Alterations in the gray matter volume in transient ischemic attack: a voxel-based morphometry study Rong Li1, Jian Guo2, Xujing Ma1, Shanshan Wang1, Jiang Zhang1, Li He2, Qiyong Gong3, Huafu Chen1 1
Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, PR China, 2Department of Neurology, West China Hospital of Sichuan University, Chengdu, PR China, 3Department of Radiology, Huaxi MR Research Center (HMRRC), West China Hospital of Sichuan University, Chengdu, PR China Background: Several studies have emphasized that transient ischemic attack (TIA) patients suffered functional impairments, but whether underlying morphological alterations exist remains unclear. This study aims to detect possible gray matter volume (GMV) alterations in patients with TIA using voxel-based morphometry (VBM) method. Methods: High-resolution T1-weighted anatomical images of 21 patients were compared with 21 healthy controls of matching age, gender, and education. Changes in the GMV were observed using VBM technique, followed by two-sample t-test analysis to detect the differences in the GMV between TIA patients and healthy controls. Correlations between the clinical parameters and the Montreal cognitive assessment (MoCA) scores, and the altered GMV in TIAs, were investigated. Results: Two-sample t-test analysis revealed a significant GMV reduction in specific regions in the default mode network (DMN) in TIA patients, including the bilateral medial frontal gyrus, anterior cingulate cortex (ACC), and precuneus. No correlation was found between the reduced GMV and MoCA scores and clinical parameters. Conclusion: Transient ischemic attack patients showed widespread morphology atrophy in DMN, suggesting that, despite the absence of a cerebral infarction, ischemic injury may induce structural abnormalities and eventually contribute to functional impairments in TIA patients. Our results may provide a valuable basis for the pathophysiological mechanism related to the cognitive dysfunction of TIA from the view of brain morphology. Keywords: Transient ischemic attack, Voxel-based morphometry, Magnetic resonance imaging, Gray matter volume, Default mode network
Introduction Transient ischemic attack (TIA) is a transient episode of reversible neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia without acute infarction.1 Transient ischemic attack conveys a high imminent risk for the development of a major stroke, although clinical symptoms of TIA are usually resolved within 24 hours.2 Various studies have shown that TIA patients can present different degrees of cognitive impairment.3,4 In our previous study, in which we used regional homogeneity method, we discovered that TIA patients had altered regional spontaneous activities in the frontal cortex, which
Correspondence to: Huafu Chen, Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, PR China. E-mail: [email protected]
ß W. S. Maney & Son Ltd 2015 DOI 10.1179/1743132814Y.0000000406
were positively correlated with cognitive assessment scores.5 Risk factors such as hypertension, carotid stenosis, and hemodynamic compromise were found to be associated with the TIA patients’ cognitive impairment, in particular, difficulties with temporal orientation and verbal recall.6,7 One possible cause of this cognitive dysfunction was considered to be structural cerebral damage resulting from thromboembolism and cerebral hypoperfusion.8,9 However, information on the structural abnormalities of patients with TIA has not been explored yet. In addition to the cognitive deficits caused by TIA, the presence of underlying morphological alterations throughout the brain associated with these functional deficits in patients with TIA remains unclear. A recent study has shown that in hemispheric TIA patients, diffusion weighted imaging (DWI) abnormalities were present in 16 out of 61 patients (26%).10
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With the use of diffusion tensor imaging (DTI), a previous study on TIA with carotid artery disease has shown that the significant mean diffusivity (MD) increases in the right anterior cingulate gyrus (ACG) and significant fractional anisotropy decreases in the right amygdala.11 Early studies, which used manual outlining of the periphery of the regions of interest (ROI), found that stroke/TIA patients had smaller right amygdala volume and more white matter hyperintensities (WMHs).12,13 However, these studies were not specifically designed to evaluate TIA patients because the subjects involved were comprehensive vascular dementia cases, which included stroke and post-stroke patients. Meanwhile, the ROI-based approach had limitations despite the studies having provided useful information. For the ROI-based approach, the manual and reproducible placement of the ROIs on thin white matter (WM) tracts may be difficult,14 which may be attributed to inconsistent findings among different studies that used this approach. Furthermore, ROIbased method can only identify changes in areas where the ROIs are placed.15 Ashburner and Friston’s voxel-based morphometry (VBM) is an automated technique that offers rapid unbiased assessment of the brain16 and enables the investigation of local brain tissue changes on a whole-brain level. Voxel-based morphometry has recently been successfully used to characterize structural brain differences in both healthy subjects17 and those with several degenerative brain disorders such as schizophrenia,18 major depressive disorder,19 Alzheimer’s disease,20 and temporal lobe epilepsy.21 To the best of our knowledge, a VBM study that explored the changes in the whole-brain gray matter volume (GMV) in TIA patients has not yet been reported. Therefore, our study was intended to detect whether structural abnormalities exist in the GMV of TIA patients using VBM technique. We hypothesized that TIA patients would have alterations in the GMV compared with healthy controls. Furthermore, we examined whether correlations exist between the GMV in TIA patients and the clinical features and neuropsychological scores.
Methods Subjects The study protocol was approved by the institutional ethics committee at Sichuan University. Written informed consent was obtained before each subject’s participation in the trial. A total of 21 TIA patients who had suffered an ischemic event in the right hemisphere from June 2010 to September 2011 were enrolled in the study. Transient ischemic attack was defined according to the WHO recommendations as any syndrome of focal neurologic dysfunction
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ascribable to a vascular territory and lasting less than 24 hours22 Prospective subjects with brain lesions shown by fluid attenuated inversion recovery (FLAIR) images or T2-weighted images, leukoaraiosis, or psychiatric diseases were excluded. The control subjects were healthy volunteers with matched age, sex, and years of education with no history of stroke/ TIA or other neurological disorders. All participants had a complete blood count and metabolic profile testing as well as a carotid duplex ultrasound examination. The degree of carotid stenosis was calculated according to Grant’s method23 by a consensus of two readers blinded to the clinical data and using carotid duplex ultrasound or magnetic resonance angiography. To detect potential cardiac sources of emboli (including atrial fibrillation and valve diseases), 12-lead electrocardiogram, Holter monitor, and transthoracic echocardiography or trans-esophageal echocardiography were used.
