Neurogastroenterology & Motility Neurogastroenterol Motil (2014) 26, 1144–1154
doi: 10.1111/nmo.12372
Altered structural covariance of the striatum in functional dyspepsia patients P. LIU ,* F. ZENG ,† F. YANG ,* J. WANG ,* X. LIU ,* Q. WANG ,* G. ZHOU ,* D. ZHANG ,‡ M. ZHU ,* R. ZHAO ,* A. WANG ,* Q. GONG §
& F. LIANG †
*Life Science Research Center, School of Life Science and Technology, Xidian University, Xi’an, China †Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China ‡Rehabilitation Medical Central of the 181st People’s Liberation Amy Hospital, Guangxi, China §Department of Radiology, The Center for Medical Imaging, Huaxi MR Research Center (HMRRC), West China Hospital of Sichuan University, Sichuan, China
Key Messages
• We found the altered gray matter volumes and related structural covariance of the striatum in patients with
functional dyspepsia, which was potentially valuable for understanding the mechanism of functional dyspepsia. imaging from 44 patients and 39 healthy controls were used for this study. VBM and structural covariance methods were applied for striatum structure changes. Results showed increased gray matter volumes in the bilateral putamen and right caudate and related differences of structural covariance patterns located in the amygdala, hippocampus/parahippocampus (HIPP/ paraHIPP), thalamus, lingual gyrus, and cerebellum.
• The MRI •
Abstract Background Functional dyspepsia (FD) is thought to be involved in dysregulation within the brain–gut axis. Recently, altered striatum activation has been reported in patients with FD. However, the gray matter (GM) volumes in the striatum and structural covariance patterns of this area are rarely explored. The purpose of this study was to examine the GM volumes and structural covariance patterns of the striatum between FD patients and healthy controls (HCs). Methods T1-weighted magnetic resonance images were obtained from 44 FD patients and 39
HCs. Voxel-based morphometry (VBM) analysis was adopted to examine the GM volumes in the two groups. The caudate- or putamen-related regions identified from VBM analysis were then used as seeds to map the whole brain voxel-wise structural covariance patterns. Finally, a correlation analysis was used to investigate the effects of FD symptoms on the striatum. Key Results The results showed increased GM volumes in the bilateral putamen and right caudate. Compared with the structural covariance patterns of the HCs, the FD-related differences were mainly located in the amygdala, hippocampus/parahippocampus (HIPP/paraHIPP), thalamus, lingual gyrus, and cerebellum. And significant positive correlations were found between the volumes in the striatum and the FD duration in the patients. Conclusions & Inferences These findings provided preliminary evidence for GM changes in the striatum and different structural covariance patterns in patients with FD. The current results might expand our understanding of the pathophysiology of FD.
Address for Correspondence Peng Liu, Life Sciences Research Center, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi 710071, China. Tel: +86-29-81891070; fax: +86-29-81891060; e-mail: [email protected] Fanrong Liang, L Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China. Tel: +86 28 66875831; fax: +86 28 61800013; e-mail: [email protected] Received: 1 October 2013 Accepted for publication: 1 May 2014
Keywords functional structural covariance.
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INTRODUCTION
Abnormalities in the striatum have also been indicated in irritable bowel syndrome (IBS) in functional, structural MRI and NK-1 receptor binding studies.26–28 However, studies assessing the structural alterations of the striatum in FD were rare. Moreover, to our knowledge, no study has directly examined the structural relationships between the striatum and other brain regions in patients with FD. Voxel-based morphometry (VBM) is a semi-automated whole brain technique,29,30 which has been widely used to interrogate group differences in brain tissue.31–34 Structural covariance is an effective method to investigate covariance in gray matter (GM) volumes between different brain regions.35 Based on structural MRI and VBM, there has been evidence indicating the pattern of structural covariance may reflect the effects of brain development or structural plasticity.35–37 Moreover, previous studies have found the structural covariance may be altered between brain disorder patients and HCs.38,39 Recently, the pattern of whole brain structural covariance of the neostriatum has been investigated in HCs.40 Hence, it was likely to be valuable to explore the altered structural covariance of brain in patients for the neural basis of certain disorders and/or to explore the potential mechanisms underpinning in healthy human brains. In the current study, VBM method was firstly adopted to investigate whether there were significant differences in the GMs of the striatum between FD patients and HCs. If there existed the differences in the striatum, we then examined the whole brain structural covariance patterns in FD patients and HCs separately, based on the striatum-related differences. Meanwhile, we tried to assess whether there was association between neuroimaging findings and clinical information about FD. Here, we hypothesized that there existed abnormal brain structure of the striatum and different structural covariance patterns of the striatum in FD patients compared with HCs, and we also hypothesized that there existed association between neuroimaging findings and FD clinical information.
Functional dyspepsia (FD) is a highly prevalent functional gastrointestinal disease with major symptoms of recurrent pain or discomfort in the upper abdomen, early satiety, and abdominal distension.1 FD has a great effect on the health-related quality of life (QOL) and high healthcare costs. However, the underlying pathogenesis of FD is not fully understood as yet. Recent neuroimaging studies have indicated that FD might be caused by dysregulation within the brain–gut axis.2,3 Evidence of abnormal central nervous system processing in FD can be found in a number of neuroimaging studies, mainly associated with homeostaticafferent,4,5 emotional-arousal and/or cortical-modulatory regions4,5 such as the thalamus, somatosensory cortex, insula, amygdala, cingulate cortex, and prefrontal cortex.6–9 It is worth noting that some interesting findings indicate a potential role of several new brain areas in FD neuropathology such as the striatum. Up to now, using brain imaging techniques, such as computed tomography, positron emission tomography (PET) and magnetic resonance imaging (MRI), certain studies have identified the abnormality of the striatum in FD. For example, Ladabaum et al. found the abnormal activity of the striatum during gastric distention.10 Braak et al. reported decreased striatal dopamine D2 receptors (D2R) binding of the caudate nucleus in patients with FD.11 One of our PET studies found that FD patients showed higher glycometabolism in the putamen compared with healthy controls (HCs) and the relatively severe group showed an increased glycometabolism in the caudate nucleus compared with the milder group.7 Another one of our studies revealed that the correlation between the right cerebellum and left putamen was increased in patients with FD using MRI.12 The studies mentioned above suggested that the striatum would likely to play an important role in the pathogenesis of FD. The striatum, including the caudate nucleus and the putamen, has a major cortical and subcortical input into the basal ganglia.13 It has been known that the striatum receive inputs from all cortical areas and, throughout the thalamus, project principally to frontal lobe areas which are concerned with motor planning.14 As an important structure of the basal ganglia, the striatum is not only related to motor and emotional processing,15–17 but also involved in cognitive functions.18–20 Moreover, it has been reported that the putamen and related neural networks could contribute to the processing of sensory and motor aspects of pain.21 There has been evidence indicating striatumrelated dysregulation in certain brain disorders.22–25
© 2014 John Wiley & Sons Ltd
MATERIALS AND METHODS Participants Forty-four FD patients (28 females, 16 males; ages ranging from 20 to 27 years) and 39 age-matched HCs (25 females, 14 males; ages ranging from 21 to 24 years) were recruited for the present study. All the patients met the Rome III criteria on FD and postprandial distress. In addition, a careful basic evaluation was performed for each patient. The evaluation included upper gastrointestinal endoscopy, upper abdominal ultrasound, electrocardiogram, hepatic function, renal function, and routine analysis of the blood,
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Image analysis
urine, and stool. All the examinations were performed by the same professional gastroenterologist in the West China Hospital of Sichuan University.
