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Structural Abnormalities in Patients with Primary Open-Angle Glaucoma: A Study with 3T MR Imaging

Wei W. Chen,1–3 Ningli Wang,1,3 Suping Cai,3,4 Zhijia Fang,5 Man Yu,2 Qizhu Wu,5 Li Tang,2 Bo Guo,2 Yuliang Feng,2 Jost B. Jonas,6 Xiaoming Chen,2 Xuyang Liu,3,4 and Qiyong Gong5

PURPOSE. We examined changes of the central CONCLUSIONS. In patients with POAG, three-dimensional MRI in patients with advanced primary open-angle glaucoma revealed widespread abnormalities in the central nervous (POAG). system beyond the . (Invest Ophthalmol Vis Sci. 2013;54:545–554) DOI:10.1167/iovs.12-9893 METHODS. The clinical observational study included 15 patients with bilateral advanced POAG and 15 healthy normal control subjects, matched for age and sex with the study group. Retinal rimary open angle glaucoma (POAG) has been defined fiber layer (RNFL) thickness was measured by optical formerly by intraocular morphologic changes, such as coherence tomography (OCT). Using a 3-dimensional magne- P progressive loss and defects in the retinal tization-prepared rapid gradient-echo sequence (3D–MP-RAGE) nerve fiber layer (RNFL), and by corresponding psychophysical of magnetic resonance imaging (MRI) and optimized voxel- abnormalities, such as visual field loss.1 Recent studies by based morphometry (VBM), we measured the cross-sectional various researchers, however, have suggested that the entire area of the optic nerve and optic , and the gray matter visual pathway may be involved in glaucoma.2–23 Findings from volume of the brain. these experimental studies, human autopsy investigations, and RESULTS. Patients in the POAG group compared to the subjects in vivo neuro-imaging studies of glaucoma patients indicated in the control group showed a significant (P < 0.001) decrease that glaucoma is a complex disorder in which the whole visual in the bilateral gray-matter volume in the lingual gyrus, pathway from the to the primary visual cortex may be calcarine gyrus, postcentral gyrus, superior frontal gyrus, involved. These studies, in particular those using neuro- inferior frontal gyrus, and rolandic operculum, as well as in imaging techniques, were limited by the age of the patients the right , right inferior occipital gyrus, left paracentral with young patients and those with advanced glaucoma usually lobule, and right supramarginal gyrus. Patients in the study not included into the studies, and by focusing on the visual group showed a significant increase in the bilateral gray matter pathway to the visual cortex mostly without examining other volume in the middle temporal gyrus, inferior parietal gyrus, cerebral regions, such as the gray matter in the superior cortex. and angular gyrus, and in the left gray matter volume in the Previous studies indicated, however, that glaucoma damage in superior parietal gyrus, precuneus, and middle occipital gyrus. the receptive fields in the retina could eliminate the In addition, the cross-sectional area of the optic nerve and stimulation of parts of the visual cortex, resulting in the , and RNFL thickness were significantly decreased degeneration of inactive cortical neuronal tissue.14 Therefore, in the POAG group. it has been hypothesized that patients with advanced POAG could experience changes in the whole brain. Also, the neuro- imaging technologies, namely magnetic resonance imaging From the 1Beijing Tongren Center, Medical Sciences College (MRI), have been refined further, resulting in higher spatial of Capital University, Beijing, China; the 2Ophthalmic Laboratories resolution. In addition, optimized voxel-based morphometry and Department of Ophthalmology, West China Hospital, Sichuan (VBM) as a whole-brain, semi-automated technique for University, Chengdu, China; the 4Shenzhen Eye Hospital, Jinan characterizing regional cerebral differences in high-resolution University, Shenzhen, China; the 5West China MR Research Center MRIs with minimal operator dependence has been devel- (HMRRC), Department of Radiology, West China Hospital, Sichuan oped.24 A so-called optimized VBM incorporates additional University, Chengdu, China; and the 6Department of Ophthalmolo- gy, Universit¨atsmedizin Mannheim, Medical Faculty Mannheim, spatial processing steps ahead of the statistical analysis. The Heidelberg University, Mannheim, Germany. optimization steps help in excluding the non-brain voxels 3These authors contributed equally to the work presented here before normalization and subsequent segmentation, and help and therefore should be regarded as equivalent authors. to avoid the potential bias due to systematic differences in skull Supported by the National Natural Science Foundation (Grant size and shape or scalp thickness between the study groups.25 Nos. 81030027, 81227002 and 81220108013), National Key In view of these new neuro-imaging technologies and in view Technologies R&D Program of China (Program No. 2012BAI01B03), of the possibilities of further improvement of the previous and China Postdoctoral Science Foundation (Grant No. investigations, we conducted the present study to examine 2012M520329). The authors alone are responsible for the content and writing of this paper. relatively young patients with advanced glaucomatous optic Submitted for publication March 21, 2012; revised August 26 neuropathy by applying optimized VBM-assisted MRI. and November 16, 2012; accepted December 12, 2012. Disclosure: W.W. Chen,None;N. Wang,None;S. Cai,None;Z. Fang,None;M. Yu,None;Q. Wu,None;L. Tang,None;B. Guo, METHODS None; Y. Feng,None;J.B. Jonas,None;X. Chen,None;X. Liu, None; Q. Gong,None Subjects Corresponding author: Xuyang Liu, Shenzhen Eye Hospital, Jinan University, Shenzhen, 518040, P. R. China; A total of 15 patients (9 men) with an age of 40 to 50 years and bilateral [email protected]. advanced POAG formed the study group, and 15 control subjects

