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Altered Primary Motor Cortex Structure, Organization, and Function in Chronic Pain: A Systematic Review and Meta-Analysis

Open AccessPublished:November 15, 2017DOI:https://doi.org/10.1016/j.jpain.2017.10.007

      Highlights

      • The evidence for primary motor cortex (M1) changes in chronic pain is conflicting.
      • M1 long-interval intracortical inhibition was increased in chronic pain.
      • Other measures of M1 changes in chronic pain were inconclusive.

      Abstract

      Chronic pain can be associated with movement abnormalities. The primary motor cortex (M1) has an essential role in the formulation and execution of movement. A number of changes in M1 function have been reported in studies of people with chronic pain. This review systematically evaluated the evidence for altered M1 structure, organization, and function in people with chronic pain of neuropathic and non-neuropathic origin. Database searches were conducted and a modified STrengthening the Reporting of OBservational studies in Epidemiology checklist was used to assess the methodological quality of included studies. Meta-analyses, including preplanned subgroup analyses on the basis of condition were performed where possible. Sixty-seven studies (2,290 participants) using various neurophysiological measures were included. There is conflicting evidence of altered M1 structure, organization, and function for neuropathic and non-neuropathic pain conditions. Meta-analyses provided evidence of increased M1 long-interval intracortical inhibition in chronic pain populations. For most measures, the evidence of M1 changes in chronic pain populations is inconclusive.

      Perspective

      This review synthesizes the evidence of altered M1 structure, organization, and function in chronic pain populations. For most measures, M1 changes are inconsistent between studies and more research with larger samples and rigorous methodology is required to elucidate M1 changes in chronic pain populations.

      Key words

      Chronic pain conditions such as low back pain (LBP), neck pain, and knee osteoarthritis (OA) are leading causes of disability globally
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      Methods

      The protocol of this review was prospectively registered with the International Prospective Register of Systematic Reviews (registration number CRD42015014823) and has been published elsewhere.
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       Search Strategy

      The search was conducted in 5 electronic databases (PubMed, MEDLINE, Embase, PsychINFO, and CINAHL) from inception to February 2017, using key words and medical subject headings terms related to chronic pain and M1 organization/function (Supplementary Appendix 1). The reference list of eligible studies and relevant reviews were manually searched for additional articles.

       Eligibility Criteria

      Inclusion criteria were: 1) full text studies published in English, including in press or accepted studies, 2) adult (aged older than 18 years) humans with non-neuropathic or neuropathic pain, 3) duration of pain >3 months,
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      4) investigated and reported measures of the organization and/or function of the M1 (regardless of the anatomical or functional definition used) using TMS, magnetic resonance imaging (MRI), electroencephalography (EEG), magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), or positron emission tomography (PET; Table 1). Studies were excluded if: 1) included participants presented chronic pain associated with neurological disorders, cancer, or visceral pain, or 2) the study did not include a healthy control group or used the unaffected limb or body side as a control. Cross-sectional or prospective studies, including case-control and randomized controlled trials that provided baseline data with information relevant to the review objective and that met the eligibility criteria, were included.
      Table 1Summary of M1 Structural, Organizational, and Functional Constructs and Their Associated Neurophysiological Methods and Outcome Measures
      M1 structureM1 organizationM1 function
      Neurophysiological methods and outcome measuresMRI: cortical thickness (VBM); white matter structure (diffusion tensor imaging)fMRI: activation/connectivity (rCBF, BOLD)

      TMS: M1 representation (map volume, CoG of M1 representation)
      TMS: corticospinal excitability (rMT, aMT, MEP amplitude and latency, CSP); ICF/intracortical inhibition

      EEG: cerebrocortical motor activity

      MEG: 20-Hz cortical rhythm (rebound amplitude/duration, reactivity)

      MRS: neurochemical metabolism

      PET: glucose metabolism
      Abbreviation: rMT, resting motor threshold.

