Neuroscience Letters 339 (2003) 49–52
Functional MRI of amblyopia before and after levodopa
Chao-I Yanga, Meng-Ling Yanga, Ju-Chuan Huangb,c, Yung-Liang Wanb,c, Ray Jui-Fang Tsaia,
Yau-Yau Waib,c, Ho-Ling Liub,c,*
aDepartment of Ophthalmology, Chang-Gung Memorial Hospital, Taoyuan, Taiwan
bDepartment of Diagnostic Radiology, Chang-Gung Memorial Hospital, Taoyuan, Taiwan
cSchool of Medical Technology, Chang-Gung University, Taoyuan, Taiwan
Received 23 October 2002; received in revised form 14 December 2002; accepted 16 December 2002
Functional magnetic resonance imaging (fMRI) was applied to five older amblyopes with monocular amblyopia before and after levodopa
treatment. During the experiment, images were acquired in two runs with visual stimulation delivered through the sound and the amblyopiceyes, respectively. The experiment was performed on each of the subjects, before and after their oral administration of levodopa/carbidopa(0.5/0.12 mg/kg) three times per day for 7 weeks. Our study demonstrated that there was no effect on the spatial extent of the visual corticalactivation during the sound eye stimulation (P ¼ 0:17), but some improvement during the amblyopic eye stimulation (P ¼ 0:06). Thevolume ratio between the amblyopic and sound eye stimulation significantly increased after the treatment (P , 0:05). This finding supportsthe previous studies of levodopa effect on amblyopia at the visual cortical level, and suggests that fMRI can be a useful tool in assessingchanges of visual cortical activity after the treatment
q 2003 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: MRI; fMRI; Vision; Amblyopia; Levodopa
Amblyopia is a unilateral or bilateral reduction of best-
amblyopia) and neurotransmitter activity. Leguire et al.
corrected visual acuity that cannot be attributed directly to
reported that contrast sensitivity function was improved in
the effect of any structural abnormality of the eye or the
patients after a single dose and a 7-week regimen of
posterior visual pathway. It is caused by abnormal visual
levodopa, combined with part-time occlusion
experience early in life, usually resulting from ocular
Recently, functional magnetic resonance imaging
misalignment or uncorrected refractive error. Recently,
(fMRI) based on blood oxygenation level-dependent
Gottlob and Stangler-Zuschrott found that a single dose of
(BOLD) contrast has been utilized to measure the neuronal
levodopa, a precursor of the dopamine, with a combination
activity within visual cortical areas in patients with
of a peripheral decarboxylase inhibitor (e.g. benzerazide or
amblyopia BOLD contrast-based imaging utilizes
carbidopa), can temporarily improve contrast sensitivity in
paramagnetic deoxyhemoglobin as an endogenous contrast
the amblyopic eyes in adults The dopamine is presented
agent During functional brain activity, the
in retinal amacrine and interplexiform cells in humans as a
relative change of cerebral metabolic rate of oxygen was
neurotransmitter and is likely involved in the visual
found to be much less than that of cerebral blood flow,
information transmission to the visual cortex . Occlusion
leading to an increase of the BOLD signal. Using fMRI,
of newborn infant monkey's eye decreased retinal
Goodyear et al. reported that there were fewer activated
dopamine concentration and demonstrated an association
voxels, in the visual cortex, during visual stimulation
between functional changes in the visual pathway (e.g.
through the amblyopic eye than that through the normal eyeChoi et al. demonstrated that the fMRI signal changes in
* Corresponding author. MRI Center, Department of Diagnostic
the calcarine activation were smaller when viewed with
Radiology, Chang Gung Memorial Hospital, 5 Fuhsing Street, Kweishan,
amblyopic eyes than with sound eyes . The purpose of the
Taoyuan 333, Taiwan. Tel.: þ 886-3-3281200x8407; fax: þ 886-3-
present study was to apply fMRI techniques in the
E-mail address: [email protected]
0304-3940/03/$ - see front matter q 2003 Elsevier Science Ireland Ltd. All rights reserved.
