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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2023, Vol. 17 Issue (5) : 993-1005    https://doi.org/10.1007/s11684-023-0989-7
RESEARCH ARTICLE
Discovery of the mechanisms of acupuncture in the treatment of migraine based on functional magnetic resonance imaging and omics
Chong Li1, Xinyi Li1, Ke He1, Yang Wu1, Xiaoming Xie1, Jiju Yang1, Fan Zhang1, Yang Yue1, Huifeng Hao2, Shaokun Zhao3, Xin Li3, Guihua Tian1()
1. Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
2. Department of Integration of Chinese and Western Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing 100142, China
3. State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, China
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Abstract

Migraine is one of the most prevalent and disabling neurological disease, but the current pharmacotherapies show limited efficacy and often accompanied by adverse effects. Acupuncture is a promising complementary therapy, but further clinical evidence is needed. The influence of acupuncture on migraine is not an immediate effect, and its mechanism remains unclear. This study aims to provide further clinical evidence for the anti-migraine effects of acupuncture and explore the mechanism involved. A randomized controlled trial was performed among 10 normal controls and 38 migraineurs. The migraineurs were divided into blank control, sham acupuncture, and acupuncture groups. Patients were subjected to two courses of treatment, and each treatment lasted for 5 days, with an interval of 1 day between the two courses. The effectiveness of treatment was evaluated using pain questionnaire. The functional magnetic resonance imaging (fMRI) data were analyzed for investigating brain changes induced by treatments. Blood plasma was collected for metabolomics and proteomics studies. Correlation and mediation analyses were performed to investigate the interaction between clinical, fMRI and omics changes. Results showed that acupuncture effectively relieved migraine symptoms in a way different from sham acupuncture in terms of curative effect, affected brain regions, and signaling pathways. The anti-migraine mechanism involves a complex network related to the regulation of the response to hypoxic stress, reversal of brain energy imbalance, and regulation of inflammation. The brain regions of migraineurs affected by acupuncture include the lingual gyrus, default mode network, and cerebellum. The effect of acupuncture on patients’ metabolites/proteins may precede that of the brain.
Keywords acupuncture      migraine      fMRI      metabolome      proteome     
Corresponding Author(s): Guihua Tian   
Just Accepted Date: 11 May 2023   Online First Date: 30 June 2023    Issue Date: 07 December 2023
 Cite this article:   
Chong Li,Xinyi Li,Ke He, et al. Discovery of the mechanisms of acupuncture in the treatment of migraine based on functional magnetic resonance imaging and omics[J]. Front. Med., 2023, 17(5): 993-1005.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-0989-7
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I5/993
Fig.1  Study flow diagram.
Characteristics of study participants at baseline
Normal control(n = 10) Blank control(n = 13) Sham acupuncture(n = 13) Acupuncture(n = 12)
Age, mean (SD), y 30.4 (7.2) 38.5 (8.6) 38.0 (10.4) 36.1 (10.5)
Female, n (%) 7 (70) 5 (38) 8(52) 9 (75)
Male, n (%) 3 (30) 8 (62) 5 (38) 3 (25)
Age at migraine diagnosis, mean (SD), y Null 24.8 (10.9) 23.6 (11.6) 26.8 (11.1)
Duration of migraine diagnosis, mean (SD), y Null 13.7 (9.4) 14.4 (8.3) 9.3 (6.9)
Health status, mean (SD) Null 3.2 (0.8) 2.8 (1.0) 3.1 (0.6)
Concomitant medications using during study, n (%) Null 6 (46) 7 (54) 7 (58)
VAS, mean (SD) Null 6.5 (1.3) 7.0 (1.6) 7.0 (1.4)