Cognitive and psychiatric assessment Cognitive and psychiatric assessments were conducted by two independent neuropsychologists. The following methods, with their corresponding areas of evaluation, were conducted: Montreal cognitive assessment (MoCA), general condition of cognitive function; auditory verbal memory test (AVMT, Chinese version based on the California verbal learning test), verbal memory; and the backward digital span test (DST-backward), working memory. The Hamilton anxiety rating scale (HARS) and Hamilton depression rating scale (HDRS) were also administered to rate the psychiatric characteristics in all subjects.
Scan acquisition All TIA patients experienced symptoms with acute onset of paralysis or numbness less than 1 month before the MRI examination. Imaging was performed on a 3 T Trio scanner (Siemens AG, Erlangen, Germany) using an eight-channel birdcage head coil. The participants were asked to lie supine with the head snugly immobilized by a belt and foam pads to minimize head movement. A set of high-resolution T1-weighted anatomical images were acquired in axial orientation using a 3D spoiled gradient-recalled sequence (MPRAGE, magnetization prepared rapid acquisition gradient echo). A total of 176 slices were obtained in the sagittal plane, with slice thickness 5 1.0 mm, field of view 5 240 6 240 mm2, acquisition matrix 5 256 6 256, TR 5 1900 ms, TE 5 2.28 ms, and voxel size 5 0.98 6 0.98 6 1 mm3.
Data processing Data were processed using VBM as implemented in the VBM8 toolbox (http://dbm.neuro.uni-jena.de/ vbm.html) in SPM8 (Wellcome Department of
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Imaging Neuroscience Group, London, UK; http:// www.fil.ion.ucl.ac.uk/spm). Preprocessing was undertaken using the default settings of VBM8 for a nonlinearly modulated normalized VBM. T1-weighted structural images were manually reoriented to the Montreal Neurological Institute (MNI) space and then segmented into gray matter (GM), WM, and cerebrospinal fluid (CSF). High-dimensional DAR TEL normalization was used to spatially normalize the segmented images. Then, the resulting images were spatially normalized into the standard template space of the MNI using affine normalization. Before the statistical analysis of GMV differences between TIA patients and healthy controls, spatial smoothing of the normalized GM images with 8 mm full-width at half-maximum Gaussian kernel was conducted.
Statistical analysis To detect the changes in the GMV throughout the brain in TIA patients compared with the controls, the processed GM images were entered into a two-sample test. Statistical significance of group differences was set to P , 0.05 (combined height threshold P , 0.001 as well as cluster size .128 voxels), using the AFNI AlphaSim program in the REST software (http:/resting-fmri.sourceforge.net). We also performed linear correlation analysis to explore whether clinical features and neuropsychological cognitive impairment were associated with the altered GMV in patients with TIA. The mean GMV values in TIA patients were extracted from brain
Altered gray matter morphometry in TIA
regions showing significant differences between patient and control groups. Correlations between mean GMV within each significant brain areas and clinical parameters including age, years of education, MoCA scores, and the duration of symptoms in TIA patients were analyzed. The threshold of P , 0.05 was considered to be significant for these analyses.
Results Subjects A total of 21 TIA patients and 21 healthy controls completed the whole study. The demographic profiles, risk factors, and clinical features of all subjects are presented in Table 1. Transient ischemic attack patients showed only significant differences compared with controls in carotid artery stenosis (P , 0.05). All TIA patients experienced symptoms of acute onset of paralysis or numbness on the left side of the body, and the median duration of symptoms in TIA patients was 48 minutes (ranging from 15 minutes to 1.5 hours). The results of the cognitive and psychiatric tests are listed in Table 2. Transient ischemic attack patients tended to have poorer scores in MoCA, AVMT, and DST-backward but without significant statistical difference. No significant differences in HARS and HDRS existed between the two groups.
Differences in GMV between TIA patients and control subjects Consistent with our hypothesis, we found that TIA patients had significant GMV reduction in the
Table 1 Demographic characteristics of participants Characteristics Age, mean (SD) Sex, males (%) Education, mean years (SD) Risk factors (%) Hypertension Diabetes Hyperlipidemia Atrial fibrillation Previous stroke Smoking Carotid artery stenosis Intracranial arteries stenosis Clinical features (%) Motor symptoms Sensory symptoms
TIA patients (n 5 21) 50.1 (6.5) 15 (71) 10.4 (2.1) 8 (38) 3 (14) 7 (33) 0 0 5 (24) 11 (52) 2 (9)
Controls (n 5 21)
P value
48.2 (7.9) 13 (62) 10.5 (2.8)
0.39 0.51 0.95
5 1 6 0 0 2 2 0
(24) (5) (28)
0.32 0.29 0.74
(9) (9) (0)
0.21 0.006 0.49
19 (90) 12 (57)
TIA: transient ischemic attack; SD: standard deviation. Bold indicates that TIA showed significant differences in carotid artery stenosis (P , 0.05). Table 2 Cognitive and psychiatric tests of participants TIA patients (n 5 21) MoCA, mean (SD) AVMT, mean (SD) DST-backward, mean (SD) HARS, mean (SD) HDRS, mean (SD)
24.5 47.9 5.1 9.3 6.5
(3.5) (15.8) (1.9) (2.7) (2.1)
Controls (n 5 21)
P value
26.2(1.6) 55.7(19.8) 5.7 (3.4) 8.3 (2.3) 5.6 (1.7)
0.053 0.065 0.060 0.224 0.142
TIA: transient ischemic attack; MoCA: Montreal cognitive assessment; AVMT: auditory verbal memory test; DST-backward: backward digital span test; HARS: Hamilton anxiety rating scales; HDRS: Hamilton depression rating scales; SD: standard deviation.
