The Effect of Simultaneous Negative and Positive Defocus on Eye Growth and Development of Refractive State in Marmosets

Article (PDF Available)inInvestigative ophthalmology & visual science 53(10):6479-87 · August 2012with96 Reads
DOI: 10.1167/iovs.12-9822 · Source: PubMed
  • 16.32 · State University of New York College of Optometry
  • 6.36 · State University of New York College of Optometry
  • 30.62 · State University of New York, College of Optometry
Abstract
Purpose: We evaluated the effect of imposing negative and positive defocus simultaneously on the eye growth and refractive state of the common marmoset, a New World primate that compensates for either negative and positive defocus when they are imposed individually. Methods: Ten marmosets were reared with multizone contact lenses of alternating powers (-5 diopters [D]/+5 D), 50:50 ratio for average pupil of 2.80 mm over the right eye (experimental) and plano over the fellow eye (control) from 10 to 12 weeks. The effects on refraction (mean spherical equivalent [MSE]) and vitreous chamber depth (VC) were measured and compared to untreated, and -5 D and +5 D single vision contact lens-reared marmosets. Results: Over the course of the treatment, pupil diameters ranged from 2.26 to 2.76 mm, leading to 1.5 times greater exposure to negative than positive power zones. Despite this, at different intervals during treatment, treated eyes were on average relatively more hyperopic and smaller than controls (experimental-control [exp-con] mean MSE ± SE +1.44 ± 0.45 D, mean VC ± SE -0.05 ± 0.02 mm) and the effects were similar to those in marmosets raised on +5 D single vision contact lenses (exp-con mean MSE ± SE +1.62 ± 0.44 D. mean VC ± SE -0.06 ± 0.03 mm). Six weeks into treatment, the interocular growth rates in multizone animals were already lower than in -5 D-treated animals (multizone -1.0 ± 0.1 μm/day, -5 D +2.1 ± 0.9 μm/day) and did not change significantly throughout treatment. Conclusions: Imposing hyperopic and myopic defocus simultaneously using concentric contact lenses resulted in relatively smaller and less myopic eyes, despite treated eyes being exposed to a greater percentage of negative defocus. Exposing the retina to combined dioptric powers with multifocal lenses that include positive defocus might be an effective treatment to control myopia development or progression.

Figures

Visual Psychophysics and Physiological Optics
The Effect of Simultaneous Negative and Positive Defocus
on Eye Growth and Development of Refractive State
in Marmosets
Alexandra Benavente-Perez, Ann Nour, and David Troilo
PURPOSE. We evaluated the effect of imposing negative and
positive defocus simultaneously on the eye growth and
refractive state of the common marmoset, a New World
primate that compensates for either negative and positive
defocus when they are imposed individually.
M
ETHODS. Ten marmosets were reared with multizone contact
lenses of alternating powers (5 diopters [D]/þ5 D), 50:50
ratio for average pupil of 2.80 mm over the right eye
(experimental) and plano over the fellow eye (control) from
10 to 12 weeks. The effects on refraction (mean spherical
equivalent [MSE]) and vitreous chamber depth (VC) were
measured and compared to untreated, and 5 D and þ5D
single vision contact lens-reared marmosets.
R
ESULTS. Over the course of the treatment, pupil diameters
ranged from 2.26 to 2.76 mm, leading to 1.5 times greater
exposure to negative than positive power zones. Despite this,
at different intervals during treatment, treated eyes were on
average relatively more hyperopic and smaller than controls
(experimental-control [exp-con] mean MSE 6 SE þ1.44 6 0.45
D, mean VC 6 SE 0.05 6 0.02 mm) and the effects were
similar to those in marmosets raised on þ5 D single vision
contact lenses (exp-con mean MSE 6 SE þ1.62 6 0.44 D. mean
VC 6 SE 0.06 6 0.03 mm). Six weeks into treatment, the
interocular growth rates in multizone animals were already
lower than in 5 D-treated animals (multizone 1.0 6 0.1 lm/
day, 5Dþ2.1 6 0.9 lm/day) and did not change significantly
throughout treatment.
C
ONCLUSIONS. Imposing hyperopic and myopic defocus simul-
taneously using concentric contact lenses resulted in relatively
smaller and less myopic eyes, despite treated eyes being
exposed to a greater percentage of negative defocus. Exposing
the retina to combined dioptric powers with multifocal lenses
that include positive defocus might be an effective treatment to
control myopia development or progression. (Invest Ophthal-
mol Vis Sci. 2012;53:6479–6487) DOI:10.1167/iovs.12-9822
T
he common marmoset (Callithrix jacchus) is a New World
primate known to respond to visual form deprivationm as
well as to imposed hyperopic and myopic defocus by adjusting
the growth rate of its ocular components.
