applied to the internal surface of each cage, including the walls, floor, and ceiling. Each cage contained three transparent chambers, each 15 × 15 × 25 cm, holding one animal per chamber. The same visual background as applied to the cage was also applied to the lateral chamber walls that were shared between neighbor chambers. Thus, the three animals in each cage could not see each other, but were able to see the visual background from both long and short distances. All chambers were cleaned daily during the dark cycle, and the claws of guinea pigs were trimmed to avoid scratches or dirty marks being made on the chamber walls. 
Figure 2. 
 
Schematic diagram of cage design. The animals were housed in cages with dimensions of 115 × 70 × 25 cm. Each cage contained three transparent chambers (15 × 15 × 25 cm each), with each chamber holding one animal. The cage walls (A, B, C, D) and chamber walls (a, b, c, d) were attached with the visual targets. The lateral walls (e and f) were transparent. The corners (α, β, γ, δ) held LED light boards. The cage floor, except in the small chambers, was covered with a mirror to reflect the visual background from the ceiling and to achieve an even luminance in the cage.
Figure 2. 
 
Schematic diagram of cage design. The animals were housed in cages with dimensions of 115 × 70 × 25 cm. Each cage contained three transparent chambers (15 × 15 × 25 cm each), with each chamber holding one animal. The cage walls (A, B, C, D) and chamber walls (a, b, c, d) were attached with the visual targets. The lateral walls (e and f) were transparent. The corners (α, β, γ, δ) held LED light boards. The cage floor, except in the small chambers, was covered with a mirror to reflect the visual background from the ceiling and to achieve an even luminance in the cage.
Four white light-emitting-diode (LED) lights, invisible to the animals, were installed at the four corners of each cage (corners α, β, γ, δ, Fig. 2), respectively. Flicker was produced by the LED lights at the 1-, 6-, and 20-Hz frequencies regulated by an automatic controller. These frequencies were selected based on the critical flicker frequency of guinea pigs and previous studies. 6,10,28,33,34 Luminance of the flicker in the center of the chamber ranged between 0 and 50 lux (mean: 25 lux) with a square waveform and equal time phase for both dark and bright phases. 
Experiment 3: Effects of Flicker in a “Natural Background.”
Using the three flicker frequencies described above, the animals (n = 6 each) were tested in regular cages having no artificial spatial stimuli. These animals were housed in barred cages with a 1-cm gap between any two bars so that they could visualize the surrounding environment. The lights were installed on top of the cages with the luminance at equal intensity to that in experiments 1 and 2. 
Normal Controls.
Nine animals were raised in barred cages with nonflickering lighting. 
Biometric Measurements
Biometric parameters, including refraction, corneal radius of curvature (CRC), anterior chamber depth (ACD), lens thickness (LT), vitreous chamber depth (VCD), and axial length (AL) were measured in all animals at 0 and 3 weeks of exposure to the different visual backgrounds. These measurements were performed by an optometrist with help from an animal care assistant during the cycle of illumination (daytime). The optometrist was masked with regard to the identity of the treatment group. 
The refraction was measured by eccentric infrared retinoscopy (EIR) with custom-made software to calculate the refraction at the vertical meridian every 33 ms. 35,36 For each reading, 10 measurements were made and the results of three readings were averaged. The CRC was measured with a keratometer (OM-4; Topcon, Tokyo, Japan) modified by attachment of an 8-diopter (D) lens mounted to the anterior surface of the keratometer. 37,38 An A-scan ultrasonagraph (11-MHz frequency; Quantel Medical, Aviso, France) was used to measure the axial components of the eye. The conducting velocity for this measurement was 1534 m/s for ACD, 1723.3 m/s for LT, and 1540 m/s for VCD, as described previously. 37,38 Each of the axial components was calculated as the mean of 10 repeated measurements. 
Statistics
Biometric results (mean ± SD) of the two eyes of each individual animal were compared using paired t-tests (SPSS Version 15.0; SPSS, Armonk, NY). Results at baseline and week 3 within the same group were compared using paired t-tests. Changes in biometric results from week 0 to week 3 were compared among different groups. One-way ANOVA was used to analyze groups exposed to the same spatial visual background or same light condition. In detail, a one-way ANOVA with Bonferroni correction was used for the following comparisons: (1) gray, sine, square, and control groups; (2) gray, gray-1-Hz, gray-6-Hz, and gray-20-Hz groups; and (3) 1-Hz-flicker, 6-Hz-flicker, 20-Hz-flicker, and control groups. 
To compare the effects of (1) the gray and regular cage backgrounds; (2) 1-, 6-, and 20-Hz flickering and normal light conditions; and (3) the interaction between (1) and (2) on refractions and ocular dimensions, a two-way analysis of variance with Bonferroni correction was applied to data from gray, gray-1-Hz, gray-6-Hz, gray-20-Hz, 1-Hz-flicker, 6-Hz-flicker, 20-Hz-flicker, and control groups. Both the intra- and intergroup differences were defined as significant with P less than 0.05 or highly significant with P less than 0.01. 
Results
There were no significant differences between the left and right eyes of the individual animals within any group at day 0 for refraction, CRC, and axial components (P > 0.05, paired t-tests, Table) except in the ACD of the square-wave and gray-20-Hz groups. Therefore, only results from the right eyes of all animals were used for comparison between different groups. 
Table. 
 