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bilateral medial frontal gyrus, anterior cingulate cortex (ACC), and precuneus, which are important brain regions of default mode network (DMN). More details of these regions are described in Table 3 and Fig. 1. On the contrary, no region showed an increased GMV compared with healthy subjects. Linear regression analyses showed no correlation between the reduced GMV, in the bilateral medial frontal gyrus, ACC, and precuneus, and MoCA scores, and the duration of symptoms in TIA patients.
Discussion Two Sydney stroke studies, which were conducted mainly in stroke/TIA subjects,13 have suggested that stroke/TIA patients showed amygdala atrophy, especially those with cognitive impairment. However, these studies have only focused on the structural abnormalities in the local brain areas using ROI-based method, and changes in the whole-brain GMV under TIA remain unclear. Transient ischemic attack is a temporary focal neurological deficit caused by a brief interruption in cerebral blood flow,24 but accumulated evidence have indicated that clinically transient spells are not transient at the tissue level and leave infarct on the brain.25 In the present study, we identified brain morphology alterations in TIA patients at the wholebrain level using VBM. Consistent with our hypothesis, the VBM analysis of the structural data in TIA patients revealed a significantly reduced GMV in the important brain regions of the DMN, including the bilateral medial frontal gyrus, ACC, and precuneus. The results suggested that the structural integrity of DMN is compromised in TIA patients, which may partly contribute to cognitive functional abnormalities in TIAs. Medial frontal gyrus, ACC, and precuneus have been identified as being a part of the DMN,26–28 which is an intrinsic brain system that exhibits higher activity during the resting state.29 Additionally, DMN brain regions function prominently in emotion processing,30 executive control,31 and cognitive functions.32 We reported in our previous studies that TIA patients Table 3 Regions showing gray matter volume (GMV) differences between transient ischemic attack (TIA) patients and healthy controls Brain region
Side
Medial frontal gyrus
Left 21.5 Right 13.5 Left 23 Right 8.5 Left 211 Right 19
Anterior cingulate cortex (ACC) Precuneus
MNI (X, Y, Z) 32 52 31.5 49.5 258.0 257
T-value
30 4.5 30 7.5 9 15
23.84 24.30 24.15 23.86 24.32 23.97
MNI: Montreal Neurological Institute; X, Y, Z: coordinates of primary peak locations in the MNI space; T: statistical value of peak voxel showing GMV differences between the TIA patients and healthy controls. P , 0.05, AlphaSim corrected, cluster size .128 voxels.
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Figure 1 Gray matter volume (GMV) reductions in transient ischemic attack (TIA) patients compared to healthy controls (P , 0.05, corrected by Alphasim, combined threshold of P , 0.001 as well as cluster size .128 voxels). Regions including bilateral medial frontal gyrus, anterior cingulate cortex (ACC), and precuneus showed significantly lower GMV in TIA patients compared to healthy controls.
showed reduced regional spontaneous activities and aberrant functional connectivity in DMN system.5,33 The present study extends the findings by demonstrating that, even without permanent cerebral infarction, TIA could have changes in structural GMV associated with the functional impairments. We found a possible anatomical disruption in TIA expressed by gray volumetric abnormalities. We found preferential volume loss in the bilateral medial frontal gyrus in TIA patients compared with controls. The medial frontal gyrus is assumed to perform a key function in emotional recognition and cognitive control, such as attention to emotion, identification, or regulation of emotion.34 Two previous fMRI studies35,36 have demonstrated that acute and chronic ischemic stroke patients had altered prefrontal activity, sharing a similar pathophysiology with TIA. The alteration in prefrontal cortex has been implicated in altered prefrontal-based attentional network in stroke patients.32 Moreover, Puh et al. reported that the bilateral activation of the prefrontal cortex may participate in the recovery process after stroke.31 Thus, the observations of GM atrophy in the bilateral medial frontal gyrus of TIA patients, as found in the current study, may result in the dysfunction of the cognitive processes, including emotional recognition and attentional system. According to the cognitive tests in our study, TIA patients tended to have lower MoCA scores compared to healthy controls, which indicated that TIAs show poor performance on the general condition of
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cognitive function. Therefore, the structural abnormality of the medial frontal gyrus may be a factor important in the abnormal recovery process of TIA patients after the onset of illness. Voxel-based morphometry of the GM partition also showed significant atrophy in the ACC and precuneus. Anterior cingulate cortex is a functionally heterogeneous region involved in diverse cognitive processes including executive, attention, social cognitive, affective, and skeleton-motor functions.37 Previous functional studies have reported that TIA patients can suffer from damage of executive function,38,39 and the ACC is a critical neural substrate for execution control.40 Furthermore, by employing voxel-based analysis (VBA) in our prior study, we found that TIA patients had increased MD in ACC. Thus, the results of GMV reduction of the ACG in our present study, along with the observations of increased MD, were believed to have implications for executive impairments in TIA. Several studies have reported on the cingulate cortex dysfunction of patients with stroke,41,42 which may be a key reason for post-stroke depression or working memory damage in these patients. Meanwhile, as an association area on the medial surface of the brain hemisphere, the precuneus has been implicated in various functions such as visuospatial imagery and memory retrieval.43,44 Evidence has indicated that stroke patients exhibited working memory damage and poor cognitive performance with visual stimuli,41 sharing similar pathophysiology with TIA patients. According to the results of the cognitive assessment scores of AVMT and DST, TIA patients performed poorly in the verbal and working memory compared with healthy controls. The GM