HM Medical Clinic


Pii: s0304-3940(02)01465-9

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] (H.-L. Liu).
0304-3940/03/$ - see front matter q 2003 Elsevier Science Ireland Ltd. All rights reserved.
doi:10.1016/S0304-3940(02)01465-9 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, was smaller.
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 functional imaging.
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 research team.
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 magnitude of the fMRI response in the activated voxels was [4] J.L. Demer, G.K. von Noorden, N.D. Volkow, K. Lance Gould, the same for each eye, regardless of the presence of Imaging of cerebral blood flow and metabolism in amblyopia bypositron emission tomography, Am. J. Ophthalmol. 105 (1988) amblyopia. However, there are always fewer activated 337 – 347.
voxels during amblyopic stimulation than during normal [5] R.S. Dyer, W.E. Howell, R.C. MacPhail, Dopamine depletion slows eye stimulation . In our study, the activated brain volume retinal transmission, Exp. Neurol. 71 (1981) 326 – 340.
during amblyopic stimulation was found to be either smaller [6] J.M. Frederick, M.E. Rayborn, A.M. Laties, D.M.K. Lam, J.G.
than (patient no. 1, 3, 4 and 5) or similar to (patient no. 2) Hollyfield, Dopaminergic neurons in human retina, J. Comp. Neurol.
210 (1982) 65 – 79.
that during normal eye stimulation, which is in agreement [7] B.G. Goodyear, D.A. Nicolle, G.K. Humphrey, R.S. Menon, Bold with previous studies.
fMRI response of early visual areas to perceived contrast in human Levodopa is a precursor of dopamine, a neurotransmitter amblyopia, J. Neurophysiol. 84 (2000) 1907 – 1913.
of the retina, and is known to influence the visual system at [8] I. Gottlob, E. Schneider, W. Heider, W. Skrandies, Alteration of visual the retinal and cortical levels Previous studies on the evoked potentials and electroretinograms in Parkinson's disease, treatment of amblyopia demonstrated that levodopa with a Electroenceph. clin. Neurophysiol. 66 (1987) 349 – 357.
[9] I. Gottlob, E. Stangler-Zuschrott, Effect of levodopa on contrast combination of carbidopa, a peripheral decarboxylase sensitivity and scotomas in human amblyopia, Invest. Ophthalmol.
inhibitor, can improve contrast sensitivity function in Vis. Sci. 31 (1990) 776 – 780.
children and adults . A retinal involvement [10] I. Gottlob, H. Weghaupt, C. Vass, E. Auff, Effect of levodopa on the was proposed by Gottlob et al. In patients with changes human pattern electroretinogram and pattern visual evoked potentials, of dopaminergic system, such as Parkinson's disease, Graefes. Arch. Clin. Exp. Ophthalmol. 227 (1989) 421 – 427.
[11] P.M. Iuvone, M. Tigges, A. Fernandes, J. Tigges, Dopamine synthesis electroretinogram changes also indicated an initial impair- and metabolism in rhesus monkey retina: Development, aging, and the ment at the retinal level . Although we have observed effects of monocular visual deprivation, Vis. Neurosci. 2 (1989) an increased activation volume in the visual cortical area 465 – 471.
after the treatment, the dopaminergic effect still cannot be [12] L. Kabasakal, K. Devranoglu, O. Arslan, T.Y. Erdil, K. Sonmezoglu, localized in a specific part of the visual pathway. With the I. Uslu, H. Tolun, A.T. Isitman, K. Ozker, C. Onsel, Brain SPECTevaluation of the visual cortex in amblyopia, J. Nucl. Med. 36 (1995) advances of extra-high spatial resolution functional neuroi- 1170 – 1174.
maging techniques, more knowledge of brain involvement [13] K.K. Kwong, J.W. Belliveau, D.A. Chesler, I.E. Goldberg, R.M.
of the levodopa effect might be discovered in the future.
