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Clinical Effects of Repetitive Transcranial Magnetic Stimulation of the Motor Cortex Are Associated with Changes in Resting-State Functional Connectivity in Patients with Fibromyalgia Syndrome

Published:November 13, 2021DOI:https://doi.org/10.1016/j.jpain.2021.11.001

      Highlights

      • Non-invasive motor cortex stimulation improves fibromyalgia pain and daily function
      • Resting-state functional connectivity reduction accompanies these clinical effects
      • Clinical and connectivity changes occur after active, but not sham, treatment
      • Connectivity changes occur in distant pain processing/modulation areas
      • Gray matter volume and white matter integrity are not affected

      Abstract

      In this double-blinded, sham-controlled, counterbalanced, and crossover study, we investigated the potential neuroplasticity underlying pain relief and daily function improvements following repetitive transcranial magnetic stimulation of the motor cortex (M1-rTMS) in fibromyalgia syndrome (FMS) patients. Specifically, we used magnetic resonance imaging (MRI) to examine changes in brain structural and resting-state functional connectivity (rsFC) that correlated with improvements in FMS symptomology following M1-rTMS. Twenty-seven women with FMS underwent real and sham treatment series, each consisting of 10 daily treatments of 10Hz M1-rTMS over 2 weeks, with a washout period in between. Before and after each series, participants underwent anatomical and resting-state functional MRI scans and questionnaire assessments of FMS-related clinical pain and functional and psychological burdens. The expected reductions in FMS-related symptomology following M1-rTMS occurred with the real treatment only and correlated with rsFC changes in brain areas associated with pain processing and modulation. Specifically, between the ventromedial prefrontal cortex and the M1 (t=-5.54, corrected p=.002), the amygdala and the posterior insula (t=5.81, corrected p=.044), and the anterior and posterior insula (t=6.01, corrected p=.029). Neither treatment significantly changed brain structure. Therefore, we provide the first evidence of an association between the acute clinical effects of M1-rTMS in FMS and functional alterations of brain areas that have a significant role in the experience of chronic pain. Structural changes could potentially occur over a more extended treatment period.
      Perspective
      We show that the neurophysiological mechanism of the improvement in fibromyalgia symptoms following active, but not sham, rTMS applied to M1 involves changes in resting-state functional connectivity in sensory, affective and cognitive pain processing brain areas, thus substantiating the essence of fibromyalgia syndrome as a treatable brain-based disorder.

      Keywords

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      References

        • Agcaoglu O
        • Miller R
        • Mayer AR
        • Hugdahl K
        • Calhoun VD
        Lateralization of resting state networks and relationship to age and gender.
        NeuroImage. 2015; 104: 310-325
        • Altas EU
        • Askin A
        • Beşiroğlu L
        • Tosun A
        Is high-frequency repetitive transcranial magnetic stimulation of the left primary motor cortex superior to the stimulation of the left dorsolateral prefrontal cortex in fibromyalgia syndrome?.
        Somatosens Mot Res. 2019; 36: 56-62
        • An X
        • Bandler R
        • Ongür D
        • Price JL
        Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in macaque monkeys.
        J Comp Neurol. 1998; 401: 455-479
        • de Andrade DC
        • Mhalla A
        • Adam F
        • Texeira MJ
        • Bouhassira D
        Neuropharmacological basis of rTMS-induced analgesia: The role of endogenous opioids.
        Pain. 2011; 152: 320-326
        • Apkarian AV
        • Bushnell MC
        • Treede R-D
        • Zubieta J-K
        Human brain mechanisms of pain perception and regulation in health and disease.
        Eur J Pain. 2005; 9 (463–463)
        • Apkarian VA
        • Hashmi JA
        • Baliki MN
        Pain and the brain: Specificity and plasticity of the brain in clinical chronic pain.
        Pain. 2011; 152: S49-S64
        • Argaman Y
        • Kisler LB
        • Granovsky Y
        • Coghill RC
        • Sprecher E
        • Manor D
        Weissman-Fogel I: The Endogenous Analgesia Signature in the Resting Brain of Healthy Adults and Migraineurs.
        J Pain. 2020; S1526590019308831
        • Ashburner J
        A fast diffeomorphic image registration algorithm.
        NeuroImage. 2007; 38: 95-113
        • Ashburner J
        • Friston KJ
        Unified segmentation.
        NeuroImage. 2005; 26: 839-851
        • Baliki MN
        • Geha PY
        • Apkarian AV
        • Chialvo DR
        Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics.
        J Neurosci Off J Soc Neurosci. 2008; 28: 1398-1403
        • Beck AT
        • Ward CH
        • Mendelson M
        • Mock J
        • Erbaugh J
        An inventory for measuring depression.
        Arch Gen Psychiatry. 1961; 4: 561-571
        • Behzadi Y
        • Restom K
        • Liau J
        • Liu TT
        A component based noise correction method (CompCor) for BOLD and perfusion based fMRI.
        NeuroImage. 2007; 37: 90-101
        • Bennett R
        The Fibromyalgia Impact Questionnaire (FIQ): a review of its development, current version, operating characteristics and uses.
