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Brain areas involved in acupuncture treatment on functional dyspepsia patients: A PET-CT study
Neuroscience Letters 456 (2009) 6–10
Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Brain areas involved in acupuncture treatment on functional dyspepsia patients: A PET-CT study Fang Zeng a , Wen-Zhong Song b , Xu-Guang Liu a , Hong-Jun Xie b , Yong Tang a , Bao-Ci Shan c , Zhao-Hui Liu b , Shu-Guang Yu a , Fan-Rong Liang a,∗ a b c
Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China PET-CT center, Sichuan Provincial People’s Hospital, Chengdu 610072, China Key Laboratory of Nuclear Analysis Techniques, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e
i n f o
Article history: Received 13 December 2008 Received in revised form 23 March 2009 Accepted 24 March 2009 Keywords: Acupuncture Functional Dyspepsia Brain image
a b s t r a c t Neuroimaging studies on brain responses to acupuncture stimulations have received considerable attention recently. The majority of these studies are centered on healthy controls (HC) and neuropathy, while little work has addressed other disorders. This study aimed to investigate the influence of acupuncture stimulations on brain activities in functional dyspepsia (FD) patients. Eight FD patients and eight healthy controls (HC) were involved in this study. Each HC received an 18F-FDG PET-CT scan at baseline, while each patient received scans at baseline and after acupuncture stimulations. Manual acupuncture stimulations were performed at ST34 (Liangqiu), ST36 (Zusanli), ST40 (Fenglong) and ST42 (Chongyang) in FD patients. The images were analyzed with the Statistical Parametric Mapping software 2.0. Compared to HC, the FD patients showed a lower glycometabolism in the right orbital gyrus, the left caudate tail and the cingulate gyrus, and a higher glycometabolism in the left inferior temporal gyrus (p < 0.005). After acupuncture stimulations, the FD patients showed a glycometabolism decrease in the postcentral gyrus and the cerebella, and an increase in the visual-related cortices(p < 0.005). The results suggest that the anterior cingulate cortex, the prefrontal cortices and the caudate tail involve in processing gastric perceptions in FD patients and that the deactivation of the primary somatosensory area and the cerebella is contributable to acupuncture stimulation, while activation of the visual-related cortex is a response to pain or acupoint actions. © 2009 Elsevier Ireland Ltd. All rights reserved.
With the application of neuroimaging techniques in acupuncture research, an abundance of data shows that acupuncture modulates a widely distributed cortical and subcortical brain areas, including the primary somatosensory (SI), the secondary somatosensory (SII), the anterior cingulate cortex (ACC), the prefrontal cortex (PFC), the insular cortex, the amygdale, the hypothalamus and the cerebella [8,11,20,22,23,24]. However, the majority of acupuncture neuroimaging studies are centered on healthy controls (HC) and neuropathy [11]. As a result, the influence of acupuncture on brain activities of other disorders is still unclear and worth investigation. Our literature review shows that no published neuroimaging studies have reported on the brain responses to acupuncture stimulations in functional dyspepsia (FD) patients. FD is a major functional gastrointestinal disorder (FGID) with a high prevalence rate [7]. It causes a complex of upper abdominal symptoms, including upper centered discomfort or pain, early satiety, abdominal
∗ Corresponding author. Tel.: +86 28 66875831; fax: +86 28 7762405. E-mail addresses: [email protected] (F. Zeng), [email protected] (F.-R. Liang). 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.03.080
distention and bloating, belching and nausea. A good deal of clinical and experimental data indicates that acupuncturing at acupoints of the stomach meridian relieves gastric symptoms such as belch, abdominal distension and stomachache, and promotes appetite [5,10,12,21]. In this study, we performed fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) scan on HC at baseline, and on FD patients at baseline and after acupuncture stimulations. Acupoints of the stomach meridian were selected for this study because they, among all other acupoints, are the best for gastric disorder treatment, as proved by traditional acupuncture theories and clinical data. The purposes of this study were to investigate : (1) If there are any differences in cerebral glycometabolism between the FD patients and HC at baseline. (2) If there are any changes in cerebral glycometabolism in the FD patients after acupuncture stimulations. Eight right-handed FD patients (four males, four females; mean age 24.25 ± 2.49) with symptoms of delayed gastric emptying were enrolled in this study. The course and severity of their diseases were similar (mean course of disease: 15.25 ± 4.20 months, mean score of the Nepean Dyspepsia Index [13]: 64.25 ± 4.43).
