The modulation effect of longitudinal acupuncture on resting state functional connectivity in knee osteoarthritis patients

Molecular Pain

Jian Kong²  Randy L. Gollub²  Robert R. Edwards³  Ajay D. Wasan¹  Jianren Mao⁵  Mark Vangel⁷  Natalia Egorova⁶  Hsiao-Ying Wey⁶  Javeria A. Hashmi⁶  Donna Moxley Scarborough⁴  Sonya G. Freeman⁶  Rosa B. Spaeth⁶  Xiaoyan Chen⁶ 

[1]Departments of Anesthesiology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

[2]MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, 120, 2nd Ave. Suite 101, Charlestown 02129, MA, USA

[3]Departments of Anesthesiology, Perioperative, and Pain Medicine, and Psychiatry, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

[4]Mass General Orthopaedics Sports Performance Center, Massachusetts General Hospital, Foxborough, MA, USA

[5]Departments of Anesthesiology, Massachusetts General Hospital, Charlestown, MA, USA

[6]Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA, USA

[7]Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA

关键词: Executive control network;    Right frontoparietal network;    Knee injury and Osteoarthritis Outcome Score (KOOS);    Independent component analysis (ICA);    Resting state fMRI;    Chronic pain;    Knee osteoarthritis;    Acupuncture;   

Others  :  1233610
DOI  :  10.1186/s12990-015-0071-9

 received in 2015-06-22, accepted in 2015-10-15,  发布年份 2015

【 摘 要 】

Recent advances in brain imaging have contributed to our understanding of the neural activity associated with acupuncture treatment. In this study, we investigated functional connectivity across longitudinal acupuncture treatments in older patients with knee osteoarthritis (OA). Over a period of 4 weeks (six treatments), we collected resting state functional magnetic resonance imaging (fMRI) scans from 30 patients before and after their first, third and sixth treatments. Clinical outcome showed a significantly greater pain subscore on the Knee Injury and Osteoarthritis Outcome Score (KOOS) (indicative of improvement) with verum acupuncture than with sham acupuncture. Independent component analysis (ICA) of the resting state fMRI data showed that the right frontoparietal network (rFPN) and the executive control network (ECN) showed enhanced functional connectivity (FC) with the rostral anterior cingulate cortex/medial prefrontal cortex, a key region in the descending pain modulatory system, in the verum groups as compared to the sham group after treatments. We also found that the rFPN connectivity with the left insula is (1) significantly associated with changes in KOOS pain score after treatments, and (2) significantly enhanced after verum acupuncture treatments as compared to sham treatment. Analysis of the acupuncture needle stimulation scan showed that compared with sham treatment, verum acupuncture activated the left operculum/insula, which also overlaps with findings observed in resting state analysis. Our results suggest that acupuncture may achieve its therapeutic effect on knee OA pain by modulating functional connectivity between the rFPN, ECN and the descending pain modulatory pathway.