        Clin Exp Rheumatol. 2005; 23: S154
        • Bergeron D
        • Obaid S
        • Fournier-Gosselin M-P
        • Bouthillier A
        • Nguyen DK
        Deep Brain Stimulation of the Posterior Insula in Chronic Pain: A Theoretical Framework.
        Brain Sci. 2021; 11: 639
        • Beynel L
        • Powers JP
        • Appelbaum LG
        Effects of repetitive transcranial magnetic stimulation on resting-state connectivity: A systematic review.
        NeuroImage. 2020; 211116596
        • Bingel U
        • Lorenz J
        • Schoell E
        • Weiller C
        • Büchel C
        Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network.
        Pain. 2006; 120: 8-15
        • Bingel U
        • Quante M
        • Knab R
        • Bromm B
        • Weiller C
        • Büchel C
        Single trial fMRI reveals significant contralateral bias in responses to laser pain within thalamus and somatosensory cortices.
        NeuroImage. 2003; 18: 740-748
        • Bingel U
        • Schoell E
        • Herken W
        • Büchel C
        • May A
        Habituation to painful stimulation involves the antinociceptive system.
        Pain. 2007; 131: 21-30
        • Bingel U
        • Tracey I
        Imaging CNS Modulation of Pain in Humans.
        Physiology. 2008; 23: 371-380
        • Bogdanov VB
        • Viganò A
        • Noirhomme Q
        • Bogdanova OV
        • Guy N
        • Laureys S
        • Renshaw PF
        • Dallel R
        • Phillips C
        • Schoenen J
        Cerebral responses and role of the prefrontal cortex in conditioned pain modulation: an fMRI study in healthy subjects.
        Behav Brain Res. 2015; 281: 187-198
        • Boyer L
        • Dousset A
        • Roussel P
        • Dossetto N
        • Cammilleri S
        • Piano V
        • Khalfa S
        • Mundler O
        • Donnet A
        Guedj E: rTMS in fibromyalgia A randomized trial evaluating QoL and its brain metabolic substrate.
        Neurology. 2014; 82: 1231-1238
        • Brügger M
        • Ettlin DA
        • Meier M
        • Keller T
        • Luechinger R
        • Barlow A
        • Palla S
        • Jäncke L
        • Lutz K
        Taking Sides with Pain – Lateralization aspects Related to Cerebral Processing of Dental Pain.
        Front Hum Neurosci [Internet]. 2011; 5 ([cited 2020 Jul 8]. Available from: 10.3389/fnhum.2011.00012)
        • Burgmer M
        • Gaubitz M
        • Konrad C
        • Wrenger M
        • Hilgart S
        • Heuft G
        • Pfleiderer B
        Decreased Gray Matter Volumes in the Cingulo-Frontal Cortex and the Amygdala in Patients With Fibromyalgia.
        Psychosom Med. 2009; 71: 566-573
        • Buskila D
        • Neumann L
        Assessing functional disability and health status of women with fibromyalgia: validation of a Hebrew version of the Fibromyalgia Impact Questionnaire.
        J Rheumatol. 1996; 23: 903-906
        • Cagnie B
        • Coppieters I
        • Denecker S
        • Six J
        • Danneels L
        • Meeus M
        Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI.
        Semin Arthritis Rheum. 2014; 44: 68-75
        • Ceko M
        • Bushnell MC
        • Fitzcharles M-A
        • Schweinhardt P
        Fibromyalgia interacts with age to change the brain.
        NeuroImage Clin. 2013; 3: 249-260
        • Chang Y-T
        • Chen W-H
        • Shih H-C
        • Min M-Y
        • Shyu B-C
        • Chen C-C
        Anterior nucleus of paraventricular thalamus mediates chronic mechanical hyperalgesia.
        Pain. 2019; 160: 1208-1223
        • Cheng JC
        • Erpelding N
        • Kucyi A
        • DeSouza DD
        • Davis KD
        Individual Differences in Temporal Summation of Pain Reflect Pronociceptive and Antinociceptive Brain Structure and Function.
        J Neurosci. 2015; 35: 9689-9700
        • Cifre I
        • Sitges C
        • Fraiman D
        • Munoz MA
        • Balenzuela P
        • Gonzalez-Roldan A
        • Martinez-Jauand M
        • Birbaumer N
        • Chialvo DR
        • Montoya P
        Disrupted Functional Connectivity of the Pain Network in Fibromyalgia.
        Psychosom Med. 2012; 74: 55-62
        • Cleeland CS
        • Ryan KM
        Pain assessment: global use of the Brief Pain Inventory. 23. Ann Acad Med Singapore, 1994: 129-138
        • Cleophas TJ
        Carryover Effects in Clinical Research.