C.-I Yang et al. / Neuroscience Letters 339 (2003) 49–52
investigation of the changes of visual cortical activity in
acquired during the stimulation states and those during the
patients with amblyopia after the levodopa treatment.
resting states, using an unpaired Student's t-test with a
Five older amblyopes (aged 13 – 17 years, cases 1, 2, and
threshold of 2.4 (P , 0:01). Regions of interest (ROIs) were
5 were anisometropic, and cases 3 and 4 were anisometropic
chosen in the gray matter area along the calcarine fissure
and strabismic) were enrolled in this study. The indications,
and enclosed the primary visual cortex, excluding the
risks and benefits of the procedures were well explained to
sagittal sinus, based on the anatomical images. For each
the patients or their family, and signed consent was obtained
subject, the volume of significantly activated voxels within
from all the parents before the procedure. All patients
the ROIs, were used to compare the neuronal activity
underwent a detailed ophthalmologic examination and were
induced by visual stimulation through the sound eye and the
considered stable amblyopes who were unresponsive to
amblyopic eye, before and after the treatment. To minimize
traditional occlusion treatment. The best-corrected visual
the variation of experimental conditions before and after
acuities (BCVAs) of their sound eye were all 1.0, while that
taking levodopa, the ratio of the activation volumes from the
of their amblyopic eye were 0.3, 0.3, 0.04, 0.3 and 0.3,
amblyopic and sound eye stimulation was calculated to
respectively. All patients received levodopa and part-time
further investigate the treatment effect.
(3 h/day) occlusion of the sound eye. Levodopa, in the
shows the functional maps of visual cortical areas
dosage of 0.5 mg/kg body weight, with a 25% fixed dose
from one of the patients, before and after levodopa
combination of carbidopa was administered orally three
medication. With the stimulation delivered through the
times a day for 7 weeks. The regimen was set according to
sound eye (a,b), approximately identical locations and
that reported by Mohan et al. FMRI with the same
volumes of the activated voxels were observed before and
protocol was performed on each patient before and after the
after the treatment. For the amblyopic eye stimulation, no
significant activation was detected before the treatment, as
Experiments were performed on a 1.5-T Magnetom
showed in c. However, after the levodopa medication,
Vision MRI scanner (Siemens, Erlangen, Germany) at the
significant activation was observed in the visual areas (
Chang Gung Memorial Hospital. Two separate fMRI scans
Comparing to the sound eye stimulation, similar
were performed on sound eye and amblyopic eye,
locations were activated in but the spatial extent
respectively. Each scan contains four resting-state blocks,
interleaved by three stimulation-state blocks. Each of the
summarizes the volumes of the activated voxels
seven blocks lasts for 30 s. A full field circular checkerboard
in the visual cortical areas detected in all the five patients.
