Abnormal cortical functional activity in patients with ischemic white matter lesions: A resting-state functional magnetic resonance imaging study

Accepted Manuscript Title: Abnormal cortical functional activity in patients with ischemic white matter lesions: A resting-state functional magnetic resonance imaging study Authors: Xin Ding, Jurong Ding, Bo Hua, Xingzhong Xiong, Li Xiao, Fang Peng, Lin Chen, Xianfang Pan, Qingsong Wang PII: DOI: Reference:

S0304-3940(17)30121-0 http://dx.doi.org/doi:10.1016/j.neulet.2017.02.015 NSL 32627

To appear in:

Neuroscience Letters

Received date: Revised date: Accepted date:

19-10-2016 27-1-2017 7-2-2017

Please cite this article as: Xin Ding, Jurong Ding, Bo Hua, Xingzhong Xiong, Li Xiao, Fang Peng, Lin Chen, Xianfang Pan, Qingsong Wang, Abnormal cortical functional activity in patients with ischemic white matter lesions: A resting-state functional magnetic resonance imaging study, Neuroscience Letters http://dx.doi.org/10.1016/j.neulet.2017.02.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Title: Abnormal cortical functional activity in patients with ischemic white matter lesions: A resting-state functional magnetic resonance imaging study

Author names: Xin Ding1*, Jurong Ding2*, Bo Hua2, Xingzhong Xiong2, Li Xiao1, Fang Peng1, Lin Chen1, Xianfang Pan1, Qingsong Wang1

Affiliations: 1, Department of Neurology, Chengdu Military General Hospital, No. 270Tianhui Road, Rongdu Avenue, Jinniu District, Chengdu, Sichuan, 610083, China; 2, School of Automation and Electronic Information, Sichuan University of Science and Engineering, No. 180 Xueyuan Street, Huixing Road, Zigong, 64300, PR China.

Corresponding author: Dr. Qingsong Wang *: These authors contribute equally to this work Present address: No. 270Tianhui Road, Rongdu Avenue, Jinniu District, Chengdu, Sichuan, 610083, China Tel.: +86 02886570333 Fax: +86 02886570333 E-mail: [email protected]

Highlights 

  

We examine the relationship between WMLs and cognitive function using a ReHo method. Abnormal regions are related to memory, attention and executive and motor function. Altered regions in the DMN, FPCN and motor area correlate with cognitive test scores. The findings improve our understanding of pathophysiological mechanisms of WMLs.

Abstract There is increasing evidence that white matter lesions (WMLs) are associated with cognitive impairments. The purpose of this study was to explore the relationship of WMLs with cognitive impairments from the aspect of cortical functional activity. Briefly, Sixteen patients with ischemic WMLs and 13 controls participated in this study. A regional 1

homogeneity (ReHo) approach was used to investigate altered neural coherence in patients with ischemic WMLs during the resting state. A correlation analysis was further performed between regions with altered ReHo and cognitive test scores, including Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), in the patient group. Finally, we found regions with altered ReHo values in patients with ischemic WMLs to be involved in default mode network (DMN), frontal-parietal control network (FPCN), dorsal attention network (DAN), motor network and right temporal cortex. Moreover, some altered regions belonging to DMN, FPCN and motor network were significantly correlated with cognitive test scores. Our results provide neuroimaging evidence for the impairments of memory, attention, executive and motor function in patients with ischemic WMLs. It is interesting to note that the decreased ReHo was mainly in the anterior brain regions, while increased ReHo in the posterior brain regions, which may indicate a failure down regulation of spontaneous activity in posterior regions. In summary, this study indicates an important role of specific cortical dysfunction in cognitive associated with WMLs.

