Abnormal Resting Brain Activity in Patients With Functional Dyspepsia Is Related to Symptom Severity

GASTROENTEROLOGY 2011;141:499 –506

Abnormal Resting Brain Activity in Patients With Functional Dyspepsia Is Related to Symptom Severity

*The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China; ‡Life Sciences Research Center, School of Life Sciences and Technology, Xidian University, Xi’an, Shaanxi, China; §PET-CT center, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; 储Biology Department, University of Pennsylvania, Philadelphia, Pennsylvania; ¶Department of Psychiatry and Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida

BACKGROUND & AIMS: Abnormal processing of visceral sensation at the level of the central nervous system is believed to be involved in functional dyspepsia. However, compared with studies of stimulation-related changes in brain activity, few studies have focused on resting brain activity, which also is important in pathogenesis. We mapped changes in resting brain glucometabolism of patients with functional dyspepsia, compared with healthy subjects, and attempted to correlate abnormal brain activity with symptom severity. METHODS: We performed fluorodeoxyglucose positron emission tomography– computed tomography on 40 patients with functional dyspepsia and 20 healthy subjects who were in resting states. The symptom index of dyspepsia and the Nepean dyspepsia index were used to determine symptom severity. The positron emission tomography– computed tomography data were analyzed using statistical parametric mapping software. RESULTS: Compared with healthy subjects, patients with functional dyspepsia had higher levels of glycometabolism in the bilateral insula, anterior cingulate cortex (ACC), middle cingulate cortex (MCC), cerebellum, thalamus, prefrontal cortex, precentral gyrus, postcentral gyrus, middle temporal gyrus, superior temporal gyrus, putamen, right parahippocampal gyrus, claustrum, and left precuneus (P ⬍ .001). The signal increase in the ACC, insula, thalamus, MCC, and cerebellum was correlated with symptom index of dyspepsia scores and Nepean dyspepsia index scores (P ⬍ .01). The glycometabolism in ACC, insula, thalamus, MCC, and cerebellum of patients with more severe functional dyspepsia was significantly higher than that of patients with less severe functional dyspepsia (P ⬍ .005). CONCLUSIONS: In patients with functional dyspepsia, resting cerebral glycometabolism differs significantly from that of healthy subjects. The ACC, insula, thalamus, MCC, and cerebellum might be the key regions that determine the severity of symptoms. Keywords: Brain; Neuroimaging; Pain; Stomach.

F

unctional dyspepsia (FD) is one of the most important categories of functional gastrointestinal disease (FGID), characterized by persistent and recurrent postprandial upper abdominal discomfort, pain, early satiety, abdominal distension, bloating, belching, and nausea in

the absence of organic or metabolic disorders. Nowadays, FD has been an important health care and social problem for its high prevalence, great influence on quality of life (QOL),1–3 and high medical cost.4 It was estimated that as many as 12%–15% of the population in Western countries experience symptoms of FD,5 and that about 23.5% of the residents in China suffer from FD.6 A community survey of several European and North American populations indicated that approximately 30% of dyspeptic patients reported having taken days off work or school because of their symptoms.7 In 1995, the market for prescription medications in the United States for the treatment of dyspepsia was a staggering $1.3 billion.8 The pathophysiology of FD remains unclear although several theories, such as gastrointestinal motility abnormalities, visceral hypersensitivity, Helicobacter pylori infection, and psychological factors, have been proposed to elucidate the symptoms. During the past 10 years, researchers proved, by using brain imaging techniques, that the pathophysiology of FGID involved abnormal processing of visceral sensation at the level of the central nervous system (CNS). However, the majority of these neuroimaging studies were performed on irritable bowel syndrome patients, although a few studies were on FD patients.9,10 Furthermore, most of these studies focused on the CNS responses to painful and/or nonpainful visceral stimulations, whereas scant attention was paid to resting brain activity. In fact, the task- or stimulus-related increases in neural metabolism are usually small (⬍5%) when compared with the large resting energy consumption.11 Spontaneous neural activity in the resting state can provide more comprehensive information on how the brain operates. Currently, the studies on resting brain activity in pathologic conditions have been proved to be an imporAbbreviations used in this paper: ACC, anterior cingulate cortex; BA, Brodmman area; FD, functional dyspepsia; FGID, functional gastrointestinal diseases; HS, healthy subjects; MCC, middle cingulate cortex; NDI, Nepean Dyspepsia Index; PET-CT, positron emission tomography– computed tomography; QOL, quality of life; SAS, Self-Rating Anxiety Scale; SDS, Self-Rating Depression Scale; SID, Symptom Index of Dyspepsia. © 2011 by the AGA Institute 0016-5085/$36.00 doi:10.1053/j.gastro.2011.05.003

