Ann Nucl Med (2012) 26:3540 DOI 10.

1007/s12149-011-0537-4

ORIGINAL ARTICLE

Cortical-limbic regions modulate depression and anxiety factors in functional dyspepsia: a PET-CT study
Mai-lan Liu Fan-rong Liang Fang Zeng Yong Tang Lei Lan Wen-zhong Song

Received: 10 May 2011 / Accepted: 5 September 2011 / Published online: 28 September 2011 The Japanese Society of Nuclear Medicine 2011

Abstract Objective To observe some specic brain areas or cerebral functional network participating in the modulation of depression and anxiety factors in functional dyspepsia (FD) patients by detecting cerebral glucose metabolism (CGM) in uorine-18 uorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) scans. Methods Eight FD patients with depression and anxiety (DA-FD group) and eight FD patients without depression and anxiety (non-DA-FD group) were recruited and evaluated by the Nepean Dyspepsia Index (NDI) and Dyspepsia Symptom Scores (DSS). Cerebral 18F-FDG PET-CT scans were performed on the DA-FD group and non-DA-FD group, respectively. The differences in CGM between the two groups were analyzed with SPM2. Results Extensive changes in the CGM signals were observed in the cerebral cortex and limbic system of FD patients with depression and anxiety. Compared to non-DAM. Liu F. Liang (&) F. Zeng Y. Tang L. Lan Traditional Chinese Medicine of Chengdu University, Chengdu, China e-mail: fanrongliang@gmail.com.cn M. Liu e-mail: liumailan2006@yahoo.com.cn F. Zeng e-mail: zeng_fang@126.com Y. Tang e-mail: tangyongcn2001@yahoo.com.cn L. Lan e-mail: shuyashudun@yahoo.com.cn W. Song PET-CT Center, Sichuan Provincial Peoples Hospital, Chengdu, China e-mail: yayannice@gmail.com

FD patients, DA-FD patients showed a higher glucose metabolism in the right postcentral gyrus (BA 1 and 5), inferior frontal gyrus (BA 45), superior temporal gyrus (BA 22), middle temporal gyrus (BA 22), inferior parietal lobule (BA 40), lingual gyrus (BA 18) and the left middle occipital gyrus (BA 37), as well as the limbic system including the left thalamus, lateral globus pallidus, parahippocampal gyrus (BA 35), right insular cortex (BA 13) and parahippocampal gyrus (BA 18); a lower glucose metabolism was presented in the left middle cingulated gyrus (BA 24), the right superior frontal gyrus (BA 6), the medial frontal gyrus (BA 6) and middle temporal gyrus (BA 21). Conclusion An extensive cortical-limbic brain network might modulate the procession of FD patients with depression and anxiety factors. Keywords FD Depression and anxiety Cerebral glucose metabolism PET-CT

Introduction Functional dyspepsia (FD) is a common gastrointestinal disorder accounted for between 20 and 40% of consultations by gastroenterologists [1]. The reported prevalence of uninvestigated dyspepsia varies between 7 and 45% globally with FD 1129.2% [2]. Patients with upper gastrointestinal symptoms were found to have more psychological, social and health problems, and needed to visit their primary care physicians more frequently [3]. The pathophysiology of FD is not well established, although a variety of pathophysiological mechanisms such as motility abnormalities, visceral hypersensitivity and Helicobacter pylori (HP) infection have been proposed to explain these symptoms. Recently, there has been increased

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attention on the inuence of psychological factors on the gastrointestinal tract. It is reported that dyspepsia symptoms have a strong relationship with anxiety and depression [4, 5]. It is estimated that the prevalence rate of FD accompanied with depression and (or) anxiety in China is around 23.6% and the severity of dyspepsia presents a positive correlation with the severities of depression and anxiety [6, 7]. Antidepressants and some psychological treatments showed effectiveness in reducing dyspeptic symptoms in patients with FD [5]. A systematic review to assess the efcacy of anti-depressive and anti-anxiety agents in FD sufferers was also consistent with this nding [8]. It is becoming increasingly clear that psychosocial factors could inuence braingut axis modulating visceral afferent input on gastrointestinal symptoms [9, 10]. However, the exact mechanisms of emotional factors exerted its inuence on FD remain without full understanding. Brain imaging technologies introduced in gastrointestinal neuroscience over the past 10 years provide exciting investigation methods for in vivo study of neurobiological mechanisms [11]. The majority of these studies are centered on healthy volunteers or irritable bowel syndrome [11]. Little work has been done on FD and much less on FD patients with emotional disorders. To the best of our knowledge, no studies on the inuence of emotional factors on cerebral glucose metabolism (CGM) in patients with FD have been published. As an emerging functional neuroimaging technique, positron emission tomography-computed tomography (PET-CT) highlighted the advantages of coregistering functional and structural image modalities in a single scan to determine the disease state of the patient [12]. In this study, a uorine18 uorodeoxyglucose (18F-FDG) PET-CT scan was performed on FD patients with or without emotional disorders, respectively. The aim of this study was to observe the brain activities in FD patients with depression and anxiety in order to investigate the possible mechanism of emotional factors inuencing gastrointestinal functions.