Ocular Biometry of All Groups
Table. 
 
Ocular Biometry of All Groups
Groups Time Refraction (D) Corneal Radius of Curvature (mm) Anterior Chamber Depth (mm) Lens Thickness (mm) Vitreous Chamber Depth (mm) Axial Length (mm)
Left Right Left Right Left Right Left Right Left Right Left Right
Gray (n = 13) d0 5.7 ± 2.2 4.9 ± 2.2 3.42 ± 0.07 3.40 ± 0.08 1.03 ± 0.07 1.03 ± 0.06 3.69 ± 0.17 3.7 ± 0.19 3.13 ± 0.10 3.12 ± 0.09 7.84 ± 0.15 7.85 ± 0.16
d21 – 0.4 ± 2.1 0.3 ± 2.2 3.56 ± 0.09 3.55 ± 0.06 1.07 ± 0.07 1.04 ± 0.07 3.90 ± 0.17 3.92 ± 0.18 3.33 ± 0.11 3.28 ± 0.09 8.29 ± 0.16 8.23 ± 0.16
Sine-wave (n = 8) d0 4.6 ± 1.5 5.0 ± 1.5 3.41 ± 0.07 3.40 ± 0.06 1.05 ± 0.08 1.04 ± 0.10 3.61 ± 0.21 3.61 ± 0.21 3.24 ± 0.07 3.21 ± 0.07 7.91 ± 0.25 7.87 ± 0.22
d21 5.4 ± 1.0 5.7 ± 1.3 3.63 ± 0.09 3.61 ± 0.10 1.11 ± 0.06 1.08 ± 0.07 3.85 ± 0.15 3.87 ± 0.13 3.27 ± 0.11 3.26 ± 0.15 8.23 ± 0.20 8.21 ± 0.25
Square-wave (n = 9) d0 4.8 ± 2.3 5.0 ± 2.0 3.38 ± 0.11 3.37 ± 0.12 0.99 ± 0.07 1.04 ± 0.07* 3.63 ± 0.21 3.59 ± 0.21 3.17 ± 0.12 3.18 ± 0.12 7.79 ± 0.33 7.82 ± 0.30
d21 4.2 ± 2.0 4.5 ± 2.7 3.54 ± 0.11 3.53 ± 0.09 1.07 ± 0.10 1.10 ± 0.09 3.82 ± 0.18 3.85 ± 0.18 3.23 ± 0.15 3.23 ± 0.17 8.13 ± 0.31 8.18 ± 0.32
Gray-1-Hz (n = 10) d0 6.6 ± 1.6 6.5 ± 1.2 3.49 ± 0.06 3.47 ± 0.06 1.08 ± 0.08 1.10 ± 0.06 3.73 ± 0.08 3.72 ± 0.06 3.14 ± 0.09 3.14 ± 0.05 7.95 ± 0.10 7.90 ± 0.08
d21 2.2 ± 2.0 1.5 ± 3.3 3.65 ± 0.04 3.67 ± 0.05 1.12 ± 0.09 1.13 ± 0.06 4.00 ± 0.07 4.00 ± 0.05 3.33 ± 0.09 3.33 ± 0.12 8.44 ± 0.15 8.47 ± 0.10
Gray-6-Hz (n = 12) d0 4.7 ± 1.9 4.6 ± 1.4 3.36 ± 0.06 3.36 ± 0.06 1.06 ± 0.06 1.07 ± 0.06 3.65 ± 0.23 3.60 ± 0.28 3.19 ± 0.09 3.18 ± 0.06 7.90 ± 0.24 7.89 ± 0.23
d21 1.3 ± 2.4 1.7 ± 2.2 3.56 ± 0.08 3.57 ± 0.06 1.09 ± 0.09 1.09 ± 0.09 3.88 ± 0.18 3.89 ± 0.13 3.31 ± 0.07 3.28 ± 0.07 8.28 ± 0.15 8.26 ± 0.22
Gray-20-Hz (n = 9) d0 6.3 ± 1.4 6.5 ± 1.3 3.38 ± 0.08 3.37 ± 0.08 1.09 ± 0.09 1.05 ± 0.07* 3.65 ± 0.10 3.67 ± 0.10 3.12 ± 0.09 3.12 ± 0.09 7.86 ± 0.16 7.85 ± 0.13