Attack frequency, mean (SD), w Null 1.9 (0.8) 1.1 (0.5) 2.1 (1.8)
PSQI, mean (SD) Null 8.8 (4.2) 6.5 (2.6) 9.2 (2.6)
GAD, mean (SD) Null 6.8 (6.6) 4.1 (2.7) 2.3 (2.6)
MSQ total, mean (SD) Null 30.9 (19.5) 26.9 (17.4) 27.3 (21.1)
Role function-restrictive, mean (SD) Null 19.5 (9.7) 18.4 (11.0) 16.0 (9.7)
Role function-preventive, mean (SD) Null 6.1 (6.2) 6.4 (7.8) 6.0 (7.6)
Emotional function, mean (SD) Null 5.3 (5.3) 4.5 (3.2) 5.3 (5.2)
Efficacy outcomes
Blank control (n = 9) Sham acupuncture (n = 9) Acupuncture (n = 10) S0 d vs A0 d S0 d vs S10 d A0 d vs A10 d S10 d vs A10 d B0 d vs B10 d
VAS, mean (SD) 6.4 (1.1) 3.4 (2.3) 2.4 (2.1) — * * — —
Attack frequency, mean (SD), w 1.9 (1.4) 1.2 (0.8) 1.5 (21) — — — — —
PSQI, mean (SD) 7.9 (4.2) 4.3 (2.5) 6.3(1.7) — — * — —
GAD, mean (SD) 4.3 (3.6) 1.8 (2.4) 1.7 (2.1) — — — — —
MSQ total, mean (SD) 22. 8 (21.1) 14.4 (11.8) 5.5 (6.7) — — * * —
Role function-restrictive, mean (SD) 14.3 (11.2) 9.2 (5.7) 3.9 (5.2) — — * * —
Role function-preventive, mean (SD) 3.8 (6.1) 3.1 (4.9) 0.6 (1.3) — — * * —
Emotional function, mean (SD) 4.7 (5.2) 2.1 (3.0) 1.0 (1.6) — — * * —
Adverse events None None None Null Null Null Null Null
Tab.1  Baseline clinical characteristics and efficacy outcomes
Fig.2  Significant differences in amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) between groups. Regions with increased and decreased ALFF (A) and ReHo values (C) after acupuncture treatment (A10 d) compared with before treatment (A0 d). Regions with increased and decreased ALFF (B) and ReHo values (D) in migraineurs (M) compared with normal controls (N). P < 0.05 two tailed, AlphaSim corrected.
Fig.3  Differential metabolites analysis between groups. (A–D) PLS-DA scores and volcano plots in positive ion mode. (E–H) PLS-DA scores and volcano plots in negative ion mode. VIP ≥ 1, fold change ≥ 1.2 or ≤ 0.83, P value < 0.05 are set as the significant threshold for differentially expression. (I) Venn diagram of differential metabolites identified in normal control (0 d) versus acupuncture (0 d) and acupuncture (0 d) versus acupuncture (10 d), indicating 25 overlaps between sample groups. Results from positive and negative mode analyses were combined. (J) Heatmap of the 25 overlapping metabolites.
Fig.4  Differential proteins analysis between groups. Volcano plots of proteins in (A) normal control (0 d) versus acupuncture (0 d), (B) acupuncture (0 d) versus acupuncture (10 d), (C) normal control (0 d) versus sham acupuncture (0 d) and (D) sham acupuncture (0 d) versus sham acupuncture (10 d). Q value < 0.05 and fold change > 1.2 or ≤ 0.83 are set as the significant threshold for differentially expression. (E) Venn diagram of differential proteins identified in normal control (0 d) versus acupuncture (0 d) and acupuncture (0 d) versus acupuncture (10 d), indicating 2 overlaps between sample groups. (F) Expression level of the two overlap proteins. TDRD3: tudor domain-containing protein 3, PLF4: platelet factor 4.
Fig.5  Integrated pathway analysis. Integrated pathway enrichment of acupuncture (A) and sham acupuncture (B) related targets based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Network map of enriched pathways (C). Targets regulated by acupuncture were marked in yellow.
Fig.6  Interactions between clinical, fMRI, and omics data. Purple circles denote brain regions with significant changes after acupuncture treatment. Blue circles denote differential metabolites/proteins after acupuncture. Green circles denote clinical outcomes that significantly changed after acupuncture. Line thickness of the edges indicates Pearson correlation coefficient between nodes, positive correlations were marked in red, negative correlations were marked in blue. Visual Analogue Scale (VAS), Pittsburgh Sleep Quality Index (PSQI), Migraine Specific Quality-of-Life Questionnaire (MSQ).