Investigative Ophthalmology & Visual Science, January 2013, Vol. 54, No. 1 Copyright 2013 The Association for Research in Vision and Ophthalmology, Inc. 545

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FIGURE 1. Reconstruction of the axial images perpendicular to the optic nerve. (A) Orbital optic nerve allowing for the construction of a plane parallel to the optic nerve (red line). The middle point was identified along the marked line parallel to the optic nerve from the beginning of the retrobulbar optic nerve to . Reconstruction of the targeted plane was performed perpendicular to the optic nerve through the middle point (green line). (B) The sagittal image showing the placement of the reconstruction plane at the middle point of the optic nerve (green line). (C) The reconstructed coronal plane showing the axial targeted image of the optical nerve.

matched for age and sex with the study group were included into the MRI Data Acquisition control group of the study. The study followed the tenets of the Declaration of Helsinki, and it was approved by the ethics committee All subjects were examined by a 3 Tesla MRI scanner (Magnetom Trio; of the West China Hospital, Sichuan University Institute, Chengdu, Siemens Co., Erlangen, Germany) with an 8-channel phased-array head Sichuan Province, P.R. China. Informed consent was obtained from the coil as a magnetic resonance signal receiver. The subjects were subjects after explanation. All participants in this study underwent an required to close their and avoid any eye movements during the ophthalmologic examination ( assessment, refractometry, image acquisition. To secure the repeatability of the MRI scan, the axial measurement of central corneal thickness, slit-lamp–assisted biomi- plane of each MRI session was set parallel to the line from the anterior commissure to the posterior commissure on sagittal localizer images.26 croscopy of the anterior and posterior segment of the eye, applanation The MRI protocol scan contained a transverse-axial turbo spin-echo tonometry, gonioscopy, photography of the optic nerve head and imaging sequence with T2-weighted and a 3-dimensional magnetiza- fundus, and standard automated perimetry; Octopus 101 perimeter; tion-prepared rapid gradient-echo (3D–MP-RAGE) sequence. T2- Interzeag, Bern, Switzerland), and a systematic body examination. All weighed images were used for conventional screening with parame- patients were followed for at least 6 months. The diagnosis of POAG ters: TR/TE ¼ 4000/83 ms and slice thickness 3 mm. Sequence was made by two glaucoma specialists (XL, XC) independently of each parameters for MP-RAGE were: TR/TE ¼ 1900/2.27 ms, field of view other. The inclusion criterion for patients in the study group was (FOV) of 240 3 240 3 170, data matrix of 256 3 256 3 176, resulting in bilateral advanced POAG, as defined by a cup-to-disc diameter ratio an approximate isotropic voxel size 1 3 1 3 1 mm. ‡0.9, a mean perimetric defect ‡15 decibels (dB), preservation of central vision in both eyes, and open anterior chamber angles upon gonioscopy. Exclusion criteria were any other ocular, neurologic or Optic Nerve Cross-Sectional Area Measurement psychiatric disorder; any history or clinical signs of auto-immune Using Syngo MultiModality Workplace (Series Number 3064, Version diseases, cardiovascular diseases, cerebrovascular diseases, and diabe- VE31A; Siemens Co.), we reconstructed axial images perpendicular to tes mellitus; and blood pressure measurements of >140/90 or the optic nerve through the middle point along the line between the antihypertensive medication. retrobulbar optic nerve and annulus tendineus of Zinn (Fig. 1A). The All study participants underwent measurement of the RNFL region of interest (ROI) of the optic nerve was drawn manually in the thickness by optical coherence tomography (OCT, Heidelberg Spec- reconstructed plane (Figs. 1, 2). To ensure the reliability of the ROI tralis OCT; Heidelberg Engineering Co. Heidelberg, Germany). The fast measurement, the same procedure was performed 3 times by three measurement scan protocol was used (3.4 mm diameter). The scanning radiologists (ZF, QW, XH) in a masked manner. A mean value of each was completed following a 10-minute dark adaptation to ascertain that optic cross-sectional area was calculated from the results of the three the pupils were large enough to permit imaging (usually 5 mm) measurements. In the targeted MP-RAGE images, the optic nerve without pharmacologic dilation of the pupil. An OCT scan of good showed a low dark signal against the cerebrospinal fluid, while the quality was defined by a uniform brightness across the scan surrounding tissue showed the bright signal. Hence, quantification of circumference. The was centered in all scans by the the optic nerve was facilitated by the excellent contrast of the nerve scanning technician. against its surroundings. The low and dark area was the ROI.