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FANG ZENG,* WEI QIN,‡ FANRONG LIANG,* JIXIN LIU,‡ YONG TANG,* XUGUANG LIU,* KAI YUAN,‡ SHUGUANG YU,* WENZHONG SONG,§ MAILAN LIU,* LEI LAN,* XIN GAO,储 YIJUN LIU,¶ and JIE TIAN‡

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tant approach to uncovering the pathogenesis of disease.12 FD is a chronic disease. The persistent and recurrent dyspepsia experience may influence the brain activity of patients. In 2007, Vandenberghe et al13 reported that during painful proximal gastric distention, the FD patients hypersensitive to gastric distension showed activations in the bilateral gyrus precentralis, gyrus frontalis inferior, gyrus frontalis medialis, gyrus temporalis superior, cerebellar hemisphere, and the left gyrus temporalis inferior. This study revealed the differences of the brain processing painful visceral stimulations between FD patients and healthy subjects (HS). In 2010, by using H215OPET, Van Oudenhove et al14 proved that the resting brain activity of FD patients differed from that of HS and showed the influence of psychosocial factors on brain activity. They found that anxiety correlated negatively with the anterior cingulate cortex (pregenual ACC [pACC]) and the middle cingulate cortex (MCC), and positively with dorsal pons activity, and that abuse history was associated with differences in insula, prefrontal, and hippocampus/amygdala activity.15 However, the differences in resting brain activity between FD patients and HS need further confirmation, and the relationship between symptom severity and resting cerebral activity in FD has not been investigated. As an attempt to fill in the knowledge gap, our study aimed to achieve the following: (1) compare the resting brain glycometabolism between FD patients and HS using fluorine-18 fluorodeoxyglucose positron emission tomography– computed tomography (PET-CT); (2) investigate the correlation of regional cerebral glycometabolism and the symptom severity of FD; and (3) preliminarily research the differences in cerebral glycometabolism between the milder FD patients and the relatively more severe FD patients.

Materials and Methods Participant Selection FD patients. Forty right-handed FD patients (20 male) were enrolled in this study after undergoing careful history taking, clinical evaluation, and laboratory examinations including upper gastrointestinal endoscopy, upper abdominal ultrasound, electrocardiogram, hepatic function, renal function, and routine analysis of blood, urine, and stool, and so forth. All the FD patients were classified as having postprandial distress syndrome according to the Rome III criteria. Inclusion criteria were as follows: (1) age 20 –30 years, (2) matching the Rome III criteria on FD, (3) matching the Rome III criteria on postprandial distress syndrome, and (4) signing a written informed consent form. Exclusion criteria were as follows: (1) having experienced upper abdominal pain, heartburn, or acid regurgitation as a predominant symptom, (2) having had esophagitis, gastric atrophy, or erosive gastroduodenal lesions on endoscopy, cholecystitis, gallstones, (3) being pregnant or during lactation, (4) having a history of gastrointestinal surgery, psychiatric and neurologic disorders, or head trauma with loss of consciousness, (5) having used aspirin, nonsteroidal anti-inflammatory drugs,

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steroids, phenothiazines, selective serotonin reuptake inhibitors, or medication affecting gastrointestinal motility, and so forth for more than 2 weeks before enrollment, or (6) having suffered from serious psychiatric, neurologic, cardiovascular, respiratory, or renal illnesses, and so forth. HS. Twenty right-handed HS (10 male), free from any gastrointestinal symptoms or signs, were enrolled in this study. Each underwent a basic evaluation, including a review of medical history, a physical examination, gastrointestinal endoscopy, upper abdominal ultrasound, and electrocardiogram to exclude organic disease carriers. Each HS provided written informed consent. The study protocol was approved by the Ethics Committee of Chengdu University of Traditional Chinese Medicine.