1–7
The ability to
compensate both types of defocus by increasing or decreasing
eye growth supports the existence of a bidirectional visual
compensatory mechanism, which is regulated locally and
regional within the eye as shown by the ability of experimental
animals to emmetropize after optic nerve section, and to
compensate for full field as well as hemifield retinal defocus.
8–16
The visual control of eye growth likely is linked to the dynamics
of daily visual experience and the different dioptric demands to
which the eyes are exposed. To understand how these might
affect eye growth, it is necessary first to characterize the spatial
and temporal integration of myopic and hyperopic defocus.
Previous work done in chicks, mammals, and Old World
primates suggests that alternating hyperopic defocus (a strong
stimulus to induce myopia) with periods of myopic defocus or
unrestricted vision can decelerate eye growth and prevent
myopia.
8,17,18
Additionally, when chick eyes are exposed to
simultaneous hyperopic and myopic defocus using multifocal
spectacle lenses
19
or a combination of cross-cylinders and single
vision lenses,
20
the eye grows slower and adjusts focus toward
the more myopic plane. This suggests that the retina does not
just compensate for the average amount of blur, but it can
differentiate the sign of competing defocus and guide the
growth of the eye toward the plane of myopic defocus.
19–22
Therefore, the compensation for simple myopic defocus in
chicks, known to be weaker in mammals or primates,
7,23–26
appears to be preferred when it is combined with hyperopic
defocus.
19,21,22
We examined the response to simultaneous
myopic and hyperopic defocus imposed in the marmoset with
multifocal contact lenses to test this hypothesis in a nonhuman
primate model of eye growth and development of refractive
state.
The effect that simultaneous defocus of opposite sign has
on the growth of the primate eye has yet to be assessed. This
question is relevant particularly since a recent small population
clinical trial using bifocal lenses in children has reported a
reduction in myopia progression,
27
and it will help understand
how the human eye integrates defocus signals of mixed nature.
Manipulating defocus across the retina in humans with
spectacles, contact lenses, or refractive surgery might be an
effective management tool for myopia. We aimed to provide
better control of lens centration under spontaneous eye
movement by using contact lenses instead of spectacle lenses.
Biometric parameters, such as anterior chamber depth (ACD),
corneal curvature (CC), lens thickness (LT), choroidal thick-
ness (CT), and retinal thickness (RT), which are suggested to
change considerably during emmetropization,
22,28–30
also were
included in our analysis.
METHODS
Ten juvenile marmosets (Callithrix jacchus) were reared with a
custom-designed concentric multizone contact lens (Medlens Innova-
From the SUNY College of Optometry, New York, New York.
Supported by the National Institutes of Health (NIH R01
EY11228).
Submitted for publication March 8, 2012; revised May 24, June
27, and August 7, 2012; accepted August 20, 2012.
Disclosure: A. Benavente-Perez,None;A. Nour,None;D.
Troilo,None
Corresponding author: Alexandra Benavente-Perez, SUNY Col-
lege of Optometry, 33 W 42
nd
Street, New York, NY, 10036;
abenavente@sunyopt.edu.
Investigative Ophthalmology & Visual Science, September 2012, Vol. 53, No. 10
Copyright 2012 The Association for Research in Vision and Ophthalmology, Inc.
6479
tions Inc., Front Royal, VA) from an average age of 72 days (range 70–76
days) for 12 weeks (range 11.7–12 weeks). The lens was made of
methafilcon A (55% water content, DK:17), and had a center zone of
1.5 mm, 5 diopters (D) followed by a þ5 D ring 0.25 mm wide and
four more rings 0.20 mm wide each, of alternating power. The total
diameters of the contact lenses used were either 6.0 or 6.5 mm, all of
which had an optical zone diameter of 3.6 mm and were plano to the
periphery. The total diameters of the alternating 5D/þ5 D zones were
designed to give a 50:50 ratio of plus versus minus surface area for the
average juvenile marmoset pupil diameter of 2.8 mm, measured under
ambient animal room illumination (~700 lux).
Contact lenses were fit 0.10 mm over the flattest keratometry reading
and an ophthalmoscope was used to assess the fit.
5,7
Because of the
anatomy of the ocular globe and eyelids of the marmosets, the fit of all
these contact lenses resembles that of a scleral fit. A topical antibiotic was
used following each measurement and no corneal complications were
observed in any of the animals throughout treatment.
Pupil diameters in the experimental marmosets were measured
without cycloplegia before and during treatment at animal room light
levels (~700 lux). Images were captured using NIH Image (NIH,
Bethesda, MD), enhanced using Image J software filters (NIH), and the
average of five measurements was obtained per eye.