F. Zeng et al. / Neuroscience Letters 456 (2009) 6–10
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The diagnosis criteria, inclusion criteria and exclusion criteria are as follows: Diagnosis criteria: (1) The Roman III diagnosis criteria on FD. (2) The Roman III diagnosis criteria on the Postprandial Distress Syndrome (PDS, one of the subtypes of FD). Inclusion criteria: Patients were enrolled if they: (1) were aged 20 to 30, and (2) matched the Roman III diagnosis criteria on FD, and (3) matched the Roman III diagnosis criteria on PDS, and (4) signed a written informed consent form. Exclusion criteria: Patients were screened out 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 currently in use of gastrointestinal dynamic promoting drugs, or (4) were suffering from serious cardiovascular, respiratory or renal illnesses, or (5) had any contraindications to acupuncture (e.g. anticoagulation therapy). Furthermore, patients with moderate or severe anxiety or depression were excluded based on the results of the self-rating anxiety scale (SAS) and the self-rating depression scale (SDS), since variations of the patient’s psychological status potentially lead to variations in brain responses, according to some researchers [15]. Eight age- and gender-matched right-handed HC (four males, four females; mean age 25.50 ± 1.85), free from any gastrointestinal symptoms or signs, were enrolled in this study. Each underwent a basic evaluation, including a review of the medical history, a physical examination and gastroscopy, to exclude organic disease carriers. A written informed consent was also provided by each HC. The study protocol was approved by the local Ethics Committee of the Chinese Academy of Sciences. Manual acupuncture (MA) was started on each FD patient after a baseline PET-CT scan and performed once daily for 5 days by one experienced acupuncturist. Acupoints used were ST34 (Liangqiu), ST36 (Zusanli), ST40 (Fenglong) and ST42 (Chongyang) on the stomach meridian (Fig. 1). After the overlying skin was cleaned with tincture iodine and alcohol, the sterile acupuncture needles (0.25 mm in diameter and 40 mm in length, manufactured by the Shuzhou Medical Appliance Factory, China) were then inserted perpendicularly into ST34 for 2.0 cm, ST36 for 2.0 cm, ST40 for 2.0 cm and ST42 for 1.5 cm, and gently twisted, lifted and thrusted in an evenly reinforcing and reducing method for 5 min. The twisting was within a range of 90–180◦ and at a rate of 60–90 times/min. The lifting and thrusting were within a range of approximately 0.6–1.0 cm and at a rate of 60–90 times/min. After a deqi response (including soreness, numbness, distention and heaviness) was obtained, the needles were remained still for 30 min. 18F-FDG PET-CT scans were performed on each HC at baseline, and each FD patient at baseline and after MA. All participants went to the PET-CT center of the Sichuan Provincial People’s Hospital at 8:00 am after at least 4 h fasting, and then went through the following sequential procedure: (1) examinations of blood pressure and blood sugar, (2) a 20 min 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 PET-CT scan. Participants were instructed to remain relaxed during the whole study with eyes blindfolded and ears plugged.
Fig. 1. Anatomical locations of the acupoints. ST34: located at 2 cun above the laterosuperior border of the patella; ST36: located at four-finger breadth below the lower margin of the patella and one-finger breadth laterally from the anterior crest of the tibia; ST40: located at 8 cun superior and anterior to the external malleolus, onefinger breadth from the anterior crest of the tibia; ST42: located in the depression between the second and the third metatarsal bones and the cuneiform.
PET-CT scans were performed on a Biograph Duo BGO scanner (Siemens, Germany). The images covered the whole brain and were paralleled to the AC-PC 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 × 256; total counts: 3 × 109 ). Upon the completion of data acquisition, the images were reconstructed using ordered subset expectation maximization (OSEM) with 6 iterations and 16 subsets. For FD patients after acupuncture, the scan procedure and the tracer dosage were the same as those of the baseline scan on the patients except that each FD patient received the fifth acupuncture stimulation during the 40 min rest. The PET-CT images were processed with the Statistical Parametric Mapping 2.0 (SPM 2.0, the Welcome Department of Cognitive Neurology, University College London, UK). After realignment and normalization, the images were smoothed spatially using a 15 mm × 15 mm × 15 mm Gaussian kernel. The data of HC and the FD patients at baseline were analyzed with a two-sample t test,
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F. Zeng et al. / Neuroscience Letters 456 (2009) 6–10
Fig. 2. The activation/deactivation areas in the FD patients at baseline compared to HC. (A) Activation area: the left inferior temporal gyrus (BA20). (B) Deactivation areas: the right orbital gyrus (BA11), the left caudate tail, the cingulate gyrus (BA24).
while the data of the FD patients at baseline and after MA were analyzed with a paired t test (extend threshold: k = 30 voxels, p < 0.005). Compared to HC, the FD patients showed a higher glycometabolism in the left inferior temporal gyrus (ITG, BA20) (Fig. 2A, Table 1), and a lower glycometabolism in the right orbital gyrus (BA11), the left caudate tail and the cingulate gyrus (BA24) (p < 0.005) (Fig. 2B, Table 1).
After MA, the FD patients showed a glycometabolism increase in the inferior occipital gyrus (IOG, BA18), the middle occipital gyrus (MOG, BA19), the precuneus (BA19), the right middle temporal gyrus (MTG, BA37) and the right medial frontal gyrus (MFG, BA25) (Fig. 3A, Table 2), and a glycometabolism decrease in the cerebellar tonsil, the left lentiform nucleus (lateral globus pallidus), the brainstem (pons) and the postcentral gyrus (BA2) (p < 0.005) (Fig. 3B, Table 2).