Symptom Assessments The symptom severity was assessed by using the Symptom Index of Dyspepsia (SID) and Nepean Dyspepsia Index (NDI). The SID focuses on the 4 chief symptoms of FD including postprandial distension, early satiety, epigastric pain, and burning.16 Symptoms were graded on a 4-point Likert scale as follows: 0 (none), asymptomatic; 1 (mild), steady but easily tolerable symptoms; 2 (moderate), symptoms sufficient to cause interference with daily activities; 3 (severe), symptoms incapacitating daily activities.17 The scores on the 4 symptoms were summed up to evaluate the severity of dyspepsia. NDI18 is a dyspepsia-specific index for measuring the QOL. It includes 4 domains, namely interference (13 items), know/control (7 items), eat/drink (3 items), and sleep/disturb (2 items). Higher scores indicate better QOL and milder symptoms. The translated version of the NDI was found, by our prior research, to be reliable and valid for measuring symptom severity and QOL in Chinese patients with FD.19

Psychosocial Evaluations Because variations of the patient’s psychological status potentially lead to variations in brain responses,10 the Zung Self-Rating Anxiety Scale (SAS),20 and the Zung Self-Rating Depression Scale (SDS)21 were used in this study to quantify the anxiety/depression-related symptoms of the participants. Both of the scales consist of 20 items. Each item is scored from 1 to 4. According to the Chinese norm,22,23 an index score of SAS (calculated by multiplying the raw score by 1.25) less than 50 or an index score of SDS (calculated by multiplying the raw score by 1.25) less than 53 falls into the normal range.

PET-CT Scan All participants went to the PET-CT center of the Sichuan Provincial People’s Hospital at 8:00 AM after an overnight fast of at least 12 hours, and then went through the following sequential procedure: (1) examination of blood pressure and blood sugar level, (2) a 20-minute rest in a darkroom, (3) a tracer injection (fluorine-18 fluorodeoxyglucose, synthesized with Mini Tracer accelerator [General Electric, Fairfield, CT], 0.11 MCi/kg) given via the back of the right hand, (4) a 40-minute rest, and (5) a PET-CT scan. Participants were instructed to remain relaxed during the whole study with their eyes blindfolded and their ears plugged. PET-CT scans were performed on a Biograph Duo BGO scanner (Siemens, Munich, Germany). The scan images covered the whole brain and were paralleled to the anterior commissure and posterior commissure line. Image acquisition was started after a 40-minute uptake period (bed, 1; collection mode, 3-di-

mensional; slice thickness, 3 mm; slice interval, 1.5 mm; matrix size, 256 ⫻ 256; total counts, 3 ⫻ 109). At the completion of data acquisition, the images were reconstructed using ordered subset expectation maximization with 6 iterations and 16 subsets.

Data Analysis The data from one FD patient were excluded from our analysis because of his relatively significant head motions during the scan. PET image analysis was performed using the software package Statistical Parametric Mapping, version 5 (available: http://www. fil.ion.ucl.ac.uk/spm). All the PET images from each subject were spatially normalized to the standard Statistical Parametric Mapping–PET template and resliced to 2-mm isotropic resolution in the Montreal Neurological Institute space. The normalized data set then was spatially smoothed with a 6-mm, full-width, halfmaximum Gaussian kernel. We calculated regional brain radioactivity relative to the global mean value for each subject, which was an indicator of relative regional cerebral glucose metabolism. To detect the brain activity changes in FD patients, we compared the cerebral glycometabolism patterns of FD patients and HS. Statistical parametrical maps were constructed by computing a 2-sample t test after controlling for the potential confounding effects (ie, SAS, SDS, and duration of symptoms). In addition, we used correlation analysis to assess the relationship between cerebral glycometabolism and the SID score, and cerebral glycometabolism and the NDI score for FD patients. For each patient, we selected the peak voxel and the neighboring 26 voxels within each cluster showing different metabolism as the region of interest for correlation analysis. After the voxels not belonging to the same anatomic region within the cluster were discarded, the activities of the survived voxels were extracted and averaged. Pearson coefficients were calculated between the mean activity of the cluster and the NDI score, and the mean activity of the cluster and the SID score. We also classified the FD patients into 2 subgroups according to their median NDI scores: the milder group and the relatively more severe group (Table 3). A 2-sample t test was used to compare cerebral glycometabolism patterns of the 2 subgroups, also controlling for the potential effects of SAS, SDS, and symptom duration. For visualization, all the results then were transformed into the Talairach stereotactic space and overlaid on MRIcro (available: http://www.sph.s.c.edu/comd/rorden/mricro.html) for presentation purposes. All the physiologic and psychological measures were analyzed by using SPSS software (SPSS Inc, Chicago, IL). All data are given as mean ⫾ standard deviation.