       Study Selection

      Search results were imported into Endnote X7 (Clarivate Analytics, Philadelphia, PA). After removing duplicates, 2 reviewers independently screened titles and abstracts of all studies to remove those not relevant to the review objective. The full text of all remaining studies were retrieved and evaluated according to the eligibility criteria. If there was uncertainty or disagreement, a third reviewer was consulted.

       Data Extraction

      Two independent reviewers extracted the following data: pain condition, country of origin, study design and setting, inclusion/exclusion criteria, source of participants, sample size, participant demographic characteristics, duration and severity of chronic pain, neurophysiological methods, specifics of the investigative model, type and location of stimulation, and outcomes (ie, M1 excitability, representation, reactivity, neurochemical or glucose metabolism). Any disagreements were resolved in consensus with a third reviewer. If data were missing, authors were contacted a maximum of 3 times, after which the data were considered irretrievable.

       Quality and Risk of Bias Assessment

      Study quality and risk of bias were assessed by 2 independent reviewers using a modified version of the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement for cross-sectional and cohort studies.
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       Data Synthesis

      Meta-analyses were performed to aggregate the data from TMS studies. Because of increased heterogeneity in the methodology of included studies, a narrative synthesis was used to summarize the findings of studies using other neurophysiological methods.
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      TMS outcome measures (resting and active motor threshold [aMT], MEP amplitude and latency, cortical silent period (CSP), map volume, intracortical inhibition and facilitation) were pooled and separate meta-analyses were performed using RevMan version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen). Cohen d effect sizes were used to analyze effect estimates (d ≤.2, small; .5, moderate; ≥.8, large).
      • Cohen J.
      Statistical Power Analysis for the Behavioural Sciences.
      Meta-analyses were performed using a random effects model when data from at least 2 studies addressing that outcome were accessible. Statistically significant heterogeneity was identified using the χ2 test and was considered when χ2 P <.10. The I2 statistic was used to evaluate the degree of heterogeneity. Substantial heterogeneity was considered present when I2 > 50%.
      • Higgins J.
      • Green S.
      Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011].
      Meta-analyzed data are presented as effect estimates (standardized mean difference [SMD] with 95% confidence intervals [CIs]).

       Subgroup and Sensitivity Analysis

      Preplanned subgroup analyses were conducted according to the type of musculoskeletal condition where significant heterogeneity was identified. The median value of the modified STROBE statement score of the TMS studies was used as a cutoff point to divide studies into either low or high risk of bias groups. The influence of high risk of bias studies was examined by rerunning the analysis with those studies excluded.

      Results

      The initial search identified 5,028 records, from which 120 full text articles were retrieved to assess eligibility. Sixty-nine studies met the inclusion criteria in the review. The authors of 14 studies were contacted to request additional data pertaining to M1 function. Two studies were excluded as a result of unsuccessful attempts to acquire these data.
      • Daligadu J.
      • Haavik H.
      • Yielder P.C.
      • Baarbe J.
      • Murphy B.
      Alterations in cortical and cerebellar motor processing in subclinical neck pain patients following spinal manipulation.
      • Vidor L.P.
      • Torres I.L.
      • Medeiros L.F.
      • Dussan-Sarria J.A.
      • Dall'agnol L.
      • Deitos A.
      • Brietzke A.
      • Laste G.
      • Rozisky J.R.
      • Fregni F.
      • Caumo W.
      Association of anxiety with intracortical inhibition and descending pain modulation in chronic myofascial pain syndrome.
      Thus, a total of 67 studies were included in this review. The study flow chart can be seen in Fig 1.
      Figure 1
      Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the screening and inclusion of studies.