The animals wore the multizone lens on the right eye (experimental
eye) and a plano lens on the fellow eye (control eye) for an average of 9
hours light/15 hours dark cycle following an established protocol for
contact lens rearing in marmosets.
5,7
Untreated (N ¼ 25), single-vision
positive (N ¼20, OD þ5 D, OS plano) and negative contact lens-reared
marmosets (N ¼ 16, OD 5 D, OS plano) from earlier studies
7
were
used as age-matched controls. All animal care, treatment, and
experimental protocols were approved by the SUNY College of
Optometry Institutional Animal Care and Use Committee, and
conformed with the ARVO Statement for the Use of Animals in
Ophthalmic and Vision Research.
Ocular biometry and refractive state were measured twice during
pretreatment (3–4 weeks before lens rearing, and immediately before
lens rearing) and four times during lens rearing (T1 four weeks, T2
eight weeks, T3 ten weeks, and T4 twelve weeks into treatment). To
gain insight into the temporal characteristics of multifocal defocus,
growth rates were calculated before treatment (pretreatment) and at
three time intervals during treatment: early (4–6 weeks into treatment),
mid (6–8 weeks into treatment), and late (8–12 weeks into treatment).
Refraction, keratometry, and ultrasound biometry were performed
as described in a previously established protocol 30 minutes after the
instillation of 2 drops of 1% cyclopentolate and measurements were
completed within two hours.
3,7,31
On-axis refraction was given as the
average of retinoscopy and Hartinger Coincidence Refractometer (Carl
Zeiss, Oberkochen, Germany), used routinely in the past in our
lab.
3,7,31
High frequency A-scan ultrasound (25 MHz, Panametrics; NDT, Ltd,
Waltham, MA) was used to measure ACD, LT, vitreous chamber depth
(VC), CT, and RT as performed in earlier studies.
3,4,7,31,32
Statistics
The statistical analysis was performed using Stata (College Station, TX).
Paired Student’s t-test was used to evaluate the differences between
treated and fellow eyes at each time point, while one-way ANOVA
examined the differences between treatment groups. Pearson’s linear
correlation was used to evaluate the relationships between interocular
differences in refraction and ultrasound biometry.
RESULTS
The average marmoset pupil diameter during treatment was
2.52 mm (range 2.26–2.76 mm), which resulted in 1.78 times
greater exposure to the negative than to the positive power
zone. The ratio of negative-to-positive contact lens surface area
that corresponded to the pupils measured during treatment
ranged from 65% negative-to-35% positive for a pupil diameter
of 2.26 mm, to 52% negative-to-48% positive for a pupil of 2.76
mm, all of which resulted in greater overall exposure to
hyperopic defocus. Since it was not possible to measure the
effective refractive state through the multizone contact lenses,
19 additional marmosets were refracted wearing plano lenses
to assess the potential effects that contact lens fit and
centration might have had on the final effective refractive
state (Table 1). The refractive changes induced by plano lenses
at 0, 20, and 40 degrees on the nasal retina, as well as at 20 on
the temporal retina were not significant. There was, however, a
significant overall effect toward increased hyperopia (mean
change 6 SE þ1.22 6 0.33 D) at 40 degrees on the temporal
retina (nasal visual field).
Biometric and refractive data were obtained pretreatment at
42 to 50 days of age, at baseline (B; 70–76 days old) and at four
consecutive time points during the 12 weeks of treatment (T1
at 98–105, T2 at 126–133, T3 at 140–147, and T4 at 153–161
days old). At the beginning of treatment there were no
differences in vitreous chamber depth or refraction (mean
spherical equivalent [MSE]) between experimental (exp) and
contralateral (con) eyes (exp VC 5.83 6 0.06 mm, control VC
5.84 6 0.07 mm, P ¼ 0.11; exp MSE mean 6 SE þ0.65 6 0.51
D, control MSE mean 6 SE þ0.08 6 0.76 D, P ¼ 0.54). The
overall effective axial myopic and hyperopic defocus on
treated eyes was þ5.65 D and 4.35 D, respectively.
Figure 1 shows refractive and vitreous chamber depth data
from treated and contralateral eyes (solid and empty symbols,
respectively). The animals that were myopic at the end of
treatment are indicated in red and the ones that were
hyperopic in black. At baseline, three animals were myopic
in both eyes (exp MSE mean 6 SE 1.24 6 0.0.60 D, control
MSE mean 6 SE 2.88 6 0.92 D, Fig. 1) and three more had
myopia in both eyes by the end of treatment, meaning that six
of 10 animals were myopic in both eyes when treatment
concluded (myopic treated eye MSE mean 6 SE 3.39 6 0.78
D, myopic fellow eye MSE mean 6 SE 3.21 6 0.78 D, Fig. 1),
and eight were myopic on their contralateral fellow eyes
(average of eight myopic contralateral eyes MSE mean 6 SE
2.53 6 0.72 D, Fig. 1).