Results Differences Between FD Patients and HS Clinical variables. Among the FD patients, the mean SID score was 4.17; the mean NDI score was 77.86, and the mean duration of symptoms was 22.74 months. According to the SAS and SDS assessment, 23.1% of the FD patients showed mild depression, 20.5% showed mild anxiety, and 10.3% showed mild depression and anxiety. There were no significant differences in the demographics including age, sex, weight, and height between FD patients and HS (P ⬎ .05). There were significant differ-

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ences in the SAS score and the SDS score between FD patients and HS (P ⬍ .01) (Table 2). Cerebral glycometabolism. Compared with HS, FD patients showed higher glycometabolism in the bilateral frontal superior medial gyrus (Brodmman area [BA]10), frontal middle orbital gyrus (BA11, BA10), ACC (BA32, BA24), MCC (BA23, BA24), insula, cerebellum, thalamus, precentral gyrus (BA4, BA6), postcentral gyrus (BA4, BA3), middle temporal gyrus (BA21), superior temporal gyrus (BA22) and putamen, right parahippocampal gyrus (BA37) and claustrum, and left precuneus (BA7) (P ⬍ .001, family-wise error corrected for multiple comparisons and a minimal cluster size of 50 voxels) (Table 3, Figure 1). The results were obtained by controlling for potential effects of the emotional variable (SAS, SDS). However, there was no significant difference between the controlled and uncontrolled results.

Correlation of PET-CT Results and Clinical Variables Correlation of PET-CT results and SID score. The increased glycometabolism in ACC (r ⫽ 0.4178; P ⫽ .0081), MCC (r ⫽ 0.5158; P ⫽ .0007), anterior insula (r ⫽ 0.4722; P ⫽ .0024), thalamus (r ⫽ 0.4329; P ⫽ .0059) and cerebellum (r ⫽ 0.4577; P ⫽ .0034) showed significantly positive correlations with the SID score (P ⬍ .01) (Figure 1). Correlation of PET-CT results and NDI score. The increased glycometabolism in ACC (r ⫽ -0.661; P ⫽ .0000), MCC (r ⫽ -0.6944; P ⫽ .0000), anterior insula (r ⫽ -0.6368; P ⫽ .0000), thalamus (r ⫽ -0.5141; P ⫽ .0000) and cerebellum (r ⫽ -0.5906; P ⫽ .0007) showed significantly negative correlations with the NDI score (P ⬍ .01) (Figure 1).

Differences Between Milder FD Patients and Relatively Severe FD Patients Clinical variables. There were no significant differences in demographics (age, sex, weight, and height),

Table 1. Comparison Between the Relatively Severe Group and the Milder Group: Clinical Variables Items

Milder group (N ⫽ 19)

Severe group (N ⫽ 20)

Mean age ⫾ SD, y 22.94 ⫾ 2.39 22.80 ⫾ 1.91 Sex distribution, % males 47.37 50 Mean weight ⫾ SD, kg 53.89 ⫾ 5.56 51.30 ⫾ 6.18 Mean height ⫾ SD, cm 165.73 ⫾ 8.44 163.60 ⫾ 5.55 Mean duration of 22.79 ⫾ 10.87 22.70 ⫾ 9.30 dyspepsia ⫾ SD, mo Mean symptoms (SID) ⫾ 3.53 ⫾ 1.35 4.80 ⫾ 1.24 SD, 0–12 Mean QOL (NDI) ⫾ SD, 84.64 ⫾ 3.79 71.42 ⫾ 5.77 20–100 Mean anxiety (SAS) ⫾ SD, 41.20 ⫾ 10.33 41.88 ⫾ 7.17 25–100 Mean depression (SDS) ⫾ 43.42 ⫾ 10.56 44.25 ⫾ 7.56 SD, 25–100 SD, standard deviation.