        Hum Exp [Internet] Dordrecht: Springer Netherlands, 2019 (page 25–361999 [citedFeb 18]. Available from)
        • Cleophas TJ
        • Zwinderman AH
        • Cleophas TF
        Crossover Studies with Continuous Variables: Power Analysis.
        in: Cleophas TJ Zwinderman AH Cleophas TF Stat Appl Clin Trials [Internet] Dordrecht: Springer Netherlands. editors. 2019: 133-422002https://doi.org/10.1007/978-94-010-0337-7_12 (page[citedNov 11]. Available from)
        • Coulombe M-A
        • KSt Lawrence
        • Moulin DE
        • Morley-Forster P
        • Shokouhi M
        • Nielson WR
        • Davis KD
        Lower Functional Connectivity of the Periaqueductal Gray Is Related to Negative Affect and Clinical Manifestations of Fibromyalgia.
        Front Neuroanat. 2017; 11: 47
      1. Cremers HR, Wager TD, Yarkoni T: The relation between statistical power and inference in fMRI. Gilbert S, editor. PLOS ONE 12:e0184923, 2017.

        • Cummiford CM
        • Nascimento TD
        • Foerster BR
        • Clauw DJ
        • Zubieta J-K
        • Harris RE
        • DaSilva AF
        Changes in resting state functional connectivity after repetitive transcranial direct current stimulation applied to motor cortex in fibromyalgia patients.
        Arthritis Res Ther [Internet]. 2016; 18 ([cited 2016 Feb 9]. Available from)
        • Deen B
        • Pitskel NB
        • Pelphrey KA
        Three Systems of Insular Functional Connectivity Identified with Cluster Analysis.
        Cereb Cortex. 2011; 21: 1498-1506
        • Dehghan M
        • Schmidt-Wilcke T
        • Pfleiderer B
        • Eickhoff SB
        • Petzke F
        • Harris RE
        • Montoya P
        • Burgmer M
        Coordinate-based (ALE) meta-analysis of brain activation in patients with fibromyalgia: Meta-Analysis in Fibromyalgia.
        Hum Brain Mapp. 2016; 37: 1749-1758
        • Deligianni F
        • Centeno M
        • Carmichael DW
        • Clayden JD
        Relating resting-state fMRI and EEG whole-brain connectomes across frequency bands.
        Front Neurosci [Internet]. 2014; 8 ([cited 2020 Jul 9]Available from: 10.3389/fnins.2014.00258)
        • Di X
        • Kim EH
        • Chen P
        • Biswal BB
        Lateralized Resting-State Functional Connectivity in the Task-Positive and Task-Negative Networks.
        Brain Connect. 2014; 4: 641-648
        • DosSantos MF
        • Ferreira N
        • Toback RL
        • Carvalho AC
        • DaSilva AF
        Potential Mechanisms Supporting the Value of Motor Cortex Stimulation to Treat Chronic Pain Syndromes.
        Front Neurosci [Internet]. 2016; 10 ([cited 2016 Mar 12]. Available from)
        • Duecker F
        • Sack AT
        Rethinking the role of sham TMS.
        Front Psychol [Internet]. 2015; 6 ([cited 2019 Aug 24]. Available from)
        • Fallon N
        • Chiu Y
        • Nurmikko T
        • Stancak A
        Functional Connectivity with the Default Mode Network Is Altered in Fibromyalgia Patients.
        PloS One. 2016; 11e0159198
        • Farokhian F
        • Beheshti I
        • Sone D
        • Matsuda H
        Comparing CAT12 and VBM8 for Detecting Brain Morphological Abnormalities in Temporal Lobe Epilepsy.
        Front Neurol [Internet]. 2017; 8 ([cited 2019 Feb 27]. Available from: http://journal.frontiersin.org/article/10.3389/fneur.2017.00428/full)
        • Fitzcharles M-A
        • Cohen SP
        • Clauw DJ
        • Littlejohn G
        • Usui C
        • Häuser W
        Nociplastic pain: towards an understanding of prevalent pain conditions.
        The Lancet. 2021; 397: 2098-2110
        • Friston KJ
        • Stephan KE
        • Lund TE
        • Morcom A
        • Kiebel S
        Mixed-effects and fMRI studies.
        NeuroImage. 2005; 24: 244-252
        • Galhardoni R
        • Correia GS
        • Araujo H
        • Yeng LT
        • Fernandes DT
        • Kaziyama HH
        • Marcolin MA
        • Bouhassira D
        • Teixeira MJ
        • de Andrade DC
        Repetitive Transcranial Magnetic Stimulation in Chronic Pain: A Review of the Literature.
        Arch Phys Med Rehabil. 2015; 96: S156-S172
        • García-Larrea L
        • Peyron R
        • Mertens P
        • Gregoire CM
        • Lavenne F
        • Le Bars D
        • Convers P
        • Mauguière F
        • Sindou M
        • Laurent B
        Electrical stimulation of motor cortex for pain control: a combined PET-scan and electrophysiological study.
        Pain. 1999; 83: 259-273
        • Geday J
        • Gjedde A
        • Boldsen A-S
        • Kupers R
        Emotional valence modulates activity in the posterior fusiform gyrus and inferior medial prefrontal cortex in social perception.
        NeuroImage. 2003; 18: 675-684
        • Gehrlach DA
        • Dolensek N
        • Klein AS
        • Roy Chowdhury R
        • Matthys A
        • Junghänel M
        • Gaitanos TN
        • Podgornik A
        • Black TD
        • Reddy Vaka N
        • Conzelmann K-K
        • Gogolla N
        Aversive state processing in the posterior insular cortex.