Abbreviations: 3DFFE, 3D fast field echo; ACG, anterior cingulate gyrus; aMCG, anterior middle cingulate cortex; ANG, angular gyrus; BA, Brodmann’s area; CUN, cuneus; DAN, dorsal attention network; DLPFC, dorsolateral prefrontal gyrus; DMN, default mode network; EPI, echo-planar-imaging; FDR, false discovery rate; FLAIR, fluid attenuated inversion recovery; FPCN, frontal-parietal control network; ING, insula; IPG, inferior parietal gyrus; KCC, Kendall’s coefficient of concordance; MMSE, Mini-Mental State Examination; MNI, Montreal Neurologic Institute; MPFC, medial prefrontal cortex; MRI, magnetic resonance imaging; MTG, middle temporal gyrus; PCC, posterior cingulate cortex; PCUN, precuneus; PET, positron emission tomography; PoCG, postcentral gyrus; PreCG, precentral gyrus; ReHo, regional homogeneity; ROL, rolandic operculum; rs-fMRI, resting-state functional magnetic resonance imaging; SMA, supplementary motor area; SOG, superior occipital gyrus; SPM8, Statistical Parametric Mapping; SPG, superior parietal gyrus; STG, superior temporal gyrus; WMLs, white matter lesions.

Keywords: Cerebral ischemia, White matter lesions, Cortical dysfunction, Regional homogeneity

1. Introduction White matter lesions (WMLs) are a common finding on magnetic resonance imaging (MRI) 2

as white matter hyperintensities in elderly people older than 65 years[1, 2]. The prevalence and severity of WMLs increases with advancing age[1, 3]. WMLs are found to be a biomarker for long-term cerebrovascular disease and dementia[4]. There is growing evidence that WMLs are associated with clinical manifestations of cognitive impairments[4-6], including executive function[7], memory[8] and attention[9]. Moreover, motor decline is also a frequent finding associated with WMLs[10, 11]. However, few studies have devoted their attention to the underlying mechanism of how WMLs influence cognitive function and behavioral performance. Nordahl et al. found that dysfunction of the prefrontal cortex caused by white matter degeneration might be a mechanism for the changes in memory function[8]. In addition, a positron emission tomography (PET) study revealed that WMLs had effects on metabolic activity of dorsolateral frontal cortex, which is related to executive function, memory and global cognitive function[12]. In our recent work, we found that cognitive impairments are associated with special cortical dysfunction in patients with WMLs using resting-state functional magnetic resonance imaging (rs-fMRI)[13]. In short, these studies suggest that dysfunction of specific cortical regions plays a vital role in cognitive impairments associated with WMLs. Therefore, investigating cortical functional activity may aid to better understand the relationship of WMLs with cognitive decline and motor disturbance. Regional homogeneity (ReHo) measures the functional coherence of a given voxel with its nearest neighbors and can effectively evaluate resting-state brain activities[14]. This method assumes that brain activity is more likely to occur in clusters than in a signal voxel. Thus, ReHo provides an approach for using fMRI to investigate local connectivity and may be useful for revealing the complexity of human brain function[15]. Until now, ReHo analysis has been widely used to investigate the cortical functional activity and reveal the pathophysiological changes in the resting state in neurologic and psychiatric disorders, such as epilepsy[16], autism spectrum disorders[17], Alzheimer’s disease[15, 18], depression[19], anxiety disorder and Parkinson’s disease[20]. Thus, this method may be helpful to understand the underlying mechanism of cognitive and motor deficits in patients with WMLs, since it can reflect the temporal homogeneity of neural activity. We hypothesized that the ReHo value would be different between patients with ischemic WMLs and control subjects, particularly in brain regions associated with cognitive and motor function. In the present study, we employed ReHo analysis to investigate differences in cortical activity between patients with ischemic WMLs and the control subjects. Furthermore, correlation analyses of the ReHo value with clinical variables (i.e., Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were carried out in the patient group to evaluate the relationship between the cortical activity and the cognitive abilities associated with WMLs. 2. Materials and methods 3