P value .832 .177 .354 .978 .004 .000 .812 .779

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Table 2. Comparison Between FD Patients and HS: Clinical Variables Items

FD patients (N ⫽ 39)

HS (N ⫽ 20)

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Mean age ⫾ SD, y 22.87 ⫾ 2.13 23.10 ⫾ 1.86 Sex distribution, % males 48.71 50 Mean weight ⫾ SD, kg 52.56 ⫾ 5.96 53.70 ⫾ 10.63 Mean height ⫾ SD, cm 164.64 ⫾ 7.10 165.25 ⫾ 8.66 Mean anxiety (SAS) ⫾ SD, 41.67 ⫾ 8.66 28.67 ⫾ 3.84 25–100 Mean depression (SDS) ⫾ 43.85 ⫾ 9.03 29.31 ⫾ 3.96 SD, 25–100

P value .686 .600 .773 .000 .000

SD, standard deviation.

the duration of symptoms, the SAS score, and the SDS score between the milder group and the relatively severe group (P ⬎ .05). The SID score and the NDI score of the relatively severe group showed significant differences from those of the milder group (P ⬍ .01) (Table 1). Cerebral glycometabolism. Compared with the milder group, the relatively severe group showed an increased glycometabolism in the bilateral cerebellum, ACC (BA32, BA24), MCC (BA23, BA24), insula, thalamus, caudate, frontal superior medial gyrus (BA10), lentiform nucleus and cuneus (BA18), right superior temporal gyrus (BA41) and parahippocampal gyrus (BA20), and left postcentral gyrus (BA6) (P ⬍ .001, uncorrected with height threshold and a minimal cluster size of 50 voxels) (Table 4, Figure 2).

Discussion This study reveals the differences in resting cerebral glycometabolism between FD patients and HS. Moreover, this study shows the correlations between abnormal brain activity and symptom severity, and preliminarily explores the differences in brain glycometabolism between the milder FD patients and the relatively severe FD patients.

Differences in Resting Brain Glycometabolism Between FD Patients and HS The resting brain activity is of great significance for understanding the pathogenesis of disease. Since Shulman et al24 found, using PET, that many brain regions remained active during the resting state, and Raichle et al25 proposed the idea of the “default mode network” with PET data, the cerebral activity during the resting state has attracted increasing attention in the neuroscience community and PET has been proven to be an effective method for investigating the default mode network.26 Recent research using functional magnetic resonance imaging showed that the brain regions in the default mode network showed low-frequency synchronization oscillation characteristics through functional connectivity. That means the areas in which the signal increase (glycometabolism, cerebral blood flow, and so forth) obtained from the PET scan in a resting state manifest temporal synchronization oscillation during the functional magnetic resonance imag-

ing scan. PET data and functional magnetic resonance imaging data differ in analytic methods but are consistent in reflecting the brain activity. The PET data acquired in the present study verify the abnormal neuron activity in a resting state through cerebral glycometabolism, which is the most important source of energy for the brain. In this study, the FD patients showed higher glycometabolism in the bilateral insula, ACC (including pACC and subgenual ACC), MCC, parahippocampal gyrus, thalamus, prefrontal cortex, somatosensory cortex and cerebellum, and so forth, compared with HS. These areas are main components of the “gastric sensation neuromatrix”10,27,28 and are involved in the “homeostatic afferent network,”29 the “cortical modulatory network,” and

Table 3. Comparison Between FD Patients and HS: Cerebral Glycometabolism Talairach Regions

Signa Side

Postcentral gyrus Precuneus Olfactory Middle temporal gyrus Superior temporal gyrus Claustrum Lentiform nucleus (putamen) Thalamus

Y

t Cluster value BA size

Z

L L R R L L R L R R

⫺2 39 20 8.75 24 ⫺2 41 15 9.75 32 4 38 11 8.50 10 2 42 16 10.26 32 ⫺3 ⫺5 ⫺39 9.75 23 ⫺2 ⫺4 39 9.50 24 5 ⫺28 40 10.25 23 ⫺44 4 3 11.49 43 7 4 12.20 30 ⫺32 ⫺6 8.58 37