        Nat Neurosci. 2019; 22: 1424-1437
        • Genovese CR
        • Lazar NA
        • Nichols T
        Thresholding of Statistical Maps in Functional Neuroimaging Using the False Discovery Rate.
        NeuroImage. 2002; 15: 870-878
        • Goldway N
        • Ablin J
        • Lubin O
        • Zamir Y
        • Keynan JN
        • Or-Borichev A
        • Cavazza M
        • Charles F
        • Intrator N
        • Brill S
        • Ben-Simon E
        • Sharon H
        • Hendler T
        Volitional limbic neuromodulation exerts a beneficial clinical effect on Fibromyalgia.
        NeuroImage. 2019; 186: 758-770
        • Gracely RH
        • Ceko M
        • Bushnell MC
        • Gracely RH
        • Ceko M
        • Bushnell MC
        Fibromyalgia and Depression.
        Pain Res Treat Pain Res Treat 2012. 2012; (2011)e486590
        • Harper DE
        • Ichesco E
        • Schrepf A
        • Hampson JP
        • Clauw DJ
        • Schmidt-Wilcke T
        • Harris RE
        • Harte SE
        Resting Functional Connectivity of the Periaqueductal Gray Is Associated With Normal Inhibition and Pathological Facilitation in Conditioned Pain Modulation.
        J Pain. 2018; 19 (e1-635.e15): 635
        • Hashmi JA
        • Baliki MN
        • Huang L
        • Baria AT
        • Torbey S
        • Hermann KM
        • Schnitzer TJ
        • Apkarian AV
        Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits.
        Brain. 2013; 136: 2751-2768
        • Häuser W
        • Ablin J
        • Fitzcharles M-A
        • Littlejohn G
        • Luciano JV
        • Usui C
        • Fibromyalgia Walitt B:
        Nat Rev Dis Primer. 2015; 1: 15022
        • Hou W-H
        • Wang T-Y
        • Kang J-H
        The effects of add-on non-invasive brain stimulation in fibromyalgia: a meta-analysis and meta-regression of randomized controlled trials.
        Rheumatology. 2016; 55: 1507-1517
        • Houde F
        • Martel M
        • Coulombe-Lévêque A
        • Harvey M-P
        • Auclair V
        • Mathieu D
        • Whittingstall K
        • Goffaux P
        • Léonard G
        Perturbing the activity of the superior temporal gyrus during pain encoding prevents the exaggeration of pain memories: A virtual lesion study using single-pulse transcranial magnetic stimulation.
        Neurobiol Learn Mem. 2020; 169107174
        • Ichesco E
        • Schmidt-Wilcke T
        • Bhavsar R
        • Clauw DJ
        • Peltier SJ
        • Kim J
        • Napadow V
        • Hampson JP
        • Kairys AE
        • Williams DA
        • Harris RE
        Altered Resting State Connectivity of the Insular Cortex in Individuals With Fibromyalgia.
        J Pain. 2014; 15 (e1): 815-826
        • Jales Junior LH
        • Costa M do DL
        • Jales Neto LH
        • Ribeiro JPM
        • Freitas WJS do N
        • Teixeira MJ
        Transcranial direct current stimulation in fibromyalgia: effects on pain and quality of life evaluated clinically and by brain perfusion scintigraphy.
        Rev Dor [Internet]. 2015; 16 ([cited 2021 Sep 11]. Available from)
        • Jay GW
        • Fibromyalgia Barkin RL:
        Dis Mon. 2015; 61: 66-111
        • Jenkinson M
        • Beckmann CF
        • Behrens TEJ
        • Woolrich MW
        • Smith SM
        FSL. NeuroImage. 2012; 62: 782-790
        • Jensen KB
        • Loitoile R
        • Kosek E
        • Petzke F
        • Carville S
        • Fransson P
        • Marcus H
        • Williams SC
        • Choy E
        • Mainguy Y
        others: Patients with fibromyalgia display less functional connectivity in the brain's pain inhibitory network.
        Mol Pain. 2012; 8: 32
        • Julian LJ
        Measures of Anxiety.
        Arthritis Care Res [Internet]. 2011; 63 ([cited 2016 Mar 26]. Available from)
        • Kang D-H
        • Kim G-W
        Changes in Diffuse Tensor Imaging and Therapeutic Effect of Repetitive Transcranial Magnetic Stimulation in Traumatic Brain Injury with Central Pain.
        Brain Sci. 2020; 10: 929
        • Kim J
        • Loggia ML
        • Cahalan CM
        • Harris RE
        • Beissner F
        • Garcia RG
        • Kim H
        • Barbieri R
        • Wasan AD
        • Edwards RR
        • Napadow V
        The Somatosensory Link in Fibromyalgia: Functional Connectivity of the Primary Somatosensory Cortex Is Altered by Sustained Pain and Is Associated With Clinical/Autonomic Dysfunction: ALTERED S1 FUNCTIONAL CONNECTIVITY IN FIBROMYALGIA.