2.1 Participants This study was approved by the medical ethics committee of Chengdu Military General Hospital, Chengdu, China. All participants gave their written informed consent after the experimental procedure had been clearly explained. Finally, a total of 16 patients (7 males, age range: 49-72 years) who were diagnosed clinically with ischemic WMLs and 16 controls (CN; 8 males, age range: 54-71 years) with no WMLs on MRI were recruited, same with those in our recently published paper[21]. All participants underwent a comprehensive clinical examination by two experienced neurologists, including medical history, physical, and neurological assessments. Patients with ischemic WMLs were determined by T2-weighted MRI images, defined as a cap or a band of 10 mm or more and a deep white matter lesion of 25 mm or more according to a modification of the Fazekas ischemia criteria[22].We excluded patients if they had psychiatric or neurological disorders that might cause cognitive impairment, such as stroke, schizophrenia, epilepsy, severe head trauma, encephalitis and brain tumors, or neurodegenerative diseases such as Parkinson’s disease. In addition, the patients with disorders that might impact their current cognitive state, including metabolic encephalopathy, thyroid disease, syphilis, alcoholic encephalopathy and severe depression, were excluded. We also excluded the patients who did not undergo MRI and neuropsychological test due to aphasia, hearing or visual impairment and sensory disorders. The control subjects did not have any neurologic or psychiatric disorders and showed no deficits on the neuropsychological test. The neuropsychological tests evaluated in this study included: Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). All participants were right-handed. 2.2 Imaging data acquisition All imaging data were collected on a 3.0-T Philips MR scanner (Philips Medical System, Best, Netherlands). Tight but comfortable foam padding was used to minimize head motion, and ear plugs were used to reduce scanner noise. Conventional MRI scans included transverse fluid attenuated inversion recovery (FLAIR), T1-weighted and T2-weighted images. Resting-state functional images were acquired using an echo-planar-imaging (EPI) sequence with the following parameters: TR/TE=2000/30ms, flip angle=90°, FOV=192×192mm2, matrix=64×64, slice thickness=3mm, without gap, 35 axial slices, voxel size=3×3×3mm3, and a total of 230 volumes for each subject. Subjects were instructed to keep their eyes closed, relax and move as little as possible. Additionally, high-resolution T1-weighted anatomical images were acquired in sagittal orientation from each subject using a 3D fast field echo (3DFFE) sequence with the following parameters: TR/TE=2500/2.0ms, flip angle=30°, matrix=192×256, slice thickness=1mm, without gap, voxel size=1×1×1mm3.Data from one control subject was discarded due to uncompleted functional images. 4

2.3 Image preprocessing All

preprocessing

steps

were

carried

out

using

SPM8

software

(http://www.fil.ion.ucl.ac.uk/spm). The first 10 volumes of each functional time series were discarded to ensure steady-state longitudinal magnetization and stabilization of participant status. The remaining 220 consecutive volumes were first corrected for the temporal difference in acquisition among different slices, and then realigned to the first volume for head-motion correction. Only participants with head motion less than 2.0mm in the x, y or z direction and less than 2.0° rotation about each axis were included. Then, two control subjects were excluded from the further analyses. Totally, 16 patients (7 males, age range: 49-72 years) and 13 controls (6 males, age range: 54-70 years) remained. Next, the functional images were realigned with the corresponding T1-volume and warped into a standard stereotaxic space at a resolution of 3×3×3mm3, using the Montreal Neurological Institute (MNI) EPI template. Subsequently, the functional images were temporally band-pass-filtered (0.01-0.08 Hz) to reduce the effects of low-frequency drift[23] and high-frequency noise[24]. The linear trend was further removed. 2.4ReHo measure Kendall’s coefficient of concordance (KCC) was calculated to measure the similarity of the time series within a functional cluster, consisting of 27 nearest neighboring voxels[14]. The formula was defined as follows[14]:

W

  Ri 

Where

2

 

n R

2

k 2  n3  n  12

W is the KCC of a cluster, ranging from 0 to 1; Ri is the sum rank of the ith time

point; n is the length of the time series; R   n  1 k 2 is the mean of the Ri ;

k is

the number of voxels within the measured cluster. Individual ReHo map was obtained voxel by voxel for each subject using the free REST software (Resting state fMRI data analysis toolkit, http://sourceforge.net/projects/resting-fmri). A whole brain mask was used to remove non-brain tissue. To reduce the effect of individual variability, the individual ReHo map was standardized by its own mean KCC within the mask[17, 20]. Finally, the ReHo maps were spatially smoothed with a 4-mm full width at half-maximum to reduce noise and residual differences, similar to our previous study [25]. 2.5Statistical analysis Statistical analysis was carried out using SPM8 software. One-sample t-tests [p<0.05, false discovery rate (FDR) correction] were performed to extract the ReHo results across subjects within each group. Then, two-sample t-tests were applied to identify the differences between the patients with ischemic WMLs and CN groups within a defined mask. This mask was defined by combining the voxels in both the two groups using 5

one-sample t-test results. The statistical significance of group comparison was set at a combined threshold of p<0.01 and a minimum cluster size of 13 voxels, corresponding to a corrected p<0.05. This correction was determined by the Monte Carlo simulations performed by the AlphaSim program in the REST toolkit. Finally, in order to explore whether the brain regions with altered ReHo values correlated with the cognitive level in the patient with ischemic WMLs, a correlation analysis was then performed between these regions and cognitive test scores (MMSE scores and MoCA scores). 3. Results 3.1 Demographic and clinical characteristics The demographics and relevant clinical characteristics are shown in Table 1. No significant differences were found between the two groups in terms of age, gender, educational level and vascular risk factors. Compared with the CN group, patients with ischemic WMLs showed significantly lower MMSE and MoCA scores, indicating obvious cognitive impairment in the patient group. 3.2 ReHo patterns Fig. 1 shows the ReHo results for patients with ischemic WMLs and controls (one-sample t-test, p<0.05, FDR corrected). The two groups both showed high ReHo values in the bilateral posterior cingulate cortex (PCC)/precuneus, angular gyrus, medial prefrontal cortex (MPFC) and inferior parietal gyrus, which are major regions of the default mode network[26]. Other regions also exhibited high ReHo values, such as the bilateral dorsolateral prefrontal gyrus (DLPFC), supplementary motor area, precentral gyrus, postcentral gyrus, median cingulate gyrus, medial temporal gyrus, cuneus and occipital cortex. 3.3 Group comparisons The results of group comparisons are shown in Fig. 2 and Table 2 (two-sample t-test, p<0.05, AlphaSim corrected). Compared with the CN group, the patients exhibited significantly decreased ReHo values in the left insula, the right superior temporal gyrus, rolandic operculum, precentral gyrus and cerebellum, and the bilateral anterior cingulate gyrus, anterior middle cingulate cortex, MPFC, DLPFC and supplementary motor area. The regions with increased ReHo values in the patient group included the left middle temporal gyrus, cuneus and superior occipital gyrus, and the bilateral angular gyrus, precuneus, postcentral gyrus, inferior and superior parietal gyrus. 3.4Correlation with cognitive performances We performed Spearman correlations between the abnormal regions and cognitive test scores (MMSE and MoCA scores) in the patient group after removing potential outliers[27]. The ReHo values of the bilateral angular gyrus, the right precuneus, MPFC, DLPFC and supplementary motor area were positively correlated with the MoCA scores. In addition, 6