Table 1 The activation/deactivation areas in the FD patients at baseline compared to HC. Region
Side
BA
Sign
Inferior temporal gyrus Orbital gyrus Caudate tail Cingulate gyrus
L R L L
20 11
↑ ↓ ↓ ↓
24
Cluster-lever
Voxel-lever
Talairach (mm)
Рcorrected
kE
Рuncorrected
РFUE-corr
РFDR-corr
T
[Z ]
Рuncorrected
X
Y
Z
0.999 0.999 0.968 0.759
43 36 146 319
0.563 0.600 0.273 0.112
0.997 0.984 0.996 0.976
0.991 0.807 0.807 0.807
7.43 4.24 3.95 4.34
3.03 3.20 3.05 3.25
0.001 0.001 0.001 0.001
−52 2 −18 −14
−6 36 −38 6
−38 −34 12 30
Sign indicates whether the structure showed a signal increase or decrease, (↑/↓) increase/decrease. Abbreviations: R, right; L, left; BA, Brodmann area. Height threshold: T = 3.11, p = 0.005 (1.000); extent threshold: k = 30 voxels, p = 0.636 (1.000). Table 2 The activation/deactivation areas in the FD patients after acupuncture stimulations. Region
Side
BA
Sign
Cluster-lever
Voxel-lever
Talairach (mm)
Рcorrected
kE
Рuncorrected
РFUE-corr
РFDR-corr
T
[Z ]
Рuncorrected
X
Y
Z
Inferior occipital gyrus
L R
18 18
↑ ↑
0.007 0.000
32 202
0.000 0.000
1.000 1.000
0.736 0736
7.18 12.55
3.09 3.68
0.001 0.000
−32 44
−100 −88
−4 −10
Middle occipital gyrus
L R
19 19
↑ ↑
0.000 0.000
130 54
0.000 0.000
1.000 1.000
0.736 0.736
9.69 6.61
3.42 3.00
0.000 0.001
−34 30
−88 −94
8 20
Medial frontal gyrus Middle temporal gyrus
R R
25 37
↑ ↑
0.001 0.002
42 38
0.000 0.000
1.000 1.000
0.736 0.736
7.43 16.52
3.13 3.95
0.001 0.000
2 54
10 −60
−18 0
Precuneus
R L
19 19
↑ ↑
0.004 0.007
35 32
0.000 0.000
1.000 1.000
0.736 0.736
11.51 14.19
3.59 3.80
0.000 0.000
12 −16
−80 −80
40 38
Cerebellar tonsil
R L
↓ ↓
0.000 0.000
386 55
0.000 0.000
1.000 1.000
0.945 0.945
24.51 8.45
4.31 3.27
0.000 0.001
18 −26
−64 −52
−32 −34
Pons Lentiform nucleus Postcentral gyrus
L L L
↓ ↓ ↓
0.010 0.000 0.000
31 50 51
0.000 0.000 0.000
1.000 1.000 1.000
0.945 0.945 0.945
10.72 8.92 14.67
3.52 3.33 3.83
0.000 0.000 0.000
−24 −20 −34
−24 −6 −28
−32 2 42
2
Sign indicates whether the structure showed a signal increase or decrease, (↑/↓) increase/decrease. Abbreviations: R, right; L, left; BA, Brodmann area. Height threshold: T = 4.60, p = 0.005 (1.000); extent threshold: k = 30 voxels, p = 0.000 (0.012).
F. Zeng et al. / Neuroscience Letters 456 (2009) 6–10
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Fig. 3. The activation/deactivation areas in the FD patients after acupuncture stimulations. (A) Activation areas: the inferior occipital gyrus (BA18), the middle occipital gyrus (BA19), the precuneus (BA19), the right middle temporal gyrus (BA37), the medial frontal gyrus (BA25). (B) Deactivation areas: the cerebellar tonsil, the left lentiform nucleus, the brainstem, the postcentral gyrus (BA2).