atrophy in the bilateral ACC and precuneus was thought to reflect the abnormal information processing from prior experiences in the form of memories because of ischemia in TIA patients. Additionally, two studies combining N-acetylaspartate (NAA) and creatine (Cr) technique have demonstrated that TIA patients exhibited significant metabolic alterations, which may be an early indicator of further disruption in the frontal–subcortical circuits that are important for cognitive function.45,46 In the present study, we also found GMV reduction in the bilateral precuneus. Our results on GVM reduction in ACC and precuneus are of particular interest, because these regions have been identified parts of DMN that are highly active in the resting state.28 Anterior cingulate cortex, the cerebral region with greater metabolism relative to the whole brain activity, is particularly sensitive to ischemic injury.28 Furthermore, precuneus shows the highest resting metabolic rate among other brain areas, consuming 35% more glucose than any other
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area of the cerebral cortex in humans47 and other species.48 Evidence indicated that patients with carotid artery occlusion and ipsilateral TIA had more severe cognitive impairment because of the presence of lactate,49 thus implying that cerebral ischemia may produce lactate, lead to metabolic changes, and eventually induce GMV abnormalities that further contribute to functional impairments. Notably, we enrolled TIA patients who suffered an ischemic event in the right hemisphere while we detected GM atrophy in the ipsilateral and contralateral hemispheres. Several studies have shown that numerous patients meeting the clinical criteria for TIA demonstrate neuroanatomically relevant infarcts,50,51 and these infarcts are observed not only in the region appropriate for the symptoms of TIA but also in other unrelated parts of the brain.52 The morphological atrophy findings suggest that structural cerebral damages are not restricted to the symptomatic hemisphere or to areas close to ischemic lesions, and that the asymptomatic hemisphere is also affected. Although we demonstrated brain GM atrophy in TIA patients, our study had limitations. First, we only included patients who had suffered an ischemic event in the right hemisphere to ensure homogeneity of the sample. Whether TIA with left hemisphere involvement also displays similar structural abnormities should be further investigated. Additionally, this study had a limited number of patients. Larger sample studies are necessary to obtain significant differences in the MoCA scores and replicate the morphological results. Finally, the absence of amygdala atrophy and correlation between the reduced GMV and cognitive impairments in the present study was relatively unexpected. Hence, studies with longer follow-up period are needed to comprehensively examine the evolvement of structural brain abnormalities.
Conclusions In summary, the current study was the first to demonstrate the presence of morphological atrophy mainly in the default circuit in TIA patients, suggesting that, despite the absence of a cerebral infarction, ischemic injury may induce structure abnormalities and eventually contribute to functional impairments. Larger sample studies and longer follow-up are warranted to replicate these results to support whether the abnormalities of the GMV in the specific brain areas are trait markers underlying a pathophysiological mechanism related to the cognitive dysfunction.
Disclaimer Statements Contributors Rong Li, Jian Guo, Li He, and Qiyong Gong contributed in data acquisition. Data analysis and processing was done by Rong Li, Shanshan
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Wang, and Jiang Zhang. Rong Li and Huafu Chen involved in paper writing. Funding Natural Science Foundation of China, Grant Nos. 61035006, 61125304, 61273361, and 81071140, the Key Technology R&D Program of Sichuan Province 2012SZ0159 and the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20120185110028). Conflicts of interest The authors declare no conflicts of interest with this work. Ethics approval The study protocol was approved by the institutional ethics committee at Sichuan University.
Acknowledgements This work was supported by the Natural Science Foundation of China, Grant Nos. 61035006, 6112 5304, 61273361, and 81071140, the Key Technology R&D Program of Sichuan Province 2012SZ0159 and by the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 2012 0185110028).
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34 Teasdale JD, Howard RJ, Cox SG, Ha Y, Brammer MJ, Williams SC, et al. Functional MRI study of the cognitive generation of affect. Am J Psychiatry. 1999;156:209–15. 35 Puh U, Vovk A, Sevsek F, Suput D. Increased cognitive load during simple and complex motor tasks in acute stage after stroke. Int J Psychophysiol. 2007;63:173–80. 36 Meehan SK, Randhawa B, Wessel B, Boyd LA. Implicit sequence-specific motor learning after subcortical stroke is associated with increased prefrontal brain activations: an fMRI study. Hum Brain Mapp. 2011;32:290–303. 37 Fornito A, Yu¨cel M, Dean B, Wood SJ, Pantelis C. Anatomical abnormalities of the anterior cingulate cortex in schizophrenia: bridging the gap between neuroimaging and neuropathology. Schizophr Bull. 2009;35:973–93. 38 Sachdev PS, Brodaty H, Valenzuela MJ, Lorentz L, Looi JC, Wen W, et al. The neuropsychological profile of vascular cognitive impairment in stroke and TIA patients. Neurology. 2004;62:912–9. 39 Wang L, Jia J, Wu L. The relationship between cognitive impairment and cerebral blood flow changes after transient ischaemic attack. Neurol Res. 2013;35:580–5. 40 Rushworth MF, Walton ME, Kennerley SW, Bannerman DM. Action sets and decisions in the medial frontal cortex. Trends Cogn Sci (Regul Ed). 2004;8:410–7. 41 Ziemus B, Baumann O, Luerding R, Schlosser R, Schuierer G, Bogdahn U, et al. Impaired working-memory after cerebellar infarcts paralleled by changes in BOLD signal of a corticocerebellar circuit. Neuropsychologia. 2007;45:2016–24. 42 Terroni L, Amaro E, Iosifescu DV, Tinone G, Sato JR, Leite CC, et al. Stroke lesion in cortical neural circuits and poststroke incidence of major depressive episode: a 4-month prospective study. World J Biol Psychiatry. 2011;12:539–48. 43 Cavanna AE, Trimble MR. The precuneus: a review of its functional anatomy and behavioural correlates. Brain. 2006;129:564–83.