currently taking gastrointestinal dynamic promoting drugs, or (4) were suffering from serious cardiovascular, respiratory or renal illnesses. All participants gave written informed consent and its protocol was approved by the afliated hospital ethics committee of the Traditional Chinese Medicine department of Chengdu University. Nepean Dyspepsia Index (NDI) and Dyspepsia Symptom Scores (DSS) were used in this study to evaluate the symptom severity. NDI is a dyspepsia-specic index for measuring the quality of life (QOL) [13]. It has 25 items and focuses on four domains, namely interference, know/control, eat/drink and sleep/disturb. The translated version of NDI was found, by our previous study, to be reliable and valid for measuring symptom severity and health-related quality of life in Chinese patients with FD [14]. The DSS was commonly used in China, and it focuses on the four chief symptoms of FD including postprandial distension, early satiety, epigastric pain and burning sensation. Symptoms were graded on a 4-point Likert scale as follows: 0, asymptomatic; 1, mild; 2, moderate; and 3, severe [15]. The Zung self-rating depression scale (SDS) [16] and the Zung self-rating anxiety scale (SAS) [17] were used to evaluate the depression and anxiety levels of the participants. SDS and SAS present 20 statements, respectively, followed by a four-point scale (from 1 = seldom, 2 = sometimes, 3 = often, 4 = absolutely most of time). The standard total scores of SDS and SAS were calculated by the original score multiplied by 1.25. After the assessment using SDS and SAS, eight of the patients (DA-FD group) were associated with mild depression and anxiety (SDS 53.9 3.1, SAS 54.6 3.5) and eight patients (nonDA-FD group) had no depression and anxiety (SDS 34.2 3.2, SAS 34.2 2.5). PET-CT scan An 18F-FDG PET-CT scan (a Biograph Duo BGO, Siemens, Munich, Germany) was performed on sixteen FD patients in the PET-CT center of the Sichuan Provincial Peoples Hospital. All patients were required to fast at least 4 h before the scan and were instructed to relax during the scan with their eyes blindfolded, ears plugged and head immobilized. The scan sequence procedure was the same as in our previous study [18] (Fig. 1). The images covered the whole brain and coincided with the ACPC line. Image acquisition was started after a 40-min uptake period (bed: 1; collection mode: 3D; slice thickness: 3 mm; slice interval: 1.5 mm; matrix size: 256 9 256; total counts: 3 9 109). These images after data acquisition were reconstructed using an ordered subset expectation maximization (OSEM) algorithm with 6 iterations and 16 subsets. They were converted to the analysis format and then analyzed by Statistical Parametric Mapping

Materials and methods Participants Sixteen right-handed FD patients were recruited from a Chinese university campus. The diagnosis criteria of FD patients met the Roman III diagnosis criteria on FD; FD patients were enrolled if they: (1) were aged between 20 and 30 years, and (2) matched the Roman III diagnosis criteria on FD, and (3) signed a written informed consent form. FD patients were excluded if they: (1) were pregnant, or (2) had a history of psychiatric and neurological disorders, or head trauma with loss of consciousness, or (3) were

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Time (min)
BP and BS test (1)

20
Rest (2) Injection (3)

40
Rest (4)

15 Scanning (5) Finish

Fig. 1 PET-CT scan ow. (1) Examinations of blood pressure (BP) and blood sugar (BS), (2) a 20 min quiet rest in a darkroom, (3) a tracer injection (18F-FDG, synthesized with Mini Tracer accelerator.

0.11 mci/kg dosage) at the back of the right hand, (4) a 40-min rest, (5) a 15-min PET-CT scan

Table 1 Demographics and baseline characteristics of FD patients DA-FD group (n = 8) Gender (M/F) Age
a

Non-DA-FD group (n = 8) 3/5 22.63 2.62 56.38 5.76 163.38 5.95 4.43 0.75 22.00 (13.75, 26.75) 40.25 3.33 3.38 1.30

P value 0.621 0.314 0.908 0.509 0.283 0.008 0.035

3/5 22.12 0.99 53.63 4.72 163.88 10.41 4.61 0.26 27.08 (18.14, 36.89) 64.12 21.58 5.63 2.39
b