        Arthritis Rheumatol. 2015; 67: 1395-1405
        • Klein A
        • Andersson J
        • Ardekani BA
        • Ashburner J
        • Avants B
        • Chiang M-C
        • Christensen GE
        • Collins DL
        • Gee J
        • Hellier P
        • Song JH
        • Jenkinson M
        • Lepage C
        • Rueckert D
        • Thompson P
        • Vercauteren T
        • Woods RP
        • Mann JJ
        • Parsey RV
        Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration.
        NeuroImage. 2009; 46: 786-802
        • Klein MM
        • Treister R
        • Raij T
        • Pascual-Leone A
        • Park L
        • Nurmikko T
        • Lenz F
        • Lefaucheur J-P
        • Lang M
        • Hallett M
        • Fox M
        • Cudkowicz M
        • Costello A
        • Carr DB
        • Ayache SS
        • Oaklander AL
        Transcranial magnetic stimulation of the brain: guidelines for pain treatment research.
        PAIN. 2015; 156: 1601-1614
        • Knijnik LM
        • Dussán-Sarria JA
        • Rozisky JR
        • Torres ILS
        • Brunoni AR
        • Fregni F
        • Caumo W
        Repetitive Transcranial Magnetic Stimulation for Fibromyalgia: Systematic Review and Meta-Analysis.
        Pain Pract. 2016; 16: 294-304
        • Kong Q-M
        • Qiao H
        • Liu C-Z
        • Zhang P
        • Li K
        • Wang L
        • Li J-T
        • Su Y
        • Li K-Q
        • Yan C-G
        • Mitchell PB
        • Si T-M
        Aberrant intrinsic functional connectivity in thalamo-cortical networks in major depressive disorder.
        CNS Neurosci Ther. 2018; 24: 1063-1072
        • Kosek E
        • Cohen M
        • Baron R
        • Gebhart GF
        • Mico J-A
        • Rice ASC
        • Rief W
        • Sluka AK
        Do we need a third mechanistic descriptor for chronic pain states?.
        Pain. 2016; 157: 1382-1386
        • Kramer PR
        • Strand J
        • Stinson C
        • Bellinger LL
        • Kinchington PR
        • Yee MB
        • Umorin M
        • Peng YB
        Role for the Ventral Posterior Medial/Posterior Lateral Thalamus and Anterior Cingulate Cortex in Affective/Motivation Pain Induced by Varicella Zoster Virus.
        Front Integr Neurosci. 2017; 11: 27
        • Kuchinad A
        • Schweinhardt P
        • Seminowicz DA
        • Wood PB
        • Chizh BA
        • Bushnell MC
        Accelerated Brain Gray Matter Loss in Fibromyalgia Patients: Premature Aging of the Brain?.
        J Neurosci. 2007; 27: 4004-4007
        • Kurth F
        • Zilles K
        • Fox PT
        • Laird AR
        • Eickhoff SB
        A link between the systems: functional differentiation and integration within the human insula revealed by meta-analysis.
        Brain Struct Funct. 2010; 214: 519-534
        • Lan MJ
        • Chhetry BT
        • Liston C
        • Mann JJ
        • Dubin M
        Transcranial Magnetic Stimulation of Left Dorsolateral Prefrontal Cortex Induces Brain Morphological Changes in Regions Associated with a Treatment Resistant Major Depressive Episode: An Exploratory Analysis.
        Brain Stimulat. 2016; 9: 577-583
        • Lefaucheur J-P
        • Aleman A
        • Baeken C
        • Benninger DH
        • Brunelin J
        • Di Lazzaro V
        • Filipović SR
        • Grefkes C
        • Hasan A
        • Hummel FC
        • Jääskeläinen SK
        • Langguth B
        • Leocani L
        • Londero A
        • Nardone R
        • Nguyen J-P
        • Nyffeler T
        • Oliveira-Maia AJ
        • Oliviero A
        • Padberg F
        • Palm U
        • Paulus W
        • Poulet E
        • Quartarone A
        • Rachid F
        • Rektorová I
        • Rossi S
        • Sahlsten H
        • Schecklmann M
        • Szekely D
        • Ziemann U
        Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014–2018).
        Clin Neurophysiol. 2020; 131: 474-528
        • Lefaucheur J-P
        • Antal A
        • Ahdab R
        • Ciampi de Andrade D
        • Fregni F
        • Khedr EM
        • Nitsche M
        • Paulus W
        The use of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) to relieve pain.
        Brain Stimulat. 2008; 1: 337-344
        • Levav I
        Psychiatric and Behavioral Disorders in Israel: From Epidemiology to Mental Health Action.
        Gefen Publishing House Ltd, 2009
        • Lewin-Epstein N
        • Sagiv-Schifter T
        • Shabtai EL
        • Shmueli A
        Validation of the 36-item short-form Health Survey (Hebrew version) in the adult population of Israel.
        Med Care. 1998; 36: 1361-1370
        • Li Z
        • Liu M
        • Lan L
        • Zeng F
        • Makris N
        • Liang Y
        • Guo T
        • Wu F
        • Gao Y
        • Dong M
        • Yang J
        • Li Y
        • Gong Q
        • Liang F
        • Kong J
        Altered periaqueductal gray resting state functional connectivity in migraine and the modulation effect of treatment.