Lower glycometabolism in the right orbital gyrus (BA11), the left caudate tail and ACC (BA24) in the FD patients at baseline were observed in our study. Many studies suggest that the paralimbic and limbic structures, such as the insular, ACC and PFC, are likely to mediate the affective and cognitive components of the visceral sensation [3]. The orbital gyrus is a part of orbitofrontal cortex (OFC) in PFC. It has been found to be a convergence zone for processing food-related stimuli and regulating hunger, appetite, satiety, and food intake [17]. ACC is a part of the limbic system and plays an important role in processing and modulating gastrointestinal sensory signals. The tail of the caudate nucleus is the attenuated caudal portion that sweeps into the temporal lobe in the roof of the inferior horn of the lateral ventricle and interacts with the central nucleus of the amygdaloid complex [14]. Some studies indicate the involvement of the caudate nucleus in the process of gastric perceptions [9]. Our findings support the hypothesis that ACC, PFC and the caudate nuclei involve in processing the gastric perceptions. Although some studies indicate that ACC, PFC and the caudate nuclei involve in acupuncture modulation [8,23], our results didn’t show significant signal changes in these area in the FD patients after MA. This discrepancy, which requires further investigation, is hypothetically contributable to differences in participants and acupuncture methods. Although SI and SII are seen as parts of the visceral area and were found to involve in processing gastrointestinal sensations by some studies [2,16], we didn’t observe any significant changes in glycometabolism in SI and SII in the FD patients at baseline compared to HC. However, using H2 O15 -PET, Vandenberghe found that during painful gastric distension, FD patients hypersensitive to gastric distension showed activations in the bilateral sensorimotor cortex (SI/SII) compared to controls. He thought it might be interpreted as a biological mechanism underlying visceral hypersensitivity in FD patients [17,18]. The discrepancy may be induced by scan process differences. After MA, decrease in glycometabolism in the left postcentral gyrus was observed. We hypothesize that the signal decease is related to the acupuncture stimulations. However, whether the sig-
nal change elicited by acupuncture is related to lowering visceral hypersensitivity would require further investigation. Human cerebella, with its complicatedly 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 [1]. Although Vandenberghe reported activations in bilateral cerebella hemisphere in FD patients during painful gastric distension [18], our study found no significant changes in glycometabolism in the cerebella of the FD patients in comparison with HC. Methodological differences may account for the conflicting results. After MA, the bilateral cerebella tonsil was remarkably deactivated. We hypothesize that the deactivation of cerebella tonsil is attributable to the acupuncture stimulation. Similarly, recent fMRI investigations have reported cerebellar activities from studies of electroacupuncture (EA) and MA in HC and provided an initial evidence of a modulatory effect of acupuncture on the cerebella [20,22,24]. In this study, we found a higher glycometabolism in the right ITG (BA20) in the FD patients at baseline compared to HC. BA20 involves in the analysis of visual form and representation of objects. This result was similar to the H2 O15 -PET study findings by Vandenberghe [18], who reported activations in the left ITG in FD patients during painful gastric distention. Some studies on FGID also identified activations in the visual cortices [4]. We hypothesize that the activations in the visual cortices in the FD patients correlate with pain perception. After MA, we found a definite glycometabolism increase in IOG (BA18), MOG (BA19), the precuneus (BA19) and the right MTG (BA37). BA18 and BA19 pertain to visual association cortices and involve in processing visual information, while BA37 involves in analyzing the visual form. The visual cortical activation in the FD patients after MA is interesting and unexpected. Some investigators found that activation in visual association cortices can be elicited by puncturing at the eye-related points such as GB34 (Yanglingquan) [20], GB37 (Guangming) [6] and Liv3 (Taichong) [22]. According to acupuncture theories, the stomach meridian connects with eyes, and these acupoints, ST34, ST36, ST40 and ST41, are all used for eye
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F. Zeng et al. / Neuroscience Letters 456 (2009) 6–10
disease treatment. However, Wu et al. identified that visual cortices might be activated by minimal EA, sham EA or true EA at GB34 and thought that activation of visual cortices was not related to acupoint specificity [19]. We hypothesize that the visual cortical activation in the FD patients after MA relates to (1) pain induced by tracer injection and needle-inserting, (2) the actions of acupoints of the stomach meridian. A definite conclusion would require further investigation. This study is focused on the immediate influences of acupuncture on cerebral activities in pathological conditions. An ideal design should further explore the long-term mechanism of acupuncture by incorporating the following: (1) evaluation of the therapeutic effects of acupuncture; (2) the second scan on FD patients in a resting condition to verify that the changes in brain activities are induced by the therapeutic effects, not the immediate effects, of acupuncture stimulations; (3) use of a sham group to differentiate the specific effects of acupuncture from the placebo responses. In summary, this study demonstrates the differences in cerebral glycometabolism between the FD patients and HC, and the changes in cerebral glycometabolism in the FD patients before and after MA. We hypothesize: (1) PFC, ACC and the caudate tail involve in processing the gastric perceptions in the FD patients; (2) the signal decreases in SI and the cerebella result from the acupuncture stimulations; (3) the signal increase in visual-related cortices is a response to pain or acupoint action. To further verify these hypotheses and better understand acupuncture mechanisms, more investigations are required. Acknowledgement This study was supported by the State Key Program for Basic Research of China (No. 2006CB504501). References [1] G. Allen, R.B. Buxton, E.C. Wong, E. Courchesne, Attentional activation of the cerebellum independent of motor involvement, Science 275 (1997) 1940–1943. [2] Q. Aziz, J.L. Andersson, S. Valind, A. Sundin, S. Hamdy, A.K. Jones, E.R. Foster, B. Langstrom, D.G. Thompson, Identification of human brain loci processing esophageal sensation using positron emission tomography, Gastroenterology 113 (1997) 50–59. [3] Q. Aziz, A. Schnitzler, P. Enck, Functional neuroimaging of visceral sensation, J. Clin. Neurophysiol. 17 (2000) 604–612. [4] M. Baciu, B. Bonaz, C. Segebarth, Central processing of rectal pain: a functional MR imaging study, Am. J. Neuroradiol. 20 (1999) 1920–1924. [5] J.Y. Chen, F. Pan, J.J. Xu, Effects of acupuncture on the gastric motility in patients with functional dyspepsia, Zhongguo Zhong Xi Yi Jie He Za Zhi 25 (2005) 880–882.