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FIGURE 2. ROI of the optic nerve defined as the cross-sectional image of both eyes at a reconstructed oblique-coronal plane.

Optic Chiasm Cross-Sectional Area Measurement The same software was applied to measure the optic chiasm cross- sectional area. A plane perpendicular to the optic chiasm through its middle point was reconstructed (Fig. 3). The ROI drawing of the optic chiasm was made manually in the reconstructed plane (Fig. 3) by the same three radiologists (ZF, QW, XH). These three radiologists performed the same procedure in a masked fashion three times. The mean value of each optic cross-sectional area was calculated from the results of the three measurements. In the targeted images, the optic chiasm yielded a high, white signal, while cerebrospinal fluid showed a gray signal. The white signaled area was the ROI.

Optimized VBM The structural images were preprocessed using the optimized VBM implemented in SPM2 (available in the public domain at www.fil.ion. ucl.ac.uk/spm), running under Matlab (MathWorks, Natick, MA). The image processing procedures already have been described in detail.27 The first step was the creation of a study-specific gray matter template image for all study participants. T1 images of each participant were normalized to the T1 template of SPM2 using an affine-only cut-off. After normalization, the images were averaged and smoothed with an 8 mm kernel, creating the customized T1 template. The normalized images then were segmented into three different tissues: gray matter, white matter, and cerebrospinal fluid. Non-brain voxels were excluded from the statistical analysis by applying a brain mask. Gray matter partitions were normalized spatially using a 12-parameter affine transformation and 7 3 8 3 7 nonlinear basis functions, which were the default normalization parameters in SPM2 to a customized gray matter template constructed from the normalized, segmented, and smoothed gray matter datasets of all study participants. The deformation parameters obtained from the normalization process were applied to the original raw images (native space) of all participants to create optimally normalized whole-brain images, which were segment- Figure 3. Reconstruction of the plane perpendicular to the optic chiasm and the ROI drawing. (A) Placement of the median sagittal ed recursively and brain–tissue-extracted. The optimally processed plane with a full sight of the optic chiasm as the primary plane, images then were smoothed with an isotropic Gaussian kernel with full reconstructing a plane perpendicular to the optic chiasm through the width-half maximum of 10 mm. The differences in gray matter volume middle point. The green line showed the position of the reconstructed of the whole brain between the two groups were assessed statistically target plane. (B) A coronal image of the target plane. ROI drawing was with two-sample t-tests. All results were presented at the voxel level. In along the edge of the white signaled area.