       Study Characteristics

      The included studies encompassed 7 neurophysiological methods: TMS (n = 35 studies), functional MRI (fMRI; n = 16 studies), MRI (n = 6 studies), MEG (n = 3 studies), MRS (n = 3 studies), EEG (n = 1 study), and PET (n = 1 study). Two studies investigated functional as well as structural MRI changes.
      • Tian T.
      • Guo L.
      • Xu J.
      • Zhang S.
      • Shi J.
      • Liu C.
      • Qin Y.
      • Zhu W.
      Brain white matter plasticity and functional reorganization underlying the central pathogenesis of trigeminal neuralgia.
      • van Velzen G.A.
      • Marinus J.
      • van Dijk J.G.
      • van Zwet E.W.
      • Schipper I.B.
      • van Hilten J.J.
      Motor cortical activity during motor tasks is normal in patients with complex regional pain syndrome.
      In total, the included studies involved 1,248 chronic pain (20 different pain conditions) and 1,042 healthy participants. CRPS (n = 16 studies) and LBP (n = 16 studies) were the most frequently investigated conditions.
      Five studies investigated 2 or more chronic pain conditions.
      • Caumo W.
      • Deitos A.
      • Carvalho S.
      • Leite J.
      • Carvalho F.
      • Dussan-Sarria J.A.
      • Lopes Tarrago Mda G.
      • Souza A.
      • Torres I.L.
      • Fregni F.
      Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology.
      • Rio E.
      • Kidgell D.
      • Moseley G.L.
      • Cook J.
      Elevated corticospinal excitability in patellar tendinopathy compared with other anterior knee pain or no pain.
      • Rittig-Rasmussen B.
      • Kasch H.
      • Fuglsang-Frederiksen A.
      • Svensson P.
      • Jensen T.S.
      Effect of training on corticomotor excitability in clinical neck pain.
      • Salerno A.
      • Thomas E.
      • Olive P.
      • Blotman F.
      • Picot M.C.
      • Georgesco M.
      Motor cortical dysfunction disclosed by single and double magnetic stimulation in patients with fibromyalgia.
      • Schwenkreis P.
      • Scherens A.
      • Ronnau A.K.
      • Hoffken O.
      • Tegenthoff M.
      • Maier C.
      Cortical disinhibition occurs in chronic neuropathic, but not in chronic nociceptive pain.
      Participant sex (n = 4 studies) and age (n = 3 studies), pain intensity (n = 22 studies), and the duration of the pain (n = 7 studies) were not reported by some of the included studies. The characteristics of included studies are summarized in Table 2, Table 3.
      Table 2Characteristics of Studies using TMS
      ReferenceConditionCountryChronic pain participantsHealthy participantsModalityStimuliTarget musclesOutcome measures
      Study size (M/F), nAge, yearsPain durationPain intensity (0–10)Study size (M/F), nAge, years
      Salerno et al
      • Salerno A.
      • Thomas E.
      • Olive P.
      • Blotman F.
      • Picot M.C.
      • Georgesco M.
      Motor cortical dysfunction disclosed by single and double magnetic stimulation in patients with fibromyalgia.
      Fibromyalgia; rheumatoid arthritisFrance13 (0/13); 5 (0/5)50.1 ± 5.6; 50.0 ± 5.1 (SEM)NANA13 (NA)49.1 ± 5 (SEM)Double cone coil on cortical representation of the target musclesSingle and paired pulsesFirst dorsal interosseous,

      tibialis anterior
      rMT, MEP amplitude, CSP, SICI, ICF, LICI
      Schwenkreis et al
      • Schwenkreis P.
      • Janssen F.
      • Rommel O.
      • Pleger B.
      • Volker B.
      • Hosbach I.
      • Dertwinkel R.
      • Maier C.
      • Tegenthoff M.
      Bilateral motor cortex disinhibition in complex regional pain syndrome (CRPS) type I of the hand.
      CRPS I: handGermany25 (9/16)49.1 ± 13.826.1 ± 47 MonthsNA20 (10/10)20 to 78 (95% CI)Circular coil (14 cm) on vertexSingle and paired pulses,

      monophasic
      Information obtained from the stimulator manufacturer's website.
      First dorsal interosseousrMT, MEP amplitude, SICI, ICF
      Strutton et al
      • Strutton P.H.
      • Catley M.
      • McGregor A.H.
      • Davey N.J.
      Corticospinal excitability in patients with unilateral sciatica.
      Chronic sciaticaUnited Kingdom9 (NA)NANANA7 (NA)NADouble cone coil on hotspotSingle pulse, monophasic
      Information obtained from the stimulator manufacturer's website.
      Tibialis anterior, lateral gastrocnemiusrMT, aMT
      On et al
      • On A.Y.
      • Uludag B.
      • Taskiran E.
      • Ertekin C.
      Differential corticomotor control of a muscle adjacent to a painful joint.
      Patello-femoral painTurkey13 (0/13)25 ± 8.1