Clinical trial number: NCT01079390

【 授权许可】

   
2015 Chen et al.

【 图 表 】

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【 参考文献 】

• [1]Ho-Pham LT, Lai TQ, Mai LD, Doan MC, Pham HN, Nguyen TV: Prevalence of radiographic osteoarthritis of the knee and its relationship to self-reported pain. PLoS One 2014, 9(4):e94563.
• [2]Nguyen US, Zhang Y, Zhu Y, Niu J, Zhang B, Felson DT: Increasing prevalence of knee pain and symptomatic knee osteoarthritis: survey and cohort data. Ann Intern Med 2011, 155(11):725-732.
• [3]Hochman JR, Davis AM, Elkayam J, Gagliese L, Hawker GA: Neuropathic pain symptoms on the modified painDETECT correlate with signs of central sensitization in knee osteoarthritis. Osteoarthr Cartil 2013, 21(9):1236-1242.
• [4]Arendt-Nielsen L, Nie H, Laursen MB, Laursen BS, Madeleine P, Simonsen OH, et al.: Sensitization in patients with painful knee osteoarthritis. Pain 2010, 149(3):573-581.
• [5]Finan PH, Buenaver LF, Bounds SC, Hussain S, Park RJ, Haque UJ, et al.: Discordance between pain and radiographic severity in knee osteoarthritis: findings from quantitative sensory testing of central sensitization. Arthritis Rheum 2013, 65(2):363-372.
• [6]Gwilym SE, Keltner JR, Warnaby CE, Carr AJ, Chizh B, Chessell I, et al.: Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients. Arthritis Rheum 2009, 61(9):1226-1234.
• [7]Gay MC, Philippot P, Luminet O: Differential effectiveness of psychological interventions for reducing osteoarthritis pain: a comparison of Erikson [correction of Erickson] hypnosis and Jacobson relaxation. Eur J Pain 2002, 6(1):1-16.
• [8]Berman BM, Lao L, Langenberg P, Lee WL, Gilpin AM, Hochberg MC: Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial. Ann Intern Med 2004, 141(12):901-910.
• [9]Felson DT, Lawrence RC, Hochberg MC, McAlindon T, Dieppe PA, Minor MA, et al.: Osteoarthritis: new insights. Part 2: treatment approaches. Ann Intern Med 2000, 133(9):726-737.
• [10]Witt C, Brinkhaus B, Jena S, Linde K, Streng A, Wagenpfeil S, et al.: Acupuncture in patients with osteoarthritis of the knee: a randomised trial. Lancet 2005, 366(9480):136-143.
• [11]Scharf HP, Mansmann U, Streitberger K, Witte S, Kramer J, Maier C, et al.: Acupuncture and knee osteoarthritis: a three-armed randomized trial. Ann Intern Med 2006, 145(1):12-20.
• [12]Mavrommatis CI, Argyra E, Vadalouka A, Vasilakos DG: Acupuncture as an adjunctive therapy to pharmacological treatment in patients with chronic pain due to osteoarthritis of the knee: a 3-armed, randomized, placebo-controlled trial. Pain 2012, 153(8):1720-1726.
• [13]Hinman RS, McCrory P, Pirotta M, Relf I, Forbes A, Crossley K, et al.: Acupuncture for chronic knee pain a randomized clinical trial. JAMA 2014, 312(13):1313-1322.
• [14]Suarez-Almazor M, Looney C, Kiu Y, Cox V, Pietz K, Marcus D, et al.: A randomized controlled trial of acupuncture for osteoarthritis of the knee: effects of patient-practitioner communication. Arthritis Care Res 2010, 62:1229-1236.
• [15]MacPherson H, Thomas K, Walters S, Fitter M: The York acupuncture safety study: prospective survey of 34 000 treatments by traditional acupuncturists. BMJ 2001, 323(7311):486-487.
• [16]White A, Hayhoe S, Hart A, Ernst E: Adverse events following acupuncture: prospective survey of 32 000 consultations with doctors and physiotherapists. BMJ 2001, 323(7311):485-486.
• [17]Melchart D, Weidenhammer W, Streng A, Reitmayr S, Hoppe A, Ernst E, et al.: Prospective investigation of adverse effects of acupuncture in 97 733 patients. Arch Intern Med 2004, 164(1):104-105.
• [18]Ochi JW: Acupuncture instead of codeine for tonsillectomy pain in children. Int J Pediatr Otorhinolaryngol 2013, 77(12):2058-2062.
