Discovery of the mechanisms of acupuncture in the treatment of migraine based on functional magnetic resonance imaging and omics

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

References

[1] Haut SR, Bigal ME, Lipton RB. Chronic disorders with episodic manifestations: focus on epilepsy and migraine. Lancet Neurol 2006; 5(2): 148–157

[2] Steiner TJ, Stovner LJ, Katsarava Z, Lainez JM, Lampl C, Lantéri-Minet M, Rastenyte D, Ruiz de la Torre E, Tassorelli C, Barré J, Andrée C. The impact of headache in Europe: principal results of the Eurolight project. J Headache Pain 2014; 15(1): 31

[3] LewCPunnapuzha S. Migraine Medications. Treasure Island (FL): StatPearls Publishing. 2022

[4] Diener HC, Antonaci F, Braschinsky M, Evers S, Jensen R, Lainez M, Kristoffersen ES, Tassorelli C, Ryliskiene K, Petersen JA. European Academy of Neurology guideline on the management of medication-overuse headache. Eur J Neurol 2020; 27(7): 1102–1116

[5] May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol 2016; 12(8): 455–464

[6] Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E; Quality Standards Subcommittee of the American Academy of Neurology, the American Headache Society. 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

[7] Urits I, Patel M, Putz ME, Monteferrante NR, Nguyen D, An D, Cornett EM, Hasoon J, Kaye AD, Viswanath O. Acupuncture and its role in the treatment of migraine headaches. Neurol Ther 2020; 9(2): 375–394

[8] Kelly RB, Willis J. Acupuncture for pain. Am Fam Physician 2019; 100(2): 89–96

[9] Kaptchuk TJ. Acupuncture: theory, efficacy, and practice. Ann Intern Med 2002; 136(5): 374–383

[10] Han JS. Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci 2003; 26(1): 17–22

[11] Zijlstra FJ, van den Berg-de Lange I, Huygen FJ, Klein J. Anti-inflammatory actions of acupuncture. Mediators Inflamm 2003; 12(2): 59–69

[12] Patel PS, Minen MT. Complementary and integrative health treatments for migraine. J Neuroophthalmol 2019; 39(3): 360–369

[13] Liu S, Luo S, Yan T, Ma W, Wei X, Chen Y, Zhan S, Wang B. Differential modulating effect of acupuncture in patients with migraine without aura: a resting functional magnetic resonance study. Front Neurol 2021; 12: 680896

[14] ColomboBMessina RRoccaMAFilippiM. 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

[15] Qiu K, Yin T, Hong X, Sun R, He Z, Liu X, Ma P, Yang J, Lan L, Li Z, Tang C, Cheng S, Liang F, Zeng F. Does the acupoint specificity exist? Evidence from functional neuroimaging studies.. Curr Med Imaging Rev 2020; 16(6): 629–638

[16] Zhang WT, Jin Z, Cui GH, Zhang KL, Zhang L, Zeng YW, Luo F, Chen AC, Han JS. 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

[17] Chang CM, Yang CP, Yang CC, Shih PH, Wang SJ. Evidence of potential mechanisms of acupuncture from functional MRI data for migraine prophylaxis. Curr Pain Headache Rep 2021; 25(7): 49

[18] Yan CG, Wang XD, Zuo XN, Zang YF. DPABI: data processing & analysis for (resting-state) brain imaging. Neuroinformatics 2016; 14(3): 339–351

[19] Zou QH, Zhu CZ, Yang Y, Zuo XN, Long XY, Cao QJ, Wang YF, Zang YF. 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

[20] Zang Y, Jiang T, Lu Y, He Y, Tian L. Regional homogeneity approach to fMRI data analysis. Neuroimage 2004; 22(1): 394–400

[21] Wen B, Zhou R, Feng Q, Wang Q, Wang J, Liu S. IQuant: an automated pipeline for quantitative proteomics based upon isobaric tags. Proteomics 2014; 14(20): 2280–2285

[22] Vachon-Presseau E, Berger SE, Abdullah TB, Huang L, Cecchi GA, Griffith JW, Schnitzer TJ, Apkarian AV. Brain and psychological determinants of placebo pill response in chronic pain patients. Nat Commun 2018; 9(1): 3397

[23] Dahlem MA, Hadjikhani N. Migraine aura: retracting particle-like waves in weakly susceptible cortex. PLoS One 2009; 4(4): e5007

[24] QinXLWang WYWangJZXieWYZhangYM GaoYQ. 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)

[25] Zhao L, Liu J, Zhang F, Dong X, Peng Y, Qin W, Wu F, Li Y, Yuan K, von Deneen KM, Gong Q, Tang Z, Liang F. 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

[26] AmeryWK. 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

[27] Gross EC, Lisicki M, Fischer D, Sándor PS, Schoenen J. The metabolic face of migraine—from pathophysiology to treatment. Nat Rev Neurol 2019; 15(11): 627–643

[28] EdvinssonLHaanes KAWarfvingeK. Does inflammation have a role in migraine? Nat Rev Neurol 2019; 15(8): 483–490 doi:10.1038/s41582-019-0216-y

[29] Liu L, Li W, Wang L, Gong P, Lyu T, Liu D, Zhang Y, Guo Y, Liu X, Tang M, Hu H, Liu C, Li B. Proteomic and metabolomic profiling of acupuncture for migraine reveals a correlative link via energy metabolism. Front Neurosci 2022; 16: 1013328

Acknowledgements

This work was supported by grants from the Ten Thousand Talents Project of the Ministry of Science and Technology, the Young Qihuang Scholars Project of the National Administration of Traditional Chinese Medicine Program and the Beijing Young Talents Program. We thank Yulong Li from Peking University School of Life Sciences as well as scientists in his laboratory for helpful discussions and viewpoints.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-0989-7 and is accessible for authorized users. Supplementary material includes Figs.S1–S4, Tables S1–S9.

Compliance with ethics guidelines

Chong Li, Xinyi Li, Ke He, Yang Wu, Xiaoming Xie, Jiju Yang, Fan Zhang, Yang Yue, Huifeng Hao, Shaokun Zhao, Xin Li, and Guihua Tian declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. The study was approved by the Ethics Committee of the Beijing University of Chinese Medicine (DZMEC-KY-2018-44).

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