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Efficacy of High-Frequency Repetitive Transcranial Magnetic Stimulation at 10 Hz in Fibromyalgia: A Systematic Review and Meta-analysis

  • Author Footnotes
    ⁎ PingAn Zhu and Ju-Ying Xie contributed equally to this work and should be considered as cofirst authors.
    Ping-an Zhu
    Footnotes
    ⁎ PingAn Zhu and Ju-Ying Xie contributed equally to this work and should be considered as cofirst authors.
    Affiliations
    Department of Rehabilitation Medicine, Yuebei People's Hospital, Shaoguan, China

    School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
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  • Author Footnotes
    ⁎ PingAn Zhu and Ju-Ying Xie contributed equally to this work and should be considered as cofirst authors.
    Ju-Ying Xie
    Footnotes
    ⁎ PingAn Zhu and Ju-Ying Xie contributed equally to this work and should be considered as cofirst authors.
    Affiliations
    Department of Rehabilitation Medicine, Affiliated Hospital of Xiangnan University, Chenzhou, China
    Search for articles by this author
  • Howe Liu
    Affiliations
    Department of Physical Therapy, University of North Texas Health Science Center, Fort Worth, TX
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  • Youliang Wen
    Affiliations
    School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
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  • Yin-Jin Shao
    Affiliations
    Department of Rehabilitation Medicine, Ganzhou People's Hospital, Ganzhou, China
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  • Xiao Bao
    Correspondence
    Corresponding author Xiao Bao, PhD, Department of Rehabilitation Medicine, Yuebei People's Hospital, Shaoguan 512025, China.
    Affiliations
    Department of Rehabilitation Medicine, Yuebei People's Hospital, Shaoguan, China
    Search for articles by this author
  • Author Footnotes
    ⁎ PingAn Zhu and Ju-Ying Xie contributed equally to this work and should be considered as cofirst authors.

      Abstract

      Objective

      The purpose of this review was to systematically assess the effectiveness of 10-Hz repetitive transcranial magnetic stimulation (rTMS) in fibromyalgia.

      Data Sources

      We searched PubMed, Cochrane Library, Embase, Web of Science, and Ovid databases as of November 6, 2021.

      Study Selection

      The inclusion criteria for this review were randomized controlled trials of 10-Hz rTMS for fibromyalgia, exploring the effects of 10-Hz rTMS on pain, depression, and quality of life in patients with fibromyalgia.

      Data Extraction

      Data extraction was performed independently by 2 evaluators according to predefined criteria, and the quality of the included literature was assessed using the Cochrane Bias Risk Assessment Tool. The measurement outcomes include visual analog scale, Hamilton Depression Rating Scale, and Fibromyalgia Impact Questionnaire, and so on.

      Data Synthesis

      A total of 488 articles were screened, and the final 7 selected high-quality articles with 217 patients met our inclusion criteria. Analysis of the results showed that high-frequency transcranial magnetic stimulation at 10 Hz was significantly associated with reduced pain compared with sham stimulation in controls (standardized mean difference [SMD]=−0.72; 95% confidence interval [CI], −1.12 to −0.33; P<.001; I2=46%) and was able to improve quality of life (SMD=−0.70; 95% CI, −1.00 to −0.40; P<.001; I2=15%) but not improve depression (SMD=−0.23; 95% CI, −0.50 to 0.05; P=.11; I2=33%). In addition, a subgroup analysis of pain conducted based on stimulation at the primary motor cortex and dorsolateral prefrontal cortex showed no significant difference (SMD=−0.72; 95% CI, −1.12 to −0.33; P=.10; I2=62%).

      Conclusions

      Overall, 10-Hz rTMS has a significant effect on analgesia and improved quality of life in patients with FMS but did not improve depression.

      Keywords

      List of abbreviations:

      BDI (Beck Depression Inventory), BPI (Brief Pain Inventory), CI (confidence interval), DLPFC (dorsolateral prefrontal cortex), FIQ (Fibromyalgia Impact Questionnaire), FMS (fibromyalgia syndrome), HADS (Hospital Anxiety and Depression Scale), HDRS (Hamilton Depression Rating Scale), M1 (primary motor cortex), rTMS (repetitive transcranial magnetic stimulation), SMD (standardized mean difference), VAS (visual analog scale)
      Fibromyalgia syndrome (FMS) is a common disease characterized by chronic, widespread, or regional musculoskeletal pain; the general public prevalence rate is 2%, and it is more common in women.
      • Clauw DJ.
      Fibromyalgia: a clinical review.
      ,
      • Neumann L
      • Buskila D.
      Epidemiology of fibromyalgia.
      The ratio of women to men in fibromyalgia is about 2:1 according to the American Rheumatic Society standard in 2010.
      • Reid P
      • Pridmore S.
      Improvement in chronic pain with transcranial magnetic stimulation.
      Chronic pain in fibromyalgia can cause excessive fatigue, mood disorders, cognitive dysfunction, and sleep disorders and ultimately affects the quality of daily life.
      • Sumpton JE
      • Moulin DE
      Fibromyalgia.
      ,
      • Bennett RM
      • Jones J
      • Turk DC
      • Russell IJ
      • Matallana L.
      An internet survey of 2,596 people with fibromyalgia.
      Fatigue, together with widespread pain, is considered the key symptom of fibromyalgia, which has the greatest effect on patients.
      • Williams DA
      • Kratz AL.
      Patient-reported outcomes and fibromyalgia.
      FMS can lead to loss of productivity and impair physical function; current research shows that FMS is a huge financial burden for both individuals and society.
      • Lacasse A
      • Bourgault P
      • Choinière M.
      Fibromyalgia-related costs and loss of productivity: a substantial societal burden.
      The etiology of FMS is still unclear. Some believed that its pathogenesis factors are related to genetic factors, environmental factors, psychological factors, neuropathy, and neuromodulation; the most credible mechanism may be pain regulation and central sensitivity disorders.
      • Bair MJ
      • Fibromyalgia Krebs EE.
      ,
      • Short EB
      • Borckardt JJ
      • Anderson BS
      • et al.
      Ten sessions of adjunctive left prefrontal rTMS significantly reduces fibromyalgia pain: a randomized, controlled pilot study.
      Central sensitization refers to a neural signal amplification mechanism within the central nervous system that results in stronger pain perception.
      • Muir 3rd, WW
      • Woolf CJ
      Mechanisms of pain and their therapeutic implications.
      Recently, it has also been reported that oxidative stress is an important factor in the pathogenesis of FMS.
      • Akkuş S
      • Naziroğlu M
      • Eriş S
      • Yalman K
      • Yilmaz N
      • Yener M.
      Levels of lipid peroxidation, nitric oxide, and antioxidant vitamins in plasma of patients with fibromyalgia.
      ,
      • Cordero MD.
      [Oxidative stress in fibromyalgia: pathophysiology and clinical implications].
      The interventions for fibromyalgia are drug treatment and non-drug treatment.
      • Clauw DJ.
      Fibromyalgia: a clinical review.
      Several drugs or classes of drugs have strong evidence (level 1A evidence) for efficacy in treating fibromyalgia,
      • Häuser W
      • Petzke F
      • Sommer C.
      Comparative efficacy and harms of duloxetine, milnacipran, and pregabalin in fibromyalgia syndrome.
      including tricyclic compounds
      • Arnold LM.
      Duloxetine and other antidepressants in the treatment of patients with fibromyalgia.
      (amitriptyline, cyclobenzaprine), gabapentinoids
      • Tzellos TG
      • Toulis KA
      • Goulis DG
      • et al.
      Gabapentin and pregabalin in the treatment of fibromyalgia: a systematic review and a meta-analysis.
      (pregabalin, gabapentin), serotonin-norepinephrine reuptake inhibitors (duloxetine,
      • Arnold LM
      • Clauw DJ
      • Wohlreich MM
      • et al.
      Efficacy of duloxetine in patients with fibromyalgia: pooled analysis of 4 placebo-controlled clinical trials.
      milnacipran
      • Geisser ME
      • Palmer RH
      • Gendreau RM
      • Wang Y
      • Clauw DJ.
      A pooled analysis of two randomized, double-blind, placebo-controlled trials of milnacipran monotherapy in the treatment of fibromyalgia.
      ), and γ-hydroxybutyrate.
      • Russell JI
      • Holman AJ
      • Swick TJ
      • Alvarez-Horine S
      • Wang GY
      • Guinta D.
      Sodium oxybate reduces pain, fatigue, and sleep disturbance and improves functionality in fibromyalgia: results from a 14-week, randomized, double-blind, placebo-controlled study.
      Nondrug treatments include education, cognitive behavioral therapy,
      • Neumann L
      • Buskila D.
      Epidemiology of fibromyalgia.
      ,
      • Page MJ
      • McKenzie JE
      • Bossuyt PM
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      exercises, tai chi, yoga, chiropractic techniques, acupuncture, and re- and moxibustion.
      • Mist SD
      • Firestone KA
      • Jones KD.
      Complementary and alternative exercise for fibromyalgia: a meta-analysis.
      In addition, in recent years, more and more scholars have studied the imbalance of fibromyalgia central sensitivity and pain regulation.
      • Hou WH
      • Wang TY
      • Kang JH.
      The effects of add-on non-invasive brain stimulation in fibromyalgia: a meta-analysis and meta-regression of randomized controlled trials.
      Various neuroelectric stimulations have been developed or adopted to treat musculoskeletal diseases,
      • Clauw DJ.
      Fibromyalgia: a clinical review.
      ,
      • O'Connell NE
      • Marston L
      • Spencer S
      • DeSouza LH
      • Wand BM.
      Non-invasive brain stimulation techniques for chronic pain.
      among which repetitive transcranial magnetic stimulation (rTMS) in neuromodulation techniques is one of such promising choices
      • Knijnik LM
      • Dussán-Sarria JA
      • Rozisky JR
      • et al.
      Repetitive transcranial magnetic stimulation for fibromyalgia: systematic review and meta-analysis.
      that has emerged as a therapeutic alternative with proven efficacy.
      • Ansari AH
      • Pal A
      • Ramamurthy A
      • Kabat M
      • Jain S
      • Kumar S.
      Fibromyalgia pain and depression: an update on the role of repetitive transcranial magnetic stimulation.
      Studies found that rTMS can cause changes in brain activity and has aftereffects on the brain, such as long-term potentiation or long-term depression, and the aftereffects induced by rTMS depend on the frequency and duration of stimulation.
      • Simonetta-Moreau M.
      Non-invasive brain stimulation (NIBS) and motor recovery after stroke.
      Low-frequency stimulation (<1Hz) has inhibitory effects on brain activity, whereas high-frequency (>5Hz) stimulation increases cortical excitability
      • Klomjai W
      • Katz R
      • Lackmy-Vallée A.
      Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS).
      ; rTMS also affects brain activity associated with pain regulation and processing, which is an intervention for pain.
      • Klomjai W
      • Katz R
      • Lackmy-Vallée A.
      Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS).
      ,
      • Lefaucheur JP
      • Aleman A
      • Baeken C
      • et al.
      Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018).
      Some studies have shown that rTMS has a positive therapeutic effect on FMS.
      • Knijnik LM
      • Dussán-Sarria JA
      • Rozisky JR
      • et al.
      Repetitive transcranial magnetic stimulation for fibromyalgia: systematic review and meta-analysis.
      ,
      • Klomjai W
      • Katz R
      • Lackmy-Vallée A.
      Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS).
      Researchers have reported that stimulation of the left dorsolateral prefrontal cortex (DLPFC) using low-frequency rTMS can significantly reduce pain and related symptoms by targeting spinal pain circuits and top-down pain modulation.
      • Tanwar S
      • Mattoo B
      • Kumar U
      • Bhatia R.
      Repetitive transcranial magnetic stimulation of the prefrontal cortex for fibromyalgia syndrome: a randomised controlled trial with 6-months follow up.
      At the same time, application of high-frequency rTMS to stimulate the left primary motor cortex (M1) was found to have an analgesic effect as well,
      • Tekin A
      • Ozdil E
      • Guleken MD
      • et al.
      Efficacy of high frequency repetitive transcranial magnetic stimulation of the primary motor cortex in patients with fibromyalgia syndrome: a randomized, double blind, sham-controlled trial.
      and high-frequency rTMS may achieve direct antinociceptive effects by activating descending pain inhibitory controls.
      • Passard A
      • Attal N
      • Benadhira R
      • et al.
      Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia.
      There is currently no consensus on the optimal parameters for rTMS in FMS treatment. Therefore, we systematically reviewed the available literature; retrieved randomized controlled trials of 10-Hz frequency rTMS for the treatment of widespread pain, depressive symptoms, and quality of life in FMS; and used meta-analysis to quantify its effects.