• [19]Han JS: Acupuncture analgesia: areas of consensus and controversy. Pain 2011, 152(3 Suppl):S41-S48.
• [20]Hans JS. Physiology of acupuncture: review of thirty years of research. J Altern Complement Med. 1997;(Suppl 1):S101–8.
• [21]Zhao ZQ: Neural mechanism underlying acupuncture analgesia. Prog Neurobiol 2008, 85(4):355-375.
• [22]Dougherty DD, Kong J, Webb M, Bonab AA, Fischman AJ, Gollub RL. A combined [11C]diprenorphine PET study and fMRI study of acupuncture analgesia. Behav Brain Res. 2008;193(1):63–8 (PMCID: PMC2538486).
• [23]Chae Y, Chang DS, Lee SH, Jung WM, Lee IS, Jackson S, et al.: Inserting needles into the body: a meta-analysis of brain activity associated with acupuncture needle stimulation. J Pain 2013, 14(3):215-222.
• [24]Huang W, Pach D, Napadow V, Park K, Long X, Neumann J, et al.: Characterizing acupuncture stimuli using brain imaging with FMRI—a systematic review and meta-analysis of the literature. PLoS One 2012, 7(4):e32960.
• [25]Kong J, Ma L, Gollub RL, Wei J, Yang X, Li D, et al.: A pilot study of functional magnetic resonance imaging of the brain during manual and electroacupuncture stimulation of acupuncture point (LI-4 Hegu) in normal subjects reveals differential brain activation between methods. J Altern Complement Med 2002, 8(4):411-419.
• [26]Kong J, Gollub RL, Webb JM, Kong JT, Vangel MG, Kwong K. Test-retest study of fMRI signal change evoked by electroacupuncture stimulation. Neuroimage. 2007;34(3):1171–81 (PMCID: PMC1994822).
• [27]Leung A, Zhao Y, Shukla S: The effect of acupuncture needle combination on central pain processing—an fMRI study. Mol Pain 2014, 10:23. BioMed Central Full Text
• [28]Zyloney CE, Jensen K, Polich G, Loiotile RE, Cheetham A, LaViolette PS, et al.: Imaging the functional connectivity of the Periaqueductal Gray during genuine and sham electroacupuncture treatment. Mol Pain 2010, 6:80. BioMed Central Full Text
• [29]Dhond RP, Yeh C, Park K, Kettner N, Napadow V: Acupuncture modulates resting state connectivity in default and sensorimotor brain networks. Pain 2008, 136(3):407-418.
• [30]Liu P, Qin W, Zhang Y, Tian J, Bai L, Zhou G, et al.: Combining spatial and temporal information to explore function-guide action of acupuncture using fMRI. J Magn Reson Imaging 2009, 30(1):41-46.
• [31]Bai L, Qin W, Tian J, Dong M, Pan X, Chen P, et al.: Acupuncture modulates spontaneous activities in the anticorrelated resting brain networks. Brain Res 2009, 1279:37-49.
• [32]Qin W, Tian J, Bai L, Pan X, Yang L, Chen P, et al.: FMRI connectivity analysis of acupuncture effects on an amygdala-associated brain network. Mol Pain 2008, 4:55. BioMed Central Full Text
• [33]Liu B, Chen J, Wang J, Liu X, Duan X, Shang X, et al.: Altered small-world efficiency of brain functional networks in acupuncture at ST36: a functional MRI study. PLoS One 2012, 7(6):e39342.
• [34]Sun R, Yang Y, Li Z, Li Y, Cheng S, Zeng F: Connectomics: a New Direction in Research to Understand the Mechanism of Acupuncture. Evid Based Complement Alternat Med 2014, 2014:568429.
• [35]Zhang Y, Qin W, Liu P, Tian J, Liang J, von Deneen KM, et al.: An fMRI study of acupuncture using independent component analysis. Neurosci Lett 2009, 449(1):6-9.
• [36]Apkarian AV, Baliki MN, Geha PY: Towards a theory of chronic pain. Prog Neurobiol 2009, 87(2):81-97.
• [37]Bushnell MC: How neuroimaging studies have challenged us to rethink: is chronic pain a disease? J Pain 2009, 10(11):1113-1120.
• [38]Davis KD, Moayedi M: Central mechanisms of pain revealed through functional and structural MRI. J Neuroimmune Pharmacol 2013, 8(3):518-534.
• [39]Baliki MN, Petre B, Torbey S, Herrmann KM, Huang L, Schnitzer TJ et al. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat Neurosci. 2012.doi:10.1038/nn.3153.