Figure 2 describes the interocular changes in refraction and
vitreous chamber over time, where it can be seen that four
weeks into treatment (at T1) five of 10 experimental eyes were
TABLE 1. Refractive Effect of Plano Lenses (Ave 6 SE) on 19 Marmosets
Angle No Lens (Av 6 SE) with Plano Lens (Av 6 SE) Difference (with Lens - No Lens) (Av 6 SE) P Value
408 0.21 6 0.47 1.42 6 0.31 1.22 6 0.33 0.002
208 0.55 6 0.50 0.59 6 0.34 0.04 6 0.36 0.91
08 1.00 6 0.45 0.54 6 0.34 0.45 6 0.40 0.28
þ208 0.65 6 0.35 0.45 6 0.35 0.20 6 0.35 0.58
þ408 0.59 6 0.37 0.58 6 0.40 0.02 6 0.38 0.72
Negative values of the angles represent the temporal retina (nasal visual field), whereas positive values of the angles represent the nasal retina
(temporal visual field).
6480 Benavente-Perez et al. IOVS, September 2012, Vol. 53, No. 10
relatively more hyperopic than their contralateral control eyes
(exp-con mean MSE 6 SE þ1.79 6 0.52 mm), and seven were
relatively smaller (exp-con mean VC 6 SE 0.09 6 0.02 mm).
At T2, six of those seven animals still had smaller eyes (exp-con
mean VC 6 SE 0.08 6 0.01 mm, Fig. 2), but now nine were
relatively more hyperopic on their treated than contralateral
eyes (exp-con mean MSE 6 SE þ1.76 6 0.34 mm, Fig. 2).
Those nine animals remained relatively more hyperopic in
FIGURE 1. Spherical equivalent refractive state (D) and VC depth (mm) over time on treated eyes (solid symbols and lines) and contralateral
control eyes (empty symbols, dotted lines). Solid and empty black symbols: those treated and contralateral eyes, respectively, that remained
hyperopic after the end of treatment. Solid and empty red symbols: the animals that had myopia on both eyes after treatment. Grey cloud: 95%
confidence interval (CI) from age-matched untreated marmosets, calculated as the average 62 SD. Note that several eyes began the experiment with
slightly more myopia than that normally seen in control animals, but the eye size as measured as VC depth fell within normal range.
TABLE 2. Interocular Differences in Biometry and Mean Spherical Equivalent Refraction over Time (Treated Eye-Control Eye, Mean 6 SE):
Pretreatment, Baseline, T1, T2, T3, and T4
Pretreatment Baseline T1 T2 T3 T4
MSE, D 0.118 6 0.369 0.099 6 0.357 0.935 6 0.478 0.545 6 0.553 0.834 6 0.401 0.576 6 0.618
VCD, mm 0.029 6 0.011 0.019 6 0.011 0.049 6 0.024 0.008 6 0.034 0.033 6 0.022 0.017 6 0.030
CC, mm 0.005 6 0.027 0.003 6 0.005 0.013 6 0.012 0.017 6 0.018 0.015 6 0.019 0.001 6 0.007
ACD, mm 0.011 6 0.013 0.005 6 0.011 0.029 6 0.012 0.016 6 0.016 0.017 6 0.011 0.001 6 0.008
CT, mm 0.005 6 0.027 0.003 6 0.005 0.013 6 0.012 0.017 6 0.018 0.015 6 0.019
0.001 6 0.007
LT, mm 0.019 6 0.019 0.018 6 0.017 0.005 6 0.008 0.008 6 0.015 0.000 6 0.009 0.022 6 0.012
RT, mm 0.010 6 0.007 0.010 6 0.015 0.003 6 0.005 0.003 6 0.005 0.003 6 0.007 0.001 6 0.004
ChT, mm 0.010 6 0.007 0.007 6 0.007 0.008 6 0.005 0.000 6 0.005 0.005 6 0.007 0.008 6 0.005
VCD, VC depth; ChT, choroidal thickness.
IOVS, September 2012, Vol. 53, No. 10 Eye Growth and Development of Refractive State 6481
their experimental than control eyes at T3 (exp-con mean MSE
6 SE þ1.32 6 0.21 mm, Fig. 2), but two more experimental
eyes grew less than their contralateral eyes and now a total of
eight animals had smaller experimental than control eyes (exp-
con mean VC 6 SE 0.06 6 0.01 mm, Fig. 2). During the last
two weeks of treatment, those same eight animals exhibited
reduced VC growth in their experimental eyes (exp-con mean
VC 6 SE 0.06 6 0.01 mm, Fig. 2), and seven were more
hyperopic (exp-con mean MSE 6 SE þ1.21 6 0.47 mm, Fig. 2).