        Sci Rep. 2016; 6: 20298
        • Lorenz J
        • Minoshima S
        • Casey KL
        Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation.
        Brain. 2003; 126: 1079-1091
        • Lui F
        • Duzzi D
        • Corradini M
        • Serafini M
        • Baraldi P
        • Porro CA
        Touch or pain? Spatio-temporal patterns of cortical fMRI activity following brief mechanical stimuli.
        Pain. 2008; 138: 362-374
        • Maarrawi J
        • Peyron R
        • Mertens P
        • Costes N
        • Magnin M
        • Sindou M
        • Laurent B
        • Garcia-Larrea L
        Motor cortex stimulation for pain control induces changes in the endogenous opioid system.
        Neurology. 2007; 69: 827-834
        • Mainero C
        • Boshyan J
        • Hadjikhani N
        Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine.
        Ann Neurol. 2011; 70: 838-845
        • Mansour AR
        • Baliki MN
        • Huang L
        • Torbey S
        • Herrmann KM
        • Schnitzer TJ
        • Apkarian VA
        Brain white matter structural properties predict transition to chronic pain.
        Pain. 2013; 154: 2160-2168
        • Mansour AR
        • Farmer MA
        • Baliki MN
        • Apkarian AV
        Chronic pain: The role of learning and brain plasticity.
        Restor Neurol Neurosci. 2014; 32: 129-139
        • Mantyh PW
        Forebrain projections to the periaqueductral gray in the monkey, with observations in the cat and rat.
        J Comp Neurol. 1982; 206: 146-158
        • Martínez JH
        • Buldú JM
        • Papo D
        • Fallani FDV
        • Chavez M
        Role of inter-hemispheric connections in functional brain networks.
        Sci Rep. 2018; 8: 10246
        • Meeker TJ
        • Keaser ML
        • Khan SA
        • Gullapalli RP
        • Seminowicz DA
        • Greenspan JD
        Non-invasive Motor Cortex Neuromodulation Reduces Secondary Hyperalgesia and Enhances Activation of the Descending Pain Modulatory Network.
        Front Neurosci [Internet]. 2019; 13 ([cited 2019 Aug 16]. Available from)
        • Melzack R
        The short-form McGill pain questionnaire.
        Pain. 1987; 30: 191-197
        • Mhalla A
        • de Andrade DC
        • Baudic S
        • Perrot S
        • Bouhassira D
        Alteration of cortical excitability in patients with fibromyalgia.
        Pain. 2010; 149: 495-500
        • Mhalla A
        • Baudic S
        • de Andrade DC
        • Gautron M
        • Perrot S
        • Teixeira MJ
        • Attal N
        • Bouhassira D
        Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia.
        Pain. 2011; 152: 1478-1485
        • Moisset X
        • de Andrade DC
        • Bouhassira D
        From pulses to pain relief: an update on the mechanisms of rTMS-induced analgesic effects.
        Eur J Pain. 2016; 20: 689-700
        • Moont R
        • Crispel Y
        • Lev R
        • Pud D
        • Yarnitsky D
        Temporal changes in cortical activation during conditioned pain modulation (CPM), a LORETA study.
        Pain. 2011; 152: 1469-1477
        • Mutso AA
        • Petre B
        • Huang L
        • Baliki MN
        • Torbey S
        • Herrmann KM
        • Schnitzer TJ
        • Apkarian AV
        Reorganization of hippocampal functional connectivity with transition to chronic back pain.
        J Neurophysiol. 2014; 111: 1065-1076
        • Napadow V
        • LaCount L
        • Park K
        • As-Sanie S
        • Clauw DJ
        • Harris RE
        Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
        Arthritis Rheum. 2010; 62: 2545-2555
      2. Neugebauer V: Amygdala—Pain Processing and Pain Modulation. In: Zhuo M, editor. Mol Pain [Internet] New York, NY: Springer New York; page 265–792007 [cited 2020 Jun 25]. Available from: http://link.springer.com/10.1007/978-0-387-75269-3_20

        • Nichols TE
        • Holmes AP
        Nonparametric permutation tests for functional neuroimaging: A primer with examples.
        Hum Brain Mapp. 2002; 15: 1-25
        • Nichols TE
        • Kiebel SJ
        • Ashburner JT
        • Friston KJ
        • Penny WD
        Statistical Parametric Mapping: The Analysis of Functional Brain Images. [Internet].
        Elsevier Science, 2011 ([cited 2019 Apr 15]. Available from)
        • Nicolo P
        • Magnin C
        • Pedrazzini E
        • Nguyen-Danse A
        • Guggisberg AG
        Transcranial direct current stimulation reduces secondary white-matter degradation after stroke.
        Brain Stimulat. 2018; 11: 1417-1419
        • Noda Y
        • Zomorrodi R
        • Daskalakis ZJ
        • Blumberger DM
        • Nakamura M
        Enhanced theta-gamma coupling associated with hippocampal volume increase following high-frequency left prefrontal repetitive transcranial magnetic stimulation in patients with major depression.