(spatial frequency ¼ 408/cycle, visual angle ¼ 178) flashing
With the sound eye stimulation, no significant difference
at 8 Hz was presented on a goggle display system
was found in the fMRI volume measurement before and
(Resonance Technology Inc., CA, USA) as the visual
after levodopa medication (9594 2106 vs. 8560 1609
stimuli. The visions of both eyes of each subject were
mm3, P ¼ 0:17). With the amblyopic eye stimulation,
corrected to the best-corrected visual acuities using lenses
during the experiments. During the resting state, a crosshair
(5227 1661 mm3) than before (3517 1470 mm3) the
was presented for the fixation. The subject's head was
administration of levodopa. However, the P-value, 0.06, did
restrained in a molded plastic facial mask to reduce subject
not reach the statistical criteria. To minimize the systematic
motion during the performance of the scan. A single-shot
variance caused by the relatively long duration between the
T2*-weighted gradient-echo echo-planar imaging sequence
experiments before and after the treatment, i.e. 7 weeks, we
was used for BOLD imaging. Seventeen oblique slices
normalized the activation volume from the amblyopic eye
along the direction of the calcarine fissure was imaged to
stimulation to which from the sound eye stimulation. As
cover the visual areas and most other parts of the brain. The
illustrated in the volume ratio showed a statistically
imaging parameters were as follows: slice thickness ¼ 5
significant improvement (from 0.47 0.21 to 0.74 0.24,
mm, in-plane spatial resolution ¼ 3.3 £ 3.3 mm, and
P , 0:05) in the data obtained after levodopa. Post-
TR/TE/FA ¼ 2000 ms/60 ms/908. During each of the two
treatment BCVAs of the patients' sound eyes were 1.0,
scans, 105 images per slice were obtained with a total time
and that of their amblyopic eyes were 0.4, 0.5, 0.04, 0.5 and
of 210 s. For anatomical detail, a high resolution (1 £ 1 mm)
0.5, respectively. Improvement of BCVAs were observed to
T1-weighted image was acquired with the same slice
be in good agreement with the fMRI results.
thickness and location being identical to that used in the
To our knowledge, this study represents the first fMRI
investigation on modulation of primary visual cortical
We used Matlab (The Math Works, Inc., Natick, MA,
activation by levodopa in older amblyopic children. The
USA) and in-house software for image data processing
results demonstrated that there was no effect on primary
Functional images were grouped into stimulation and
visual cortical activation by contrast-based visual stimu-
resting states. To minimize the transient effects of
lation to the sound eye. For the visual stimulation delivered
hemodynamic responses, images from the first 8 s of each
through the amblyopic eye, there was some improvement on
block were excluded from further functional data proces-
the spatial extents of fMRI signal after levodopa. However,
sing. Activation maps were calculated by comparing images
it did not reach the statistical significance (P ¼ 0:06), which
C.-I Yang et al. / Neuroscience Letters 339 (2003) 49–52
Fig. 1. Functional maps of visual cortical areas from one of the patients, before (a, c) and after (b, d) levodopa medication, with the stimulation deliveredthrough the sound eye (a, b) and through the amblyopic eye (c, d). Significantly activated areas (P , 0:01) are displayed in color and overlaid onto thecorresponding echo-planar images.
may be attributed to the limited number of patients,
(P , 0:05) after levodopa. Our results showed that the
significant inter-subject variation and the variance between
treatment effects in improving visual function in amblyopes,
the two experiments that were performed before and after
as previously demonstrated with monocular log Snellen
treatment. The inter-subject variability was mainly resulted
fraction and contrast sensitivity functions , can
from the poor visual activity of the subject 3 and/or different
now be observed in visual cortical activation using fMRI.
types of amblyopia . The poor pre- and post-activity of
To evaluate the sensitivity of fMRI as a tool for assessing
subject 3 may be due to the poor visual acuity of the subject.
the levodopa effect, studies with larger groups of patients
In addition, because the 7-week interval between the two
are required and are currently under investigation in our
experiments was relatively long, significant variation may
be introduced from the different physiological conditions
Functional neuroimaging techniques have been recently
(noise) and/or other systematic errors during the exper-
employed to study the cortical activity in human amblyopia
imental setup. To minimize this possible effect, we
Reduced visual cortical response of the amblyo-
calculated the ratio of the activation volume from the
pic eye to light stimulation was found using either positron
amblyopic eye stimulation and that from the sound eye
emission tomography or single photon emission computed
stimulation, and found a significant improvement
tomography Goodyear et al. reported that the
Table 1Volumes of significantly activated voxels within visual cortical areas
pSignificantly different (P , 0:05).
a Ratio ¼ amblyopic eye stimulation (mm3)/sound eye stimulation (mm3).
C.-I Yang et al. / Neuroscience Letters 339 (2003) 49–52
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