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44 Thompson WL, Slotnick SD, Burrage MS, Kosslyn SM. Two forms of spatial imagery: neuroimaging evidence. Psychol Sci. 2009;20:1245–53. 45 Bisschops RH, Kappelle LJ, Mali WP, van der Grond J. Hemodynamic and metabolic changes in transient ischemic attack patients: a magnetic resonance angiography and (1)Hmagnetic resonance spectroscopy study performed within 3 days of onset of a transient ischemic attack. Stroke. 2002;33:110–5. 46 Ross AJ, Sachdev PS, Wen W, Brodaty H, Joscelyne A, Lorentz LM. Prediction of cognitive decline after stroke using proton magnetic resonance spectroscopy. J Neurol Sci. 2006;251:62–9. 47 Gusnard DA, Raichle ME. Searching for a baseline: functional imaging and the resting human brain. Nat Rev Neurosci. 2001;2:685–94. 48 Harley CA, Bielajew CH. A comparison of glycogen phosphorylase a and cytochrome oxidase histochemical staining in rat brain. J Comp Neurol. 1992;322:377–89. 49 Bakker FC, Klijn CJ, Jennekens-Schinkel A, van der Tweel I, van der Grond J, van Huffelen AC, et al. Cognitive impairment is related to cerebral lactate in patients with carotid artery occlusion and ipsilateral transient ischemic attacks. Stroke. 2003;34:1419–24. 50 Kidwell CS, Alger JR, Di Salle F, Starkman S, Villablanca P, Bentson J, et al. Diffusion MRI in patients with transient ischemic attacks. Stroke. 1999;30:1174–80. 51 Awad I, Modic M, Little JR, Furlan AJ, Weinstein M. Focal parenchymal lesions in transient ischemic attacks: correlation of computed tomography and magnetic resonance imaging. Stroke. 1986;17:399–403. 52 Bogousslavsky J, Regli F. Cerebral infarct in apparent transient ischemic attack. Neurology. 1985;35:1501–3.
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Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, PR China, 2Department of Neurology, West China Hospital of Sichuan University, Chengdu, PR China, 3Department of Radiology, Huaxi MR Research Center (HMRRC), West China Hospital of Sichuan University, Chengdu, PR China Background: Several studies have emphasized that transient ischemic attack (TIA) patients suffered functional impairments, but whether underlying morphological alterations exist remains unclear. This study aims to detect possible gray matter volume (GMV) alterations in patients with TIA using voxel-based morphometry (VBM) method. Methods: High-resolution T1-weighted anatomical images of 21 patients were compared with 21 healthy controls of matching age, gender, and education. Changes in the GMV were observed using VBM technique, followed by two-sample t-test analysis to detect the differences in the GMV between TIA patients and healthy controls. Correlations between the clinical parameters and the Montreal cognitive assessment (MoCA) scores, and the altered GMV in TIAs, were investigated. Results: Two-sample t-test analysis revealed a significant GMV reduction in specific regions in the default mode network (DMN) in TIA patients, including the bilateral medial frontal gyrus, anterior cingulate cortex (ACC), and precuneus. No correlation was found between the reduced GMV and MoCA scores and clinical parameters. Conclusion: Transient ischemic attack patients showed widespread morphology atrophy in DMN, suggesting that, despite the absence of a cerebral infarction, ischemic injury may induce structural abnormalities and eventually contribute to functional impairments in TIA patients. Our results may provide a valuable basis for the pathophysiological mechanism related to the cognitive dysfunction of TIA from the view of brain morphology. Keywords: Transient ischemic attack, Voxel-based morphometry, Magnetic resonance imaging, Gray matter volume, Default mode network
Introduction Transient ischemic attack (TIA) is a transient episode of reversible neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia without acute infarction.1 Transient ischemic attack conveys a high imminent risk for the development of a major stroke, although clinical symptoms of TIA are usually resolved within 24 hours.2 Various studies have shown that TIA patients can present different degrees of cognitive impairment.3,4 In our previous study, in which we used regional homogeneity method, we discovered that TIA patients had altered regional spontaneous activities in the frontal cortex, which
Correspondence to: Huafu Chen, Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, PR China. E-mail: [email protected]
ß W. S. Maney & Son Ltd 2015 DOI 10.1179/1743132814Y.0000000406
were positively correlated with cognitive assessment scores.5 Risk factors such as hypertension, carotid stenosis, and hemodynamic compromise were found to be associated with the TIA patients’ cognitive impairment, in particular, difficulties with temporal orientation and verbal recall.6,7 One possible cause of this cognitive dysfunction was considered to be structural cerebral damage resulting from thromboembolism and cerebral hypoperfusion.8,9 However, information on the structural abnormalities of patients with TIA has not been explored yet. In addition to the cognitive deficits caused by TIA, the presence of underlying morphological alterations throughout the brain associated with these functional deficits in patients with TIA remains unclear. A recent study has shown that in hemispheric TIA patients, diffusion weighted imaging (DWI) abnormalities were present in 16 out of 61 patients (26%).10
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With the use of diffusion tensor imaging (DTI), a previous study on TIA with carotid artery disease has shown that the significant mean diffusivity (MD) increases in the right anterior cingulate gyrus (ACG) and significant fractional anisotropy decreases in the right amygdala.11 Early studies, which used manual outlining of the periphery of the regions of interest (ROI), found that stroke/TIA patients had smaller right amygdala volume and more white matter hyperintensities (WMHs).12,13 However, these studies were not specifically designed to evaluate TIA patients because the subjects involved were comprehensive vascular dementia cases, which included stroke and post-stroke patients. Meanwhile, the ROI-based approach had limitations despite the studies having provided useful information. For the ROI-based approach, the manual and reproducible placement of the ROIs on thin white matter (WM) tracts may be difficult,14 which may be attributed to inconsistent findings among different studies that used this approach. Furthermore, ROIbased method can only identify changes in areas where the ROIs are placed.15 Ashburner and Friston’s voxel-based morphometry (VBM) is an automated technique that offers rapid unbiased assessment of the brain16 and enables the investigation of local brain tissue changes on a whole-brain level. Voxel-based morphometry has recently been successfully used to characterize structural brain differences in both healthy subjects17 and those with several degenerative brain disorders such as schizophrenia,18 major depressive disorder,19 Alzheimer’s disease,20 and temporal lobe epilepsy.21 To the best of our knowledge, a VBM study that explored the changes in the whole-brain gray matter volume (GMV) in TIA patients has not yet been reported. Therefore, our study was intended to detect whether structural abnormalities exist in the GMV of TIA patients using VBM technique. We hypothesized that TIA patients would have alterations in the GMV compared with healthy controls. Furthermore, we examined whether correlations exist between the GMV in TIA patients and the clinical features and neuropsychological scores.