      (SEM)
      3.46 ± 1.9 Years (SEM)NA13 (0/13)25.1 ± 7.4 (SEM)Circular coil (9 cm) on hotspotSingle pulse, monophasicVastus medialis obliques, vastus lateralis, extensor digitorum brevisMEP amplitude
      Eisenberg et al
      • Eisenberg E.
      • Chistyakov A.V.
      • Yudashkin M.
      • Kaplan B.
      • Hafner H.
      • Feinsod M.
      Evidence for cortical hyperexcitability of the affected limb representation area in CRPS: A psychophysical and transcranial magnetic stimulation study.
      CRPS I: hand; CRPS I: footIsrael6 (4/2); 6 (5/1)33 ± 12.7; 32 ± 931 ± 41 Months; 20 ± 21 months7.3 ± 3.1; 6.7 ± 2.314 (10/4)30.9 ± 12.7Figure of 8 coil (9 cm) on hotspotSingle and paired pulses, monophasic
      Information obtained from the stimulator manufacturer's website.
      Abductor pollicis brevisSICI
      Krause et al
      • Krause P.
      • Foerderreuther S.
      • Straube A.
      Effects of conditioning peripheral repetitive magnetic stimulation in patients with complex regional pain syndrome.
      CRPS I: handGermany12 (2/10)55.9 ± 15.6NANA10 (NA)42.4Figure of 8 coil (9 cm) on hotspotSingle pulse, monophasic
      Information obtained from the stimulator manufacturer's website.
      Long extensor musclerMT, MEP amplitude, CSP
      Strutton et al
      • Strutton P.H.
      • Theodorou S.
      • Catley M.
      • McGregor A.H.
      • Davey N.J.
      Corticospinal excitability in patients with chronic low back pain.
      LBPUnited Kingdom24 (15/9)39.1 ± 2.2NANA11 (7/4)35.9 ± 3.2Double cone coil on vertexSingle pulse, monophasic
      Information obtained from the stimulator manufacturer's website.
      Erector spinaeaMT, MEP latency, CSP
      Krause et al
      • Krause P.
      • Forderreuther S.
      • Straube A.
      TMS motor cortical brain mapping in patients with complex regional pain syndrome type I.
      CRPS: handGermany14 (4/10)37 (17–72)>6 MonthsNA1038 (24–63)Figure of 8 coil (7 cm) on M1Single pulse, monophasic
      Information obtained from the stimulator manufacturer's website.
      Long extensor musclerMT, MEP amplitude, map volume
      Turton et al
      • Turton A.J.
      • McCabe C.S.
      • Harris N.
      • Filipovic S.R.
      Sensorimotor integration in Complex Regional Pain Syndrome: A transcranial magnetic stimulation study.
      CRPS I: handUnited Kingdom8 (1/7)45 ± 136.6 ± 4.9 Years6.3 ± 1.48 (1/7)45 ± 13Figure of 8 coil (9.5 m) on hotspotSingle pulse, monophasic
      Information obtained from the stimulator manufacturer's website.
      Abductor pollicis brevisMEP amplitude
      Tsao et al
      • Tsao H.
      • Galea M.P.
      • Hodges P.W.
      Reorganization of the motor cortex is associated with postural control deficits in recurrent low back pain.
      LBPAustralia11 (5/6)24 ± 75.6 ± 4.2 Years5.5 ± 211 (4/7)23 ± 3Figure of 8 coil (7 cm) and double cone coil (11 cm) on hotspot and M1Single pulse, monophasicTransversus abdominusrMT, aMT, map volume
      Berth et al
      • Berth A.
      • Pap G.
      • Neuman W.
      • Awiszus F.
      Central neuromuscular dysfunction of the deltoid muscle in patients with chronic rotator cuff tears.
      Rotator cuff tearGermany10 (10/0)64.9 ± 4.6>6 MonthsNA13 (10/3)27.2 ± 8.1Figure of 8 coil on hotspotSingle pulse, monophasic
      Information obtained from the stimulator manufacturer's website.
      DeltoidMEP amplitude
      Turgut et al
      • Turgut N.
      • Altun B.U.
      Cortical disinhibition in diabetic patients with neuropathic pain.
      Diabetic neuropathic painTurkey20 (5/15)63.9 ± 7.312.4 ± 6.7 Years8.1 ± 1.330 (14/16)58.3 ± 6.5Circular coil (14 cm) on hotspotSingle pulse,