• [40]Loggia ML, Kim J, Gollub RL, Vangel MG, Kirsch I, Kong J, et al.: Default mode network connectivity encodes clinical pain: an arterial spin labeling study. Pain 2013, 154:24-33.
• [41]Kong J, Spaech R, Wey HY, Cheetham A, Cook A, Jensen K et al. S1 is associated with chronic low back pain: a functional and structural MRI study. Molecular pain. 2013;9(43):doi:10.1186/744-8069-9-43.
• [42]Niesters M, Khalili-Mahani N, Martini C, Aarts L, van Gerven J, van Buchem MA, et al.: Effect of subanesthetic ketamine on intrinsic functional brain connectivity: a placebo-controlled functional magnetic resonance imaging study in healthy male volunteers. Anesthesiology 2012, 117(4):868-877.
• [43]Harris RE, Napadow V, Huggins JP, Pauer L, Kim J, Hampson J, et al.: Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. Anesthesiology 2013, 119(6):1453-1464.
• [44]Roos EM, Toksvig-Larsen S: Knee injury and Osteoarthritis Outcome Score (KOOS) – validation and comparison to the WOMAC in total knee replacement. Health Quality Life Outcomes 2003, 1(17):1-10.
• [45]Spaeth RB, Camhi S, Hashmi JA, Vangel M, Wasan AD, Edwards RR, et al.: A longitudinal study of the reliability of acupuncture deqi sensations in knee osteoarthritis. Evid Based Complement Alternat Med. 2013, 2013:204259.
• [46]Kong J, Gollub R, Huang T, Polich G, Napadow V, Hui K, et al.: Acupuncture de qi, from qualitative history to quantitative measurement. J Altern Complement Med 2007, 13(10):1059-1070.
• [47]Kong J, Jensen K, Loiotile R, Cheetham A, Wey HY, Tan T, et al.: Functional connectivity of frontoparietal network predicts cognitive modulation of pain. Pain 2013, 154(3):459-467.
• [48]Biswal BB, Mennes M, Zuo XN, Gohel S, Kelly C, Smith SM, et al.: Toward discovery science of human brain function. Proc Natl Acad Sci USA 2010, 107(10):4734-4739.
• [49]Goldin PR, Ziv M, Jazaieri H, Hahn K, Heimberg R, Gross JJ: Impact of cognitive behavioral therapy for social anxiety disorder on the neural dynamics of cognitive reappraisal of negative self-beliefs: randomized clinical trial. JAMA Psychiatry 2013, 70(10):1048-1056.
• [50]Pavuluri MN, Ellis JA, Wegbreit E, Passarotti AM, Stevens MC: Pharmacotherapy impacts functional connectivity among affective circuits during response inhibition in pediatric mania. Behav Brain Res 2012, 226(2):493-503.
• [51]Fang J, Rong P, Hong Y, Fan Y, Liu J, Wang H, et al.: Transcutaneous vagus nerve stimulation modulates default mode network in major depressive disorder. Biol Psychiatry 2015.
• [52]Apkarian AV, Bushnell MC, Treede RD, Zubieta JK: Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 2005, 9(4):463-484.
• [53]Tracey I, Mantyh PW: The cerebral signature for pain perception and its modulation. Neuron 2007, 55(3):377-391.
• [54]Kong J, Gollub RL, Rosman IS, Webb JM, Vangel MG, Kirsch I, et al.: Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging. J Neurosci 2006, 26(2):381-388.
• [55]Kong J, Loggia ML, Zyloney C, Tu P, Laviolette P, Gollub RL: Exploring the brain in pain: activations, deactivations and their relation. Pain 2010, 148:257-267.
• [56]Smith SM, Fox PT, Miller KL, Glahn DC, Fox PM, Mackay CE, et al.: Correspondence of the brain’s functional architecture during activation and rest. Proc Natl Acad Sci USA 2009, 106(31):13040-13045.
• [57]Downar J, Crawley AP, Mikulis DJ, Davis KD: A multimodal cortical network for the detection of changes in the sensory environment. Nat Neurosci 2000, 3(3):277-283.
• [58]Vincent JL, Kahn I, Snyder AZ, Raichle ME, Buckner RL: Evidence for a frontoparietal control system revealed by intrinsic functional connectivity. J Neurophysiol 2008, 100(6):3328-3342.
• [59]Mayer EA, Berman S, Suyenobu B, Labus J, Mandelkern MA, Naliboff BD, et al.: Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis. Pain 2005, 115(3):398-409.