The refractive state at baseline did not correlate with the
refractive state after treatment (R
2
¼ 0.23, P ¼ 0.16) or the
growth rates experienced during treatment (R
2
¼ 0.18, P ¼
0.22).
A quadrant plot was used to display visually the changes in
interocular refraction and vitreous chamber depth over time in
multizone lens-reared animals (Fig. 3), and similar quadrant
plots allowed the comparison with negative and positive-single
vision lens-reared animals (Fig. 4).
FIGURE 2. Interocular differences (treated eye-control eye) at pretreatment (pre-treat), baseline (arrow), and during treatment (T1–T4) in refractive
error (D) and VC depth (mm) in multizone lens-reared animals. Each line represents one animal, and each symbol indicates the measurement point
in time. Grey cloud: 95% CI from age-matched untreated marmosets, calculated as the average 62SD.
6482 Benavente-Perez et al. IOVS, September 2012, Vol. 53, No. 10
Figure 3 shows how at the end of treatment (represented by
an arrowhead), six of 10 multizone lens-treated animals had
smaller and relatively more hyperopic experimental than
control eyes. These compensatory changes qualitatively
resembled the effects of those raised with single vision positive
defocus (Fig. 4, exp-con mean MSE 6 SE multizone þ0.38 6
0.46 D, positive þ1.62 6 0.44 D, P ¼0.10; exp-con mean VC 6
SE multizone 0.02 6 0.03 mm, positive 0.06 6 0.03 mm, P
¼ 0.35), and were unlike those of single vision negative lens-
reared animals, whose treated eyes were bigger and more
myopic than the contralateral controls (Fig. 4, exp-con mean
MSE 6 SE multizone þ0.38 6 0.46 D, negative 2.13 6 1.10D,
P ¼ 0.048; exp-con mean VC 6 SE multizone 0.02 6 0.03
mm, negative þ0.12 6 0.06 mm, P ¼ 0.06).
The overall relation between interocular differences in
vitreous chamber depth and refraction over time also can be
noticed by the diagonal trend of the data in Figure 3 (R
2
¼
0.66, P < 0.001). The correlation remained significantly
unchanged at each measurement during treatment and
compared to baseline (ANOVA repeated measures, P > 0.05).
Changes in CC, ACD, LT, RT, or CT did not change significantly
during treatment (Table 2), and did not correlate with
refractive state or vitreous chamber changes (all P > 0.05).
The temporal characteristics of the effect that multizone
lenses had compared to untreated, single vision negative and
positive lenses showed no significant differences in growth
rates between treatment groups before treatment started (P ¼
0.36, Fig. 5). However, six weeks into treatment the interocular
growth rates of multizone lens-reared animals were significant-
ly lower than those of single vision negative lenses (growth
rate mean 6 SE multizone 1.0 6 0.1 lm/day, negative single
vision þ2.1 6 0.9 lm/day, P ¼ 0.024, Fig. 5), but similar to
untreated (growth rate mean 6 SE 0.2 6 0.4 lm/day, P ¼
0.33, Fig. 5) and single vision positive lenses (growth rate mean
6 SE 2.2 6 0.7 lm /day, P ¼0.37, Fig. 5). Later, between six
and eight weeks of treatment, only the rates between single
vision positive and negative lens-treated marmosets remained
significantly different, with negative single vision lens-reared
animals exhibiting higher interocular growth rates than
positive, essentially zero at that time (growth rate-negative,
lens-treated mean 6 SE þ2.7 6 1.1 lm/day, positive lens-
treated 9.8439 e
3
6 0.5 lm/day, P ¼ 0.043, Fig. 5). After
eight weeks of treatment all treatment groups showed similar
interocular growth rates (P > 0.05, Fig. 5).
DISCUSSION
Imposing mixed myopic and hyperopic defocus simultaneously
using concentric multizone contact lenses tended to result,
overall, in relatively more hyperopic refractions and slower
growth rates in treated than fellow eyes. The effects on the
vitreous chamber growth rates and refractive development
differed from single vision negative lens-reared animals, and
were comparable to those of single vision positive lens-reared
and untreated animals.
FIGURE 3. Quadrant plot describing the relation between interocular differences (exp-control) in vitreous chamber depth (x axis), and refraction (y
axis) in the multizone-lens reared group. The refractive and growth changes of each animal are represented with a line that starts at the baseline
measurement and finishes at the last measurement after treatment (arrowhead), plotted over a grey cloud that represents the 95% CI of the age-
matched untreated data. Lines outside of the 95% CI indicate significant changes. Data points in the top left quadrant indicate eyes that are smaller
and more hyperopic than contralateral control eyes, points in the top right quadrant indicate eyes that are larger but more hyperopic, points in the
bottom left quadrant show eyes that are smaller but more myopic than contralateral controls, and points in the bottom right quadrant show eyes
that are larger and more myopic.