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Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Brain areas involved in acupuncture treatment on functional dyspepsia patients: A PET-CT study Fang Zeng a , Wen-Zhong Song b , Xu-Guang Liu a , Hong-Jun Xie b , Yong Tang a , Bao-Ci Shan c , Zhao-Hui Liu b , Shu-Guang Yu a , Fan-Rong Liang a,∗ a b c
Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China PET-CT center, Sichuan Provincial People’s Hospital, Chengdu 610072, China Key Laboratory of Nuclear Analysis Techniques, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e
i n f o
Article history: Received 13 December 2008 Received in revised form 23 March 2009 Accepted 24 March 2009 Keywords: Acupuncture Functional Dyspepsia Brain image
a b s t r a c t Neuroimaging studies on brain responses to acupuncture stimulations have received considerable attention recently. The majority of these studies are centered on healthy controls (HC) and neuropathy, while little work has addressed other disorders. This study aimed to investigate the influence of acupuncture stimulations on brain activities in functional dyspepsia (FD) patients. Eight FD patients and eight healthy controls (HC) were involved in this study. Each HC received an 18F-FDG PET-CT scan at baseline, while each patient received scans at baseline and after acupuncture stimulations. Manual acupuncture stimulations were performed at ST34 (Liangqiu), ST36 (Zusanli), ST40 (Fenglong) and ST42 (Chongyang) in FD patients. The images were analyzed with the Statistical Parametric Mapping software 2.0. Compared to HC, the FD patients showed a lower glycometabolism in the right orbital gyrus, the left caudate tail and the cingulate gyrus, and a higher glycometabolism in the left inferior temporal gyrus (p < 0.005). After acupuncture stimulations, the FD patients showed a glycometabolism decrease in the postcentral gyrus and the cerebella, and an increase in the visual-related cortices(p < 0.005). The results suggest that the anterior cingulate cortex, the prefrontal cortices and the caudate tail involve in processing gastric perceptions in FD patients and that the deactivation of the primary somatosensory area and the cerebella is contributable to acupuncture stimulation, while activation of the visual-related cortex is a response to pain or acupoint actions. © 2009 Elsevier Ireland Ltd. All rights reserved.
With the application of neuroimaging techniques in acupuncture research, an abundance of data shows that acupuncture modulates a widely distributed cortical and subcortical brain areas, including the primary somatosensory (SI), the secondary somatosensory (SII), the anterior cingulate cortex (ACC), the prefrontal cortex (PFC), the insular cortex, the amygdale, the hypothalamus and the cerebella [8,11,20,22,23,24]. However, the majority of acupuncture neuroimaging studies are centered on healthy controls (HC) and neuropathy [11]. As a result, the influence of acupuncture on brain activities of other disorders is still unclear and worth investigation. Our literature review shows that no published neuroimaging studies have reported on the brain responses to acupuncture stimulations in functional dyspepsia (FD) patients. FD is a major functional gastrointestinal disorder (FGID) with a high prevalence rate [7]. It causes a complex of upper abdominal symptoms, including upper centered discomfort or pain, early satiety, abdominal
∗ Corresponding author. Tel.: +86 28 66875831; fax: +86 28 7762405. E-mail addresses: [email protected] (F. Zeng), [email protected] (F.-R. Liang). 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.03.080
distention and bloating, belching and nausea. A good deal of clinical and experimental data indicates that acupuncturing at acupoints of the stomach meridian relieves gastric symptoms such as belch, abdominal distension and stomachache, and promotes appetite [5,10,12,21]. In this study, we performed fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) scan on HC at baseline, and on FD patients at baseline and after acupuncture stimulations. Acupoints of the stomach meridian were selected for this study because they, among all other acupoints, are the best for gastric disorder treatment, as proved by traditional acupuncture theories and clinical data. The purposes of this study were to investigate : (1) If there are any differences in cerebral glycometabolism between the FD patients and HC at baseline. (2) If there are any changes in cerebral glycometabolism in the FD patients after acupuncture stimulations. Eight right-handed FD patients (four males, four females; mean age 24.25 ± 2.49) with symptoms of delayed gastric emptying were enrolled in this study. The course and severity of their diseases were similar (mean course of disease: 15.25 ± 4.20 months, mean score of the Nepean Dyspepsia Index [13]: 64.25 ± 4.43).