the ReHo values of the right angular gyrus and precuneus also showed a positive correlation with the MMSE scores (Fig. 3). 4. Discussions The present study investigated for the first time patterns of regional homogeneity changes in patients with ischemic WMLs during the resting state using the ReHo analysis. Altered ReHo is thought to indicate abnormal neural activity in the regional brain, since ReHo reflects intrinsic coherent neural activity within a functional cluster[14]. We found regions with altered ReHo values in patients with ischemic WMLs to be involved in default mode network (DMN), frontal-parietal control network (FPCN), dorsal attention network (DAN), motor network and right temporal cortex. It is interesting that the decreased ReHo was found mainly in the anterior extent of cerebral cortex, while increased ReHo in the posterior extent of cerebral cortex. Moreover, some altered regions belonging to DMN, FPCN and motor network, such as the bilateral angular gyrus, the right precuneus, MPFC, DLPFC and supplementary motor area, were positively correlated with MoCA and MMSE scores. Compared with the controls, patients with ischemic WMLs presented decreased ReHo values in the MPFC, which belongs to the anterior part of DMN, and increased ReHo values in left middle temporal gyrus, the bilateral angular gyrus, inferior parietal gyrus, and precuneus, which are parts of the posterior DMN. The DMN is thought to play a vital role in higher cognition, especially in self-relevant, internally-directed cognition[28, 29]. The MPFC, an important region of the anterior DMN, is involved in self-related processing[28, 29], decision-making[30]and social cognition[31], which can integrate salient external or internal information relayed from the PCC/precuneus with one’s current affective experience and prior conceptual or episodic knowledge[29]. The middle temporal gyrus, precuneus, angular and inferior parietal gyrus constitute the major posterior extent of DMN[28]. The middle temporal gyrus is associated with mnemonic processes and provides information from prior experiences in the form of memories[28]. The precuneus is involved in a wide range of higher-order cognitive functions, such as self-processing, spatial attention and episodic memory retrieval[32]. The angular gyrus and the inferior parietal gyrus participate in mediating the automatic bottom-up attentional resources and monitoring episodic memory retrieval[33]. To sum up, the posterior DMN functions to provide and integrate information from memory and mediate bottom-up attention to information retrieval, while the anterior DMN facilitates the flexible use of this information and derive self-relevant mental simulations[28, 29]. The decreased ReHo in the anterior DMN (MPFC) and increased ReHo in the posterior DMN in the present study may reflect diminished downregulation of activity in posterior regions[34]. Recent studies have found that abnormalities of the DMN in disease and normal aging are often associated with cognitive impairments, including memory function and attention[35, 36]. Thus, our findings 7

of altered ReHo values in the DMN and the correlations with cognitive test scores may provide neuroimaging evidence for impairments of memory and attention in patients with ischemic WMLs[5]. The decreased ReHo values in patients with ischemic WMLs were also observed in the left insula, and the bilateral anterior cingulate gyrus, anterior midcingulate cortex and DLPFC, which are major regions of FPCN[37, 38]. The DLPFC has been associated with cognitive control and top-down modulation of attention and working memory[34]. Previous studies have reported the involvement of the insula, anterior cingulate gyrus and anterior midcingulate cortex in cognitive control processes, particularly in conflict monitoring, information integration and response selection[39]. It is now widely considered that the FPCN are crucial for executive control of attention and top-down cognitive control processes[37, 38]. Combining these findings, we speculate that the reduced ReHo in regions within the FPCN may account for the cognitive deficits including attention and executive function in patients with ischemic WMLs. The correlation of ReHo values in the DLPFC with MoCA scores may further support this speculation. In the present study, increased ReHo values were found in some regions within DAN, including the left superior occipital gyrus and bilateral superior parietal gyrus. The DAN is related to goal-directed cognitions, participating in eye movements, the allocation of attentional resources, the generation and selection of movements for execution[40, 41]. In addition, several studies have proved that the FPCN has potential regulation role to the DAN[37, 38]. Considering the reduced ReHo in the FPCN, we therefore suggest that the increased ReHo in the regions within DAN partly reflect the impaired cognitive function in patients with ischemic WMLs, which may be interpreted as a failure of the FPCN to properly engage in regulation processes. The superior temporal gyrus and rolandic operculum are involved in speech and language recognition[42]. Recently, altered grey matter volume in the right superior temporal gyrus and rolandic operculum was found in children who stutter relative to fluent children, indicating widespread anatomic abnormalities throughout the cortical network for speech motor control[43]. Moreover, the right superior temporal gyrus has been implicated in social cognition, which may play a critical role in processing and integrating different types of information, as well as analyzing the intentions of other people’s actions in order to give proper meaning to the surrounding world[44, 45]. Our results of reduced ReHo values in the right temporal gyrus and rolandic operculum indicate insufficient participation in language recognition and information integration, which may underlie impaired ability in verbal fluency and memory retrieval in patients with WMLs[46]. In addition to cognitive impairments, WMLs were also found to be associated with motor decline[10, 11], as manifested in gait disturbance and falls[47, 48]. Xiong et al. has suggested that gait disturbance in patients with WMLs may be attributed to the disruptions 8