      NA
      First dorsal interosseousrMT, MEP amplitude, MEP latency, CSP
      Mhalla et al
      • Mhalla A.
      • de Andrade D.C.
      • Baudic S.
      • Perrot S.
      • Bouhassira D.
      Alteration of cortical excitability in patients with fibromyalgia.
      FibromyalgiaFrance21 (0/21)52.2 ± 10.414.1 ± 11.9 Years5.5 ± 1.321 (0/21)46.7 ± 11.6Figure of 8 coilSingle and paired pulses,

      NA
      First dorsal interosseousrMT, SICI, ICF
      Schwenkreis et al
      • Schwenkreis P.
      • Scherens A.
      • Ronnau A.K.
      • Hoffken O.
      • Tegenthoff M.
      • Maier C.
      Cortical disinhibition occurs in chronic neuropathic, but not in chronic nociceptive pain.
      Neuralgia: hand; OA: handGermany26 (14/12); 20 (10/10)50.9 ± 11.7; 56.6 ± 10.239.3 ± 44.8 Months; 35.6 ± 42.9 months4.7 ± 2.1; 3.9 ± 214 (6/8)58.8 ± 12.7Circular coil (14 cm) on vertexSingle and paired pulses, monophasicFirst dorsal interosseousrMT, SICI, ICF
      Clark et al
      • Clark B.C.
      • Goss D.A.
      • Walkowski S.
      • Hoffman R.L.
      • Ross A.
      • Thomas J.S.
      Neurophysiologic effects of spinal manipulation in patients with chronic low back pain.
      LBP

      United States10 (5/5)23.7 ± 6.13.2 ± 3.1 Years2.6 ± 1.610 (5/5)22.9 ± 1.9 (SEM)Custom-modified 110-mm double cone coil on vertexSingle pulse,