        Int J Psychophysiol. 2018; 133: 169-174
        • O'Connell NE
        • Marston L
        • Spencer S
        • DeSouza LH
        • Wand BM
        Non-invasive brain stimulation techniques for chronic pain.
        editor. Cochrane Pain, Palliative and Supportive Care Group, 2018 (Cochrane Database Syst Rev [Internet][cited 2019 May 3]. Available from)
        • Ong W-Y
        • Stohler CS
        • Herr DR
        Role of the Prefrontal Cortex in Pain Processing.
        Mol Neurobiol. 2019; 56: 1137-1166
        • Oxington KV
        Psychology of Stress.
        Nova Publishers, 2005
        • Passard A
        • Attal N
        • Benadhira R
        • Brasseur L
        • Saba G
        • Sichere P
        • Perrot S
        • Januel D
        • Bouhassira D
        Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia.
        Brain. 2007; 130: 2661-2670
        • Pei Q
        • Zhuo Z
        • Jing B
        • Meng Q
        • Ma X
        • Mo X
        • Liu H
        • Liang W
        • Ni J
        • Li H
        The effects of repetitive transcranial magnetic stimulation on the whole-brain functional network of postherpetic neuralgia patients.
        Medicine (Baltimore) [Internet]. 2019; 98 ([cited 2019 Aug 21]. Available from)
        • Petrovic P
        • Kalso E
        • Petersson KM
        • Ingvar M
        Placebo and opioid analgesia– imaging a shared neuronal network.
        Science. 2002; 295: 1737-1740
        • Peyron R
        • Faillenot I
        • Mertens P
        • Laurent B
        • Garcia-Larrea L
        Motor cortex stimulation in neuropathic pain. Correlations between analgesic effect and hemodynamic changes in the brain. A PET study.
        NeuroImage. 2007; 34: 310-321
        • Peyron R
        • Laurent B
        • Garcia-Larrea L
        Functional imaging of brain responses to pain. A review and meta-analysis (2000).
        Neurophysiol Clin Neurophysiol. 2000; 30: 263-288
        • Reis GM
        • Dias QM
        • Silveira JWS
        • Del Vecchio F
        • Garcia-Cairasco N
        • Prado WA
        Antinociceptive Effect of Stimulating the Occipital or Retrosplenial Cortex in Rats.
        J Pain. 2010; 11: 1015-1026
        • GA Reyes del Paso
        • Á Pulgar
        • Duschek S
        • Garrido S
        Cognitive impairment in fibromyalgia syndrome: The impact of cardiovascular regulation, pain, emotional disorders and medication: Cognitive impairment in fibromyalgia syndrome.
        Eur J Pain. 2012; 16: 421-429
        • Ridgway G
        • Omar R
        • Ourselin S
        • Hill D
        • Warren J
        • Fox N
        Issues with threshold masking in voxel-based morphometry of atrophied brains.
        NeuroImage. 2009; 44: 99-111
        • Ruddy KL
        • Leemans A
        • Carson RG
        Transcallosal connectivity of the human cortical motor network.
        Brain Struct Funct. 2017; 222: 1243-1252
        • Sandström A
        • Ellerbrock I
        • Tour J
        • Kadetoff D
        • Jensen KB
        • Kosek E
        Neural correlates of conditioned pain responses in fibromyalgia subjects indicate preferential formation of new pain associations rather than extinction of irrelevant ones.
        Pain. 2020; 161: 2079-2088
        • Sankoh AJ
        • Huque MF
        • Dubey SD
        Some comments on frequently used multiple endpoint adjustment methods in clinical trials.
        Stat Med. 1997; 16: 2529-2542
        • Schmidt-Wilcke T
        • Clauw DJ
        Fibromyalgia: from pathophysiology to therapy.
        Nat Rev Rheumatol. 2011; 7: 518-527
        • Shen S
        • Sterr A
        Is DARTEL-based voxel-based morphometry affected by width of smoothing kernel and group size? A study using simulated atrophy.
        J Magn Reson Imaging. 2013; 37: 1468-1475
        • Shvartzman P
        • Friger M
        • Shani A
        • Barak F
        • Yoram C
        • Singer Y
        Pain control in ambulatory cancer patients—can we do better?.
        J Pain Symptom Manage. 2003; 26: 716-722
        • Simmons WK
        • Avery JA
        • Barcalow JC
        • Bodurka J
        • Drevets WC
        • Bellgowan P
        Keeping the body in mind: Insula functional organization and functional connectivity integrate interoceptive, exteroceptive, and emotional awareness: Functional Organization.
        Hum Brain Mapp. 2013; 34: 2944-2958
        • Sloman R
        • Rosen G
        • Rom M
        • Shir Y
        Nurses’ assessment of pain in surgical patients.
        J Adv Nurs. 2005; 52: 125-132
        • Sluka KA
        • Clauw DJ
        Neurobiology of fibromyalgia and chronic widespread pain.
        Neuroscience. 2016; 338: 114-129
        • Smith SM
        • Jenkinson M
        • Johansen-Berg H
        • Rueckert D
        • Nichols TE
        • Mackay CE
        • Watkins KE
        • Ciccarelli O
        • Cader MZ
        • Matthews PM
        • Behrens TEJ
        Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data.