d21 1.3 ± 3.8 1.9 ± 4.0 3.58 ± 0.08 3.58 ± 0.07 1.13 ± 0.07 1.12 ± 0.06 3.91 ± 0.11 3.92 ± 0.12 3.34 ± 0.09 3.31 ± 0.08 8.38 ± 0.15 8.36 ± 0.14
1-Hz-flicker (n = 6) d0 6.6 ± 0.5 6.8 ± 0.7 3.59 ± 0.06 3.57 ± 0.08 1.05 ± 0.06 1.05 ± 0.07 3.91 ± 0.11 3.92 ± 0.10 3.20 ± 0.08 3.17 ± 0.12 8.16 ± 0.08 8.13 ± 0.08
d21 3.3 ± 1.2 3.5 ± 1.8 3.78 ± 0.08 3.75 ± 0.03 1.13 ± 0.09 1.11 ± 0.07 4.10 ± 0.06 4.12 ± 0.06 3.33 ± 0.07 3.33 ± 0.09 8.56 ± 0.08 8.56 ± 0.05
6-Hz-flicker (n = 6) d0 6.1 ± 0.7 5.6 ± 1.2 3.45 ± 0.12 3.50 ± 0.09 1.01 ± 0.08 0.97 ± 0.07 3.84 ± 0.13 3.86 ± 0.14 3.14 ± 0.09 3.12 ± 0.10 8.00 ± 0.23 7.95 ± 0.23
d21 4.3 ± 1.0 5.0 ± 1.4 3.64 ± 0.10 3.67 ± 0.11 1.03 ± 0.14 0.98 ± 0.12 4.04 ± 0.08 4.07 ± 0.09 3.19 ± 0.08 3.19 ± 0.11 8.26 ± 0.24 8.23 ± 0.27
20-Hz-flicker (n = 6) d0 4.9 ± 1.2 5.1 ± 1.5 3.40 ± 0.08 3.41 ± 0.05 1.07 ± 0.09 1.04 ± 0.06 3.76 ± 0.21 3.75 ± 0.19 3.09 ± 0.11 3.09 ± 0.09 7.91 ± 0.15 7.88 ± 0.16
d21 5.0 ± 1.4 4.6 ± 0.6 3.59 ± 0.05 3.60 ± 0.06 1.07 ± 0.08 1.11 ± 0.07 3.98 ± 0.11 3.98 ± 0.11 3.23 ± 0.06 3.24 ± 0.08 8.28 ± 0.08 8.26 ± 0.11
Normal control (n = 9) d0 5.5 ± 0.8 5.7 ± 0.6 3.35 ± 0.07 3.34 ± 0.05 1.05 ± 0.04 1.05 ± 0.06 3.59 ± 0.10 3.59 ± 0.13 3.19 ± 0.07 3.18 ± 0.06 7.82 ± 0.08 7.83 ± 0.12
d21 5.8 ± 1.0 5.5 ± 0.98 3.51 ± 0.03 3.56 ± 0.07 1.12 ± 0.07 1.09 ± 0.08 3.82 ± 0.08 3.79 ± 0.07 3.22 ± 0.10 3.24 ± 0.10 8.16 ± 0.12 8.13 ± 0.10
Animals Raised in Spatial Visual Backgrounds
Changes in refraction from 0 to 3 weeks were −6.1 ± 2.1 D, 0.9 ± 2.3 D, −0.5 ± 1.0 D, and 0.2 ± 1.30 D for gray, sine-wave, square-wave, and normal control groups, respectively (P < 0.01: gray versus the other three groups, one-way ANOVA, Fig. 3A). The VCD increased by 0.2 ± 0.08 mm, 0.03 ± 0.09 mm, 0.08 ± 0.10 mm, and 0.04 ± 0.04 mm for the same group order over the same period (P < 0.05: gray versus the other three groups, one-way ANOVA, Fig. 3B). The AL increased similar to the vitreous lengthening among the three groups (Fig. 3C). 
Figure 3. 
 