Weighta Heighta Blood glucosea Courseb NDI Scores

a

DSS Scoresa * Signicant difference, P \ 0.05

P values based on a independent samples T test or Data presented as

a

MannWhitney test

mean SD or

median (25th percentiles, 75th percentiles)

2.0 (SPM 2.0, the Wellcome Department of Cognitive Neurology, University College London, UK) based on Matlab (version 6.5). After realignment and normalization, the images were spatially smoothed using a 10 mm 9 10 mm 9 10 mm Gaussian kernel. Statistical parametrical maps were constructed by computing a two-sample t test after controlling for potential confounding effects, i.e., duration of symptoms. For visualization, all of the results were then transformed into the Talairach stereotactic space, and overlaid on MRIcro (http://www.sph.s.c.edu/comd/ rorden/mricro.html) for presentation purposes.

(BA 1 and 5), inferior frontal gyrus (BA 45), superior temporal gyrus (BA 22), middle temporal gyrus (BA 22), inferior parietal lobule (BA 40), lingual gyrus (BA 18) and the left middle occipital gyrus (BA 37), as well as the limbic system including the left thalamus, lateral globus pallidus, parahippocampal gyrus (BA 35), right insular cortex (BA 13) and parahippocampal gyrus (BA 18); lower glucose metabolism was presented in the left middle cingulated gyrus (BA 24), the right superior frontal gyrus (BA 6), the medial frontal gyrus (BA 6) and middle temporal gyrus (BA 21) (P \ 0.001, uncorrected with height threshold and a minimal cluster size of 20 voxels) (Fig. 2; Table 2).

Results Clinical results No signicant differences were detected between the DAFD group and non-DA-FD group in terms of gender, age, weight, height, blood glucose and course. Demographics and baseline characteristics, NDI Scores and DSS Scores of the sample population are presented in Table 1. Compared to the non-DA-FD group, the DA-FD group presented a trend of higher scores for the NDI Scores and DSS Scores. Glucose metabolism results Compared to non-DA-FD patients, DA-FD patients showed a higher glucose metabolism in the right postcentral gyrus Discussion With the emerging braingut axis as a generally accepted explanation of functional gastrointestinal (GI) symptoms, various functional neuroimaging modalities imaging the living human brain enhance our ability to study their interactions. Neuroimaging studies have provided some evidence that the insular cortex and dorsal anterior cingulate cortex played a crucial role in interactions between the braingut axis and functional GI disorders [19]. Our group previously found that an increased glucose metabolism was presented in the left inferior temporal gyrus (BA 20) and a decreased glucose metabolism was found in the right orbital gyrus (BA 11), the left caudate tail and the cingulate

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38 Fig. 2 The activation/ deactivation areas compared DA-FD patients to non-DA-FD patients. P presents posterior; L presents left hemisphere. A higher CGM were presented in the thalamus, lateral globus pallidus, BA 1, BA 5, BA 13, BA 18, BA 22, BA 35, BA 37, BA 40 and BA 45; a lower CGM were presented in the BA 6, BA 21 and BA 24

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Table 2 The activation/deactivation areas DA-FD patients versus non-DA-FD patients Brain area Side Sign BA Talairach X Postcentral gyrus Postcentral gyrus Insula Thalamus Lateral globus pallidus Parahippocampal gyrus Parahippocampal gyrus Inferior frontal gyrus Superior temporal gyrus Middle temporal gyrus Inferior parietal lobule Lingual gyrus Middle occipital gyrus Middle cingulate gyrus Superior frontal gyrus Medial frontal gyrus Middle temporal gyrus R R R L L R L R R R R R L L R R R : : : : : : : : : : : : : ; ; ; ; 1 5 13 18 35 45 22 22 40 18 37 24 6 6 21 51 36 42 -8 -16 26 -20 59 67 69 55 24 -42 4 6 4 50 Y -23 -44 -13 -29 0 -56 -22 20 -35 -33 -28 -56 -64 6 -3 -1 -29 Z 53 61 12 7 -2 3 -11 10 9 5 33 5 3 37 63 61 2 3.72 3.79 3.36 3.54 3.10 3.85 3.20 3.14 3.79 3.32 3.15 3.78 3.47 -3.18 -3.29 -3.62 -3.19 T value