59 173 65 154 118 63 295 243 239 56

1 1 1 1 1 1 1 1 1 1 1 1 1

L R L R R L R L L R R L R R L L L R

⫺30 32 ⫺4 4 6 ⫺2 3 ⫺50 ⫺46 55 38 ⫺51 42 55 ⫺3 ⫺3 ⫺61 55

⫺67 ⫺41 50 58 51 51 ⫺43 ⫺9 4 ⫺6 ⫺9 ⫺11 ⫺21 ⫺46 ⫺68 15 ⫺26 ⫺2

⫺26 23 ⫺16 2 12 12 ⫺4 45 37 43 59 45 47 16 37 ⫺12 ⫺14 ⫺10

— — 11 11 10 10 10 4 6 4 6 3 3 4 7 25 21 21

288 333 85 62 125 115 103 82 107 111 197 90 202 77 75 87 205 226

1 1

L R

⫺57 ⫺7 61 ⫺30

6 8

9.56 22 8.64 22

132 191

1 1 1

R L R

32 ⫺24 25

5 11.76 — 5 9.98 — 3 10.16 —

127 293 219

1 1

L R

⫺13 ⫺19 16 ⫺19

1 1 1 1 MCC 1 1 1 Insula 1 1 Parahippocampal 1 gyrus Cerebellum 1 1 Frontal middle 1 orbital gyrus 1

ACC

Frontal superior medial gyrus Precentral gyrus

X

8 6 11

10 10

9.42 11.00 10.80 8.50 11.01 9.73 11.00 10.56 9.80 9.88 10.38 11.41 9.99 10.25 8.13 9.75 10.63 10.06

8.75 — 9.06 —

83 72

NOTE. P ⬍ .001, family-wise error corrected for multiple comparisons and a minimal cluster size of 50 voxels. R, right; L, left. aWhether the structure showed a signal increase or decrease.

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Figure 1. Differences in cerebral glycometabolism between FD patients and HS. The FD patients showed higher glycometabolism in the bilateral insula, ACC, MCC, parahippocampal gyrus, thalamus, prefrontal cortex, primary somatosensory cortex, secondary somatosensory cortex, and cerebellum, and so forth (P ⬍ .001, family-wise error corrected). The increased glycometabolism in ACC, insula, thalamus, MCC, and cerebellum showed a significantly positive correlation with SID score and a negative correlation with the NDI score. r, correlation coefficient.

the “emotional arousal network.” For example, ACC, thalamus, MCC, and insula are the essential nodes in the homeostatic afferent network. The glycometabolism increase in these regions might relate to the abnormal homeostatic regulation of FD patients. The prefrontal cortex is classically included in the cortical modulatory network and plays an important role in cognitive regulation. We hypothesize that the increased activity in the prefrontal cortex and other cognitive regions might be because the patients selectively attended to sensations that arose from the stomach, such as postprandial upper

abdominal discomfort, early satiety, abdominal distension, and so forth. Moreover, pregenual cingulate, insula, and parahippocampal gyrus are the key regions of the emotional arousal network. In this study, although the brain imaging results were obtained after controlling emotional variables (SAS and SDS), we found that the influence of emotional variables on brain glycometabolism, especially the activity of some key regions, was insignificant after comparing the present controlled results and the uncontrolled results (not reported in this article). The reason might lie in the following: (1) although there

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Table 4. Comparison Between the Relatively Severe Group and the Milder Group: Cerebral Glycometabolism Talairach Regions Cerebellum

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Frontal superior medial gyrus Anterior cingulate gyrus Middle cingulate gyrus Insula Thalamus Caudate Lentiform nucleus Cuneus

Signa Side 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

Postcentral gyrus Superior 1 temporal gyrus Parahippocampal 1 gyrus

L R L R L R L L R R L R L R L R L R L R L

X ⫺45 27 ⫺2 3 ⫺2 4 ⫺3 ⫺1 6 8 ⫺40 39 ⫺12 7 ⫺10 11 ⫺26 20 ⫺3 12 ⫺51

Y

Z

t Cluster value BA size

⫺56 ⫺27 5.13 ⫺41 ⫺19 6.16 55 8 5.68 10 51 3 5.00 10 51 10 5.96 32 47 9 5.62 32 37 19 4.38 24 9 33 5.53 24 3 45 5.97 24 ⫺29 39 5.41 23 15 3 7.03 14 ⫺1 6.27 ⫺26 5 5.59 ⫺24 3 5.82 10 ⫺2 6.57 12 2 5.89 ⫺2 6 4.28 3 4 5.25 ⫺73 25 4.61 18 ⫺66 20 4.56 18 ⫺11 55 4.84 6