Structural images processing and analysis were performed in SPM5 (http://www.fil.ion.ucl.ac.uk/spm) including the VBM5 toolbox which is running under MATLAB (Mathworks, Natick, MA, USA). All structural images were transformed into Montreal Neurological Institute (MNI) 152 standard space using linear transformations and re-sampled to 1 9 1 9 1 mm3. The images were then segmented into GM, white matter (WM), and cerebrospinal fluid (CSF). The modulation step was added to incorporate volume changes during spatial normalization.45 This step involved multiplying each spatially normalized GM image by its relative volume before and after normalization. Finally, the resulting GM images were smoothed with an isotropic Gaussian kernel of 8 mm full-width at half maximum (FWHM).
Exclusion criteria for FD patients were as follows: (a) having other gastrointestinal or pain disorder (such as IBS, fibromyalgia [FM], and temporomandibular disorder), (b) being pregnant or lactating, (c) having been taking medications that affect gastrointestinal motility such as selective serotonin reuptake inhibitors, non-steroidal anti-inflammatory drugs, aspirin, phenothiazines, and/or steroids for over 2 weeks before enrollment, (d) having a history of gastrointestinal surgery, (e) having suffered from serious cardiovascular, neurological, psychiatric, renal, or respiratory diseases, (f) having been experiencing acid regurgitation, heart burn, or upper abdominal pain as the predominant symptom, (g) having had gastric atrophy or erosive gastroduodenal lesions, and (h) having had cholecystitis, gallstones, or esophagitis. Furthermore, all of the FD patients were forbidden to take medications, which potentially influenced gastrointestinal motility and sensitivity (such as prokinetic and antinausea drugs) at least 24 h before study participation.
Because we focused on the group differences in GM of the whole striatum including the caudate and putamen, we firstly extracted mean GM volumes across each voxel in the bilateral caudate and bilateral putamen regions which were defined based on the automated anatomical labeling template using the Wake Forest University PickAtlas software (http://www.fmri.wfubmc. edu/download.htm). A two-tailed, two-sample t-test was applied to compare the GM volume of the whole putamen or caudate in the bilateral hemispheres at p < 0.01 (Bonferroni corrected), separately. Secondly, a two-sample t-test was adopted to produce the VBM group statistical parametric map in the only striatum and the significant level were thresholded at p < 0.05 (fall discovery error corrected [FDR corrected]) with a cluster size >5 voxels. Finally, based on the statistical parametric map, the caudate- or putamen-related regions, showing the differences between FD patients and HCs were enrolled as seed regions of interest (ROIs) for structural covariance analyses. Each seed ROI was defined with the MarsBar region-of-interest toolbox for SPM (http://marsbar.sourceforge.net/) as 2 mm radial spheres centered at the voxel with the peak Z-score. Recent studies have suggested that body mass index (BMI) is associated with changes in GM, and GM differences have been specially demonstrated in both the obese and lean subjects.46–49 The emotional factors might exert their role in FD, such as anxiety and depression.6 Therefore, the age, sex, BMI, SAS, and SDS were deemed as covariates of no interest in the VBM analysis and structural covariance analyses.
The age- and gender-matched HCs underwent similar basic evaluations mentioned above. They had no history of neurological or psychiatric disorders and had refrained from alcohol or drug consumption in the previous week. All research procedures of the present study were approved by the Ethics Committee of Chengdu University of Traditional Chinese Medicine (No. 2011KL003) and were conducted in accordance with the Declaration of Helsinki. Verbal and written consent was obtained from each subject.
Behavioral measures The Nepean Dyspepsia Index (NDI) was used to evaluate the severity of the symptoms and the QOL.41 The Chinese-translated version of NDI was applied to measure the symptom severity of the disease.42 According to 15 dyspepsia-related physical signs, the symptom index of the NDI could be rated for frequency (0–4), intensity (0–5), and bothersomeness (0–4). The QOL index of the NDI included four domains, namely interference (13 items), know/control (7 items), eat/drink (3 items), and sleep/disturb (2 items).
In this study, structural covariance analyses were used to determine the relationship between the GM volume of each voxel across the whole brain and that of each seed for each group (FD patients or HCs). Statistical analysis was performed on the modulated GM images using the general linear model in SPM5. To identify the whole brain voxel-wise structural covariance of the ROIs, multiple regression models were established for each ROI. In each regression model, the mean GM volume that derived from each ROI was entered as a covariate of interest, and the whole GM volumes, age, sex, BMI, SAS, and SDS were seen as covariates of no interest. With this design, we obtained group level structural covariance pattern. One-sample t-tests with covariates were performed to map the voxels that expressed a significant positive GM covariance with each ROI in each group. Resulting correlation maps were thresholded at p < 0.05 (FDR corrected) with a cluster size >5 voxels. It has been indicated that the structural covariance patterns are linked to the architecture of the intrinsic functional networks, and regions having a positive association in the GM volume were demonstrated to be part of the same functional network.38,50 A recent study was conducted for only the positive structural covariance of the neostriatum.40 Therefore, our study focused on estimating the positive correlations of the ROIs with the other brain regions.
The depression/anxiety related symptoms were evaluated using the Zung Self-Rating Depression Scale (SDS) and the Zung Self-Rating Anxiety Scale (SAS). Both the SDS and SAS consisted of 20 items, each of them was scored from 1 to 4. The final scores were determined by the sum of all the items which was multiplied by a factor of 1.25. A score less than 53 (SDS) or 50 (SAS) was considered to be in the normal range according to the Chinese norm.43,44
Image acquisition Images were collected using a 3T Siemens scanner (Allegra, Siemens Medical System, Erlangen, Germany) at the Huaxi MR Research Center, West China Hospital of Sichuan University, Chengdu, China. A standard birdcage head coil along with a restraining foam pad was used to minimize the head motion. T1-weighted images were obtained using a volumetric threedimensional spoiled gradient recall sequence (TR/TE: 1900 ms/ 2.26 ms, flip angle = 9°, field of view: 256 9 256 mm, matrix size: 256 9 256, in-plane resolution: 1 9 1 mm, slice thickness = 1 mm, 176 slices). During the entire session, subjects were instructed to keep eyes closed, not to think about anything and to stay awake.