      Methods

      Protocol and registration

      Our systematic review was designed and implemented based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
      • Page MJ
      • McKenzie JE
      • Bossuyt PM
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      The study has been registered with PROSPERO (CRD42021289778).

      Search strategy

      The search strategy study was determined by searching an electronic database (PubMed, Embase, Cochrane, Ovid, Web of Science) from the beginning until November 6, 2021, and the retrieval strategy consisted of 2 parts, regardless of language, using Medical Subject Headings of the National Library of Medicine terminology and keyword combination search. In the PubMed database we conducted a combined search using “Transcranial Magnetic Stimulation” “(Mesh)” match with keywords “Fibromyalgias/Fibromyalgia-Fibromyositis Syndrome/Fibromyalgia, Secondary.”

      Inclusion and exclusion criteria

      According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 requirements,
      • Page MJ
      • McKenzie JE
      • Bossuyt PM
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      eligibility for the study should include (1) only patients diagnosed with FMS according to the American Rheumatic Society diagnostic criteria; (2) intervention method including 10-Hz high-frequency rTMS, but the treatment site is not limited; and (3) outcome indicators must have a scale for assessing pain, depression, and quality of life, such as visual analog scale (VAS), Brief Pain Inventory (BPI), Hamilton Depression Rating Scale (HDRS), Beck Depression Inventory (BDI), and Fibromyalgia Impact Questionnaire (FIQ). If the literature on pain has both VAS and BPI, VAS as the main evaluation criteria, secondary outcome indicators are about depression (HDRS or BDI) and quality of life (FIQ) scale, (4) literature is original and provides sufficient information, and data. The following conditions were excluded: (1) animal experiments; (2) nonrandomized controlled trials; and (3) non-10 Hz frequency rTMS treatment.