F. Zeng et al. / Neuroscience Letters 456 (2009) 6–10
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The diagnosis criteria, inclusion criteria and exclusion criteria are as follows: Diagnosis criteria: (1) The Roman III diagnosis criteria on FD. (2) The Roman III diagnosis criteria on the Postprandial Distress Syndrome (PDS, one of the subtypes of FD). Inclusion criteria: Patients were enrolled if they: (1) were aged 20 to 30, and (2) matched the Roman III diagnosis criteria on FD, and (3) matched the Roman III diagnosis criteria on PDS, and (4) signed a written informed consent form. Exclusion criteria: Patients were screened out 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 currently in use of gastrointestinal dynamic promoting drugs, or (4) were suffering from serious cardiovascular, respiratory or renal illnesses, or (5) had any contraindications to acupuncture (e.g. anticoagulation therapy). Furthermore, patients with moderate or severe anxiety or depression were excluded based on the results of the self-rating anxiety scale (SAS) and the self-rating depression scale (SDS), since variations of the patient’s psychological status potentially lead to variations in brain responses, according to some researchers [15]. Eight age- and gender-matched right-handed HC (four males, four females; mean age 25.50 ± 1.85), free from any gastrointestinal symptoms or signs, were enrolled in this study. Each underwent a basic evaluation, including a review of the medical history, a physical examination and gastroscopy, to exclude organic disease carriers. A written informed consent was also provided by each HC. The study protocol was approved by the local Ethics Committee of the Chinese Academy of Sciences. Manual acupuncture (MA) was started on each FD patient after a baseline PET-CT scan and performed once daily for 5 days by one experienced acupuncturist. Acupoints used were ST34 (Liangqiu), ST36 (Zusanli), ST40 (Fenglong) and ST42 (Chongyang) on the stomach meridian (Fig. 1). After the overlying skin was cleaned with tincture iodine and alcohol, the sterile acupuncture needles (0.25 mm in diameter and 40 mm in length, manufactured by the Shuzhou Medical Appliance Factory, China) were then inserted perpendicularly into ST34 for 2.0 cm, ST36 for 2.0 cm, ST40 for 2.0 cm and ST42 for 1.5 cm, and gently twisted, lifted and thrusted in an evenly reinforcing and reducing method for 5 min. The twisting was within a range of 90–180◦ and at a rate of 60–90 times/min. The lifting and thrusting were within a range of approximately 0.6–1.0 cm and at a rate of 60–90 times/min. After a deqi response (including soreness, numbness, distention and heaviness) was obtained, the needles were remained still for 30 min. 18F-FDG PET-CT scans were performed on each HC at baseline, and each FD patient at baseline and after MA. All participants went to the PET-CT center of the Sichuan Provincial People’s Hospital at 8:00 am after at least 4 h fasting, and then went through the following sequential procedure: (1) examinations of blood pressure and blood sugar, (2) a 20 min 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 PET-CT scan. Participants were instructed to remain relaxed during the whole study with eyes blindfolded and ears plugged.
Fig. 1. Anatomical locations of the acupoints. ST34: located at 2 cun above the laterosuperior border of the patella; ST36: located at four-finger breadth below the lower margin of the patella and one-finger breadth laterally from the anterior crest of the tibia; ST40: located at 8 cun superior and anterior to the external malleolus, onefinger breadth from the anterior crest of the tibia; ST42: located in the depression between the second and the third metatarsal bones and the cuneiform.
PET-CT scans were performed on a Biograph Duo BGO scanner (Siemens, Germany). The images covered the whole brain and were paralleled to the AC-PC 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 × 256; total counts: 3 × 109 ). Upon the completion of data acquisition, the images were reconstructed using ordered subset expectation maximization (OSEM) with 6 iterations and 16 subsets. For FD patients after acupuncture, the scan procedure and the tracer dosage were the same as those of the baseline scan on the patients except that each FD patient received the fifth acupuncture stimulation during the 40 min rest. The PET-CT images were processed with the Statistical Parametric Mapping 2.0 (SPM 2.0, the Welcome Department of Cognitive Neurology, University College London, UK). After realignment and normalization, the images were smoothed spatially using a 15 mm × 15 mm × 15 mm Gaussian kernel. The data of HC and the FD patients at baseline were analyzed with a two-sample t test,
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Fig. 2. The activation/deactivation areas in the FD patients at baseline compared to HC. (A) Activation area: the left inferior temporal gyrus (BA20). (B) Deactivation areas: the right orbital gyrus (BA11), the left caudate tail, the cingulate gyrus (BA24).
while the data of the FD patients at baseline and after MA were analyzed with a paired t test (extend threshold: k = 30 voxels, p < 0.005). Compared to HC, the FD patients showed a higher glycometabolism in the left inferior temporal gyrus (ITG, BA20) (Fig. 2A, Table 1), and a lower glycometabolism in the right orbital gyrus (BA11), the left caudate tail and the cingulate gyrus (BA24) (p < 0.005) (Fig. 2B, Table 1).
After MA, the FD patients showed a glycometabolism increase in the inferior occipital gyrus (IOG, BA18), the middle occipital gyrus (MOG, BA19), the precuneus (BA19), the right middle temporal gyrus (MTG, BA37) and the right medial frontal gyrus (MFG, BA25) (Fig. 3A, Table 2), and a glycometabolism decrease in the cerebellar tonsil, the left lentiform nucleus (lateral globus pallidus), the brainstem (pons) and the postcentral gyrus (BA2) (p < 0.005) (Fig. 3B, Table 2).