Changes in ocular biometry for the gray, sine-wave, square-wave, and normal control groups. (A) Change in refraction; (B) change in VCD; (C) change in AL (*P < 0.05, one-way ANOVA).
Figure 3. 
 
Changes in ocular biometry for the gray, sine-wave, square-wave, and normal control groups. (A) Change in refraction; (B) change in VCD; (C) change in AL (*P < 0.05, one-way ANOVA).
Animals Raised with Flicker in a Gray Background
Changes in refraction over 3 weeks in gray, gray-1-Hz, gray-6-Hz, and gray-20-Hz groups were −6.1 ± 2.1 D, −4.6 ± 3.1 D, −2.7 ± 2.7 D, and −5.0 ± 3.7D respectively (P > 0.05 among these four groups, one-way ANOVA, Fig. 4A), but the 6-Hz-gray group showed a tendency of less myopic shift compared with the gray group with no flicker (P = 0.15, one-way ANOVA). The VCD in these four groups was 0.2 ± 0.08 mm, 0.19 ± 0.08 mm, 0.12 ± 0.06 mm, and 0.22 ± 0.10 mm with a greater value in the gray-20-Hz than in the gray-6-Hz group (P < 0.05: gray-6-Hz versus gray-20-Hz, one-way ANOVA, Fig. 4B). The AL in these four groups was 0.44 ± 0.12 mm, 0.49 ± 0.08 mm, 0.37 ± 0.11 mm, and 0.52 ± 0.14 mm with a greater value in the gray-20-Hz than in the gray-6-Hz (P < 0.05: gray-6-Hz versus gray-20-Hz, one-way ANOVA, Fig. 4C). 
Figure 4. 
 
Changes in ocular biometry with a gray background in presence of various frequencies of flicker. (A) Change in refraction; (B) change in VCD; (C) change in AL (*P < 0.05, one-way ANOVA).
Figure 4. 
 
Changes in ocular biometry with a gray background in presence of various frequencies of flicker. (A) Change in refraction; (B) change in VCD; (C) change in AL (*P < 0.05, one-way ANOVA).
Animals Raised under Flicker in Regular Cages That Mimicked Natural Visual Environments
Refractive changes in animals subjected to 3 weeks of flicker in regular cages were −3.1 ± 1.6 D, −1.2 ± 1.6 D, 0.2 ± 1.8 D, and 0.24 ± 1.3 D for the 1-Hz-flicker, 6-Hz-flicker, 20-Hz-flicker, and normal control groups, respectively (P < 0.05: 1-Hz-flicker versus 20-Hz-flicker or normal control, one-way ANOVA, Fig. 5A). The VCD was 0.13 ± 0.03 mm in the 1-Hz-flicker group, 0.05 ± 0.03 mm in the 6-Hz-flicker group, 0.14 ± 0.07 mm in the 20-Hz-flicker group, and 0.04 ± 0.04 mm in the normal control group. The 1-Hz-flicker and 20-Hz-flicker groups were significantly greater than the normal control group (P < 0.05: 20-Hz-flicker versus 6-Hz-flicker or normal control, one-way ANOVA, Fig. 5B). Changes in the AL among different flicker groups showed a similar trend as the VCD (Fig. 5C). 
Figure 5. 
 
Changes in ocular biometry with a regular cage background in the presence of flicker with various frequencies. (A) Change in refraction; (B) change in VCD; (C) change in AL (*P < 0.05, one-way ANOVA).
Figure 5. 
 