      Data extraction

      Two experienced researchers independently evaluated the studies based on the above inclusion/exclusion criteria. The extracted data and description information included the first author's last name, year of publication, type of study, rTMS intervention (frequency), treatment site, control method, number of intervention and control groups, outcome assessment of depression, quality of life, and pain scores.
      The meta-analysis used the mean and SD of the results. The average and SD of the main clinical results were obtained from the tables published in each study. If no direct results are provided, the data are obtained using the GetData Graph Digitizer software diagram, or the data are obtained through the author of the communication. Any disagreement is resolved through discussion and consultation with the third reviewer.

      Data synthesis and statistical analysis

      The effect size was calculated by the standardized mean difference (SMD) of clinical scale scores after 1 month of treatment. The z test was used to evaluate the 95% confidence interval (CI). Heterogeneity between groups was tested by the Cochran's Q statistics and I2 test. If there was no heterogeneity between the groups (Q test shows P>.05 or I2<50%), a fixed-effect model would be applied. Otherwise, if the Q test results were significant (P<.05 or I2>50%), a random-effect model would be used in the meta-analysis. Data analysis used RevMan5.4.1 statistics software.a

      Results

      Literature search and study characteristics

      A total of 488 articles were searched in the database search, with titles, abstracts, and full texts read under the criteria, and 7 studies were eventually included, with fig 1 showing the screening process.
      Fig 1
      Fig 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart of study selection.
      Table 1 shows that a total of 217 patients with FMS were included in the study, all of whom used 10-Hz high-frequency rTMS as an intervention. As of the intervention sites used, there are 3 studies on the left MI,
      • Tekin A
      • Ozdil E
      • Guleken MD
      • et al.
      Efficacy of high frequency repetitive transcranial magnetic stimulation of the primary motor cortex in patients with fibromyalgia syndrome: a randomized, double blind, sham-controlled trial.
      ,
      • Passard A
      • Attal N
      • Benadhira R
      • et al.
      Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia.
      ,
      • Mhalla A
      • Baudic S
      • De Andrade DC
      • et al.
      Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia.
      ,
      • Guedj E
      • Dousset A
      • Boyer L
      • et al.
      Transcranial magnetic stimulation in fibromyalgia: a randomized trial evaluating quality of life and its brain metabolic substrate.
      3 studies on the left DLPFC,
      • Short EB
      • Borckardt JJ
      • Anderson BS
      • et al.
      Ten sessions of adjunctive left prefrontal rTMS significantly reduces fibromyalgia pain: a randomized, controlled pilot study.
      ,
      • Bilir I
      • Askin A
      • Sengul I
      • Tosun A.
      Effects of high-frequency neuronavigated repetitive transcranial magnetic stimulation in fibromyalgia syndrome: a double-blinded, randomized controlled study.
      ,
      • Fitzgibbon BM
      • Hoy KE
      • Knox LA
      • et al.
      Evidence for the improvement of fatigue in fibromyalgia: a 4-week left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation randomized-controlled trial.
      and 1 study on both the left MI and the left DLPFC.
      • 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?.
      Therefore, the subgroup analysis was conducted based on these 2 different intervention sites: MI and DLPFC. All studies compared the intervention and control groups, the outcome indicator, and the pain evaluation. To assess the pain 4 studies were used VAS,
      • Tekin A
      • Ozdil E
      • Guleken MD
      • et al.
      Efficacy of high frequency repetitive transcranial magnetic stimulation of the primary motor cortex in patients with fibromyalgia syndrome: a randomized, double blind, sham-controlled trial.
      ,
      • 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?.
      • Bilir I
      • Askin A
      • Sengul I
      • Tosun A.
      Effects of high-frequency neuronavigated repetitive transcranial magnetic stimulation in fibromyalgia syndrome: a double-blinded, randomized controlled study.
      2 studies used BPI,
      • Passard A
      • Attal N
      • Benadhira R
      • et al.
      Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia.
      ,
      • Mhalla A
      • Baudic S
      • De Andrade DC
      • et al.
      Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia.
      and 1 study used average daily pain.
      • Short EB
      • Borckardt JJ
      • Anderson BS
      • et al.
      Ten sessions of adjunctive left prefrontal rTMS significantly reduces fibromyalgia pain: a randomized, controlled pilot study.
      To assess depression evaluation, 4 studies used BDI,
      • Passard A
      • Attal N
      • Benadhira R
      • et al.
      Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia.
      ,
      • 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?.
      ,
      • Fitzgibbon BM
      • Hoy KE
      • Knox LA
      • et al.
      Evidence for the improvement of fatigue in fibromyalgia: a 4-week left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation randomized-controlled trial.
      ,
      • Mhalla A
      • Baudic S
      • De Andrade DC
      • et al.
      Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia.
      while the other 3 studies used Montgomery-Asberg Depression Rating Scale,
      • Tekin A
      • Ozdil E
      • Guleken MD
      • et al.
      Efficacy of high frequency repetitive transcranial magnetic stimulation of the primary motor cortex in patients with fibromyalgia syndrome: a randomized, double blind, sham-controlled trial.
      Hospital Anxiety and Depression Scale,
      • Bilir I
      • Askin A
      • Sengul I
      • Tosun A.
      Effects of high-frequency neuronavigated repetitive transcranial magnetic stimulation in fibromyalgia syndrome: a double-blinded, randomized controlled study.
      and HDRS.
      • Short EB
      • Borckardt JJ
      • Anderson BS
      • et al.
      Ten sessions of adjunctive left prefrontal rTMS significantly reduces fibromyalgia pain: a randomized, controlled pilot study.
      To evaluate the quality of life, 6 studies used FIQ,
      • Short EB
      • Borckardt JJ
      • Anderson BS
      • et al.
      Ten sessions of adjunctive left prefrontal rTMS significantly reduces fibromyalgia pain: a randomized, controlled pilot study.
      ,
      • Passard A
      • Attal N
      • Benadhira R
      • et al.
      Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia.
      • 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?.
      • Bilir I
      • Askin A
      • Sengul I
      • Tosun A.
      Effects of high-frequency neuronavigated repetitive transcranial magnetic stimulation in fibromyalgia syndrome: a double-blinded, randomized controlled study.
      • Fitzgibbon BM
      • Hoy KE
      • Knox LA
      • et al.
      Evidence for the improvement of fatigue in fibromyalgia: a 4-week left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation randomized-controlled trial.
      while 1 used World Briefing on Health Quality of Life.
      • Tekin A
      • Ozdil E
      • Guleken MD
      • et al.
      Efficacy of high frequency repetitive transcranial magnetic stimulation of the primary motor cortex in patients with fibromyalgia syndrome: a randomized, double blind, sham-controlled trial.
      Table 1Characteristics of the included studies
      AuthorAge (y), Mean ± SDExperimental Group (n)Control Group (n)Intervention ProtocolStimulation SiteOutcome
      Altas et al
      • 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?.
      M1: 46.3±9.01 DLPFC: 47.9±7.89 Sham: 48.2±9.38MI: 10 DLPFC:101010-Hz rTMS, 90% strength; 15 times (5 times/wk)Left M1 and left DLPFCPain: VAS Depression: BDI