Methods Subjects The study protocol was approved by the institutional ethics committee at Sichuan University. Written informed consent was obtained before each subject’s participation in the trial. A total of 21 TIA patients who had suffered an ischemic event in the right hemisphere from June 2010 to September 2011 were enrolled in the study. Transient ischemic attack was defined according to the WHO recommendations as any syndrome of focal neurologic dysfunction
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ascribable to a vascular territory and lasting less than 24 hours22 Prospective subjects with brain lesions shown by fluid attenuated inversion recovery (FLAIR) images or T2-weighted images, leukoaraiosis, or psychiatric diseases were excluded. The control subjects were healthy volunteers with matched age, sex, and years of education with no history of stroke/ TIA or other neurological disorders. All participants had a complete blood count and metabolic profile testing as well as a carotid duplex ultrasound examination. The degree of carotid stenosis was calculated according to Grant’s method23 by a consensus of two readers blinded to the clinical data and using carotid duplex ultrasound or magnetic resonance angiography. To detect potential cardiac sources of emboli (including atrial fibrillation and valve diseases), 12-lead electrocardiogram, Holter monitor, and transthoracic echocardiography or trans-esophageal echocardiography were used.
Cognitive and psychiatric assessment Cognitive and psychiatric assessments were conducted by two independent neuropsychologists. The following methods, with their corresponding areas of evaluation, were conducted: Montreal cognitive assessment (MoCA), general condition of cognitive function; auditory verbal memory test (AVMT, Chinese version based on the California verbal learning test), verbal memory; and the backward digital span test (DST-backward), working memory. The Hamilton anxiety rating scale (HARS) and Hamilton depression rating scale (HDRS) were also administered to rate the psychiatric characteristics in all subjects.
Scan acquisition All TIA patients experienced symptoms with acute onset of paralysis or numbness less than 1 month before the MRI examination. Imaging was performed on a 3 T Trio scanner (Siemens AG, Erlangen, Germany) using an eight-channel birdcage head coil. The participants were asked to lie supine with the head snugly immobilized by a belt and foam pads to minimize head movement. A set of high-resolution T1-weighted anatomical images were acquired in axial orientation using a 3D spoiled gradient-recalled sequence (MPRAGE, magnetization prepared rapid acquisition gradient echo). A total of 176 slices were obtained in the sagittal plane, with slice thickness 5 1.0 mm, field of view 5 240 6 240 mm2, acquisition matrix 5 256 6 256, TR 5 1900 ms, TE 5 2.28 ms, and voxel size 5 0.98 6 0.98 6 1 mm3.
Data processing Data were processed using VBM as implemented in the VBM8 toolbox (http://dbm.neuro.uni-jena.de/ vbm.html) in SPM8 (Wellcome Department of
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Imaging Neuroscience Group, London, UK; http:// www.fil.ion.ucl.ac.uk/spm). Preprocessing was undertaken using the default settings of VBM8 for a nonlinearly modulated normalized VBM. T1-weighted structural images were manually reoriented to the Montreal Neurological Institute (MNI) space and then segmented into gray matter (GM), WM, and cerebrospinal fluid (CSF). High-dimensional DAR TEL normalization was used to spatially normalize the segmented images. Then, the resulting images were spatially normalized into the standard template space of the MNI using affine normalization. Before the statistical analysis of GMV differences between TIA patients and healthy controls, spatial smoothing of the normalized GM images with 8 mm full-width at half-maximum Gaussian kernel was conducted.
Statistical analysis To detect the changes in the GMV throughout the brain in TIA patients compared with the controls, the processed GM images were entered into a two-sample test. Statistical significance of group differences was set to P , 0.05 (combined height threshold P , 0.001 as well as cluster size .128 voxels), using the AFNI AlphaSim program in the REST software (http:/resting-fmri.sourceforge.net). We also performed linear correlation analysis to explore whether clinical features and neuropsychological cognitive impairment were associated with the altered GMV in patients with TIA. The mean GMV values in TIA patients were extracted from brain
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regions showing significant differences between patient and control groups. Correlations between mean GMV within each significant brain areas and clinical parameters including age, years of education, MoCA scores, and the duration of symptoms in TIA patients were analyzed. The threshold of P , 0.05 was considered to be significant for these analyses.