in motor network[48]. In this study, we found that patients with ischemic WMLs showed reduced ReHo values in the right cerebellum and precentral gyrus, and the bilateral supplementary motor area, while increased ReHo in the bilateral postcentral gyrus, reflecting disruptions of neural activity in motor network. Therefore, our findings may provide an interpretation for motor disturbance in patients with ischemic WMLs. Furthermore, the reduce ReHo values in the right supplementary motor area were positively correlated with MoCA scores, which is consistent with previous finding that behavior performances are affected by cognitive function[49]. However, we should consider several limitations when interpreting the results of the present study. First, this study is limited by the small sample size of each group. Further investigations are warranted to confirm our results using a larger sample size of WMLs subjects. Second, as an exploratory study, the correlation results with cognitive test scores are uncorrected. Further studies can increase the statistical power by enlarging the sample size. Finally, the present study is a cross-sectional investigation, which may limit the understanding of the associations of cognitive performance with altered ReHo regions. Thus, a longitudinal study is needed to better uncover the relationship between cognitive progress and neuroimaging alterations. 5. Conclusions In summary, the present study demonstrated that patterns of neural coherence in the resting state were altered in patients with ischemic WMLs. Compared with the CN group, patients with ischemic WMLs exhibited altered ReHo in the DMN, FPCN, DAN, SMN and right temporal cortex. Moreover, the angular gyrus, precuneus, MPFC, DLPFC and supplementary motor area showed correlations with cognitive test scores. Our findings provide neuroimaging evidence for the impaired memory, attention, executive and motor function in patients with ischemic WMLs. Interestingly, we noticed that the decreased ReHo was found mainly in the anterior extent of cerebral cortex, while increased ReHo in the posterior extent of cerebral cortex, which may indicate a failure down regulation of spontaneous activity in posterior regions. This study may aid us to further understand the relationship of WMLs with cognitive and motor deficits from the aspect of cortical functional activity. 6. Competing interests We declare that we have no conflict of interest. 7. Acknowledgments This work was supported by the National Natural Science Foundation of China (81401482), the Health Department of Sichuan Province (No. 140005), and Scientific Research Foundation of Sichuan University of Science and Engineering (2014RC12).

9

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Figure Legends Fig. 1 ReHo maps for patients with ischemic WMLs (A) and CN (B). The results were corrected by FDR procedure (p<0.05). Numbers in the upper left of each image refer to the z-plane coordinates of the MNI space. WMLs, white matter lesions; CN, controls; MNI, Montreal Neurological Institute; L, left; R, right.

Fig. 2 Maps showing ReHo differences between patients with ischemic WMLs and CN. The results were corrected by AlphaSim (p<0.05, with a combined threshold of p<0.01 and a minimum cluster size of 13 voxels). Numbers in the upper left of each image refer to the z-plane coordinates of the MNI space. Hot and cold colors indicate ReHo increases and decreases in patient group, respectively. WMLs, white matter lesions; CN, controls; MNI, Montreal Neurological Institute; L, left; R, right.

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Fig. 3 Correlations between regions with altered ReHo and cognitive test scores (MMSE and MoCA scores) in patients with ischemic WMLs (p<0.05). Spearman correlations were calculated over the data after removing outliers marked by circles. WMLs, white matter lesions; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; ANG, angular gyrus; PCUN, precuneus; MPFC, medial prefrontal cortex; DLPFC, dorsolateral prefrontal gyrus; SMA, supplementary motor area; L, left; R, right.