      Living quality: FIQ
      Tekin et al
      • Tekin A
      • Ozdil E
      • Guleken MD
      • et al.
      Efficacy of high frequency repetitive transcranial magnetic stimulation of the primary motor cortex in patients with fibromyalgia syndrome: a randomized, double blind, sham-controlled trial.
      Experimental group: 42.4±7.63 Control group: 46.5±8.36272410-Hz frequency, 100% strength, and 10 consecutive treatments were performedLeft M1Pain: VAS Depression: MADRS Living quality: World Briefing on Healthy Quality of Life
      Bilir et al
      • Bilir I
      • Askin A
      • Sengul I
      • Tosun A.
      Effects of high-frequency neuronavigated repetitive transcranial magnetic stimulation in fibromyalgia syndrome: a double-blinded, randomized controlled study.
      Experimental group: 46.70±9.06 Control group: 43.80±9.37101010-Hz rTMS, 14 sessions: 10 daily (5d/wk, 2 wk), and 4 weekly (1d/wk, 4 wk)Left DLPFCPain: VAS Depression: HADS

      Living quality: FIQ
      Fitzgibbon et al
      • Fitzgibbon BM
      • Hoy KE
      • Knox LA
      • et al.
      Evidence for the improvement of fatigue in fibromyalgia: a 4-week left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation randomized-controlled trial.
      Experimental group: 45.07±11.02

      Control group: 46.25±15.04
      141210-Hz frequency, 120% strength, daily (Monday-Friday) rTMS for 4 consecutive weeks (20 times in total)Left DLPFCPain: VAS Depression: BDI

      Living quality: FIQ
      Mhalla et al
      • Mhalla A
      • Baudic S
      • De Andrade DC
      • et al.
      Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia.
      Experimental group: 51.8±11.6 Control group: 49.6±10.0202010-Hz frequency, 80% strength, 14 sessions of stimulationLeft M1Pain: BPI Depression: BDI

      Living quality: FIQ
      Passard et al
      • Passard A
      • Attal N
      • Benadhira R
      • et al.
      Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia.
      Experimental group: 52.6±7.9 Control group: 55.3±8.9151510-Hz frequency, 80% strength, 10 sessions in 2 wkLeft M1Pain: BPI Depression: BDI

      Living quality: FIQ
      Short et al
      • Short EB
      • Borckardt JJ
      • Anderson BS
      • et al.
      Ten sessions of adjunctive left prefrontal rTMS significantly reduces fibromyalgia pain: a randomized, controlled pilot study.
      Experimental group: 54.20±8.28 Control group: 51.67±18.1910105 times/wk for 2 wk 10-Hz pulse train duration (on time) 5 s, power (intensity) 120% strengthLeft DLPFCPain: average daily pain Depression: HDRS

      Living quality: FIQ
      Abbreviations: HADS, Hospital Anxiety and Depression Scale; MADRS, Montgomery-Asberg Depression Rating Scale.