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TABLE 1. Ocular Characteristics (Mean 6 SD) in the POAG Group the coordinates obtained for the peak voxels) of the maximal gray matter loss in each significant cluster was transferred into Talairach Right Eyes Left Eyes Value P space using Matthew Brett’s mni2tal routine (available in the public Visual acuity, LogMAR 0.15 6 0.13 0.16 6 0.15 0.43 domain at http://imaging.mrc-cbu.cam.acuk/down load /MNI2tal). IOP before treatment 28.1 6 3.9 30.1 6 4.3 0.64 Data were analyzed on a personal computer by means of Windows IOP after treatment 15.6 6 3.6 15.0 6 3.4 0.78 XP Professional V.5.1, and Matlab7.0.1 and SPM2 (available in the MD of 20.6 6 2.9 21.6 6 3.2 0.36 public domain at http://www.fil.ion.ucl.ac.uk/spm). sLV of visual field 5.36 6 0.97 5.52 6 1.02 0.62 Statistical analysis was performed by using the Statistical Package for the Social Sciences (SPSS, version 20.0; IBM-SPSS, Chicago, IL). IOP, (mm Hg); MD, mean perimetric defect; sLV, square root of the perimetric loss of variance; LogMAR, logarithm Comparison between patients and control subjects was performed of the minimum angle of resolution; P value, statistical significance of using an independent-sample t-test. All P values < 0.05 were difference between right and left eyes. considered statistically significant based on a 2-tailed test.

addition, a small volume correction was performed using the WFU RESULTS PickAtlas software V.2 to reduce the number of voxels entering the statistical computation,27 and corrected for multiple comparisons The mean age of the 15 patients (9 men) in the advanced using a family-wise error rate of P < 0.05. The anatomic location (i.e., POAG study group was 43.3 6 4.1 years (mean 6 SD). The

FIGURE 4. Visual field result of the right eye of a patient with POAG.

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FIGURE 5. Visual field result of the left eye of a patient with POAG.

subjects in the control group were matched for age (43.9 6 3.8 35.10 6 4.63 mm2) as measured on the MRI images were years, P ¼ 0.68) and sex (9 men) with the POAG patients. significantly (all P < 0.001) smaller in the study group than in Visual acuity, indices of visual field examinations and intraoc- the control group. ular pressure in the glaucoma group were summarized in Table The VBM analysis revealed that the glaucomatous study 1. The right and left eyes did not differ significantly (P > 0.05) group compared to the control group showed a significantly in these parameters (Table 1). Visual acuity in the control decreased gray matter volume in the lingual gyrus, calcarine group was at least 20/20, and intraocular pressure was within gyrus, postcentral gyrus, superior frontal gyrus, inferior frontal the range of 10 to 21 mm Hg. Typical visual fields of patients of gyrus, and rolandic operculum of both sides, and in the right the glaucoma group were presented in Figures 4 and 5. The inferior occipital gyrus, left paracentral lobule, right supra- mean thickness of the RNFL as a whole (48.5 6 15.1 vs. 102.7 marginal gyrus, and right cuneus (Table 2, Fig. 6). The gray 6 22.7 lm) and measured separately in the four quadrants was matter volume was significantly larger in the study group than significantly (all P < 0.001) lower in the study group than in in the control group in both sides of the middle temporal the control group. gyrus, inferior parietal gyrus, angular gyrus, and left superior The cross-sectional areas of the optic nerve (6.67 6 2.23 vs. parietal gyrus, left precuneus, and left middle occipital gyrus 10.10 6 3.14 mm2) and the optic chiasm (20.38 6 4.94 vs. (Table 3, Fig. 7).