Changes in ocular biometry with a regular cage background in the presence of flicker with various frequencies. (A) Change in refraction; (B) change in VCD; (C) change in AL (*P < 0.05, one-way ANOVA).
Increases in the CRC and LT were significant over the 3 weeks in all eyes of each group (P < 0.05, paired t-tests). The ACD over the period of 3 weeks increased significantly in gray, gray-6-Hz, gray-20-Hz, 6-Hz-flicker, and 20-Hz-flicker groups (P > 0.05, paired t-tests) but remained unchanged statistically in sine, square, gray-1-Hz, 1-Hz-flicker, and normal control groups (P < 0.05, paired t-tests). However, these parameters were similar at all time points among all of the groups (P > 0.05, one-way ANOVA). 
The results of the two-way ANOVA analysis showed that animals raised in the gray background developed significant myopia with greater VCDs and ALs compared with animals raised in regular cages (P < 0.05, gray versus regular cage for refraction, VCD, and AL). The lighting conditions also significantly affected VCD and AL (VCD: P = 0.03; AL: P = 0.04), but had no effect on refraction (P = 0.38). Animals raised in 6-Hz-flicker had shorter VCDs and ALs than animals raised in 1- and 20-Hz-flicker (VCD: 6 vs. 1 Hz: P < 0.01, 6 vs. 20 Hz: P < 0.01; AL: 6 vs. 1 Hz: P < 0.01, 6 vs. 20 Hz: P < 0.01). 
Discussion
This study created artificial environments composed of nonspatial, spatial, and temporal visual stimuli to explore the effect of each individual stimulus or a combination of the stimuli on refractive development of guinea pig eyes following natural emmetropization. It should be noted that the visual environment designed for the different groups may not be ideally perceived by animals due to some unavoidable limiting factors. For example, any eye or head movement of the animal invariably induces a concurrent temporal component. This temporal component may interfere with the manipulation of spatial stimuli. However, the results were significantly different among the experimental groups, indicating that the various visual environments designed in this study did cause changes in the refraction of guinea pigs after emmetropization. Therefore, these results provide further understanding of the refractive development guided by changes in visual environments. 
Effects of Spatial Signals on Refractive Status and the Associated Biometry
In the present study, the gray visual background with no additional spatial signals induced significant myopia and vitreous elongation. However, animals exposed to spatially different visual backgrounds (e.g., sine- or square-wave gratings) maintained a stable refractive status. These results indicate that spatial signals are essential for guinea pigs to maintain a stable refraction after emmetropization. Therefore, spatial visual stimuli are necessary for the animals to accomplish emmetropization and to maintain a stable refractive status after the emmetropization. 8,17,19 A previous study showed that spatial frequency components between 2 and 4 cpd are essential for emmetropization of neonatal chickens. 19 However, a spatial stimulus with much lower frequency components such as the sine-wave grating used in this study, 0.07 to 0.7 cpd, is sufficient for the animal eyes to maintain a stable refraction. There was no significant difference in refraction or axial components among animals exposed to the sine-wave grating, square-wave grating, or regular-cage visual backgrounds. 
Form deprivation induces axial myopia by attenuating frequency components of the image received by the deprived eye. 1719 Based on the results from our study, the retinal image frequency components in the deprived eye are probably lower than 0.07 cpd and therefore could be similar to an image formed on a gray visual background. In the current study, the difference in edge pattern between sine- and square-wave stimuli did not influence the refraction of the guinea pigs, indicating that a lack of medium to high spatial frequency components plays a critical role in the myopic development rather than the nature of the edge pattern itself. This suggestion is consistent with a previous study in which a blurred visual target did not induce myopia in 8-day-old chicks. 9  
Effects of Luminance on Refractive Development
The gray visual background mimics form deprivation in terms of attenuation of spatial stimulation, but form deprivation also attenuates light luminance. However, in the present study, myopia induced by a gray visual background suggests that light attenuation by form deprivation may not play a critical role in the development of form deprivation myopia. This hypothesis is supported by findings of a previous study in which a neutral-density filter that decreased only the intensity of light transmission rather than spatial information did not induce myopia in chickens. 8 Therefore, spatial frequency components from the environment play a critical role in refractive development of the eye. 