85 171 73 86 169 193 62 106 97 77 110 74 51 76 53 51 66 57 57 63 55

R

55 ⫺25

10 6.36 41

52

R

26 ⫺13 ⫺12 5.13 20

59

NOTE. P ⬍ .001, uncorrected with height threshold and a minimal cluster size of 50 voxels. aWhether the structure showed a signal increase or decrease.

were significant differences in SAS and SDS scores between FD patients and HS, the anxiety and depression scores of most FD patients in this study were still within the normal range; and (2) most of the key regions showing an increasing glycometabolism, such as ACC and insula, pertain to integration cortex. They are involved in processing the visceral and somatic sensory, emotion, cogni-

tion, behavior, and so forth. Multiple factors, including dyspepsia symptoms, memories of past experiences, as well as cognitive and emotional factors, might account for the abnormal cerebral activity of FD patients. Recently, Van Oudenhove et al15 reported the differences in baseline brain activity between HS and FD patients by using H215O-PET. They found that HS showed higher activity in insula, rolandic operculum, and dorsolateral-prefrontal cortex, whereas FD patients showed higher activity in occipital and posterior temporal areas. Although not completely consistent, our results and the findings of Van Oudenhove et al15 confirmed that CNS processing and modulation of visceral activity in FD patients was in an abnormal manner in the resting state. Previous studies have pointed out that the dysfunction of CNS processing visceral stimulations was one of the important pathophysiologic mechanisms causing dyspepsia.30,31

Key Regions Related to the Severity of FD In this study, many brain regions in FD patients showed significant signal increases in resting activity compared with HS. To explore which brain regions might relate to the symptom severity of FD, a correlation analysis and a subgroup analysis were performed. First, we analyzed the correlation of cerebral glycometabolism with the SID score that directly indicated the symptom severity by evaluating the chief symptoms, and the correlation of cerebral glycometabolism with the NDI score that indirectly indicated the symptom severity through the QOL. The results revealed that the glycometabolism increase in ACC, insula, thalamus, MCC, and cerebellum were related positively to the SID score and related negatively to the NDI score (Figure 1). Second, we classified the FD patients into 2 subgroups according to their median NDI score and analyzed the cerebral glycometabolism differences between the milder group and the relatively severe group. The result indicated that the glycometabolism of ACC, cerebellum, thalamus, MCC, and insula in the rela-

Figure 2. Differences in cerebral glycometabolism between the relatively severe group and the milder group. The differences in resting cerebral glycometabolism between the milder FD patients and the relatively severe FD patients mainly lie in thalamus, ACC, MCC, insula, cerebellum, and so forth (P ⬍ .001, uncorrected).

tively severe group were still higher than those in the milder group (Table 4, Figure 2). The cingulate cortex is an integral part of the limbic system, involved in emotion formation and processing, learning, and pain. It is also important for executive function and visceral modulation. Although cingulate cortex can be divided into several subregions, the activation of the ACC and the MCC was seen commonly in neuroimaging studies on FGIDs.10 The activation of ACC has especially been highly reproducible in FGIDs studies.32,33 ACC has a close interconnection with the insula, prefrontal, limbic, and other subcortical structures, and is considered to play an important role in processing pain and gastrointestinal sensory signals.34 MCC is related to pain, emotion, and cognition. The insula, an important limbic integration cortex, serves as a primary cortical area for olfactory, taste, and viscerosensory information, and a multimodal cortical association area in the emotional, cognitive, limbic, and autonomic systems in the brain. Efferent output from the insula to the amygdala, hypothalamus, periaqueductal gray, and other brainstem regions is involved in higherorder control of autonomic visceromotor responses.35 The activation in insula can be found in nearly all reported FGID studies, regardless of study paradigms and analysis methods.9 In the current study, insula, especially anterior insula, showed higher glycometabolism in FD patients than in HS, and the increased activity in anterior insula was related significantly to the symptom severity. Wang et al,36 showed that the insula processes interoceptive signals of fullness produced by gastric distention. In this study, postprandial bloating and early satiety were the chief complaints of all FD patients, whereas Van Oudenhove et al15 found HS showed higher activity in insula. The methodologic issues, such as patient selection, sample size, and study design, might contribute to the conflicting results. The thalamus acts as the gateway to the cortex. Its function includes relaying sensation, spatial sense, and motor signals to the cerebral cortex, along with the regulation of consciousness, sleep, and alertness. ACC, thalamus, MCC, and insula all play important roles in homeostatic regulation. Cerebellum, with its complicated afferent and efferent connections with the cerebrum and adjacent midbrain regions, provides a crucial role in regulating viscera activities, high-order cognitive functions, and affective behaviors.37 In our study, FD patients, compared with HS, showed increased glycometabolism in some regions of cerebellum. This is consistent with some studies on FGID patients. For example, Berman et al38 found that rectal pressure increased regional cerebral blood flow in cerebellum in irritable bowel syndrome patients. Vandenberghe et al13 reported activations in bilateral cerebellum hemisphere in FD patients during painful gastric distension. Although these regions mentioned earlier pertain to integration cortex, they are not specific to visceral modulation. Based on the current results and the knowledge