IOVS, September 2012, Vol. 53, No. 10 Eye Growth and Development of Refractive State 6483
FIGURE 4. Quadrant plots describing the relation between interocular differences (exp-control) in vitreous chamber depth (x axis), and refraction
(y axis) in the positive single-vision reared group (blue arrows), and in the negative single-vision reared group (red arrows). For detailed
explanation of the graphs, see Figure 3 caption.
6484 Benavente-Perez et al. IOVS, September 2012, Vol. 53, No. 10
The outcomes of our study suggested that the marmoset,
like the chick,
21,22
can integrate defocus of competing sign
presented simultaneously. The multizone contact lens was
designed to provide a 50:50 ratio of hyperopic-to-myopic
defocus for an average pupil of 2.8 mm diameter, but the pupils
of the marmosets treated in our study were significantly
smaller, 2.26 to 2.76 mm, which resulted in greater overall
exposure to hyperopic than myopic defocus. Despite the fact
that the smaller pupil diameters led to greater percentage of
hyperopic defocus, seven of 10 animals had smaller vitreous
chambers in their treated than in their contralateral control
eyes as early as four weeks into treatment. The effects
decreased but remained by the end of treatment. These results
suggested that a relatively smaller percentage of myopic
defocus imposed simultaneously along a larger percentage of
hyperopic defocus leads to relatively smaller and less myopic
eyes.
Despite the relatively reduced growth response in eyes
with mixed defocus compared to the contralateral control
eyes, at the end of treatment six monkeys were myopic in
both eyes. Three of these were myopic at baseline, so it could
be argued that the final refractive state was related to their
baseline refraction. However, a significant correlation was not
found between baseline and final refraction. Another possibil-
ity is that the subset of treated eyes in fact compensated for
the imposed hyperopic defocus in the multizone contact lens,
but the average compensatory change in refraction after
treatment was less than five diopters, suggesting that the
response to negative defocus was reduced by the simulta-
neously imposed myopic defocus. It also could be possible
that the contrast information of the retinal image, affected by
the presence of five transition zones and the alternation of six
rings of opposite power, behaved as a myopia-inducing
stimulus,
21,33,34
or the multizone lenses acted like diffusers
and affected form vision enough to trigger mild form
deprivation myopia.
7,13,35
It is important to note that three
of the six animals that had myopia in both eyes were less
myopic in their treated eye compared to the contralateral
control eye at the end of treatment. Because only one of these
animals was myopic before treatment, we concluded that the
interocular difference during treatment was the result of the
positive defocus in the multizone lens; however, we cannot
rule out the possibility that the experimental lens had a
contralateral effect on the control eye because of yoked
accommodation, which has been described in the past,
7
and
requires further investigation.
The myopic shift observed in four of the 10 contralateral
eyes (3.79 6 0.71 D) also might have been due to a residual
refractive effect related to the fit and centration of the plano
contact lens. However, the overall refractive change induced
by plano contact lenses was only significant at 40 degrees on
the temporal retina (1.22 6 0.33 D), and does not entirely
explain the overall myopic shift.
The multizone contact lens effects were less strong and also
more transient than those treated with single vision lenses
(Figs. 4, 5), and they should be interpreted with caution due to
the variability between animals and the contralateral effects
observed (Fig. 1). The differences in the temporal character-
istics between responses to mixed and single vision defocus
might be linked to interactions between the temporal response
properties to hyperopic and myopic defocus, known to behave
in a nonlinear manner.
33,36
The accommodative response through the multizone lens
could not be recorded in our study, but accommodation
through positive and negative single vision lenses has been
measured in marmosets before,
7
and the results showed that
most of the negative-lens-treated animals did not accommodate
through the lens and so experienced effective hyperopic
FIGURE 5. Growth rates in multizone lens-reared marmosets (black),
untreated (white), and single vision lens-reared marmosets (positive, blue
and negative, red). Before treatment (pretreatment) and at early, mid, and
late time intervals during treatment. The data are given as box plots,where
the top and bottom end of the box represent the25th and 75thpercentile of
thedata,and theerrorbarsrepresent theSD. The underlying dots represent
individual data points,andthehorizontal line represents the mean.