Pearson’s correlation analysis was applied to examine the relationship between the mean GM volume in each ROI and
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correlated with BMI (r = 0.29, p > 0.05 in the FD patients; r = 0.24, p > 0.05 in the HCs). Compared with the HCs, the FD patients had higher mean GM value in the caudate (left caudate: 0.426 0.056 mL in the FD patients, 0.416 0.056 mL in the HCs; right caudate: 0.415 0.053 mL in the FD patients, 0.402 0.055 mL in the HCs) and the putamen (left putamen: 0.226 0.043 mL in the FD patients, 0.205 0.049 mL in the HCs; right putamen: 0.233 0.039 mL in the FD patients, 0.213 0.043 mL in the HCs). Furthermore, the mean GM values of the left and right putamen are significantly higher in the FD patients (Fig. 1). The three identified regions, showing differences between the FD patients and the HCs, were located in the bilateral putamen and right caudate, which were selected as the ROIs for structural covariance analysis. These spherical ROIs were centered at the following MNI coordinates: right caudate (10, 18, 2), left putamen ( 19, 8, 7), and right putamen (26, 7, 6) (Fig. 2). The intergroup differences in structural covariance patterns associated with the three ROIs were shown in Fig. 3 and Table 2. For the right caudate ROI, structural covariance patterns with bilateral thalamus were
Table 1 Demographics and clinical characteristics of the FD patients and the healthy controls Mean SD Variable
FD patient
Healthy control
p value
Sex (female/male) Age (years) BMI (kg/m2) SAS SDS NDI Duration of disease (months)
28/16 22.64 19.44 41.70 43.49 46.66 35.32
25/14 22.18 19.56 33.85 34.81 — —
0.96* 0.16† 0.76† 8.30 7.59 4.44 5.69 6.05 5.54 4.26 4.59 4.02 3.83
15 32 689 629 236 298 60 87 89 20 89 25
16 24 26 23 25 26 6 8 16 28 17 26 26 26
78 94 77 74 10 8 8 12 8 10 0 6 2 3
13 13 23 21 5 5 3
3.69 3.68 5.40 5.19 7.26 >8.30 4.42 5.20 5.51 4.67 4.33 4.83 4.92 3.79
38 50 1179 2538 683 628 136 280 42 76 91 44 110 53
5
1 3 3 20 18 14 14
Thalamus Lingual gyrus Cerebellum
L R L R
16 28 17 34
77 84 78 76
13 17 20 26
3.74 3.34 4.67 4.71
24 57 752 1647
Hem
x
y
L R L R L R
11 11 21 20 21 20
18 18 15 15 1 6
R L R L R L R L R L R
24 13 41 6 20 22 8 8 20 18
6 14 16 39 84 10 14 13 12 5 9
L
22
19
L R L R L R
26 26 6 6 21 22
L
24
6
L R
22 14
16 16
R
18
89
5
Z-value
Cluster extent
3 3
7.66 >8.30 5.56 5.10 4.86 4.42
509 580 735 565 57 28
12 13 15 46 33 4 2 3 5 0 0
3.69 4.00 4.46 3.33 3.58 >8.30 7.51 5.09 5.16 5.27 5.05
6 143 75 9 660 672 543 314 338 59 20
6
4.20
10
6 6
6.77 >8.30 4.50 4.61 4.85 5.47
645 655 108 233 28 43
15
3.60
8
4.02 3.55
7 8
3.81
6
z 2 1 4 2
8 7 14 14 2 2
3 2 3 3
6 16 12
HC, healthy controls; FD, functional dyspepsia; Hem, hemisphere; MNI, Montreal Neurological Institute; L, Left; R, Right; HIPP, hippocampus.
were deemed as the ROIs. Different structural covariance patterns of the ROIs were then demonstrated between the patients with FD and the HCs. Structural covariance patterns of the three ROIs (including left putamen ROI and bilateral putamen ROIs) and the thalamus were only found in FD patients, whereas the patterns of structural covariance of the three ROIs and the HIPP/paraHIPP were only detected in HCs. In addition, structural covariance patterns of all the three ROIs and the amygdala were much stronger in HCs than in patients with FD. For the bilateral putamen ROIs, the associations with the lingual gyrus and
There were no significant correlations between the mean GM volume of the ROIs and the NDI scores (p > 0.05).
DISCUSSION In the present study, we reported the GM volume changes and the structural covariance patterns of the striatum in the FD patients compared with the HCs for increasing our understanding of the neural mechanisms of FD patients. Firstly, we found that the patients had higher GM volumes in the bilateral putamen and right caudate using VBM analysis, which
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Figure 4 The significantly positive correlation between the gray matter volumes of the right caudate and bilateral putamen and the duration of FD patients.
above-mentioned findings in the FM, PVD, and M-TMD.57–59 It was reported that the striatum, as the major input structure of the basal ganglia, importantly contributed to pain modulation and analgesia.58,60,61 It was indicated that there was a positive correlation between cortical volumes and function.62,63 Thus, we supposed that the GM changes in the striatum might reflect structural plasticity and represent pathophysiological effects of the FD disease. And the changes of the cortical volumes could yield dysfunction of the striatum, which needed further studies in the future. Furthermore, these GM volume changes would be expected to be associated with the duration of disease. The positive correlation between the GM volumes in the bilateral putamen and right caudate and FD duration might present the long aversive experiment of FD could make striatum have a worse effect on structural plasticity. However, a recent study was
cerebellum were indentified in HCs, which were not seen in FD patients. Moreover, there were positive correlations between the mean GM values of ROIs and the duration of disease in the patients group. Previous studies have demonstrated that chronic pain or aversive experiment may induce changes of GM volumes.51,52 Altered GM volumes in brain regions have been constantly reported in a variety of pain disorders including IBS, migraine, trigeminal neuralgia, and cluster headache.53–56 The recent studies, using MRI technique and VBM analysis method, revealed increased GM volumes in the striatum in chronic pain conditions such as FM, provoked vestibulodynia (PVD), and myofascial pain of the temporomandibular region (M-TMD).57–59 In this study, the increased GM volumes were also observed in the bilateral putamen and right caudate in the patients with FD, which were consistent with the
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visceral afferent processing circuits,5 alteration of the thalamus in FD patients has been typically found in many studies.7,12,73 It could speculate that FD-related brain responses in the thalamus may be mediated by the increased structural covariance patterns between structures of the three ROIs and the thalamus. Furthermore, there has been evidence indicating that the putamen is structurally connected with the thalamus in nociceptive information processing.21 Therefore, increased patterns of structural covariance between structures indentified in FD in our study may reflect abnormal structural plasticity compensatory strategy in visceral afferent processing and/or nociceptive information processing in patients with FD. The limitations should be noted in the present study. Two conditions (hyper- and normosensitive groups) were included in FD group and the confounding effect of these two subtypes was not considered in the present study. In the future, the relationships between structural covariance and functional/structural connectivity would be further examined in FD patients. In summary, we found increased GM volumes in the striatum, especially in the bilateral putamen and the right caudate in patients with FD. Our results also showed different structural covariance patterns of the ROIs related to the putamen and caudate in the FD patients and HCs. Meanwhile, GM changes of the striatum were correlated with FD duration. These findings demonstrated that altered GM and structural covariance patterns between the striatum and certain regions in the brain–gut axis in FD. It was hoped that the current study might contribute to improving our understanding the neural basis of FD.