Results Subjects A total of 21 TIA patients and 21 healthy controls completed the whole study. The demographic profiles, risk factors, and clinical features of all subjects are presented in Table 1. Transient ischemic attack patients showed only significant differences compared with controls in carotid artery stenosis (P , 0.05). All TIA patients experienced symptoms of acute onset of paralysis or numbness on the left side of the body, and the median duration of symptoms in TIA patients was 48 minutes (ranging from 15 minutes to 1.5 hours). The results of the cognitive and psychiatric tests are listed in Table 2. Transient ischemic attack patients tended to have poorer scores in MoCA, AVMT, and DST-backward but without significant statistical difference. No significant differences in HARS and HDRS existed between the two groups.
Differences in GMV between TIA patients and control subjects Consistent with our hypothesis, we found that TIA patients had significant GMV reduction in the
Table 1 Demographic characteristics of participants Characteristics Age, mean (SD) Sex, males (%) Education, mean years (SD) Risk factors (%) Hypertension Diabetes Hyperlipidemia Atrial fibrillation Previous stroke Smoking Carotid artery stenosis Intracranial arteries stenosis Clinical features (%) Motor symptoms Sensory symptoms
TIA patients (n 5 21) 50.1 (6.5) 15 (71) 10.4 (2.1) 8 (38) 3 (14) 7 (33) 0 0 5 (24) 11 (52) 2 (9)
Controls (n 5 21)
P value
48.2 (7.9) 13 (62) 10.5 (2.8)
0.39 0.51 0.95
5 1 6 0 0 2 2 0
(24) (5) (28)
0.32 0.29 0.74
(9) (9) (0)
0.21 0.006 0.49
19 (90) 12 (57)
TIA: transient ischemic attack; SD: standard deviation. Bold indicates that TIA showed significant differences in carotid artery stenosis (P , 0.05). Table 2 Cognitive and psychiatric tests of participants TIA patients (n 5 21) MoCA, mean (SD) AVMT, mean (SD) DST-backward, mean (SD) HARS, mean (SD) HDRS, mean (SD)
24.5 47.9 5.1 9.3 6.5
(3.5) (15.8) (1.9) (2.7) (2.1)
Controls (n 5 21)
P value
26.2(1.6) 55.7(19.8) 5.7 (3.4) 8.3 (2.3) 5.6 (1.7)
0.053 0.065 0.060 0.224 0.142
TIA: transient ischemic attack; MoCA: Montreal cognitive assessment; AVMT: auditory verbal memory test; DST-backward: backward digital span test; HARS: Hamilton anxiety rating scales; HDRS: Hamilton depression rating scales; SD: standard deviation.
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bilateral medial frontal gyrus, anterior cingulate cortex (ACC), and precuneus, which are important brain regions of default mode network (DMN). More details of these regions are described in Table 3 and Fig. 1. On the contrary, no region showed an increased GMV compared with healthy subjects. Linear regression analyses showed no correlation between the reduced GMV, in the bilateral medial frontal gyrus, ACC, and precuneus, and MoCA scores, and the duration of symptoms in TIA patients.
Discussion Two Sydney stroke studies, which were conducted mainly in stroke/TIA subjects,13 have suggested that stroke/TIA patients showed amygdala atrophy, especially those with cognitive impairment. However, these studies have only focused on the structural abnormalities in the local brain areas using ROI-based method, and changes in the whole-brain GMV under TIA remain unclear. Transient ischemic attack is a temporary focal neurological deficit caused by a brief interruption in cerebral blood flow,24 but accumulated evidence have indicated that clinically transient spells are not transient at the tissue level and leave infarct on the brain.25 In the present study, we identified brain morphology alterations in TIA patients at the wholebrain level using VBM. Consistent with our hypothesis, the VBM analysis of the structural data in TIA patients revealed a significantly reduced GMV in the important brain regions of the DMN, including the bilateral medial frontal gyrus, ACC, and precuneus. The results suggested that the structural integrity of DMN is compromised in TIA patients, which may partly contribute to cognitive functional abnormalities in TIAs. Medial frontal gyrus, ACC, and precuneus have been identified as being a part of the DMN,26–28 which is an intrinsic brain system that exhibits higher activity during the resting state.29 Additionally, DMN brain regions function prominently in emotion processing,30 executive control,31 and cognitive functions.32 We reported in our previous studies that TIA patients Table 3 Regions showing gray matter volume (GMV) differences between transient ischemic attack (TIA) patients and healthy controls Brain region
Side
Medial frontal gyrus
Left 21.5 Right 13.5 Left 23 Right 8.5 Left 211 Right 19
Anterior cingulate cortex (ACC) Precuneus
MNI (X, Y, Z) 32 52 31.5 49.5 258.0 257
T-value
30 4.5 30 7.5 9 15
23.84 24.30 24.15 23.86 24.32 23.97
MNI: Montreal Neurological Institute; X, Y, Z: coordinates of primary peak locations in the MNI space; T: statistical value of peak voxel showing GMV differences between the TIA patients and healthy controls. P , 0.05, AlphaSim corrected, cluster size .128 voxels.
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Figure 1 Gray matter volume (GMV) reductions in transient ischemic attack (TIA) patients compared to healthy controls (P , 0.05, corrected by Alphasim, combined threshold of P , 0.001 as well as cluster size .128 voxels). Regions including bilateral medial frontal gyrus, anterior cingulate cortex (ACC), and precuneus showed significantly lower GMV in TIA patients compared to healthy controls.