Effects of Temporal Signals at Different Visual Backgrounds on Refractive Status
All of the groups exposed to gray visual backgrounds developed significant myopia regardless of the presence of flicker of various frequencies. This indicates that guinea pigs cannot maintain a stable refractive status without spatial signals, even when temporal signals are available. However, when compared with the animals exposed only to a gray visual background, the 6-Hz-flicker inhibited 55% of the myopia. This effect might be caused by the inhibition of 6-Hz-flicker to vitreous lengthening. This result is consistent with a previous study in which 6-Hz-flicker inhibited 80% of the form deprivation myopia and 12-Hz-flicker inhibited only 30% of form deprivation myopia in 6-day-old chicks. 25 In chickens, a 1-Hz-flicker enhances form deprivation myopia, 6 but in the present study, it had no effect on the refraction of guinea pigs raised in a gray visual background, similar to form deprivation, as discussed earlier. However, the 1-Hz-flicker did induce axial myopia in guinea pigs raised in regular cages. This result is consistent with a study in which a 2-Hz-flicker induced axial myopia in mice raised in a natural visual environment. 38 Furthermore, a medium-frequency flicker helps to stabilize the refraction of animals raised with a gray background (i.e., minimal spatial visual stimuli), but it has no significant effect on animals raised in a spatially rich environment. These results indicate that flickering light with a specific range of frequencies is necessary only in prevention of refractive errors in a visual environment that lacks spatial information. 
Generally, three pathways (ON, OFF, and ON/OFF respectively) are involved in retinal signal processing. Both the ON and OFF pathways act coordinately to process spatial information, but the ON/OFF pathway mainly processes signals produced by flicker. 1012,15,16 The smaller influence of flicker at medium to high frequencies in a natural visual environment (e.g., regular cage conditions in this present study) suggests that adequate activity in ON and OFF pathways may suppress the growth regulatory influence of the ON/OFF pathway in guinea pig eyes. 
In this study, the VCD of eyes of the 20-Hz-flicker group was greater than that of the normal control group, although the refraction did not change accordingly. This is probably due to the relative shortening of the anterior chamber that offsets the effect of VCD lengthening on refraction in this group. For both the gray visual background and regular cage environment, guinea pigs exposed to 6-Hz-flicker had a slower VCD lengthening than those exposed to either 1-Hz- or 20-Hz-flicker, suggesting that medium temporal frequency stimuli most favor the maintenance of stable refractions after emmetropization. 
In summary, naturally emmetropized mammals require both spatial and temporal stimuli to maintain a stable refraction. Emmetropized guinea pigs are capable of maintaining a stable refractive status in an environment with only low-frequency spatial components. The role of temporal signals in the refractive development of these animals depends on whether spatial information is present or absent in the visual environment. 
Acknowledgments
The authors appreciate Mark Willcox from the School of Optometry and Vision Science, University of New South Wales, Australia; Debbie Sweeny from the University of Western Sydney, Australia; and Britt Bromberg of Xenofile Editing for providing critical review and editing for this manuscript. The authors also thank two biostatisticians: Thomas John Naduvilath from the University of New South Wales, Sydney, Australia, and Jianping Guo from Brigham and Women's Hospital, Boston, Massachusetts, for providing statistical suggestions. 
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Footnotes
 Supported by the National Basic Research Program of China (973 project) No. 2011CB504602, National Natural Science Foundation of China (30830107, 30973278, and 81070751), the Research Fund for the Doctoral Program of Higher Education of China (20060343002), the Key Grant from Education Bureau of Zhejiang (2005004), Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents, and Program for New Century Excellent Talents in University, National Ministry of Education Grant NCET-10–0977.
Footnotes
3  These authors contributed equally to the work presented here and should therefore be regarded as equivalent authors.
Footnotes
 Disclosure: Z. Zhi, None; M. Pan, None; R. Xie, None; S. Xiong, None; X. Zhou, None; J. Qu, None
Figure 1. 
 