      Quality assessment

      The evaluation criteria of the Cochrane Bias Risk Assessment Tool were divided into 7 items. Each item used low bias, uncertain risk of bias, and high bias to judge and classify the study quality and evaluate whether the study was a randomized, blind, data integrity, and bias study. Two reviewers assessed the risk of bias in 7 study groups using the Cochrane Collaboration guidelines, as shown in figs 2A and 2B.
      Fig 2
      Fig 2(A) Risk of bias graph; (B) risk of bias summary.

      Effect of 10-Hz frequency rTMS on pain

      High frequency transcranial magnetic stimulation at 10 Hz was significantly associated with reduced pain compared with sham stimulation in controls (SMD=−0.72; 95% CI, −1.12 to −0.33; P<.001; I2=46%) (fig 3A). After sensitivity analysis, excluding the only study
      • Tekin A
      • Ozdil E
      • Guleken MD
      • et al.
      Efficacy of high frequency repetitive transcranial magnetic stimulation of the primary motor cortex in patients with fibromyalgia syndrome: a randomized, double blind, sham-controlled trial.
      that observed an acute analgesic effect of 10-Hz rTMS application did not change the results, but heterogeneity was reduced (SMD=−0.53; 95% CI, −0.85 to −0.22; P<.001; I2=0%) (see fig 3B).
      Fig 3
      Fig 3(A) Effects of 10-Hz high-frequency transcranial magnetic stimulation on pain; (B) sensitivity analysis.

      Effect of 10-Hz high-frequency rTMS on depression

      Compared with the pseudo-stimulation in the control group, the effect of 10-Hz high-frequency transcranial magnetic stimulation on depression was not significantly better than that of the control group (SMD=−0.23; 95% CI, −0.50 to 0.05; P=.11; I2=33%) (fig 4).
      Fig 4
      Fig 4Effects of 10-Hz frequency transcranial magnetic stimulation on depression.

      Effects of 10-Hz frequency rTMS on quality of life

      Compared with the pseudo-stimulation in the control group, 10-Hz high-frequency rTMS intervention significantly improved the quality of life (SMD=−0.70; 95% CI, −1.00 to −0.40; P<.001; I2=15%) (fig 5).
      Fig 5
      Fig 5Effects of 10-Hz frequency rTMS on quality of life.

      Subgroup analysis

      The effects of 10-Hz rTMS intervention on pain in different parts of the brain were analyzed, and the MI region and DLPFC region were selected for subgroup analysis. The results showed no statistical significance, but the trend of analgesic effect in the M1 region was better than that in the DLPFC region (SMD=−0.72; 95% CI, −1.12 to −0.33; P=.10; I2=62%) (fig 6).
      Fig 6
      Fig 6Effect of stimulation on pain in different areas.