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TABLE 2. Clusters of Decreased Gray Matter Volume in Patients with POAG

Cluster Size (cm3) Talairach x,y,z (mm) Voxel T Voxel P (unc) Cluster P (unc) Cluster P (c) Brain Region

Control group > Glaucoma study group 16.9 8,63,0 8.87 <0.001 <0.001 <0.001 Lingual, calcarine 30,90,13 7.6 <0.001 Occipital_inf_R 14,70,20 7.05 <0.001 Cuneus_R 7.2 60,2,28 6.93 <0.001 <0.001 <0.001 Postcentral_R 55,3,10 6.29 <0.001 Rolandic_oper_R 59,18,19 6.09 <0.001 Frontal_inf_oper_R 6.1 33,4,15 6.16 <0.001 <0.001 <0.001 Rolandic_oper_L 44,5,11 5.14 <0.001 Frontal_inf_oper_L 63,25,20 Supramarginal_L 56,6,28 5.04 <0.001 Postcentral_L 4 5,20,64 5.59 <0.001 <0.001 <0.001 Paracentral_lobule_L 15,10,76 5.02 <0.001 Frontal_super_R 17,10,73 4.96 <0.001 Frontal_super_L

DISCUSSION formed. Using 1.5-T vivo MRI, Gupta et al. detected an atrophy in the lateral in patients with POAG.5 Glaucoma is an characterized by apoptotic Applying a 3-T Diffusion-Tensor MRI, Garaci et al. noticed an death of retinal ganglion cells. To date, the pathology of increased diffusion tensor and decreased fractional anisotropy, glaucoma has been examined extensively at the level of the reflecting axonal disruption of the optic and optic retina, optic nerve head, intracranial optic nerves, lateral radiations in patients with POAG.28 Kitsos et al. reported on an geniculate ganglion, and primary visual cortex.3–8 Most of increase in the number of white matter hyperintensities, these studies on glaucoma-associated changes in the human suggesting cerebrovascular changes in POAG.12 In a recent brain were postmortem investigations studies or assessed study, Zikou et al. used a conventional VBM and diffusion biochemical changes (e.g., cytochrome oxidase) in primates. In tension imaging, and examined the visual pathway in patients recent years, few neuro-imaging studies on the lateral with POAG who showed a thinning of the left temporal and geniculate ganglion and the visual central area were per- right nasal retinal nerve fiber layer.23 VBM revealed a significant

FIGURE 6. Comparison of areas of reduced gray matter among patients with an advanced POAG and in normal controls. The figure shows areas of regional changes in visual cortex area. (A) Cluster map of the whole brain. (B) Lingual gyrus and Calcarine fissure. (C) Right and left postcentral gyri. (D) Right and left superior frontal gyri. (E) right and left inferior frontal gyri. (F) Right and left Rolandic operculums. (G) Right inferior occipital gyrus. (H) Left paracentral lobule. (I) Left supramarginal gyrus.

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TABLE 3. Clusters of Increased Gray Matter Volume in Patients with POAG

Cluster Size (cm3) Talairach x,y,z (mm) Voxel T Voxel P (unc) Cluster P (unc) Cluster P (c) Brain Region

POAG > NC 5.5 52,38,4 5.17 <0.001 <0.001 0.01 Temple_mid_R 51,58,46 4.96 <0.001 Parietal_inf_R 37,50,44 4.3 <0.001 Parietal_inf_R 59,55,25 Angular_R 1.4 27,50,53 4.86 <0.001 0.043 0.732 Parietal_inf_L 32,56,57 4.77 <0.001 Parietal_sup_L 32,67,55 4.59 <0.001 Parietal_sup_L 1.7 9,64,49 4.74 <0.001 0.027 0.557 Precuneus_L 5,71,60 4.64 <0.001 Precuneus_L 8,53,51 3.83 <0.001 Precuneus_L 1.7 40,77,25 4.59 <0.001 0.025 0.535 Occipital_mid_L 49,69,16 3.71 0.001 Temporal_mid_L 36,82,30 3.46 0.001 Occipital_mid_L 3.2 48,56,26 4.42 <0.001 0.004 0.111 Angular_L 55,46,4 4.29 <0.001 Temporal_mid_L 42,71,38 4.05 <0.001 Angular_L

reduction in the left visual cortex volume, left lateral geniculate has remained unclear whether the higher brain cortex is nucleus, and chiasm. In addition, fraction analysis of diffusion affected or which other regions of the brain than those tension imaging was decreased significantly in the inferior described above are affected in patients with POAG. fronto-occipital fasciculus, longitudinal and inferior frontal VBM is a whole-brain, nonbiased, semi-automated technique fasciculi, putamen, caudate nucleus, anterior and posterior for characterizing regional cerebral differences in high-resolu- thalamic radiations, and anterior and posterior limbs of the tion MRIs, suitable for the comparison of the gray or white internal capsule of the left hemisphere. Zikou et al. concluded matter. VBM is useful in characterizing subtle and gross that neurodegenerative changes beyond of the optic pathway structural changes in the brain in a variety of neurologic and could be found in patients with POAG.23 Besides this recent psychiatric diseases, such as schizophrenia, , investigation by Zikou et al., who used a conventional VBM, it and Alzheimer’s disease. It also has been used in studies of