Visual backgrounds used in different groups.
Figure 1. 
 
Visual backgrounds used in different groups.
Figure 2. 
 
Schematic diagram of cage design. The animals were housed in cages with dimensions of 115 × 70 × 25 cm. Each cage contained three transparent chambers (15 × 15 × 25 cm each), with each chamber holding one animal. The cage walls (A, B, C, D) and chamber walls (a, b, c, d) were attached with the visual targets. The lateral walls (e and f) were transparent. The corners (α, β, γ, δ) held LED light boards. The cage floor, except in the small chambers, was covered with a mirror to reflect the visual background from the ceiling and to achieve an even luminance in the cage.
Figure 2. 
 
Schematic diagram of cage design. The animals were housed in cages with dimensions of 115 × 70 × 25 cm. Each cage contained three transparent chambers (15 × 15 × 25 cm each), with each chamber holding one animal. The cage walls (A, B, C, D) and chamber walls (a, b, c, d) were attached with the visual targets. The lateral walls (e and f) were transparent. The corners (α, β, γ, δ) held LED light boards. The cage floor, except in the small chambers, was covered with a mirror to reflect the visual background from the ceiling and to achieve an even luminance in the cage.
Figure 3. 
 
Changes in ocular biometry for the gray, sine-wave, square-wave, and normal control groups. (A) Change in refraction; (B) change in VCD; (C) change in AL (*P < 0.05, one-way ANOVA).
Figure 3. 
 
Changes in ocular biometry for the gray, sine-wave, square-wave, and normal control groups. (A) Change in refraction; (B) change in VCD; (C) change in AL (*P < 0.05, one-way ANOVA).
Figure 4. 
 
Changes in ocular biometry with a gray background in presence of various frequencies of flicker. (A) Change in refraction; (B) change in VCD; (C) change in AL (*P < 0.05, one-way ANOVA).
Figure 4. 
 
Changes in ocular biometry with a gray background in presence of various frequencies of flicker. (A) Change in refraction; (B) change in VCD; (C) change in AL (*P < 0.05, one-way ANOVA).
Figure 5. 
 
Changes in ocular biometry with a regular cage background in the presence of flicker with various frequencies. (A) Change in refraction; (B) change in VCD; (C) change in AL (*P < 0.05, one-way ANOVA).
Figure 5. 
 
Changes in ocular biometry with a regular cage background in the presence of flicker with various frequencies. (A) Change in refraction; (B) change in VCD; (C) change in AL (*P < 0.05, one-way ANOVA).
Table. 
 
Ocular Biometry of All Groups
Table. 
 