• [60]Kong J, Kaptchuk TJ, Polich G, Kirsch I, Gollub RL: Placebo analgesia: findings from brain imaging studies and emerging hypotheses. Rev Neurosci 2007, 18(3–4):173-190.
• [61]Goldman-Rakic PS: Topography of cognition: parallel distributed networks in primate association cortex. Annu Rev Neurosci 1988, 11:137-156.
• [62]Parks EL, Geha PY, Baliki MN, Katz J, Schnitzer TJ, Apkarian AV. Brain activity for chronic knee osteoarthritis: dissociating evoked pain from spontaneous pain. Eur J Pain. 2011;15(8):843 e1–14. doi:10.1016/j.ejpain.2010.12.007.
• [63]Howard MA, Sanders D, Krause K, O’Muircheartaigh J, Fotopoulou A, Zelaya F, et al.: Alterations in resting-state regional cerebral blood flow demonstrate ongoing pain in osteoarthritis: an arterial spin-labeled magnetic resonance imaging study. Arthritis Rheum 2012, 64(12):3936-3946.
• [64]Miller EK: The prefrontal cortex and cognitive control. Nat Rev Neurosci 2000, 1(1):59-65.
• [65]Corbetta M, Shulman GL: Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci 2002, 3(3):201-215.
• [66]Ridderinkhof KR, Ullsperger M, Crone EA, Nieuwenhuis S: The role of the medial frontal cortex in cognitive control. Science 2004, 306(5695):443-447.
• [67]Matsumoto K, Tanaka K: Neuroscience. Conflict and cognitive control. Science 2004, 303(5660):969-970.
• [68]Carter CS, van Veen V: Anterior cingulate cortex and conflict detection: an update of theory and data. Cogn Affect Behav Neurosci 2007, 7(4):367-379.
• [69]Crone EA, Wendelken C, Donohue SE, Bunge SA: Neural evidence for dissociable components of task-switching. Cereb Cortex 2006, 16(4):475-486.
• [70]Fields H: State-dependent opioid control of pain. Nat Rev Neurosci 2004, 5(7):565-575.
• [71]Tracey I, Ploghaus A, Gati JS, Clare S, Smith S, Menon RS, et al.: Imaging attentional modulation of pain in the periaqueductal gray in humans. J Neurosci 2002, 22(7):2748-2752.
• [72]Jensen KB, Loitoile R, Kosek E, Petzke F, Carville S, Fransson P, et al.: Patients with fibromyalgia display less functional connectivity in the brain’s pain inhibitory network. Mol Pain. 2012, 8(1):32. BioMed Central Full Text
• [73]Yu R, Gollub R, Spaetha R, Napadowa V, Wasana A, Kong J. Disrupted functional connectivity of the periaqueductal gray in chronic low back pain. NeuroImage. 2014;6:100–8.
• [74]Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J, et al.: Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 2009, 63(4):533-543.
• [75]Kong J, Tu PC, Zyloney C, Su TP: Intrinsic functional connectivity of the periaqueductal gray, a resting fMRI study. Behav Brain Res 2010, 211(2):215-219.
• [76]Kucyi A, Salomons TV, Davis KD: Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks. Proc Natl Acad Sci USA 2013, 110(46):18692-18697.
• [77]Salomons TV, Johnstone T, Backonja MM, Davidson RJ: Perceived controllability modulates the neural response to pain. J Neurosci 2004, 24:7199-7203.
• [78]Egorova N, Gollub R, J K. Repeated verum but not placebo acupuncture normalizes connectivity in brain regions dysregulated in chronic pain. NeuroImage. 2015. doi:10.1016/j.nicl.2015.09.012.
• [79]Chen XY, Spaeth RB, Retzepi K, Ott D, Kong J. Acupuncture modulates cortical thickness and functional connectivity in knee osteoarthritis patients. Sci Rep 2014;4(6482). doi:10.1038/srep06482.
• [80]Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC: Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 1997, 277:968-971.
• [81]Price DD: Psychological and neural mechanisms of the affective dimension of pain. Science 2000, 288:1769-1772.
• [82]Kong J, Gollub RL, Polich G, Kirsch I, Laviolette P, Vangel M et al. A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. J Neurosci. 2008;28(49):13354–62 (PMCID: PMC2649754).