indicated that IBS was associated with decreased GM volumes in the ventral striatum,27 which was inconsistent with our results. We suggested that the inconsistence might be related to the different pathogenic mechanism between FD and IBS.64 The structural covariance patterns centered on the three ROIs within the right caudate and bilateral putamen of FD patients and HCs were indentified in our study. Overall, the structural covariance patterns of the bilateral putamen ROIs were mainly associated with some limbic structures such as the amygdala and HIPP/paraHIPP, lingual cortex, and the cerebellum in the HCs. And the right caudate ROI was mainly correlated with the amygdala, HIPP/paraHIPP, and the cerebellum in the HCs. These findings were partly overlapped with the results of the previous study,40 while the different results might attribute to the different locations of the ROIs and subject variability. However, the structural covariance patterns of the three ROIs in the FD patients were distinct compared with the HCs. FD patients showed the associations between the three ROIs and the thalamus. In addition, structural covariance patterns of the left putamen ROI mostly overlapped with those of the right putamen ROI in both the FD patients and HCs groups. These findings showed structural covariance patterns of putamen were highly symmetrical, similar to the study from Soriano-Mas et al.40 The patterns of structural covariance between the three ROIs and some limbic structures in FD patients were less spatial extended than those in HCs. The current findings in HCs were in accordance with corresponding functional connectivity results65 (Fig. 3). However, structural covariance of the three ROIs and the HIPP/paraHIPP were not found in FD patients. Meanwhile, it was found that FD patients had weaker spatial extents of structural covariance patterns between the three ROIs and the amygdala. The HIPP and amygdala were considered to be the inputs of the striatum.66 The HIPP/paraHIPP is not only involved in processing pain and visceral sensations, but also importantly contributes to the memory of visceral pain and unpleasant visceral sensations.67–69 The amygdala plays an important role in cognitive reappraisal and affective modulation of pain.70–72 Taken together, the present results could suggest that altered structural covariance patterns of the three ROIs and the amygdala as well as HIPP/paraHIPP may be induced by the recurrent pain or unpleasant perceptions from the viscera in patients with FD. In comparison to HCs, FD patients showed abnormal patterns of structural covariance of the three ROIs and the thalamus. As an important component of the
© 2014 John Wiley & Sons Ltd
ACKNOWLEDGMENTS This study was supported by the Project for the National Key Basic Research and Development Program (973) under grant no’s. 2012CB518501 and 2011CB707702, the National Natural Science Foundation of China under grant no’s. 81001504, 30930112, 30970774, 81000641, 81000640, 81101036, 81101108, 31150110171, 30901900, 81271644, 31200837, 81030027, 81102662, the Fundamental Research Funds for the Central Universities and the Program for New Century Excellent Talents in University of Education Ministry of China and the Youth Foundation of Sichuan Province (no. 2012JQ053).
FUNDING No funding declared.
DISCLOSURE No conflicts of interest, financial or otherwise, are declared by the author(s).
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AUTHOR CONTRIBUTION
interpretation of findings; PL drafted the manuscript; PL, JW, and RZ provided critical revision of the manuscript for important intellectual content; all authors critically reviewed the content and approved the final version for publication.
PL and ZF were responsible for the study concept and design; DZ, QG, and FL contributed to the acquisition of fMRI data; JW, FY, GZ, MZ, XL, QW, and AW assisted with data analysis and
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30 Mechelli A, Price CJ, Friston KJ, Ashburner J. Voxel-based morphometry of the human brain: methods and applications. Curr Med Imaging Rev 2005; 1: 105–13. 31 Lubin A, Rossi S, Simon G, Lanoe C, Leroux G, Poirel N, Pineau A, Houde O. Numerical transcoding proficiency in 10-year-old schoolchildren is associated with gray matter inter-individual differences: a voxel-based morphometry study. Front Psychol 2013; 4: 197. 32 Hashimoto R-i, Javan AK, Tassone F, Hagerman RJ, Rivera SM. A voxelbased morphometry study of grey matter loss in fragile X-associated tremor/ataxia syndrome. Brain 2011; 134: 863–78. 33 Williams LM. Voxel-based morphometry in schizophrenia: implications for neurodevelopmental connectivity models, cognition and affect. Expert Rev Neurother 2008; 8: 1049–65. 34 Whitwell JL, Josephs KA. Voxel-based morphometry and its application to movement disorders. Parkinsonism Relat Disord 2007; 13: S406–16. 35 Mechelli A, Friston KJ, Frackowiak RS, Price CJ. Structural covariance in the human cortex. J Neurosci 2005; 25: 8303–10. 36 Butz M, W€ org€ otter F, van Ooyen A. Activity-dependent structural plasticity. Brain Res Rev 2009; 60: 287–305. 37 Zielinski BA, Gennatas ED, Zhou J, Seeley WW. Network-level structural covariance in the developing brain. Proc Natl Acad Sci U S A 2010; 107: 18191–6. 38 Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron 2009; 62: 42–52. 39 Modinos G, Vercammen A, Mechelli A, Knegtering H, McGuire PK, Aleman A. Structural covariance in the hallucinating brain: a voxel-based morphometry study. J Psychiatry Neurosci 2009; 34: 465–9. 40 Soriano-Mas C, Harrison B, Pujol J, Lopez-Sola M, Hernandez-Ribas R, Alonso P, Contreras-Rodriguez O, Gimenez M et al. Structural covariance of the neostriatum with regional gray matter volumes. Brain Struct Funct 2013; 218: 697–709. 41 Talley NJ, Verlinden M, Jones M. Validity of a new quality of life scale for functional dyspepsia: a United States multicenter trial of the Nepean
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Dyspepsia Index. Am J Gastroenterol 1999; 94: 2390–7. Tian X, Li Y, Liang F, Sun G, Yan J, Chang X, Ma T, Yu S et al. Translation and validation of the Nepean Dyspepsia Index for functional dyspepsia in China. World J Gastroenterol 2009; 15: 3173–7. Wenyuan W. Self-rating anxiety scale (SAS). Shanghai Arch Psychol 1990; 2: 44. Chunfang W, Zehuan C, Qing X. Selfrating depression Scale (SDS): an analysis on 1340 health subjects. Chin J Nerv Menl Dis 1986; 12: 267– 8. Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. A voxel-based morphometric study of ageing in 465 normal adult human brains. NeuroImage 2001; 14: 21–36. Raji C, Ho A, Parikshak N, Becher J, Lopez O, Kuller L, Hua X, Leow A et al. Brain structure and obesity. Hum Brain Mapp 2010; 31: 353–64. Pannacciulli N, Del Parigi A, Chen K, Le DSN, Reiman EM, Tataranni PA. Brain abnormalities in human obesity: a voxel-based morphometric study. Neuroimage 2006; 31: 1419– 25. He Q, Chen C, Dong Q, Xue G, Chen C, Lu Z, Bechara A. Gray and white matter structures in the midcingulate cortex region contribute to body mass index in Chinese young adults. Brain Struct Funct 2013. doi: 10.1007/ s00429-013-0657-9. Gunstad J, Paul RH, Cohen RA, Tate DF, Spitznagel MB, Grieve S, Gordon E. Relationship between body mass index and brain volume in healthy adults. Int J Neurosci 2008; 118: 1582–93. Montembeault M, Joubert S, Doyon J, Carrier J, Gagnon J, Monchi O, Lungu O, Belleville S et al. The impact of aging on gray matter structural covariance networks. Neuroimage 2012; 63: 754–9. Rodriguez-Raecke R, Niemeier A, Ihle K, Ruether W, May A. Brain gray matter decrease in chronic pain is the consequence and not the cause of pain. J Neurosci 2009; 29: 13746–50. Wood PB. Variations in brain gray matter associated with chronic pain. Curr Rheumatol Rep 2010; 12: 462–9. Davis K, Pope G, Chen J, Kwan C, Crawley A, Diamant N. Cortical thinning in IBS: implications for