      NA
      Erector spinaeMEP amplitude
      Schwenkreis et al
      • Schwenkreis P.
      • Voigt M.
      • Hasenbring M.
      • Tegenthoff M.
      • Vorgerd M.
      • Kley R.A.
      Central mechanisms during fatiguing muscle exercise in muscular dystrophy and fibromyalgia syndrome: A study with transcranial magnetic stimulation.
      FibromyalgiaGermany16 (2/14)48.7 ± 8.4NANA23 (7/16)37.7 ± 11.5Circular coil (14 cm) on vertexSingle and paired pulses, mono-phasic
      Information obtained from the stimulator manufacturer's website.
      Forearm superficial flexorrMT, MEP amplitude, CSP, SICI, ICF
      Tsao et al
      • Tsao H.
      • Danneels L.A.
      • Hodges P.W.
      ISSLS prize winner: Smudging the motor brain in young adults with recurrent low back pain.
      LBPAustralia9 (4/5)25 ± 3.43.6 ± 2.3 Years4.7 ± 1.111 (5/6)24 ± 5Figure of 8 coil (7 cm) on M1Single pulse, monophasicDeep multifidus, erector spinaeMap volume
      Masse-Alarie et al
      • Masse-Alarie H.
      • Flamand V.H.
      • Moffet H.
      • Schneider C.
      Corticomotor control of deep abdominal muscles in chronic low back pain and anticipatory postural adjustments.
      LBPCanada13 (6/7)53.7 ± 7.416 ± 10 Years2.9 ± 2.59 (4/5)48.7 ± 6.8Double cone coil (7 cm) on hotspotSingle and paired pulses, mono-phasicTransversus abdominus, internal obliqueMEP amplitude, SICI
      Vallence et al
      • Vallence A.M.
      • Smith A.
      • Tabor A.
      • Rolan P.E.
      • Ridding M.C.
      Chronic tension-type headache is associated with impaired motor learning.
      Chronic tension type headacheAustralia11 (5/6)35 ± 13.2NANA18 (7/11)28 ± 8 (unclear)Figure of 8 (9 cm) on hotspotSingle pulse, mono-phasic
      Information obtained from the stimulator manufacturer's website.
      Abductor pollicis brevisrMT, MEP amplitude
      Kittelson et al
      • Kittelson A.J.
      • Thomas A.C.
      • Kluger B.M.
      • Stevens-Lapsley J.E.
      Corticospinal and intracortical excitability of the quadriceps in patients with knee osteoarthritis.
      OA kneeUnited States17 (8/9)63.9 ± 1.8 (SEM)NANA20 (10/10)58.3 ± 2.5 (SEM)Double cone coil on hotspotSingle and paired pulses, mono-phasic
      Information obtained from the stimulator manufacturer's website.
      Vastus lateralisrMT, MEP amplitude, SICI, ICF
      Marker et al
      • Marker R.J.
      • Stephenson J.L.
      • Kluger B.M.
      • Curran-Everett D.
      • Maluf K.S.
      Modulation of intracortical inhibition in response to acute psychosocial stress is impaired among individuals with chronic neck pain.
      Neck painUnited States9 (2/7)42.4 ± 11>12 Months1.7 ± 1.48 (4/4)31.5 ± 14.5Figure of 8 coil (7 cm) on hotspotSingle and paired pulses, mono-phasicUpper trapeziusrMT, aMT, MEP amplitude, SICI
      Rittig-Rasmussen et al
      • Rittig-Rasmussen B.
      • Kasch H.
      • Fuglsang-Frederiksen A.
      • Svensson P.
      • Jensen T.S.
      Effect of training on corticomotor excitability in clinical neck pain.
      Neck pain; knee painDenmark20 (14/6); 15 (10/5)29 ± 7; 27 ± 6>3 Months1.7 ± .6