Ocular Biometry of All Groups
Groups Time Refraction (D) Corneal Radius of Curvature (mm) Anterior Chamber Depth (mm) Lens Thickness (mm) Vitreous Chamber Depth (mm) Axial Length (mm)
Left Right Left Right Left Right Left Right Left Right Left Right
Gray (n = 13) d0 5.7 ± 2.2 4.9 ± 2.2 3.42 ± 0.07 3.40 ± 0.08 1.03 ± 0.07 1.03 ± 0.06 3.69 ± 0.17 3.7 ± 0.19 3.13 ± 0.10 3.12 ± 0.09 7.84 ± 0.15 7.85 ± 0.16
d21 – 0.4 ± 2.1 0.3 ± 2.2 3.56 ± 0.09 3.55 ± 0.06 1.07 ± 0.07 1.04 ± 0.07 3.90 ± 0.17 3.92 ± 0.18 3.33 ± 0.11 3.28 ± 0.09 8.29 ± 0.16 8.23 ± 0.16
Sine-wave (n = 8) d0 4.6 ± 1.5 5.0 ± 1.5 3.41 ± 0.07 3.40 ± 0.06 1.05 ± 0.08 1.04 ± 0.10 3.61 ± 0.21 3.61 ± 0.21 3.24 ± 0.07 3.21 ± 0.07 7.91 ± 0.25 7.87 ± 0.22
d21 5.4 ± 1.0 5.7 ± 1.3 3.63 ± 0.09 3.61 ± 0.10 1.11 ± 0.06 1.08 ± 0.07 3.85 ± 0.15 3.87 ± 0.13 3.27 ± 0.11 3.26 ± 0.15 8.23 ± 0.20 8.21 ± 0.25
Square-wave (n = 9) d0 4.8 ± 2.3 5.0 ± 2.0 3.38 ± 0.11 3.37 ± 0.12 0.99 ± 0.07 1.04 ± 0.07* 3.63 ± 0.21 3.59 ± 0.21 3.17 ± 0.12 3.18 ± 0.12 7.79 ± 0.33 7.82 ± 0.30
d21 4.2 ± 2.0 4.5 ± 2.7 3.54 ± 0.11 3.53 ± 0.09 1.07 ± 0.10 1.10 ± 0.09 3.82 ± 0.18 3.85 ± 0.18 3.23 ± 0.15 3.23 ± 0.17 8.13 ± 0.31 8.18 ± 0.32
Gray-1-Hz (n = 10) d0 6.6 ± 1.6 6.5 ± 1.2 3.49 ± 0.06 3.47 ± 0.06 1.08 ± 0.08 1.10 ± 0.06 3.73 ± 0.08 3.72 ± 0.06 3.14 ± 0.09 3.14 ± 0.05 7.95 ± 0.10 7.90 ± 0.08
d21 2.2 ± 2.0 1.5 ± 3.3 3.65 ± 0.04 3.67 ± 0.05 1.12 ± 0.09 1.13 ± 0.06 4.00 ± 0.07 4.00 ± 0.05 3.33 ± 0.09 3.33 ± 0.12 8.44 ± 0.15 8.47 ± 0.10
Gray-6-Hz (n = 12) d0 4.7 ± 1.9 4.6 ± 1.4 3.36 ± 0.06 3.36 ± 0.06 1.06 ± 0.06 1.07 ± 0.06 3.65 ± 0.23 3.60 ± 0.28 3.19 ± 0.09 3.18 ± 0.06 7.90 ± 0.24 7.89 ± 0.23
d21 1.3 ± 2.4 1.7 ± 2.2 3.56 ± 0.08 3.57 ± 0.06 1.09 ± 0.09 1.09 ± 0.09 3.88 ± 0.18 3.89 ± 0.13 3.31 ± 0.07 3.28 ± 0.07 8.28 ± 0.15 8.26 ± 0.22
Gray-20-Hz (n = 9) d0 6.3 ± 1.4 6.5 ± 1.3 3.38 ± 0.08 3.37 ± 0.08 1.09 ± 0.09 1.05 ± 0.07* 3.65 ± 0.10 3.67 ± 0.10 3.12 ± 0.09 3.12 ± 0.09 7.86 ± 0.16 7.85 ± 0.13
d21 1.3 ± 3.8 1.9 ± 4.0 3.58 ± 0.08 3.58 ± 0.07 1.13 ± 0.07 1.12 ± 0.06 3.91 ± 0.11 3.92 ± 0.12 3.34 ± 0.09 3.31 ± 0.08 8.38 ± 0.15 8.36 ± 0.14
1-Hz-flicker (n = 6) d0 6.6 ± 0.5 6.8 ± 0.7 3.59 ± 0.06 3.57 ± 0.08 1.05 ± 0.06 1.05 ± 0.07 3.91 ± 0.11 3.92 ± 0.10 3.20 ± 0.08 3.17 ± 0.12 8.16 ± 0.08 8.13 ± 0.08
d21 3.3 ± 1.2 3.5 ± 1.8 3.78 ± 0.08 3.75 ± 0.03 1.13 ± 0.09 1.11 ± 0.07 4.10 ± 0.06 4.12 ± 0.06 3.33 ± 0.07 3.33 ± 0.09 8.56 ± 0.08 8.56 ± 0.05
6-Hz-flicker (n = 6) d0 6.1 ± 0.7 5.6 ± 1.2 3.45 ± 0.12 3.50 ± 0.09 1.01 ± 0.08 0.97 ± 0.07 3.84 ± 0.13 3.86 ± 0.14 3.14 ± 0.09 3.12 ± 0.10 8.00 ± 0.23 7.95 ± 0.23
d21 4.3 ± 1.0 5.0 ± 1.4 3.64 ± 0.10 3.67 ± 0.11 1.03 ± 0.14 0.98 ± 0.12 4.04 ± 0.08 4.07 ± 0.09 3.19 ± 0.08 3.19 ± 0.11 8.26 ± 0.24 8.23 ± 0.27
20-Hz-flicker (n = 6) d0 4.9 ± 1.2 5.1 ± 1.5 3.40 ± 0.08 3.41 ± 0.05 1.07 ± 0.09 1.04 ± 0.06 3.76 ± 0.21 3.75 ± 0.19 3.09 ± 0.11 3.09 ± 0.09 7.91 ± 0.15 7.88 ± 0.16
d21 5.0 ± 1.4 4.6 ± 0.6 3.59 ± 0.05 3.60 ± 0.06 1.07 ± 0.08 1.11 ± 0.07 3.98 ± 0.11 3.98 ± 0.11 3.23 ± 0.06 3.24 ± 0.08 8.28 ± 0.08 8.26 ± 0.11
Normal control (n = 9) d0 5.5 ± 0.8 5.7 ± 0.6 3.35 ± 0.07 3.34 ± 0.05 1.05 ± 0.04 1.05 ± 0.06 3.59 ± 0.10 3.59 ± 0.13 3.19 ± 0.07 3.18 ± 0.06 7.82 ± 0.08 7.83 ± 0.12
d21 5.8 ± 1.0 5.5 ± 0.98 3.51 ± 0.03 3.56 ± 0.07 1.12 ± 0.07 1.09 ± 0.08 3.82 ± 0.08 3.79 ± 0.07 3.22 ± 0.10 3.24 ± 0.10 8.16 ± 0.12 8.13 ± 0.10
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