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64 Cheung CK, Lee Y, Chan Y, Cheong P, Law W, Lee S, Sung J, Chan F et al. Decreased basal and postprandial plasma serotonin levels in patients with functional dyspepsia. Clin Gastroenterol Hepatol 2013; 11: 1125–9. 65 Postuma RB, Dagher A. Basal ganglia functional connectivity based on a meta-analysis of 126 positron emission tomography and functional magnetic resonance imaging publications. Cerebl Cortex 2006; 16: 1508–21. 66 Marchand WR, Yurgelun-Todd D. Striatal structure and function in mood disorders: a comprehensive review. Bipolar Disord 2010; 12: 764–85. 67 Wilder-Smith C, Schindler D, Lovblad K, Redmond S, Nirkko A. Brain
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doi: 10.1111/nmo.12372
Altered structural covariance of the striatum in functional dyspepsia patients P. LIU ,* F. ZENG ,† F. YANG ,* J. WANG ,* X. LIU ,* Q. WANG ,* G. ZHOU ,* D. ZHANG ,‡ M. ZHU ,* R. ZHAO ,* A. WANG ,* Q. GONG §
& F. LIANG †
*Life Science Research Center, School of Life Science and Technology, Xidian University, Xi’an, China †Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China ‡Rehabilitation Medical Central of the 181st People’s Liberation Amy Hospital, Guangxi, China §Department of Radiology, The Center for Medical Imaging, Huaxi MR Research Center (HMRRC), West China Hospital of Sichuan University, Sichuan, China
Key Messages
• We found the altered gray matter volumes and related structural covariance of the striatum in patients with
functional dyspepsia, which was potentially valuable for understanding the mechanism of functional dyspepsia. imaging from 44 patients and 39 healthy controls were used for this study. VBM and structural covariance methods were applied for striatum structure changes. Results showed increased gray matter volumes in the bilateral putamen and right caudate and related differences of structural covariance patterns located in the amygdala, hippocampus/parahippocampus (HIPP/ paraHIPP), thalamus, lingual gyrus, and cerebellum.
• The MRI •
Abstract Background Functional dyspepsia (FD) is thought to be involved in dysregulation within the brain–gut axis. Recently, altered striatum activation has been reported in patients with FD. However, the gray matter (GM) volumes in the striatum and structural covariance patterns of this area are rarely explored. The purpose of this study was to examine the GM volumes and structural covariance patterns of the striatum between FD patients and healthy controls (HCs). Methods T1-weighted magnetic resonance images were obtained from 44 FD patients and 39
HCs. Voxel-based morphometry (VBM) analysis was adopted to examine the GM volumes in the two groups. The caudate- or putamen-related regions identified from VBM analysis were then used as seeds to map the whole brain voxel-wise structural covariance patterns. Finally, a correlation analysis was used to investigate the effects of FD symptoms on the striatum. Key Results The results showed increased GM volumes in the bilateral putamen and right caudate. Compared with the structural covariance patterns of the HCs, the FD-related differences were mainly located in the amygdala, hippocampus/parahippocampus (HIPP/paraHIPP), thalamus, lingual gyrus, and cerebellum. And significant positive correlations were found between the volumes in the striatum and the FD duration in the patients. Conclusions & Inferences These findings provided preliminary evidence for GM changes in the striatum and different structural covariance patterns in patients with FD. The current results might expand our understanding of the pathophysiology of FD.
Address for Correspondence Peng Liu, Life Sciences Research Center, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi 710071, China. Tel: +86-29-81891070; fax: +86-29-81891060; e-mail: [email protected] Fanrong Liang, L Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China. Tel: +86 28 66875831; fax: +86 28 61800013; e-mail: [email protected] Received: 1 October 2013 Accepted for publication: 1 May 2014
Keywords functional structural covariance.
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MRI,
striatum,
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INTRODUCTION
Abnormalities in the striatum have also been indicated in irritable bowel syndrome (IBS) in functional, structural MRI and NK-1 receptor binding studies.26–28 However, studies assessing the structural alterations of the striatum in FD were rare. Moreover, to our knowledge, no study has directly examined the structural relationships between the striatum and other brain regions in patients with FD. Voxel-based morphometry (VBM) is a semi-automated whole brain technique,29,30 which has been widely used to interrogate group differences in brain tissue.31–34 Structural covariance is an effective method to investigate covariance in gray matter (GM) volumes between different brain regions.35 Based on structural MRI and VBM, there has been evidence indicating the pattern of structural covariance may reflect the effects of brain development or structural plasticity.35–37 Moreover, previous studies have found the structural covariance may be altered between brain disorder patients and HCs.38,39 Recently, the pattern of whole brain structural covariance of the neostriatum has been investigated in HCs.40 Hence, it was likely to be valuable to explore the altered structural covariance of brain in patients for the neural basis of certain disorders and/or to explore the potential mechanisms underpinning in healthy human brains. In the current study, VBM method was firstly adopted to investigate whether there were significant differences in the GMs of the striatum between FD patients and HCs. If there existed the differences in the striatum, we then examined the whole brain structural covariance patterns in FD patients and HCs separately, based on the striatum-related differences. Meanwhile, we tried to assess whether there was association between neuroimaging findings and clinical information about FD. Here, we hypothesized that there existed abnormal brain structure of the striatum and different structural covariance patterns of the striatum in FD patients compared with HCs, and we also hypothesized that there existed association between neuroimaging findings and FD clinical information.