Weisskoff, B.P. Poncelet, D.N. Kennedy, B.E. Hoppel, M.S. Cohen, Previous studies on treatment of amblyopia with R. Turner, H.M. Cheng, T.J. Brady, B.R. Rosen, Dynamic magnetic levodopa have shown an improvement in contrast sensi- resonance imaging of human brain activity during primary sensorystimulation, Proc. Natl. Acad. Sci. USA 89 (1992) 5675 – 5679.
tivity function. This study represents the first fMRI [14] L.E. Leguire, G.L. Rogers, D.L. Bremer, Functional amblyopia is a investigation on the modulation of visual cortical activation single continuum of visual impairment on contrast sensitivity by levodopa in older amblyopic children. Our results functions, Binocular vision 2 (1987) 199 – 208.
demonstrated that the spatial extent of the visual cortical [15] L.E. Leguire, G.L. Rogers, D.L. Bremer, P. Walson, M. Hadjicon- activation, illustrated as the volume ratio between the stantinou-Neff, Levodopa and childhood amblyopia, J. Pediatr.
Ophthalmol. Strabismus 29 (1992) 290 – 298.
abnormal and sound eye stimulation, significantly increased [16] L.E. Leguire, G.L. Rogers, P.D. Walson, D.L. Bremer, M.L.
after treatment with levodopa. This finding supports the McGregor, Occlusion and levodopa-carbidopa treatment for child- previous studies of the treatment effect of levodopa on hood amblyopia, J. AAPOS. 2 (1998) 257 – 264.
amblyopia at the visual cortical level.
[17] L.E. Leguire, P.D. Walson, G.L. Rogers, D.L. Bremer, M.L.
McGregor, Longitudinal study of levodopa/carbidopa for childhoodamblyopia, J. Pediatr. Ophthalmol. Strabismus 30 (1993) 354 – 360.
[18] L.E. Leguire, P.D. Walson, G.L. Rogers, D.L. Bremer, M.L.
McGregor, Levodopa/carbidopa treatment for amblyopia in olderchildren, J. Pediatr. Ophthalmol. Strabismus 32 (1995) 143 – 151.
[1] P.A. Bandettini, E.C. Wong, R.S. Hinks, R.S. Tikofsky, J.S. Hyde, [19] K. Mohan, V. Dhankar, A. Sharma, Visual acuities after levodopa Time course EPI of human brain function during task activation, administration in amblyopia, J. Pediatr. Ophthalmol. Strabismus 38 Magn. Reson. Med. 25 (1992) 390 – 397.
(2001) 62 – 67.
[2] M.Y. Choi, K.M. Lee, J.M. Hwang, D.G. Choi, D.S. Lee, K.H. Park, [20] S. Ogawa, D.W. Tank, R.S. Menon, J.M. Ellermann, S.G. Kim, H.
Y.S. Yu, Comparison between anisometropic and strabismic amblyo- Merkle, K. Ugurbil, Intrinsic signal changes accompanying sensory pia using functional magnetic resonance imaging, Br. J. Ophthalmol.
stimulation: functional brain mapping using MRI, Proc. Natl. Acad.
85 (2001) 1052 – 1056.
Sci. USA 89 (1992) 5951 – 5955.
[3] N.W. Daw, R.K. Rader, T.W. Robertson, M. Ariel, Effect of 6- [21] J. Xiong, J.H. Gao, J.L. Lancaster, P.T. Fox, Clustered pixels analysis hydroxydopamine on visual deprivation in the kitten striate cortex, for functional MRI activation studies in the human brain, Hum. Brain J. Neurosci. 3 (1983) 907 – 914.
Mapp. 3 (1995) 209 – 223.


Microsoft word - examensarbete2

Köp av bostad i Spanien - en riskfylld affär? Cecilia Nykvist Institutionen för teknik och samhälle Fastighetsvetenskap Lunds Tekniska Högskola Lunds universitet The Departement of Technology and Society Real Estate Science Lund's Institute of Technology Lund University, Sweden Köp av bostad i Spanien – en riskfylld affär?

Dc110660 2279.2284

Metformin in Gestational Diabetes: The Offspring Follow-Up (MiG TOFU)Body composition at 2 years of age ANET A. ROWAN, MBCHB MALCOLM BATTIN, MD that because of continued exposure to nu- LAINE C. RUSH, PHD TRECIA WOULDES, PHD trient excess in utero, the subcutaneous ICTOR OBOLONKIN, BSC WILLIAM M. HAGUE, MD fat stores become overloaded and, thus,the fetus develops leptin and insulin re-sistance and deposits excess nutrients as