FIGURE 7. The comparison of areas of increased gray matter among patients with advanced POAG and in normal control subjects. (A) Cluster map of the whole brain. (B) Right and left middle temporal gyri. (C) Right and left angular gyri. (D) Right inferior parietal gyrus. (E) Left inferior parietal gyrus. (F) Left superior parietal gyrus. (G) Left middle occipital gyrus. (H) Left precuneus.

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Figure 8. Possible trend of the central nerve system changes in advanced POAG.

normal subjects, focusing on the impact of learning and potential cortical network for visual reaching.33 The frontal practice on the brain structure. For instance, some changes lobe has an important role in the formation of the optic were reported in the structure of the brain when humans localization, multiple retinal correspondence, and of learned to navigate and to speak a second language.29,30 An the fixation point. It has been known that the postcentral gyrus optimized VBM can help to quantify group differences in is an important region for processing of higher order neuro-anatomy without any prior hypothesis. Previous studies somatosensory and visual information, and the supramarginal in this area focused mainly on case reports, and none of the gyrus has a critical role in visual word recognition.34 studies used an optimized VBM to examine damages in the The optimized VBM analysis showed that the patients with higher cortex of patients with POAG. In our study, patients POAG had an increased gray matter volume in regions with with advanced POAG showed a significant reduction of the different functions. It might have been due to a functional gray matter in the visual cortex. Based on an optimized VBM reconstruction of the brain in the of cerebral plasticity. analysis, the patients with advanced POAG demonstrated not Longstanding vision loss may lead to a decrease in cerebral only an extensive decrease of the gray matter volume in various centers primarily or secondarily related to vision, and to a regions of the brain, but also an increased gray matter volume transmodal compensatory increase in nonvisual functions and in other specific brain areas (Tables 2 and 3, Fig. 8). According corresponding morphologic changes in the brain. One of the to the VBM analysis in our study, patients with POAG showed a important regions involved was the middle temporal visual bilateral symmetric decrease in the gray matter volume in the area, which has a critical role in visual motion processing. The occipital cortex. The clusters contained the primary visual parietal lobe is associated with the spatial awareness and cortex (Brodmann area 17) and the secondary visual cortex redirecting visual attention.35 Functional imaging findings in (Brodmann areas 18 and 19), with the occipital pole area healthy subjects suggested a central role for the precuneus in a corresponding to the central retina.31 The decreased clusters wide spectrum of highly integrated tasks, including visuospa- in the patients with POAG excluded the occipital pole, which tial imagery, episodic memory retrieval, and self-processing might be due to the preserved central vision of the involved operations, namely first-person perspective taking and an patients as an inclusion criterion of the study. Consistent with experience of agency.36 The damage in the angular gyrus might this result, Boucard et al. found a reduction of the cortical gray cause dyslexia.37 Neural plasticity to compensate for the matter density in glaucoma patients in the anterior half of the glaucoma-related loss of visual input thus may have been medial occipital cortex.13 Dai et al. showed a disrupted responsible for the changes observed in the cerebral centers functional connectivity between the visual cortex and associa- beyond the visual cortex. tive visual areas using resting-state functional MRI in patients With family-wise error rate rectifications, the measurements with POAG.32 Our study detected extensive structural atrophy obtained in some of the clusters were statistically significant in patients with advanced POAG. All the brain regions involved only for one side of the brain (Tables 2, 3), although the were associated with visual functions. The parietal and frontal glaucomatous damage to the optic nerve and visual field were areas, along with their association connections, represent a bilateral. Such a statistical phenomenon occurs commonly in