15

Table 1 Demographic and clinical characteristics Characteristics

Patients with WMLs

CN

(n=16)

(n=13)

49-72 (61.6±6.1)

54-70 (60.2±4.7)

0.5235a

7/9

6/7

>0.9999b

6-15 (8.5±2.8)

6-12 (8.5±1.9)

0.8881c

Hypertension

7 (43.8%)

4 (30.8%)

0.7021b

Diabetes mellitus

2 (12.5%)

2 (15.4%)

>0.9999b

Hyperlipidemia

6 (37.5%)

3 (23.1%)

0.4543b

Current smoker

1 (6.3%)

1 (7.7%)

>0.9999b

MMSE

16-30 (23.7±3.9)

27-29 (28±0.8)

0.0006a

MoCA

10-24 (18.3±4.1)

26-29 (27.2±0.9)

<0.0001a

Age (years) Gender (male/female) Education (years)

P-value

Vascular risk factors

Data were expressed as the range from min-max (mean ± SD). Abbreviations: WMLs, white matter lesions; CN, controls; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment. aP-value

was obtained using the two-sample, two-tailed t-test.

bP-value

was obtained using the two-tailed Fisher’s exact test.

cP-value

was obtained using the two-tailed Mann-Whitney U test.

16

Table 2 Regions of increased/decreased ReHo in patients with ischemic WMLs. BA

MNI (x, y, z)a

Voxels

tb

L MTG

39

-48, -60, 24

75

4.64

L IPG

39

-54, -54, 42

135

4.31

R IPG

40

48, -48, 39

21

4.05

L ANG

39

-51, -63, 33

129

4.81

R ANG

39

39, -57, 24

23

3.19

L PCUN

—

-3, -45, 45

76

4.12

R PCUN

—

3, -48, 51

122

3.76

L SOG

19

-15, -84, 45

27

3.88

L CUN

—

0, -75, 33

20

2.91

L SPG

7

-30, -51, 60

58

4.71

R SPG

5

15, -48, 60

13

3.02

L PoCG

2

-30, -42, 57

42

3.57

R PoCG

2

30, -39, 60

14

3.04

L MPFC

—

0, 18, 42

24(9)

-4.02

R MPFC

10

9, 51, 6

18(7)

-4.02

R STG

48

60, -12, 9

58

-4.76

R ROL

48

60, -18, 15

45

-4.57

L ING

48

-33, 18, 3

24

-3.73

L ACG

24

-3, 21, 30

90

-5.52

R ACG

24

3, 21, 30

55

-4.31

L aMCG

—

0, 21, 33

27

-5.42

R aMCG

24

3, 18, 39

38

-5.14

L DLPFC

46

-30, 48, 18

17 (30)

-3.39

R DLPFC

9

30, 30, 48

15 (16)

-3.59

L SMA

32

0, 15, 45

16

-3.96

R SMA

32

3, 12, 48

15 (7)

-3.82

R PreCG

6

63, 6, 21

16

-3.42

R Cerebellum

—

45, -69, -51

15

-3.44

Anatomical region ReHo increased regions

ReHo decreased regions

Abbreviations: ReHo, regional homogeneity; WMLs, white matter lesions; CN, controls; BA, Brodmann’s area; MNI, Montreal Neurologic Institute; L, left; R, right; MTG, middle temporal gyrus; IPG, inferior parietal gyrus; ANG, angular gyrus; PCUN, precuneus; SOG, superior occipital gyrus; CUN, cuneus; SPG, superior parietal gyrus; PoCG, postcentral gyrus; MPFC, medial prefrontal cortex; STG, superior temporal gyrus; ROL, rolandic 17

operculum; ING, insula; ACG, anterior cingulate gyrus; aMCG, anterior middle cingulate cortex; DLPFC, dorsolateral prefrontal gyrus; SMA, supplementary motor area; PreCG, precentral gyrus. a

Coordinates of primary peak locations in the MNI space.

b

Represents the statistical value of peak voxel showing ReHo differences comparing

patients with ischemic WMLs and controls. Positive t value indicates increased ReHo, and negative t value indicates decreased ReHo.

18