      Discussion

      The meta-analysis integrates quantitative data on pain, depression, and quality of life in patients with FMS treated with 10-Hz frequency rTMS. Data analysis shows that 10-Hz frequency rTMS has a significant effect on pain reduction and quality of life improvement, but it has no significant improvement in depression and makes no statistically significant difference in pain in M1 and DLPFC.
      The mechanism behind the effect of rTMS is not fully understood. Some studies suggest that the aftereffect of rTMS may induce electrical changes in brain activity through an electromagnetic field generated by a coil on a patient's scalp, generating a superficial cortical current,
      • Ansari AH
      • Pal A
      • Ramamurthy A
      • Kabat M
      • Jain S
      • Kumar S.
      Fibromyalgia pain and depression: an update on the role of repetitive transcranial magnetic stimulation.
      and its cortical effects may not only be limited to the stimulation site but also extend to the distal region.
      • Bestmann S
      • Baudewig J
      • Siebner HR
      • Rothwell JC
      • Frahm J.
      Functional MRI of the immediate impact of transcranial magnetic stimulation on cortical and subcortical motor circuits.
      In addition, rTMS affects brain activity might be associated with pain regulation and processing.
      • Klomjai W
      • Katz R
      • Lackmy-Vallée A.
      Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS).
      Some investigators believe that high-frequency rTMS may have analgesic effects on chronic pain by restoring the damaged cortical inhibitory mechanism and affecting the structures involved in pain and sensory processing.
      • Lefaucheur JP
      • Drouot X
      • Ménard-Lefaucheur I
      • Keravel Y
      • Nguyen JP.
      Motor cortex rTMS restores defective intracortical inhibition in chronic neuropathic pain.
      The rTMS on M1 may be able to reduce pain by activating subcortical structures related to the endogenous pain regulation system, such as the thalamus, cingulate gyrus, periductal gray matter, and dorsal reticular subnucleus.
      • Giannoni-Luza S
      • Pacheco-Barrios K
      • Cardenas-Rojas A
      • et al.
      Noninvasive motor cortex stimulation effects on quantitative sensory testing in healthy and chronic pain subjects: a systematic review and meta-analysis.
      The DLPFC site is a functional and structurally heterogeneous region, which is a key node of several brain networks related to cognition, emotion, and sensory processing.
      • Fitzgibbon BM
      • Hoy KE
      • Knox LA
      • et al.
      Evidence for the improvement of fatigue in fibromyalgia: a 4-week left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation randomized-controlled trial.
      ,
      • Seminowicz DA
      • Moayedi M.
      The dorsolateral prefrontal cortex in acute and chronic pain.
      Because DLPFC is associated with other brain areas such as the rostral anterior cingulate cortex (the brain barrier is known to play an important role in pain processing),
      • Jensen KB
      • Kosek E
      • Petzke F
      • et al.
      Evidence of dysfunctional pain inhibition in fibromyalgia reflected in rACC during provoked pain.
      it can potentially modulate this nexus. rTMS on the DLPFC may modulate nociception indirectly through its connections with the cingulate cortex and medial thalamus known to be involved in the pain regulation.
      • Reid P
      • Pridmore S.
      Improvement in chronic pain with transcranial magnetic stimulation.
      ,
      • Tanwar S
      • Mattoo B
      • Kumar U
      • Bhatia R.
      Repetitive transcranial magnetic stimulation of the prefrontal cortex for fibromyalgia syndrome: a randomised controlled trial with 6-months follow up.
      Neuroimaging studies have also established that the DLPFC may play a role in top-down patterns of inhibition, modulating pain perception through descending fibers of the prefrontal cortex.
      • Lorenz J
      • Cross DJ
      • Minoshima S
      • Morrow TJ
      • Paulson PE
      • Casey KL.
      A unique representation of heat allodynia in the human brain.
      ,
      • Lorenz J
      • Minoshima S
      • Casey KL.
      Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation.
      Recent noninvasive brain stimulation studies have suggested that interhemispheric DLPFC connectivity influences pain tolerance and discomfort by altering interhemispheric inhibition.
      • Sevel LS
      • Letzen JE
      • Staud R
      • Robinson ME.
      Interhemispheric dorsolateral prefrontal cortex connectivity is associated with individual differences in pain sensitivity in healthy controls.
      In addition, there are studies evaluating pain tolerance and nociceptive flexion reflex thresholds during the cold pressor test demonstrating that rTMS of the DLPFC can modulate pain sensation related to the cingulate cortex and medial thalamus, which together are thought to be involved in this type of modulation of pain.
      • Tanwar S
      • Mattoo B
      • Kumar U
      • Bhatia R.
      Repetitive transcranial magnetic stimulation of the prefrontal cortex for fibromyalgia syndrome: a randomised controlled trial with 6-months follow up.
      ,
      • Russo JF
      • Sheth SA.
      Deep brain stimulation of the dorsal anterior cingulate cortex for the treatment of chronic neuropathic pain.
      ,
      • Chai SC
      • Kung JC
      • Shyu BC.
      Roles of the anterior cingulate cortex and medial thalamus in short-term and long-term aversive information processing.
      These 2 brain regions may be feasible as a targeted site of rTMS. This explains the analysis of the 7 high-frequency rTMS studies included in this meta-analysis, which showed a significant effect of high-frequency stimulation on FMS analgesia.
      Our subgroup analysis showed that although there was no obvious advantage in stimulating the M1 region compared with the stimulating DLPFC region, a trend better than DLPFC could be observed. It may be that the sample size of the 2 is too different, and the specific parameters of each research stimulus are different, which leads to this result. A randomized controlled trial showed that left M1 rTMS significantly reduced pain, and left DLPFC stimulation could better improve body role function than M1 stimulation.
      • 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?.
      However, 1 study showed a different view, suggesting that there was no significant difference in pain intensity in patients with FMS with left M1 rTMS compared with sham stimulation.
      • Hodaj H
      • Payen JF
      • Lefaucheur JP.
      Therapeutic impact of motor cortex rTMS in patients with chronic neuropathic pain even in the absence of an analgesic response. A case report.
      A previous study showed that high-frequency rTMS on rTMS can significantly relieve pain
      • Short EB
      • Borckardt JJ
      • Anderson BS
      • et al.
      Ten sessions of adjunctive left prefrontal rTMS significantly reduces fibromyalgia pain: a randomized, controlled pilot study.
      ; moreover, some scholars believe that high-frequency rTMS of left DLPFC is more effective for pain.
      • Lefaucheur JP
      • Aleman A
      • Baeken C
      • et al.
      Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018).
      Thus, from these literature analyses, it seems that DLPFC rTMS is more effective for pain.
      It is well known that the DLPFC region is closely related to depression.
      • Ochsner KN
      • Bunge SA
      • Gross JJ
      • Gabrieli JD.
      Rethinking feelings: an FMRI study of the cognitive regulation of emotion.
      • Ochsner KN
      • Ray RD
      • Cooper JC
      • et al.
      For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion.
      • Eippert F
      • Veit R
      • Weiskopf N
      • Erb M
      • Birbaumer N
      • Anders S.
      Regulation of emotional responses elicited by threat-related stimuli.
      Functional imaging studies found that depression was associated with low DLPFC activity, and the recovery of depression was associated with increased DLPFC activity as well as lesion studies, which correlated DLPFC lesions with increased depression severity.
      • Koenigs M
      • Grafman J.
      The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex.
      In conclusion, DLPFC may be an effective target for the treatment of depression in FMS. In addition to the uncertainty of the target, there is no unified standard for the selection of frequency at present. A meta-analysis showed that high-frequency and low-frequency rTMS had considerable antidepressant efficacy.
      • Chen J
      • Zhou C
      • Wu B
      • et al.
      Left versus right repetitive transcranial magnetic stimulation in treating major depression: A meta-analysis of randomised controlled trials.
      However, some scholars have pointed out that low-frequency rTMS is generally better tolerated than high-frequency rTMS, which produces greater local scalp discomfort during stimulation.
      • Berlim MT
      • Van den Eynde F
      • Jeff Daskalakis Z
      Clinically meaningful efficacy and acceptability of low-frequency repetitive transcranial magnetic stimulation (rTMS) for treating primary major depression: a meta-analysis of randomized, double-blind and sham-controlled trials.
      From the analysis of current evidence, low-frequency rTMS may have greater prospects. In our study, all included high-frequency rTMS as an intervention method, and only 4 studies selected the left DLPFC as the treatment area. These factors may be the cause of negative results in depression.
      High-frequency rTMS has been shown to affect the emotional dimensions of quality of life, improving quality of life.53 However, the choice of the treatment area (M1 vs DLPFC) is still controversial. Recently, it has been shown that M1 rTMS is more beneficial for the improvement of daily living abilities in patients with FMS.
      • Tekin A
      • Ozdil E
      • Guleken MD
      • et al.
      Efficacy of high frequency repetitive transcranial magnetic stimulation of the primary motor cortex in patients with fibromyalgia syndrome: a randomized, double blind, sham-controlled trial.
      ,
      • Hodaj H
      • Payen JF
      • Lefaucheur JP.
      Therapeutic impact of motor cortex rTMS in patients with chronic neuropathic pain even in the absence of an analgesic response. A case report.
      ,
      • Boyer L
      • Dousset A
      • Roussel P
      • et al.
      rTMS in fibromyalgia: a randomized trial evaluating QoL and its brain metabolic substrate.
      However, there is a study that suggests that rTMS on DLPFC can improve fatigue in patients with FMS.
      • Fitzgibbon BM
      • Hoy KE
      • Knox LA
      • et al.
      Evidence for the improvement of fatigue in fibromyalgia: a 4-week left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation randomized-controlled trial.
      At present, there are few direct comparative studies on the effect of the 2 (M1 vs DLPFC) on the quality of life. Thus, from the current evidence, it seems that the high-frequency rTMS on M1 is more effective in improving the quality of life.