1 SR Haut, ME Bigal, RB Lipton. Chronic disorders with episodic manifestations: focus on epilepsy and migraine. Lancet Neurol 2006; 5(2): 148–157
https://doi.org/10.1016/S1474-4422(06)70348-9 pmid: 16426991
2 TJ Steiner, LJ Stovner, Z Katsarava, JM Lainez, C Lampl, M Lantéri-Minet, D Rastenyte, de la Torre E Ruiz, C Tassorelli, J Barré, C Andrée. The impact of headache in Europe: principal results of the Eurolight project. J Headache Pain 2014; 15(1): 31
https://doi.org/10.1186/1129-2377-15-31 pmid: 24884549
3 C LewS Punnapuzha. Migraine Medications. Treasure Island (FL): StatPearls Publishing. 2022
4 HC Diener, F Antonaci, M Braschinsky, S Evers, R Jensen, M Lainez, ES Kristoffersen, C Tassorelli, K Ryliskiene, JA Petersen. European Academy of Neurology guideline on the management of medication-overuse headache. Eur J Neurol 2020; 27(7): 1102–1116
https://doi.org/10.1111/ene.14268 pmid: 32430926
5 A May, LH Schulte. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol 2016; 12(8): 455–464
https://doi.org/10.1038/nrneurol.2016.93 pmid: 27389092
6 SD Silberstein, S Holland, F Freitag, DW Dodick, C Argoff, E; Quality Standards Subcommittee of the American Academy of Neurology Ashman, American Headache Society the. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012; 78(17): 1337–1345
https://doi.org/10.1212/WNL.0b013e3182535d20 pmid: 22529202
7 I Urits, M Patel, ME Putz, NR Monteferrante, D Nguyen, D An, EM Cornett, J Hasoon, AD Kaye, O Viswanath. Acupuncture and its role in the treatment of migraine headaches. Neurol Ther 2020; 9(2): 375–394
https://doi.org/10.1007/s40120-020-00216-1 pmid: 33001385
8 RB Kelly, J Willis. Acupuncture for pain. Am Fam Physician 2019; 100(2): 89–96
pmid: 31305037
9 TJ Kaptchuk. Acupuncture: theory, efficacy, and practice. Ann Intern Med 2002; 136(5): 374–383
https://doi.org/10.7326/0003-4819-136-5-200203050-00010 pmid: 11874310
10 JS Han. Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci 2003; 26(1): 17–22
https://doi.org/10.1016/S0166-2236(02)00006-1 pmid: 12495858
11 FJ Zijlstra, I van den Berg-de Lange, FJ Huygen, J Klein. Anti-inflammatory actions of acupuncture. Mediators Inflamm 2003; 12(2): 59–69
https://doi.org/10.1080/0962935031000114943 pmid: 12775355
12 PS Patel, MT Minen. Complementary and integrative health treatments for migraine. J Neuroophthalmol 2019; 39(3): 360–369
https://doi.org/10.1097/WNO.0000000000000841 pmid: 31403967
13 S Liu, S Luo, T Yan, W Ma, X Wei, Y Chen, S Zhan, B Wang. Differential modulating effect of acupuncture in patients with migraine without aura: a resting functional magnetic resonance study. Front Neurol 2021; 12: 680896
https://doi.org/10.3389/fneur.2021.680896 pmid: 34122321
14 B ColomboR MessinaMA RoccaM Filippi. Imaging the migrainous brain: the present and the future. Neurol Sci 2019; 40(S1 Suppl 1): 49–54 doi:10.1007/s10072-019-03851-1
pmid: 30906964
15 K Qiu, T Yin, X Hong, R Sun, Z He, X Liu, P Ma, J Yang, L Lan, Z Li, C Tang, S Cheng, F Liang, F Zeng. Does the acupoint specificity exist? Evidence from functional neuroimaging studies.. Curr Med Imaging Rev 2020; 16(6): 629–638
https://doi.org/10.2174/1573405615666190220113111 pmid: 32723234