      1.5 ± .6
      15 (12/3)25 ± 3.5Figure of 8 coil on hotspotSingle pulse, monophasicUpper trapezius, abductor pollicis brevisaMT, MEP amplitude, MEP latency
      Bradnam et al
      • Bradnam L.
      • Shanahan E.M.
      • Hendy K.
      • Reed A.
      • Skipworth T.
      • Visser A.
      • Lennon S.
      Afferent inhibition and cortical silent periods in shoulder primary motor cortex and effect of a suprascapular nerve block in people experiencing chronic shoulder pain.
      Shoulder painAustralia8 (1/7)64.9 (49–75)>12 Months4.4 ± 1.218 (9/8)41.3 (20–68)Figure of 8 (7 cm) on hotspotSingle pulse, monophasic
      Information obtained from the stimulator manufacturer's website.
      InfraspinatusaMT, MEP amplitude, CSP
      Schabrun et al
      • Schabrun S.M.
      • Elgueta-Cancino E.L.
      • Hodges P.W.
      Smudging of the motor cortex is related to the severity of low back pain.
      LBPAustralia27 (13/14)30 ± 95.3 ± 4 Years4.6 ± 1.923 (12/11)27 ± 5Figure of 8 coil on M1Single pulse, monophasicL3 and L5 erector spinaeMap volume
      Schabrun et al
      • Schabrun S.M.
      • Hodges P.W.
      • Vicenzino B.
      • Jones E.
      • Chipchase L.S.
      Novel adaptations in motor cortical maps: The relation to persistent elbow pain.
      Lateral epicondylalgiaAustralia11 (5/6)44 ± 119 ± 6 Months2.7 ± 211 (5/6)42 ± 11Figure of 8 coil (7 cm) on M1Single pulse, monophasic
      Information obtained from the stimulator manufacturer's website.
      Extensor carpi radialis brevis, extensor digitorumrMT, MEP amplitude, map volume
      Van Velzen et al
      • van Velzen G.A.
      • Marinus J.
      • van Dijk J.G.
      • van Zwet E.W.
      • Schipper I.B.
      • van Hilten J.J.
      Motor cortical activity during motor tasks is normal in patients with complex regional pain syndrome.
      CRPS I: handNetherlands12 (2/10)51 ± 9.588 ± 26.9 Months6.7 ± 1.812 (1/11)52 ± 13Figure of 8 coil on hotspotSingle pulse, biphasic
      Information obtained from the stimulator manufacturer's website.
      First dorsal interosseousrMT, MEP amplitude
      Burns et al
      • Burns E.
      • Chipchase L.S.
      • Schabrun S.M.
      Altered function of intracortical networks in chronic lateral epicondylalgia.
      Lateral epicondylalgiaAustralia14 (4/10)41.5 ± 9.937.3 ± 74.8 Months3.5 ± 2.814 (4/10)42.1 ± 11.1Circular coil (9 cm) on hotspotSingle and paired pulses, monophasic
      Information obtained from the stimulator manufacturer's website.
      Extensor carpi radialis brevisrMT, aMT, MEP amplitude, SICI, ICF, LICI
      Caumo et al
      • Caumo W.
      • Deitos A.
      • Carvalho S.
      • Leite J.
      • Carvalho F.
      • Dussan-Sarria J.A.
      • Lopes Tarrago Mda G.
      • Souza A.
      • Torres I.L.
      • Fregni F.
      Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology.
      Myofascial pain; fibromyalgia; OA kneeBrazil54 (0/54); 19 (0/19); 27 (0/27)46.1 ± 12.1; 50.4 ± 8.8; 64.4 ± 7.8NA7.2 ± 2.2; 7.9 ± 1.9; 6.3 ± 2.214 (0/14)32.4 ± 10.8Figure of 8 coil on M1Single and paired pulsesFirst dorsal interosseousMEP amplitude, CSP, SICI, ICF
      Masse-Alarie et al
      • Masse-Alarie H.
      • Beaulieu L.D.
      • Preuss R.
      • Schneider C.
      Corticomotor control of lumbar multifidus muscles is impaired in chronic low back pain: Concurrent evidence from ultrasound imaging and double-pulse transcranial magnetic stimulation.
      LBPCanada35 (20/15)38 ± 14.665.8 ± 72.8 Months4.2 ± 2.113 (6/7)37.6 ± 12.5Double cone coil on hotspotSingle and paired pulses, monophasicMultifidusaMT, MEP amplitude, CSP, SICI, SICF
      Masse-Alarie et al
      • Massé-Alarie H.
      • Beaulieu L.D.
      • Preuss R.
      • Schneider C.
      The side of chronic low back pain matters: Evidence from the primary motor cortex excitability and the postural adjustments of multifidi muscles.
      LBPCanada11 (6/5)33.8 ± 12.5NA2 ± 1.913 (6/7)37.6 ± 12.5Double cone coil (7 cm) on hotspotSingle and paired pulses, monophasic
      Information obtained from the stimulator manufacturer's website.
      MultifidusaMT, MEP amplitude, CSP, SICI, SICF
      Rio et al
      • Rio E.
      • Kidgell D.
      • Moseley G.L.
      • Cook J.
      Elevated corticospinal excitability in patellar tendinopathy compared with other anterior knee pain or no pain.
      Patellar tendon pain; anterior knee painAustralia11 (10/1); 10 (6/4)26 (18–37); 26.5 (18–37)90 Months (5–192);