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of neurophysiology, we hold that ACC, insula, thalamus, MCC, and cerebellum are related closely to the severity of FD and might play a central role in the abnormal integration of gastroenterologic information in FD. In fact, multiple factors including cognitive, emotional, and reward processes, as well as memories of past experiences, are integrated in specific brain circuits including the anterior insula and ACC, and so forth, which ultimately determine the subjective experience.39

Limitations of This Study and Direction for Future Studies The main limitations of the present study included the following: the use of the median NDI score to classify the milder and the severe FD patients, and the lack of an objective index to access the severity of FD. In the future, we plan to investigate the changes of brain activity of FD patients with multiple neuroimaging techniques, and to explore the correlation of emotions, symptoms, and abnormal brain activity. In summary, the present results show the differences in resting cerebral glycometabolism between FD patients and HS, as well as the cerebral glycometabolism differences between the milder FD patients and the relatively severe FD patients, and the correlation of abnormal cerebral activity and symptom severity. We hypothesize that the hyperactivity of ACC, MCC, thalamus, insula, and cerebellum are involved in the pathologic mechanism of FD, and that ACC, MCC, thalamus, insula, and cerebellum are the key regions associated with the severity of FD. References 1. Monés J, Adan A, Segú JL, et al. Quality of life in functional dyspepsia. Dig Dis Sci 2002;47:20 –26. 2. El-Serag HB, Talley NJ. Health-related quality of life in functional dyspepsia. Aliment Pharmacol Ther 2003;18:387–393. 3. Talley NJ, Locke GR 3rd, Lahr BD, et al. Functional dyspepsia, delayed gastric emptying, and impaired quality of life. Gut 2006; 55:933–939. 4. Moyyedi P, Mason J. Clinical and economic consequences of dyspepsia in the community. Gut 2002;50:10 –12. 5. EI-Serag HB, Talley NJ. Systemic review: the prevalence and clinical course of functional dyspepsia. Aliment Pharmacol Ther 2004; 19:643– 654. 6. Li Y, Nie Y, Sha W. The link between psychosocial factors and functional dyspepsia: an epidemiological study. Chin Med J 2002; 115:1082–1084. 7. Chang L. Review article: epidemiology and quality of life in functional gastrointestinal disorders. Aliment Pharmacol Ther 2004; 20(Suppl 7):31–39. 8. Rabeneck L, Wray N, Graham D. Managing dyspepsia: what do we know and what do we need to know? Am J Gastroenterol 1998; 93:920 –924. 9. Mayer EA, Aziz Q, Coen S, et al. Brain imaging approaches to the study of functional GI disorders: a Rome working team report. Neurogastroenterol Motil 2009;21:579 –596. 10. Van Oudenhove L, Coen SJ, Aziz Q. Functional brain imaging of gastrointestinal sensation in health and disease. World J Gastroenterol 2007;13:3438 –3445. 11. Raichle ME, Mintun MA. Brain work and brain imaging. Annu Rev Neurosci 2006;29:449 – 476.

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