Functional dyspepsia (FD) is a highly prevalent functional gastrointestinal disease with major symptoms of recurrent pain or discomfort in the upper abdomen, early satiety, and abdominal distension.1 FD has a great effect on the health-related quality of life (QOL) and high healthcare costs. However, the underlying pathogenesis of FD is not fully understood as yet. Recent neuroimaging studies have indicated that FD might be caused by dysregulation within the brain–gut axis.2,3 Evidence of abnormal central nervous system processing in FD can be found in a number of neuroimaging studies, mainly associated with homeostaticafferent,4,5 emotional-arousal and/or cortical-modulatory regions4,5 such as the thalamus, somatosensory cortex, insula, amygdala, cingulate cortex, and prefrontal cortex.6–9 It is worth noting that some interesting findings indicate a potential role of several new brain areas in FD neuropathology such as the striatum. Up to now, using brain imaging techniques, such as computed tomography, positron emission tomography (PET) and magnetic resonance imaging (MRI), certain studies have identified the abnormality of the striatum in FD. For example, Ladabaum et al. found the abnormal activity of the striatum during gastric distention.10 Braak et al. reported decreased striatal dopamine D2 receptors (D2R) binding of the caudate nucleus in patients with FD.11 One of our PET studies found that FD patients showed higher glycometabolism in the putamen compared with healthy controls (HCs) and the relatively severe group showed an increased glycometabolism in the caudate nucleus compared with the milder group.7 Another one of our studies revealed that the correlation between the right cerebellum and left putamen was increased in patients with FD using MRI.12 The studies mentioned above suggested that the striatum would likely to play an important role in the pathogenesis of FD. The striatum, including the caudate nucleus and the putamen, has a major cortical and subcortical input into the basal ganglia.13 It has been known that the striatum receive inputs from all cortical areas and, throughout the thalamus, project principally to frontal lobe areas which are concerned with motor planning.14 As an important structure of the basal ganglia, the striatum is not only related to motor and emotional processing,15–17 but also involved in cognitive functions.18–20 Moreover, it has been reported that the putamen and related neural networks could contribute to the processing of sensory and motor aspects of pain.21 There has been evidence indicating striatumrelated dysregulation in certain brain disorders.22–25
© 2014 John Wiley & Sons Ltd
MATERIALS AND METHODS Participants Forty-four FD patients (28 females, 16 males; ages ranging from 20 to 27 years) and 39 age-matched HCs (25 females, 14 males; ages ranging from 21 to 24 years) were recruited for the present study. All the patients met the Rome III criteria on FD and postprandial distress. In addition, a careful basic evaluation was performed for each patient. The evaluation included upper gastrointestinal endoscopy, upper abdominal ultrasound, electrocardiogram, hepatic function, renal function, and routine analysis of the blood,
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Image analysis
urine, and stool. All the examinations were performed by the same professional gastroenterologist in the West China Hospital of Sichuan University.
Structural images processing and analysis were performed in SPM5 (http://www.fil.ion.ucl.ac.uk/spm) including the VBM5 toolbox which is running under MATLAB (Mathworks, Natick, MA, USA). All structural images were transformed into Montreal Neurological Institute (MNI) 152 standard space using linear transformations and re-sampled to 1 9 1 9 1 mm3. The images were then segmented into GM, white matter (WM), and cerebrospinal fluid (CSF). The modulation step was added to incorporate volume changes during spatial normalization.45 This step involved multiplying each spatially normalized GM image by its relative volume before and after normalization. Finally, the resulting GM images were smoothed with an isotropic Gaussian kernel of 8 mm full-width at half maximum (FWHM).
Exclusion criteria for FD patients were as follows: (a) having other gastrointestinal or pain disorder (such as IBS, fibromyalgia [FM], and temporomandibular disorder), (b) being pregnant or lactating, (c) having been taking medications that affect gastrointestinal motility such as selective serotonin reuptake inhibitors, non-steroidal anti-inflammatory drugs, aspirin, phenothiazines, and/or steroids for over 2 weeks before enrollment, (d) having a history of gastrointestinal surgery, (e) having suffered from serious cardiovascular, neurological, psychiatric, renal, or respiratory diseases, (f) having been experiencing acid regurgitation, heart burn, or upper abdominal pain as the predominant symptom, (g) having had gastric atrophy or erosive gastroduodenal lesions, and (h) having had cholecystitis, gallstones, or esophagitis. Furthermore, all of the FD patients were forbidden to take medications, which potentially influenced gastrointestinal motility and sensitivity (such as prokinetic and antinausea drugs) at least 24 h before study participation.
Because we focused on the group differences in GM of the whole striatum including the caudate and putamen, we firstly extracted mean GM volumes across each voxel in the bilateral caudate and bilateral putamen regions which were defined based on the automated anatomical labeling template using the Wake Forest University PickAtlas software (http://www.fmri.wfubmc. edu/download.htm). A two-tailed, two-sample t-test was applied to compare the GM volume of the whole putamen or caudate in the bilateral hemispheres at p < 0.01 (Bonferroni corrected), separately. Secondly, a two-sample t-test was adopted to produce the VBM group statistical parametric map in the only striatum and the significant level were thresholded at p < 0.05 (fall discovery error corrected [FDR corrected]) with a cluster size >5 voxels. Finally, based on the statistical parametric map, the caudate- or putamen-related regions, showing the differences between FD patients and HCs were enrolled as seed regions of interest (ROIs) for structural covariance analyses. Each seed ROI was defined with the MarsBar region-of-interest toolbox for SPM (http://marsbar.sourceforge.net/) as 2 mm radial spheres centered at the voxel with the peak Z-score. Recent studies have suggested that body mass index (BMI) is associated with changes in GM, and GM differences have been specially demonstrated in both the obese and lean subjects.46–49 The emotional factors might exert their role in FD, such as anxiety and depression.6 Therefore, the age, sex, BMI, SAS, and SDS were deemed as covariates of no interest in the VBM analysis and structural covariance analyses.
The age- and gender-matched HCs underwent similar basic evaluations mentioned above. They had no history of neurological or psychiatric disorders and had refrained from alcohol or drug consumption in the previous week. All research procedures of the present study were approved by the Ethics Committee of Chengdu University of Traditional Chinese Medicine (No. 2011KL003) and were conducted in accordance with the Declaration of Helsinki. Verbal and written consent was obtained from each subject.