R right hemisphere, L left hemisphere, : a higher CGM, ; a lower CGM, BA Brodmann area

gyrus in FD patients compared to healthy controls [18]. In the present study, we observed extensive cortical-limbic system involvement in modulation of FD patients with depression and anxiety factors, including three major parts: (1) postcentral gyrus, which plays a role in general somatic sensation; (2) frontal, temporal, parietal and occipital cortices, which belong to extensive cortical regions; (3) insula, thalamus, lateral globus pallidus, parahippocampal gyrus and middle cingulated gyrus, which pertain to the limbic system. Comparing the DA-FD group to the non-DA-FD group, the glucose metabolism of the postcentral gyrus (BA 1 and 5)

was increased, which may correspond to a higher trend of DNI scores and the DSS scores in the DA-FD group (Table 1); extensive cortical regions involving frontal, temporal, parietal and occipital cortices were increased, which were associated with a decrease in the superior, medial frontal and superior temporal cortices to a certain extent. These results were not completely the same as for former neuroimaging ndings considering only depression or anxiety or FD. Baxter et al. [20] observed a reduction of glucose metabolism in the prefrontal cortex in depressed subjects. Taylor et al. [21] showed disrupted topdown control by the prefrontal cortex of the amygdala which may

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be responsible for negative feedback in unipolar depression. Hassel et al. [22] found decreased left dorsolateral prefrontal cortical activity in response to fearful emotion in patients with bipolar disorder relative to controls. Van Oudenhove [23, 24] used H2O15-PET in hypersensitive FD patients to explore the neurobiological mechanism of visceral hypersensitivity, and discovered that bilateral somatosensory cortexes (SI/SII) and the ventrolateral prefrontal cortex were activated in hypersensitive FD patients compared to controls. Taken together, former studies found the response of the cerebral cortex to FD or depression or anxiety was mainly located in the prefrontal cortex [20 28]. In the current study, cerebral activities were not just contained in the frontal cortex, but they were also located in the temporal, parietal and occipital regions as observed in FD patients with depression and anxiety factors. In the present study, we also found that the limbic system played an important role in emotional procession in FD patients. Comparing the DA-FD group to the nonDA-FD group, the insula (BA 13), thalamus, lateral globus pallidus, and parahippocampal gyrus (BA 35 and 18) showed a higher glucose metabolism and the middle cingulated gyrus (BA 24) presented a lower glucose metabolism, which showed some similarity to earlier ndings with regards to depression or anxiety or FD with anxiety. Brooks [25] posed that corticolimbic dysregulation with excessive anterior limbic activity and diminished prefrontal activity was related to depression. Zhao et al. [26] observed deactivation in the medial prefrontal cortex and posterior cingulate cortex in anxiety patients relative to controls. Taken together, the responses of the limbic system to depression or anxiety were mainly in the anterior or posterior cingulate gyrus, striatum, amygdala, caudate nucleus and parahippocampal gyrus [2022, 2528]. Van Oudenhove et al. [29] found that the bilateral ventral posterior cingulate cortex was activated in normosensitives relative to hypersensitives. Jeffrey et al. [30], using the O-15 water PET, studied brain regions corresponding to the improvement of psychological functioning (e.g., anxiety, worry) in patients with irritable bowel syndrome after cognitive therapy, and then identied that limbic activity changed and deactivation in the left pons was correlated with anxiety symptom improvement. Van Oudenhove et al. [24] also used the H2O15PET to detect brain activity corresponding to the anxiety level in FD patients, and found that anxiety scores were negatively correlated with cingulate activation and were positively correlated with dorsal pons activation. Taken together, brain regions for functional gastrointestinal disorders with anxiety were reported in the limbic system and brainstem. However, the majority of these studies were centered on depression or anxiety alone compared with healthy controls. The comparison of our study

subjects was conducted between FD patients, whose emotional factors included both depression and anxiety. Overall, extensive bilateral cerebral regions were involved in processing and modulation of FD patients with emotional factors from depression and anxiety, from which a concentration trend of brain responses in the corticallimbic lobes was delineated. Changes in neural activity of the cortical-limbic regions may represent the neurobiological mechanisms that mediate the inuence of depression and anxiety factors in FD patients. Some limitations were presented in the current study. The tendency of correlation between the depression/anxiety scores of the FD patients and CGM could not be conducted and clearly explained due to the small sample size and the unexpanded sample size based on the provisions of the Ethics Committee for the PET-CT study. Larger sample size studies with other neuroimaging technologies such as functional magnetic resonance imaging need to be performed to further identify the emotion-related difference in brain activity of FD patients.

Conclusion In summary, the present results demonstrated the differences in resting cerebral glucose metabolism between FD patients with depression and anxiety and those without depression and anxiety; this showed that an extensive cortical-limbic brain network might modulate the procession of FD patients with depression and anxiety. It might be an exploration to explain the neurobiological mechanisms that mediate the inuence of depression and anxiety factors in FD patients and further studies need to be conducted due to small sample size.
Acknowledgments This study was supported by the National Basic Research Program of China (973 Program), No. 2006CB504501 and the State Key Program of National Natural Science of China (No. 30930112/C190301).

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