• [83]Zhang Y, Meng X, Li A, Xin J, Berman BM, Lao L, et al.: Electroacupuncture alleviates affective pain in an inflammatory pain rat model. Eur J Pain 2012, 16(2):170-181.
• [84]Fang J, Jin Z, Wang Y, Li K, Kong J, Nixon EE, et al.: The salient characteristics of the central effects of acupuncture needling: limbic-paralimbic-neocortical network modulation. Hum Brain Mapp 2009, 30(4):1196-1206.
• [85]Qin W, Bai L, Dai J, Liu P, Dong M, Liu J, et al.: The temporal-spatial encoding of acupuncture effects in the brain. Mol Pain 2011, 7:19. BioMed Central Full Text
• [86]Kong J, Ma L, Gollub RL, Wei J, Yang X, Li D, et al.: A pilot study of functional magnetic resonance imaging of the brain during manual and electroacupuncture stimulation of acupuncture point (LI-4 Hegu) in normal subjects reveals differential brain activation between methods. J Altern Complement Med 2002, 8(4):411-419.
• [87]Pariente J, White P, Frackowiak RS, Lewith G: Expectancy and belief modulate the neuronal substrates of pain treated by acupuncture. Neuroimage 2005, 25(4):1161-1167.
• [88]Eickhoff SB, Schleicher A, Zilles K, Amunts K: The human parietal operculum. I. Cytoarchitectonic mapping of subdivisions. Cereb Cortex 2006, 16(2):254-267.
• [89]Menon V, Uddin LQ: Saliency, switching, attention and control: a network model of insula function. Brain Struct Funct 2010, 214(5–6):655-667.
• [90]Melzack R: Folk Medicine and the sensory modulation of pain. In Textbook of Pain. Edited by Wall PD, Melzack R. Churchill Livingstone, London; 1994:1209-1217.
• [91]Dumville J, Hahn S, Miles J, Torgerson D: The use of unequal randomisation ratios in clinical trials: a review. Contemp Clin Trials 2006, 27:1-12.
• [92]Streitberger K, Kleinhenz J: Introducing a placebo needle into acupuncture research. Lancet 1998, 352:364-365.
• [93]Kong J, Fufa DT, Gerber AJ, Rosman IS, Vangel MG, Gracely RH, et al.: Psychophysical outcomes from a randomized pilot study of manual, electro, and sham acupuncture treatment on experimentally induced thermal pain. J Pain 2005, 6(1):55-64.
• [94]Zhu D, Gao Y, Chang J, Kong J: Placebo acupuncture devices: considerations for acupuncture research. Evid Based Complement Alternat Med 2013, 2013:628907.
• [95]Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, et al.: Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004, 23(Suppl 1):S208-S219.
• [96]Beckmann CF, Smith SM: Probabilistic independent component analysis for functional magnetic resonance imaging. IEEE Trans Med Imaging 2004, 23(2):137-152.
• [97]Xue T, Yuan K, Zhao L, Yu D, Dong T, Cheng P, et al.: Intrinsic brain network abnormalities in migraines without aura revealed in resting-state fMRI. PLoS One 2012, 7(12):e52927.
• [98]Russo A, Tessitore A, Giordano A, Corbo D, Marcuccio L, De Stefano M, et al.: Executive resting-state network connectivity in migraine without aura. Cephalalgia 2012, 32(14):1041-1048.
• [99]Bai L, Qin W, Tian J, Liu P, Li L, Chen P, et al.: Time-varied characteristics of acupuncture effects in fMRI studies. Hum Brain Mapp 2009, 30(11):3445-3460.
• [100]Bai L, Tian J, Zhong C, Xue T, You Y, Liu Z, et al.: Acupuncture modulates temporal neural responses in wide brain networks: evidence from fMRI study. Mol Pain 2010, 6:73. BioMed Central Full Text
• [101]Wiech K, Jbabdi S, Lin CS, Andersson J, Tracey I: Differential structural and resting state connectivity between insular subdivisions and other pain-related brain regions. Pain 2014, 155(10):2047-2055.
• [102]Wiech K, Lin CS, Brodersen KH, Bingel U, Ploner M, Tracey I: Anterior insula integrates information about salience into perceptual decisions about pain. J Neurosci 2010, 30(48):16324-16331.