16 WT Zhang, Z Jin, GH Cui, KL Zhang, L Zhang, YW Zeng, F Luo, AC Chen, JS Han. Relations between brain network activation and analgesic effect induced by low vs high frequency electrical acupoint stimulation in different subjects: a functional magnetic resonance imaging study. Brain Res 2003; 982(2): 168–178
https://doi.org/10.1016/S0006-8993(03)02983-4 pmid: 12915252
17 CM Chang, CP Yang, CC Yang, PH Shih, SJ Wang. Evidence of potential mechanisms of acupuncture from functional MRI data for migraine prophylaxis. Curr Pain Headache Rep 2021; 25(7): 49
https://doi.org/10.1007/s11916-021-00961-4 pmid: 34036477
18 CG Yan, XD Wang, XN Zuo, YF Zang. DPABI: data processing & analysis for (resting-state) brain imaging. Neuroinformatics 2016; 14(3): 339–351
https://doi.org/10.1007/s12021-016-9299-4 pmid: 27075850
19 QH Zou, CZ Zhu, Y Yang, XN Zuo, XY Long, QJ Cao, YF Wang, YF Zang. An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: fractional ALFF. J Neurosci Methods 2008; 172(1): 137–141
https://doi.org/10.1016/j.jneumeth.2008.04.012 pmid: 18501969
20 Y Zang, T Jiang, Y Lu, Y He, L Tian. Regional homogeneity approach to fMRI data analysis. Neuroimage 2004; 22(1): 394–400
https://doi.org/10.1016/j.neuroimage.2003.12.030 pmid: 15110032
21 B Wen, R Zhou, Q Feng, Q Wang, J Wang, S Liu. IQuant: an automated pipeline for quantitative proteomics based upon isobaric tags. Proteomics 2014; 14(20): 2280–2285
https://doi.org/10.1002/pmic.201300361 pmid: 25069810
22 E Vachon-Presseau, SE Berger, TB Abdullah, L Huang, GA Cecchi, JW Griffith, TJ Schnitzer, AV Apkarian. Brain and psychological determinants of placebo pill response in chronic pain patients. Nat Commun 2018; 9(1): 3397
https://doi.org/10.1038/s41467-018-05859-1 pmid: 30209286
23 MA Dahlem, N Hadjikhani. Migraine aura: retracting particle-like waves in weakly susceptible cortex. PLoS One 2009; 4(4): e5007
https://doi.org/10.1371/journal.pone.0005007 pmid: 19337363
24 XL QinWY WangJZ WangWY XieYM Zhang YQ Gao. Analysis on regional homogeneity of resting brain during balance acupuncture-induced analgesic effect in migraine patients without aura. Acupunct Res (Zhen Ci Yan Jiu) 2019; 44(6): 446–450 (in Chinese)
pmid: 31368270
25 L Zhao, J Liu, F Zhang, X Dong, Y Peng, W Qin, F Wu, Y Li, K Yuan, KM von Deneen, Q Gong, Z Tang, F Liang. Effects of long-term acupuncture treatment on resting-state brain activity in migraine patients: a randomized controlled trial on active acupoints and inactive acupoints. PLoS One 2014; 9(6): e99538
https://doi.org/10.1371/journal.pone.0099538 pmid: 24915066
26 WK Amery. Brain hypoxia: the turning-point in the genesis of the migraine attack? Cephalalgia 1982; 2(2): 83–109 doi:10.1046/j.1468-2982.1982.0202083.x
pmid: 6751554
27 EC Gross, M Lisicki, D Fischer, PS Sándor, J Schoenen. The metabolic face of migraine—from pathophysiology to treatment. Nat Rev Neurol 2019; 15(11): 627–643
https://doi.org/10.1038/s41582-019-0255-4 pmid: 31586135
28 L EdvinssonKA HaanesK Warfvinge. Does inflammation have a role in migraine? Nat Rev Neurol 2019; 15(8): 483–490 doi:10.1038/s41582-019-0216-y
pmid: 31263254
29 L Liu, W Li, L Wang, P Gong, T Lyu, D Liu, Y Zhang, Y Guo, X Liu, M Tang, H Hu, C Liu, B Li. Proteomic and metabolomic profiling of acupuncture for migraine reveals a correlative link via energy metabolism. Front Neurosci 2022; 16: 1013328
https://doi.org/10.3389/fnins.2022.1013328 pmid: 36248663
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