      Study limitations

      In this study, several limitations should be taken into account. First, the meta-analysis was based on only 7 randomized controlled trials, and all of them had relatively small sample sizes (N<100); small sample size trials were more likely to overestimate treatment effects than large trials. Second, the included studies used inconsistent scales such as BDI, Montgomery-Asberg Depression Rating Scale, HADS and HDRS to assess depression, which focused on different aspects of depression or were insensitive to minor changes in depression.
      • Schneibel R
      • Brakemeier EL
      • Wilbertz G
      • Dykierek P
      • Zobel I
      • Schramm E.
      Sensitivity to detect change and the correlation of clinical factors with the Hamilton Depression Rating Scale and the Beck Depression Inventory in depressed inpatients.
      Finally, although we obtained positive results in terms of quality of life, The difference in efficacy between the 2 (M1 vs DLPFC) was not further analyzed.
      There is only 1 study in this meta-analysis that compared M1 and DLPFC with a small sample size. Future studies may be needed to compare differences in the effects of different intervention sites (M1 vs DLPFC) for patients with FMS. In addition, multicenter, randomized controlled, double-blind experimental studies of different stimulus programs should be carried out in clinical practice, which is conducive to longitudinal and transverse comparison between different stimulus parameters to determine the best stimulus protocol.

      Conclusions

      After treating patients with FMS with 10-Hz high-frequency rTMS, there was a significant improvement in pain and quality of life, but no significant effect was shown in depression. Based on the current evidence analysis, DLPFC high-frequency rTMS appears to be more effective for analgesia, DLPFC low-frequency rTMS may be more promising in the treatment of depression, and M1 high-frequency rTMS may be more effective in improving quality of life.

      Supplier

      • a.
        RevMan5.4.1 statistics software.

      Acknowledgments

      We thank all the professors and coworkers for their tireless assistance in this project. We also thank the individuals who participated in this study as well as all of the administrative support staff for this study.

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