Table 1 The activation/deactivation areas in the FD patients at baseline compared to HC. Region
Side
BA
Sign
Inferior temporal gyrus Orbital gyrus Caudate tail Cingulate gyrus
L R L L
20 11
↑ ↓ ↓ ↓
24
Cluster-lever
Voxel-lever
Talairach (mm)
Рcorrected
kE
Рuncorrected
РFUE-corr
РFDR-corr
T
[Z ]
Рuncorrected
X
Y
Z
0.999 0.999 0.968 0.759
43 36 146 319
0.563 0.600 0.273 0.112
0.997 0.984 0.996 0.976
0.991 0.807 0.807 0.807
7.43 4.24 3.95 4.34
3.03 3.20 3.05 3.25
0.001 0.001 0.001 0.001
−52 2 −18 −14
−6 36 −38 6
−38 −34 12 30
Sign indicates whether the structure showed a signal increase or decrease, (↑/↓) increase/decrease. Abbreviations: R, right; L, left; BA, Brodmann area. Height threshold: T = 3.11, p = 0.005 (1.000); extent threshold: k = 30 voxels, p = 0.636 (1.000). Table 2 The activation/deactivation areas in the FD patients after acupuncture stimulations. Region
Side
BA
Sign
Cluster-lever
Voxel-lever
Talairach (mm)
Рcorrected
kE
Рuncorrected
РFUE-corr
РFDR-corr
T
[Z ]
Рuncorrected
X
Y
Z
Inferior occipital gyrus
L R
18 18
↑ ↑
0.007 0.000
32 202
0.000 0.000
1.000 1.000
0.736 0736
7.18 12.55
3.09 3.68
0.001 0.000
−32 44
−100 −88
−4 −10
Middle occipital gyrus
L R
19 19
↑ ↑
0.000 0.000
130 54
0.000 0.000
1.000 1.000
0.736 0.736
9.69 6.61
3.42 3.00
0.000 0.001
−34 30
−88 −94
8 20
Medial frontal gyrus Middle temporal gyrus
R R
25 37
↑ ↑
0.001 0.002
42 38
0.000 0.000
1.000 1.000
0.736 0.736
7.43 16.52
3.13 3.95
0.001 0.000
2 54
10 −60
−18 0
Precuneus
R L
19 19
↑ ↑
0.004 0.007
35 32
0.000 0.000
1.000 1.000
0.736 0.736
11.51 14.19
3.59 3.80
0.000 0.000
12 −16
−80 −80
40 38
Cerebellar tonsil
R L
↓ ↓
0.000 0.000
386 55
0.000 0.000
1.000 1.000
0.945 0.945
24.51 8.45
4.31 3.27
0.000 0.001
18 −26
−64 −52
−32 −34
Pons Lentiform nucleus Postcentral gyrus
L L L
↓ ↓ ↓
0.010 0.000 0.000
31 50 51
0.000 0.000 0.000
1.000 1.000 1.000
0.945 0.945 0.945
10.72 8.92 14.67
3.52 3.33 3.83
0.000 0.000 0.000
−24 −20 −34
−24 −6 −28
−32 2 42
2
Sign indicates whether the structure showed a signal increase or decrease, (↑/↓) increase/decrease. Abbreviations: R, right; L, left; BA, Brodmann area. Height threshold: T = 4.60, p = 0.005 (1.000); extent threshold: k = 30 voxels, p = 0.000 (0.012).
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Fig. 3. The activation/deactivation areas in the FD patients after acupuncture stimulations. (A) Activation areas: the inferior occipital gyrus (BA18), the middle occipital gyrus (BA19), the precuneus (BA19), the right middle temporal gyrus (BA37), the medial frontal gyrus (BA25). (B) Deactivation areas: the cerebellar tonsil, the left lentiform nucleus, the brainstem, the postcentral gyrus (BA2).