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VBM analysis, and future studies on a larger number of study 5. Luthra A, Gupta N, Kaufman PL, Weinreb RN, Yucel¨ YH. participants may address whether a bilateral glaucomatous Oxidative injury by peroxynitrite in neural and vascular tissue damage to the visual afferent system leads mostly to bilateral of the lateral geniculate nucleus in experimental glaucoma. changes in the cerebral cortex. Exp Eye Res. 2005;80:43–49. In our study, the patients with advanced POAG showed a 6. Gupta N, Ang LC, No¨el de Tilly L, Bidaisee L, Yucel¨ YH. Human decrease in RNFL thickness, and cross-sectional areas of the glaucoma and neural degeneration in intracranial optic nerve, optic nerve and optic chiasm, as well as an extensive gray lateral geniculate nucleus, and visual cortex. Br J Ophthalmol. matter volume change. Most previous studies with routine MRI 2006;90:674–678. sequences usually measured the cross-sectional area of the 7. Gupta N, Ly T, Zhang Q, Kaufman PL, Weinreb RN, Yucel¨ YH. optic chiasm by an approximation through a section not Chronic induces dendrite pathology in perpendicular to the optic nerve or optic chiasm.12,38 Other the lateral geniculate nucleus of the brain. Exp Eye Res. 2007; investigations applied twice or multiple times the MRI scan to 84:176–184. obtain the targeted plane of the precise cross-section. 8. Sasaoka M, Nakamura K, Shimazawa M, Ito Y, Araie M, Hara H. However, the use of high resolution 3D–MP-RAGE and the Changes in visual fields and lateral geniculate nucleus in reconstruction procedure helped to resolve the problem by monkey laser-induced high intraocular pressure model. Exp using a single scan in the present study. The advantages of this Eye Res. 2008;86:770–782. sequence included its relatively high soft tissue contrast and 9. Gupta N, Greenberg G, de Tilly LN, Gray B, Polemidiotis M. decreased imaging time, leading to a lower likelihood for Atrophy of the lateral geniculate nucleus in human glaucoma motion artifacts.39 It resulted in a high resolution imaging detected by magnetic resonance imaging. Br J Ophthalmol. protocol for cross-sections of the optic nerve and optic chiasm 2009;93:56–60. with no change in scanning time. A high resolution of the MRI 10. Ito Y, Shimazawa M, Chen YN, et al. Morphological changes in images with a voxel size of 1 3 1 3 1 mm made the the visual pathway induced by experimental glaucoma in reconstruction results identifiable. Obtaining any part of the Japanese monkeys. Exp Eye Res. 2009;89:246–255. optic nerve cross-section in both eyes and in the optic chiasm 11. Garaci FG, Bolacchi F, Cerulli A, et al. Optic nerve and optic during a single scanning sequence by using the method radiation neurodegeneration in patients with glaucoma: in presented was feasible. vivo analysis with 3-T diffusion-tensor MR imaging. Radiology. 2009;252:496–501. Potential limitations of our study should be mentioned. First, the number of patients included into the study was 12. Kitsos G, Zikou AK, Bagli E, Kosta P, Argyropoulou MI. relatively small. Despite of this weakness, however, the Conventional MRI and magnetisation transfer imaging of the differences between the study and control groups were brain and optic pathway in primary open-angle glaucoma. Br J Radiol. 2009;82:896–900. statistically significant. Second, our study was hospital-based, so that a confounding effect by a selection bias is possible as for 13. Boucard CC, Hernowo AT, Maguire RP, et al. Changes in any hospital-based investigation. Third, some of the observed cortical gray matter density associated with long-standing retinal visual field defects. Brain. 2009;132:1898–1906. differences between the study and control groups were significant for only one side of the brain. Future studies may 14. Liu X, Chen X, Wang N. Is glaucoma a address whether, with a larger number of study participants, disease: re-evaluation. Zhonghua Yan Ke Za Zhi. 2010;46: 1062–1065. these differences become significant, or whether biologic phenomena were the reason. Fourth, the imaging techniques 15. Qing G, Zhang S, Wang B, Wang N. Functional MRI signal applied in our study had their own limitations, namely in changes in primary visual cortex corresponding to the central normal visual field of patients with primary open-angle spatial resolution. Future investigations applying the then most glaucoma. 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