showed reduced regional spontaneous activities and aberrant functional connectivity in DMN system.5,33 The present study extends the findings by demonstrating that, even without permanent cerebral infarction, TIA could have changes in structural GMV associated with the functional impairments. We found a possible anatomical disruption in TIA expressed by gray volumetric abnormalities. We found preferential volume loss in the bilateral medial frontal gyrus in TIA patients compared with controls. The medial frontal gyrus is assumed to perform a key function in emotional recognition and cognitive control, such as attention to emotion, identification, or regulation of emotion.34 Two previous fMRI studies35,36 have demonstrated that acute and chronic ischemic stroke patients had altered prefrontal activity, sharing a similar pathophysiology with TIA. The alteration in prefrontal cortex has been implicated in altered prefrontal-based attentional network in stroke patients.32 Moreover, Puh et al. reported that the bilateral activation of the prefrontal cortex may participate in the recovery process after stroke.31 Thus, the observations of GM atrophy in the bilateral medial frontal gyrus of TIA patients, as found in the current study, may result in the dysfunction of the cognitive processes, including emotional recognition and attentional system. According to the cognitive tests in our study, TIA patients tended to have lower MoCA scores compared to healthy controls, which indicated that TIAs show poor performance on the general condition of
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cognitive function. Therefore, the structural abnormality of the medial frontal gyrus may be a factor important in the abnormal recovery process of TIA patients after the onset of illness. Voxel-based morphometry of the GM partition also showed significant atrophy in the ACC and precuneus. Anterior cingulate cortex is a functionally heterogeneous region involved in diverse cognitive processes including executive, attention, social cognitive, affective, and skeleton-motor functions.37 Previous functional studies have reported that TIA patients can suffer from damage of executive function,38,39 and the ACC is a critical neural substrate for execution control.40 Furthermore, by employing voxel-based analysis (VBA) in our prior study, we found that TIA patients had increased MD in ACC. Thus, the results of GMV reduction of the ACG in our present study, along with the observations of increased MD, were believed to have implications for executive impairments in TIA. Several studies have reported on the cingulate cortex dysfunction of patients with stroke,41,42 which may be a key reason for post-stroke depression or working memory damage in these patients. Meanwhile, as an association area on the medial surface of the brain hemisphere, the precuneus has been implicated in various functions such as visuospatial imagery and memory retrieval.43,44 Evidence has indicated that stroke patients exhibited working memory damage and poor cognitive performance with visual stimuli,41 sharing similar pathophysiology with TIA patients. According to the results of the cognitive assessment scores of AVMT and DST, TIA patients performed poorly in the verbal and working memory compared with healthy controls. The GM atrophy in the bilateral ACC and precuneus was thought to reflect the abnormal information processing from prior experiences in the form of memories because of ischemia in TIA patients. Additionally, two studies combining N-acetylaspartate (NAA) and creatine (Cr) technique have demonstrated that TIA patients exhibited significant metabolic alterations, which may be an early indicator of further disruption in the frontal–subcortical circuits that are important for cognitive function.45,46 In the present study, we also found GMV reduction in the bilateral precuneus. Our results on GVM reduction in ACC and precuneus are of particular interest, because these regions have been identified parts of DMN that are highly active in the resting state.28 Anterior cingulate cortex, the cerebral region with greater metabolism relative to the whole brain activity, is particularly sensitive to ischemic injury.28 Furthermore, precuneus shows the highest resting metabolic rate among other brain areas, consuming 35% more glucose than any other
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area of the cerebral cortex in humans47 and other species.48 Evidence indicated that patients with carotid artery occlusion and ipsilateral TIA had more severe cognitive impairment because of the presence of lactate,49 thus implying that cerebral ischemia may produce lactate, lead to metabolic changes, and eventually induce GMV abnormalities that further contribute to functional impairments. Notably, we enrolled TIA patients who suffered an ischemic event in the right hemisphere while we detected GM atrophy in the ipsilateral and contralateral hemispheres. Several studies have shown that numerous patients meeting the clinical criteria for TIA demonstrate neuroanatomically relevant infarcts,50,51 and these infarcts are observed not only in the region appropriate for the symptoms of TIA but also in other unrelated parts of the brain.52 The morphological atrophy findings suggest that structural cerebral damages are not restricted to the symptomatic hemisphere or to areas close to ischemic lesions, and that the asymptomatic hemisphere is also affected. Although we demonstrated brain GM atrophy in TIA patients, our study had limitations. First, we only included patients who had suffered an ischemic event in the right hemisphere to ensure homogeneity of the sample. Whether TIA with left hemisphere involvement also displays similar structural abnormities should be further investigated. Additionally, this study had a limited number of patients. Larger sample studies are necessary to obtain significant differences in the MoCA scores and replicate the morphological results. Finally, the absence of amygdala atrophy and correlation between the reduced GMV and cognitive impairments in the present study was relatively unexpected. Hence, studies with longer follow-up period are needed to comprehensively examine the evolvement of structural brain abnormalities.
Conclusions In summary, the current study was the first to demonstrate the presence of morphological atrophy mainly in the default circuit in TIA patients, suggesting that, despite the absence of a cerebral infarction, ischemic injury may induce structure abnormalities and eventually contribute to functional impairments. Larger sample studies and longer follow-up are warranted to replicate these results to support whether the abnormalities of the GMV in the specific brain areas are trait markers underlying a pathophysiological mechanism related to the cognitive dysfunction.
Disclaimer Statements Contributors Rong Li, Jian Guo, Li He, and Qiyong Gong contributed in data acquisition. Data analysis and processing was done by Rong Li, Shanshan
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Wang, and Jiang Zhang. Rong Li and Huafu Chen involved in paper writing. Funding Natural Science Foundation of China, Grant Nos. 61035006, 61125304, 61273361, and 81071140, the Key Technology R&D Program of Sichuan Province 2012SZ0159 and the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20120185110028). Conflicts of interest The authors declare no conflicts of interest with this work. Ethics approval The study protocol was approved by the institutional ethics committee at Sichuan University.
Acknowledgements This work was supported by the Natural Science Foundation of China, Grant Nos. 61035006, 6112 5304, 61273361, and 81071140, the Key Technology R&D Program of Sichuan Province 2012SZ0159 and by the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 2012 0185110028).
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