Lower glycometabolism in the right orbital gyrus (BA11), the left caudate tail and ACC (BA24) in the FD patients at baseline were observed in our study. Many studies suggest that the paralimbic and limbic structures, such as the insular, ACC and PFC, are likely to mediate the affective and cognitive components of the visceral sensation [3]. The orbital gyrus is a part of orbitofrontal cortex (OFC) in PFC. It has been found to be a convergence zone for processing food-related stimuli and regulating hunger, appetite, satiety, and food intake [17]. ACC is a part of the limbic system and plays an important role in processing and modulating gastrointestinal sensory signals. The tail of the caudate nucleus is the attenuated caudal portion that sweeps into the temporal lobe in the roof of the inferior horn of the lateral ventricle and interacts with the central nucleus of the amygdaloid complex [14]. Some studies indicate the involvement of the caudate nucleus in the process of gastric perceptions [9]. Our findings support the hypothesis that ACC, PFC and the caudate nuclei involve in processing the gastric perceptions. Although some studies indicate that ACC, PFC and the caudate nuclei involve in acupuncture modulation [8,23], our results didn’t show significant signal changes in these area in the FD patients after MA. This discrepancy, which requires further investigation, is hypothetically contributable to differences in participants and acupuncture methods. Although SI and SII are seen as parts of the visceral area and were found to involve in processing gastrointestinal sensations by some studies [2,16], we didn’t observe any significant changes in glycometabolism in SI and SII in the FD patients at baseline compared to HC. However, using H2 O15 -PET, Vandenberghe found that during painful gastric distension, FD patients hypersensitive to gastric distension showed activations in the bilateral sensorimotor cortex (SI/SII) compared to controls. He thought it might be interpreted as a biological mechanism underlying visceral hypersensitivity in FD patients [17,18]. The discrepancy may be induced by scan process differences. After MA, decrease in glycometabolism in the left postcentral gyrus was observed. We hypothesize that the signal decease is related to the acupuncture stimulations. However, whether the sig-
nal change elicited by acupuncture is related to lowering visceral hypersensitivity would require further investigation. Human cerebella, with its complicatedly 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 [1]. Although Vandenberghe reported activations in bilateral cerebella hemisphere in FD patients during painful gastric distension [18], our study found no significant changes in glycometabolism in the cerebella of the FD patients in comparison with HC. Methodological differences may account for the conflicting results. After MA, the bilateral cerebella tonsil was remarkably deactivated. We hypothesize that the deactivation of cerebella tonsil is attributable to the acupuncture stimulation. Similarly, recent fMRI investigations have reported cerebellar activities from studies of electroacupuncture (EA) and MA in HC and provided an initial evidence of a modulatory effect of acupuncture on the cerebella [20,22,24]. In this study, we found a higher glycometabolism in the right ITG (BA20) in the FD patients at baseline compared to HC. BA20 involves in the analysis of visual form and representation of objects. This result was similar to the H2 O15 -PET study findings by Vandenberghe [18], who reported activations in the left ITG in FD patients during painful gastric distention. Some studies on FGID also identified activations in the visual cortices [4]. We hypothesize that the activations in the visual cortices in the FD patients correlate with pain perception. After MA, we found a definite glycometabolism increase in IOG (BA18), MOG (BA19), the precuneus (BA19) and the right MTG (BA37). BA18 and BA19 pertain to visual association cortices and involve in processing visual information, while BA37 involves in analyzing the visual form. The visual cortical activation in the FD patients after MA is interesting and unexpected. Some investigators found that activation in visual association cortices can be elicited by puncturing at the eye-related points such as GB34 (Yanglingquan) [20], GB37 (Guangming) [6] and Liv3 (Taichong) [22]. According to acupuncture theories, the stomach meridian connects with eyes, and these acupoints, ST34, ST36, ST40 and ST41, are all used for eye
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disease treatment. However, Wu et al. identified that visual cortices might be activated by minimal EA, sham EA or true EA at GB34 and thought that activation of visual cortices was not related to acupoint specificity [19]. We hypothesize that the visual cortical activation in the FD patients after MA relates to (1) pain induced by tracer injection and needle-inserting, (2) the actions of acupoints of the stomach meridian. A definite conclusion would require further investigation. This study is focused on the immediate influences of acupuncture on cerebral activities in pathological conditions. An ideal design should further explore the long-term mechanism of acupuncture by incorporating the following: (1) evaluation of the therapeutic effects of acupuncture; (2) the second scan on FD patients in a resting condition to verify that the changes in brain activities are induced by the therapeutic effects, not the immediate effects, of acupuncture stimulations; (3) use of a sham group to differentiate the specific effects of acupuncture from the placebo responses. In summary, this study demonstrates the differences in cerebral glycometabolism between the FD patients and HC, and the changes in cerebral glycometabolism in the FD patients before and after MA. We hypothesize: (1) PFC, ACC and the caudate tail involve in processing the gastric perceptions in the FD patients; (2) the signal decreases in SI and the cerebella result from the acupuncture stimulations; (3) the signal increase in visual-related cortices is a response to pain or acupoint action. To further verify these hypotheses and better understand acupuncture mechanisms, more investigations are required. Acknowledgement This study was supported by the State Key Program for Basic Research of China (No. 2006CB504501). References [1] G. Allen, R.B. Buxton, E.C. Wong, E. Courchesne, Attentional activation of the cerebellum independent of motor involvement, Science 275 (1997) 1940–1943. [2] Q. Aziz, J.L. Andersson, S. Valind, A. Sundin, S. Hamdy, A.K. Jones, E.R. Foster, B. Langstrom, D.G. Thompson, Identification of human brain loci processing esophageal sensation using positron emission tomography, Gastroenterology 113 (1997) 50–59. [3] Q. Aziz, A. Schnitzler, P. Enck, Functional neuroimaging of visceral sensation, J. Clin. Neurophysiol. 17 (2000) 604–612. [4] M. Baciu, B. Bonaz, C. Segebarth, Central processing of rectal pain: a functional MR imaging study, Am. J. Neuroradiol. 20 (1999) 1920–1924. [5] J.Y. Chen, F. Pan, J.J. Xu, Effects of acupuncture on the gastric motility in patients with functional dyspepsia, Zhongguo Zhong Xi Yi Jie He Za Zhi 25 (2005) 880–882.
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