IOVS, September 2012, Vol. 53, No. 10 Eye Growth and Development of Refractive State 6485
defocus during treatment, while a small percentage of animals
sporadically accommodated through the single vision negative
lens and cleared the defocus. Therefore, we speculate that the
marmosets in our study most likely did not accommodate at
near and used instead the most myopic image of the treated
eye (similar to monovision), leaving the fellow eye exposed to
more hyperopic defocus because of yoked accommodation.
Supporting this hypothesis, accommodation under imposed
anisometropia in humans appears to behave so that the eye
with less hyperopia dominates and drives the response, leaving
the eye with relatively more imposed hyperopic defocus
effectively hyperopic (Benavente-Perez A, et al. IOVS 2010;51:
ARVO E-Abstract 3932). This mechanism might explain the
effects we observed in the marmosets in our study, where not
only the multizone lens-treated eyes, but also the contralateral
eyes wearing plano contact lenses increased their axial growth
rates and became myopic. There is, however, evidence from
other human studies suggesting that accommodation can occur
at near for the more hyperopic image of a bifocal contact
lens.
27,37
Therefore, we cannot rule out that the marmoset eyes
treated with the multizone contact lenses might do this on
occasion. If this were the case, the contralateral eyes also
would have accommodated because of the consensual nature
of accommodation, and would have experienced myopic
defocus at least some of the time.
The similarities between our study and a preliminary
multizone soft contact lens trial in humans
27
suggested that
multizone designs with a positive addition may be effective in
slowing myopia progression in humans. Similar to the response
given by our animal model, and despite the variability in
refraction and axial length changes, the overall changes in
refractive state and axial growth rate were significantly slower
in the eyes wearing the multizone lens (referred to as dual
focus, DF) than in those eyes wearing single vision (SV) lenses
(DF prescription changes 0.44 6 0.33 D, SV 0.69 6 0.38, P
< 0.001. DF axial length changes 0.11 6 0.09 mm, SV 0.22 6
0.10 mm, P < 0.001). The agreement in outcomes between the
results obtained in humans and marmosets suggested that
when myopic defocus is presented simultaneously with a clear
image (humans) or hyperopic defocus (marmosets), the signal
is sufficient to reduce eye growth, as reported previously in
chicks.
21,22
The treatment duration in humans was 20 months
and it appeared to slow down the progression of myopia in
70% of the children, which is a greater percentage than the
outcomes obtained in past optical manipulation trials.
38–41
The
myopic defocus induced by the DF at distance and near design
is thought to be responsible for the efficacy of this treatment;
however, the therapeutic effects of such bifocal designs must
be investigated over longer periods of time. If imposing
positive defocus peripherally is effective, adding plus to the
periphery is a promising optical manipulation, as not only it
does not seem to affect VA or contrast sensitivity,
27
but the
patient also might tolerate it better than undercorrection,
progressive, or bifocal lenses.
In conclusion, imposing positive and negative defocus
simultaneously on the marmoset eye results in relatively slower
growth rates and more hyperopia, despite treated eyes being
exposed to greater amounts of negative defocus. The response
to mixed defocus is less strong, and more transient than that to
full-field defocus, but it indicates that it is possible to control
eye growth and refractive error development in the primate
model by manipulating the visual environment using optical
treatments of combined refractive nature.
Acknowledgments
Josh Wallman provided comments and suggestions, and Nancy
Coletta provided earlier discussions on the lens designs.
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    • "Improvements in accommodation performance, i.e., reduced lags, have also been reported with orthokeratology [31], lending further support to the notion that reduction or elimination of accommodative lags contributes to the myopia control effects of such treatments. The notion that the peripheral retina plays a critical role in refractive error development and thus in myopia progression also has its origins in animal model studies3233343536 and is driving the development of some novel designs of spectacles [7,8] and soft contact lenses (SCLs)91011 for myopia control. The underlying premise is that by manipulating the defocus experience of the peripheral retina, one can either neutralise the optical defocus in young adults, Contact Lens & Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.09.004 "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: To characterise the effects on accommodation and binocular vision in young adults of 2 distance centre multifocal soft contact lenses (MFSCLs), differing in add power. Methods: Twenty-four young adult myopes (18-28 years; 20 females, 4 males) had baseline visual acuity, accommodation, near phoria, fixation disparity and stereopsis data collected with single vision (SV) SCLs. The same set of measurements was repeated immediately after subjects were fitted with each of two MFSCLs (with either +1.50 or +3.00 D add), and after 2 weeks of daily wear in each case. The order of testing was randomised and a one-week washout period was allowed between the first and second MFSCL trials. Results: Differences in distance and near acuities with MFSCLs compared to SVSCLs were small and clinically insignificant. Compared to responses with SVSCLs, MFSCLs increased accommodative lags with this change reaching statistical significance for the +1.50 D add lens. Furthermore, both MFSCLs induced significant shifts in near phorias in the exo direction. Finally, there were no significant differences in stereopsis and fixation disparity with MFSCLs compared to SVSCLs. Conclusion: Differences in acuities, accommodation accuracy and binocular posture with MFSCLs compared to SVSCLs were clinically small and mostly not significant. These results predict good tolerance of MFSCLs in young patients fitted with them for myopia control.