Behavioral measures The Nepean Dyspepsia Index (NDI) was used to evaluate the severity of the symptoms and the QOL.41 The Chinese-translated version of NDI was applied to measure the symptom severity of the disease.42 According to 15 dyspepsia-related physical signs, the symptom index of the NDI could be rated for frequency (0–4), intensity (0–5), and bothersomeness (0–4). The QOL index of the NDI included four domains, namely interference (13 items), know/control (7 items), eat/drink (3 items), and sleep/disturb (2 items).
In this study, structural covariance analyses were used to determine the relationship between the GM volume of each voxel across the whole brain and that of each seed for each group (FD patients or HCs). Statistical analysis was performed on the modulated GM images using the general linear model in SPM5. To identify the whole brain voxel-wise structural covariance of the ROIs, multiple regression models were established for each ROI. In each regression model, the mean GM volume that derived from each ROI was entered as a covariate of interest, and the whole GM volumes, age, sex, BMI, SAS, and SDS were seen as covariates of no interest. With this design, we obtained group level structural covariance pattern. One-sample t-tests with covariates were performed to map the voxels that expressed a significant positive GM covariance with each ROI in each group. Resulting correlation maps were thresholded at p < 0.05 (FDR corrected) with a cluster size >5 voxels. It has been indicated that the structural covariance patterns are linked to the architecture of the intrinsic functional networks, and regions having a positive association in the GM volume were demonstrated to be part of the same functional network.38,50 A recent study was conducted for only the positive structural covariance of the neostriatum.40 Therefore, our study focused on estimating the positive correlations of the ROIs with the other brain regions.
The depression/anxiety related symptoms were evaluated using the Zung Self-Rating Depression Scale (SDS) and the Zung Self-Rating Anxiety Scale (SAS). Both the SDS and SAS consisted of 20 items, each of them was scored from 1 to 4. The final scores were determined by the sum of all the items which was multiplied by a factor of 1.25. A score less than 53 (SDS) or 50 (SAS) was considered to be in the normal range according to the Chinese norm.43,44
Image acquisition Images were collected using a 3T Siemens scanner (Allegra, Siemens Medical System, Erlangen, Germany) at the Huaxi MR Research Center, West China Hospital of Sichuan University, Chengdu, China. A standard birdcage head coil along with a restraining foam pad was used to minimize the head motion. T1-weighted images were obtained using a volumetric threedimensional spoiled gradient recall sequence (TR/TE: 1900 ms/ 2.26 ms, flip angle = 9°, field of view: 256 9 256 mm, matrix size: 256 9 256, in-plane resolution: 1 9 1 mm, slice thickness = 1 mm, 176 slices). During the entire session, subjects were instructed to keep eyes closed, not to think about anything and to stay awake.
Pearson’s correlation analysis was applied to examine the relationship between the mean GM volume in each ROI and
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correlated with BMI (r = 0.29, p > 0.05 in the FD patients; r = 0.24, p > 0.05 in the HCs). Compared with the HCs, the FD patients had higher mean GM value in the caudate (left caudate: 0.426 0.056 mL in the FD patients, 0.416 0.056 mL in the HCs; right caudate: 0.415 0.053 mL in the FD patients, 0.402 0.055 mL in the HCs) and the putamen (left putamen: 0.226 0.043 mL in the FD patients, 0.205 0.049 mL in the HCs; right putamen: 0.233 0.039 mL in the FD patients, 0.213 0.043 mL in the HCs). Furthermore, the mean GM values of the left and right putamen are significantly higher in the FD patients (Fig. 1). The three identified regions, showing differences between the FD patients and the HCs, were located in the bilateral putamen and right caudate, which were selected as the ROIs for structural covariance analysis. These spherical ROIs were centered at the following MNI coordinates: right caudate (10, 18, 2), left putamen ( 19, 8, 7), and right putamen (26, 7, 6) (Fig. 2). The intergroup differences in structural covariance patterns associated with the three ROIs were shown in Fig. 3 and Table 2. For the right caudate ROI, structural covariance patterns with bilateral thalamus were
Table 1 Demographics and clinical characteristics of the FD patients and the healthy controls Mean SD Variable
FD patient
Healthy control
p value
Sex (female/male) Age (years) BMI (kg/m2) SAS SDS NDI Duration of disease (months)
28/16 22.64 19.44 41.70 43.49 46.66 35.32
25/14 22.18 19.56 33.85 34.81 — —
0.96* 0.16† 0.76† 8.30 7.59 4.44 5.69 6.05 5.54 4.26 4.59 4.02 3.83
15 32 689 629 236 298 60 87 89 20 89 25
16 24 26 23 25 26 6 8 16 28 17 26 26 26
78 94 77 74 10 8 8 12 8 10 0 6 2 3
13 13 23 21 5 5 3
3.69 3.68 5.40 5.19 7.26 >8.30 4.42 5.20 5.51 4.67 4.33 4.83 4.92 3.79
38 50 1179 2538 683 628 136 280 42 76 91 44 110 53
5
1 3 3 20 18 14 14
Thalamus Lingual gyrus Cerebellum
L R L R
16 28 17 34
77 84 78 76
13 17 20 26
3.74 3.34 4.67 4.71
24 57 752 1647
Hem
x
y
L R L R L R
11 11 21 20 21 20
18 18 15 15 1 6
R L R L R L R L R L R
24 13 41 6 20 22 8 8 20 18
6 14 16 39 84 10 14 13 12 5 9
L
22
19
L R L R L R
26 26 6 6 21 22
L
24
6
L R
22 14
16 16
R
18
89
5
Z-value
Cluster extent
3 3
7.66 >8.30 5.56 5.10 4.86 4.42
509 580 735 565 57 28
12 13 15 46 33 4 2 3 5 0 0
3.69 4.00 4.46 3.33 3.58 >8.30 7.51 5.09 5.16 5.27 5.05
6 143 75 9 660 672 543 314 338 59 20
6
4.20
10
6 6
6.77 >8.30 4.50 4.61 4.85 5.47
645 655 108 233 28 43
15
3.60
8
4.02 3.55
7 8
3.81
6
z 2 1 4 2
8 7 14 14 2 2
3 2 3 3
6 16 12
HC, healthy controls; FD, functional dyspepsia; Hem, hemisphere; MNI, Montreal Neurological Institute; L, Left; R, Right; HIPP, hippocampus.
were deemed as the ROIs. Different structural covariance patterns of the ROIs were then demonstrated between the patients with FD and the HCs. Structural covariance patterns of the three ROIs (including left putamen ROI and bilateral putamen ROIs) and the thalamus were only found in FD patients, whereas the patterns of structural covariance of the three ROIs and the HIPP/paraHIPP were only detected in HCs. In addition, structural covariance patterns of all the three ROIs and the amygdala were much stronger in HCs than in patients with FD. For the bilateral putamen ROIs, the associations with the lingual gyrus and
There were no significant correlations between the mean GM volume of the ROIs and the NDI scores (p > 0.05).