        NeuroImage. 2006; 31: 1487-1505
        • Smith SM
        • Jenkinson M
        • Woolrich MW
        • Beckmann CF
        • Behrens TEJ
        • Johansen-Berg H
        • Bannister PR
        • De Luca M
        • Drobnjak I
        • Flitney DE
        • Niazy RK
        • Saunders J
        • Vickers J
        • Zhang Y
        • De Stefano N
        • Brady JM
        • Matthews PM
        Advances in functional and structural MR image analysis and implementation as FSL.
        NeuroImage. 2004; 23: S208-S219
        • Sprenger C
        • Bingel U
        • Büchel C
        Treating pain with pain: Supraspinal mechanisms of endogenous analgesia elicited by heterotopic noxious conditioning stimulation.
        Pain. 2011; 152: 428-439
        • Sprenger T
        • Borsook D
        Migraine Changes the Brain – Neuroimaging Imaging Makes its Mark.
        Curr Opin Neurol. 2012; 25: 252-262
        • Sun X
        • Long H
        • Zhao C
        • Duan Q
        • Zhu H
        • Chen C
        • Sun W
        • Ju F
        • Sun X
        • Zhao Y
        • Xue B
        • Tian F
        • Mou X
        • Yuan H
        Analgesia-enhancing effects of repetitive transcranial magnetic stimulation on neuropathic pain after spinal cord injury:An fNIRS study.
        Restor Neurol Neurosci. 2019; 37: 497-507
        • Talairach J
        • Tournoux P
        • Rayport M
        Co-planar stereotaxic atlas of the human brain: 3-dimensional proportional system: an approach to cerebral imaging.
        Reprint. Stuttgart: Thieme [u.a.]. 1997;
        • Taylor KS
        • Seminowicz DA
        • Davis KD
        Two systems of resting state connectivity between the insula and cingulate cortex.
        Hum Brain Mapp. 2009; 30: 2731-2745
        • Teichman Y
        • Malinack F
        Manual for the Hebrew state-trait anxiety inventory.
        Tel-Aviv Univ Press, 1978
        • Thieme K
        • Turk DC
        • Flor H
        Comorbid depression and anxiety in fibromyalgia syndrome: relationship to somatic and psychosocial variables.
        Psychosom Med. 2004; 66: 837-844
        • Thompson JM
        • Neugebauer V
        Amygdala Plasticity and Pain.
        Pain Res Manag. 2017; 2017: 1-12
        • Tzourio-Mazoyer N
        • Landeau B
        • Papathanassiou D
        • Crivello F
        • Etard O
        • Delcroix N
        • Mazoyer B
        • Joliot M
        Automated Anatomical Labeling of Activations in SPM Using a Macroscopic Anatomical Parcellation of the MNI MRI Single-Subject Brain.
        NeuroImage. 2002; 15: 273-289
        • Vincent A
        • Whipple MO
        • Rhudy LM
        Fibromyalgia Flares: A Qualitative Analysis: Qualitative Analysis of Fibromyalgia Flares.
        Pain Med:n/a-n/a, 2015
        • Vogt BA
        Pain and emotion interactions in subregions of the cingulate gyrus.
        Nat Rev Neurosci. 2005; 6: 533-544
        • Wadden KP
        • Peters S
        • Borich MR
        • Neva JL
        • Hayward KS
        • Mang CS
        • Snow NJ
        • Brown KE
        • Woodward TS
        • Meehan SK
        • Boyd LA
        White Matter Biomarkers Associated with Motor Change in Individuals with Stroke: A Continuous Theta Burst Stimulation Study.
        Neural Plast. 2019; 2019: 1-15
        • Wager TD
        Placebo-Induced Changes in fMRI in the Anticipation and Experience of Pain.
        Science. 2004; 303: 1162-1167
        • Whitfield-Gabrieli S
        • CONN  Nieto-Castanon A:
        A Functional Connectivity Toolbox for Correlated and Anticorrelated Brain Networks.
        Brain Connect. 2012; 2: 125-141
        • WHO
        International classification of functioning, disability and health: ICF.
        editor. Geneva: World Health Organization, 2001
        • Wolfe F
        • Clauw DJ
        • Fitzcharles M-A
        • Goldenberg DL
        • Katz RS
        • Mease P
        • Russell AS
        • Russell IJ
        • Winfield JB
        • Yunus MB
        The American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and Measurement of Symptom Severity.
        Arthritis Care Res. 2010; 62: 600-610
        • Yarnitsky D
        • Granot M
        • Granovsky Y
        Pain modulation profile and pain therapy: Between pro- and antinociception.
        Pain. 2014; 155: 663-665
        • Zubieta J-K
        Placebo Effects Mediated by Endogenous Opioid Activity on -Opioid Receptors.
        J Neurosci. 2005; 25: 7754-7762
        • Zubieta J-K
        • Stohler CS
        Neurobiological Mechanisms of Placebo Responses.
        Ann N Y Acad Sci. 2009; 1156: 198-210