    Full-text · Article · Oct 2015
    • "In particular , experiments in monkeys have indicated that visual signals from the peripheral retina are essential for several aspects of regulation of vision-dependent ocular growth [4]. Moreover, recent studies have shown that inducing a multifocal image on the eye and moving the image forward at the peripheral retina, leaving it myopically defocused, generates a visual stimulus to slow ocular growth [5, 6]. Several strategies using optical devices have been developed to reduce myopic progression. "
    [Show abstract] [Hide abstract] ABSTRACT: Objective. To evaluate the degree of axial elongation with soft radial refractive gradient (SRRG) contact lenses, orthokeratology (OK), and single vision (SV) spectacle lenses (control) during a period of 1 year before treatment and 2 years after treatment. Methods. This was a prospective, longitudinal, nonrandomized study. The study groups consisted of 30, 29, and 41 children, respectively. The axial length (AL) was measured during 2 years after recruitment and lens fitting. Results. The baseline refractive sphere was correlated significantly (Spearman's Rho (í µí¼Œ) correlation = 0.542; P < 0.0001) with the amount of myopia progression before baseline. After 2 years, the mean myopia progression values for the SRRG, OK, and SV groups were −0.56 ± 0.51, −0.32 ± 0.53, and −0.98 ± 0.58 diopter, respectively. The results represent reductions in myopic progression of 43% and 67% for the SRRG and OK groups, respectively, compared to the SV group. The AL increased 27% and 38% less in the SRRG and OK groups, respectively compared with the SV group at the 2-year visit (P < 0.05). Axial elongation was not significantly different between SRRG and OK (P = 0.430). Conclusion. The SRRG lens significantly decreased AL elongation compared to the SV control group. The SRRG lens was similarly effective to OK in preventing myopia progression in myopic children and adolescent.
    Full-text · Article · Oct 2015
    • "Visual experience plays an important role in refractive development. In response to form deprivation and spherical defocuses, a wide variety of animal models developed refractive er- rors3536373839404041424344. By the way of illustration, both chicks and macaque monkeys developed ametropia primarily axial in nature, with the former animal model responsive to a broader range of spherical defocus than the latter (-30.00D to +15.00D [45,46] vs. -3.00D to +6.00D [47] ). "
    [Show abstract] [Hide abstract] ABSTRACT: To determine the effects of optically imposed astigmatism on early eye growth in chicks. 5-day-old (P5) White Leghorn chicks were randomly assigned to either wear, monocularly, a "high magnitude" (H: +4.00DS/-8.00DC) crossed-cylindrical lens oriented at one of four axes (45, 90, 135, and 180; n = 20 in each group), or were left untreated (controls; n = 8). Two additional groups wore a "low magnitude" (L: +2.00DS/-4.00DC) cylindrical lens orientated at either axis 90 or 180 (n = 20 and n = 18, respectively). Refractions were measured at P5 and after 7 days of treatment for all chicks (P12), whereas videokeratography and ex-vivo eyeshape analysis were performed at P12 for a subset of chicks in each group (n = 8). Compared to controls, chicks in the treatment groups developed significant amounts of refractive astigmatism (controls: 0.03±0.22DC; treatment groups: 1.34±0.22DC to 5.51±0.26DC, one-way ANOVAs, p≤0.05) with axes compensatory to those imposed by the cylindrical lenses. H cylindrical lenses induced more refractive astigmatism than L lenses (H90 vs. L90: 5.51±0.26D vs. 4.10±0.16D; H180 vs. L180: 2.84±0.44D vs. 1.34±0.22D, unpaired two-sample t-tests, both p≤0.01); and imposing with-the-rule (H90 and L90) and against-the-rule astigmatisms (H180 and L180) resulted in, respectively, steeper and flatter corneal shape. Both corneal and internal astigmatisms were moderately to strongly correlated with refractive astigmatisms (Pearson's r: +0.61 to +0.94, all p≤0.001). In addition, the characteristics of astigmatism were significantly correlated with multiple eyeshape parameters at the posterior segments (Pearson's r: -0.27 to +0.45, all p≤0.05). Chicks showed compensatory ocular changes in response to the astigmatic magnitudes imposed in this study. The correlations of changes in refractive, corneal, and posterior eyeshape indicate the involvement of anterior and posterior ocular segments during the development of astigmatism.
    Full-text · Article · Dec 2014
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