DISCUSSION In the present study, we reported the GM volume changes and the structural covariance patterns of the striatum in the FD patients compared with the HCs for increasing our understanding of the neural mechanisms of FD patients. Firstly, we found that the patients had higher GM volumes in the bilateral putamen and right caudate using VBM analysis, which
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Figure 4 The significantly positive correlation between the gray matter volumes of the right caudate and bilateral putamen and the duration of FD patients.
above-mentioned findings in the FM, PVD, and M-TMD.57–59 It was reported that the striatum, as the major input structure of the basal ganglia, importantly contributed to pain modulation and analgesia.58,60,61 It was indicated that there was a positive correlation between cortical volumes and function.62,63 Thus, we supposed that the GM changes in the striatum might reflect structural plasticity and represent pathophysiological effects of the FD disease. And the changes of the cortical volumes could yield dysfunction of the striatum, which needed further studies in the future. Furthermore, these GM volume changes would be expected to be associated with the duration of disease. The positive correlation between the GM volumes in the bilateral putamen and right caudate and FD duration might present the long aversive experiment of FD could make striatum have a worse effect on structural plasticity. However, a recent study was
cerebellum were indentified in HCs, which were not seen in FD patients. Moreover, there were positive correlations between the mean GM values of ROIs and the duration of disease in the patients group. Previous studies have demonstrated that chronic pain or aversive experiment may induce changes of GM volumes.51,52 Altered GM volumes in brain regions have been constantly reported in a variety of pain disorders including IBS, migraine, trigeminal neuralgia, and cluster headache.53–56 The recent studies, using MRI technique and VBM analysis method, revealed increased GM volumes in the striatum in chronic pain conditions such as FM, provoked vestibulodynia (PVD), and myofascial pain of the temporomandibular region (M-TMD).57–59 In this study, the increased GM volumes were also observed in the bilateral putamen and right caudate in the patients with FD, which were consistent with the
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visceral afferent processing circuits,5 alteration of the thalamus in FD patients has been typically found in many studies.7,12,73 It could speculate that FD-related brain responses in the thalamus may be mediated by the increased structural covariance patterns between structures of the three ROIs and the thalamus. Furthermore, there has been evidence indicating that the putamen is structurally connected with the thalamus in nociceptive information processing.21 Therefore, increased patterns of structural covariance between structures indentified in FD in our study may reflect abnormal structural plasticity compensatory strategy in visceral afferent processing and/or nociceptive information processing in patients with FD. The limitations should be noted in the present study. Two conditions (hyper- and normosensitive groups) were included in FD group and the confounding effect of these two subtypes was not considered in the present study. In the future, the relationships between structural covariance and functional/structural connectivity would be further examined in FD patients. In summary, we found increased GM volumes in the striatum, especially in the bilateral putamen and the right caudate in patients with FD. Our results also showed different structural covariance patterns of the ROIs related to the putamen and caudate in the FD patients and HCs. Meanwhile, GM changes of the striatum were correlated with FD duration. These findings demonstrated that altered GM and structural covariance patterns between the striatum and certain regions in the brain–gut axis in FD. It was hoped that the current study might contribute to improving our understanding the neural basis of FD.
indicated that IBS was associated with decreased GM volumes in the ventral striatum,27 which was inconsistent with our results. We suggested that the inconsistence might be related to the different pathogenic mechanism between FD and IBS.64 The structural covariance patterns centered on the three ROIs within the right caudate and bilateral putamen of FD patients and HCs were indentified in our study. Overall, the structural covariance patterns of the bilateral putamen ROIs were mainly associated with some limbic structures such as the amygdala and HIPP/paraHIPP, lingual cortex, and the cerebellum in the HCs. And the right caudate ROI was mainly correlated with the amygdala, HIPP/paraHIPP, and the cerebellum in the HCs. These findings were partly overlapped with the results of the previous study,40 while the different results might attribute to the different locations of the ROIs and subject variability. However, the structural covariance patterns of the three ROIs in the FD patients were distinct compared with the HCs. FD patients showed the associations between the three ROIs and the thalamus. In addition, structural covariance patterns of the left putamen ROI mostly overlapped with those of the right putamen ROI in both the FD patients and HCs groups. These findings showed structural covariance patterns of putamen were highly symmetrical, similar to the study from Soriano-Mas et al.40 The patterns of structural covariance between the three ROIs and some limbic structures in FD patients were less spatial extended than those in HCs. The current findings in HCs were in accordance with corresponding functional connectivity results65 (Fig. 3). However, structural covariance of the three ROIs and the HIPP/paraHIPP were not found in FD patients. Meanwhile, it was found that FD patients had weaker spatial extents of structural covariance patterns between the three ROIs and the amygdala. The HIPP and amygdala were considered to be the inputs of the striatum.66 The HIPP/paraHIPP is not only involved in processing pain and visceral sensations, but also importantly contributes to the memory of visceral pain and unpleasant visceral sensations.67–69 The amygdala plays an important role in cognitive reappraisal and affective modulation of pain.70–72 Taken together, the present results could suggest that altered structural covariance patterns of the three ROIs and the amygdala as well as HIPP/paraHIPP may be induced by the recurrent pain or unpleasant perceptions from the viscera in patients with FD. In comparison to HCs, FD patients showed abnormal patterns of structural covariance of the three ROIs and the thalamus. As an important component of the
© 2014 John Wiley & Sons Ltd
ACKNOWLEDGMENTS This study was supported by the Project for the National Key Basic Research and Development Program (973) under grant no’s. 2012CB518501 and 2011CB707702, the National Natural Science Foundation of China under grant no’s. 81001504, 30930112, 30970774, 81000641, 81000640, 81101036, 81101108, 31150110171, 30901900, 81271644, 31200837, 81030027, 81102662, the Fundamental Research Funds for the Central Universities and the Program for New Century Excellent Talents in University of Education Ministry of China and the Youth Foundation of Sichuan Province (no. 2012JQ053).
FUNDING No funding declared.
DISCLOSURE No conflicts of interest, financial or otherwise, are declared by the author(s).
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AUTHOR CONTRIBUTION
interpretation of findings; PL drafted the manuscript; PL, JW, and RZ provided critical revision of the manuscript for important intellectual content; all authors critically reviewed the content and approved the final version for publication.
PL and ZF were responsible for the study concept and design; DZ, QG, and FL contributed to the acquisition of fMRI data; JW, FY, GZ, MZ, XL, QW, and AW assisted with data analysis and
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