      9 months (12–264) (median)
      5.4 ± 2.0; 5.0 ± 2.48 (7/1)26 (18–37) (median)Double cone coil (110 mm) on hotspotSingle pulse, monophasic
      Information obtained from the stimulator manufacturer's website.
      Rectus femorisaMT
      Tarrago et al
      • Tarrago Mda G.
      • Deitos A.
      • Brietzke A.P.
      • Vercelino R.
      • Torres I.L.
      • Fregni F.
      • Caumo W.
      Descending control of nociceptive processing in knee osteoarthritis is associated with intracortical disinhibition: An exploratory study.
      OA kneeBrazil21 (0/21)64.5 ± 7.726.73 ± 2.53 YearsNA10 (0/10)34.1 ± 11.64Figure of 8 coil on hotspotSingle and paired pulsesFirst dorsal interosseousrMT, MEP amplitude, CSP, SICI, ICF
      Morgante et al
      • Morgante F.
      • Naro A.
      • Terranova C.
      • Russo M.
      • Rizzo V.
      • Risitano G.
      • Girlanda P.
      • Quartarone A.
      Normal sensorimotor plasticity in complex regional pain syndrome with fixed posture of the hand.
      CRPS I: handUnited States10 (1/9)48.2 ± 5.5 (SE)11.3 ± 1.8 Months (SE)8.1 ± .7310 (1/9)48.3 ± 12.5 (SE)Figure of 8 coil on hotspotSingle and paired pulses, monophasicAbductor pollicis brevisrMT, aMT, CSP, SICI, ICF
      Parker et al
      • Parker R.S.
      • Lewis G.N.
      • Rice D.A.
      • McNair P.J.
      The association between corticomotor excitability and motor skill learning in people with painful hand arthritis.
      OA handNew Zealand23 (6/17)72 ± 613.5 ± 13.1 yearsNA20 (6/14)71 ± 7Figure of 8 coil on hotspotSingle and paired pulses, monophasicFirst dorsal interosseousrMT, MEP amplitude, CSP, SICI, LICI, SICF
      Te et al
      • Te M.
      • Baptista A.F.
      • Chipchase L.S.
      • Schabrun S.M.
      Primary motor cortex organisation is altered in persistent patellofemoral pain.
      Patello-femoral painAustralia11 (3/8)21 ± 729 ± 6 months2.3 ± 2.211 (3/8)24 ± 6Figure of 8 coil on M1Single pulse, monophasicRectus femoris,

      vastus lateralis,

      vastus medialis
      aMT, map volume
      Abbreviations: M, male; F, female; SEM, standard error of the mean; NA, not available; rMT, resting motor threshold; SE, standard error.
      NOTE. Values are mean ± SD unless otherwise stated.
      * Information obtained from the stimulator manufacturer's website.
      Table 3Characteristics of Included Studies Using Other Neurophysiological Methods
      ReferenceConditionCountryChronic pain participantsHealthy participantsModalityStimuliOutcome measures
      Study size (M/F)AgePain durationPain intensity (0–10)Study size (M/F)Age
      Cook et al
      • Cook D.B.
      • Lange G.
      • Ciccone D.S.
      • Liu W.C.
      • Steffener J.
      • Natelson B.H.
      Functional imaging of pain in patients with primary fibromyalgia.
      FibromyalgiaUnited States9 (0/9)37 ± 5NA1.03 ± .79 (0/9)35 ± 3fMRIHeat pain on left thenar eminenceBOLD at 1.5 T
      Napadow et al
      • Napadow V.
      • Kettner N.
      • Ryan A.
      • Kwong K.K.
      • Audette J.
      • Hui K.K.
      Somatosensory cortical plasticity in carpal tunnel syndrome–a cross-sectional fMRI evaluation.
      Carpal tunnel syndromeUnited States10 (4/6)51.1 (31–60)4 months to 10 yearsNA9 (3/6)46.9 (32–59)fMRIInnocuous electrical stimulation to digit 2, 3, and 5BOLD at 3 T
      Maihöfner et al
      • Maihofner C.
      • Baron R.
      • DeCol R.
      • Binder A.
      • Birklein F.
      • Deuschl G.
      • Handwerker H.O.
      • Schattschneider J.
      The motor system shows adaptive changes in complex regional pain syndrome.
      CRPS I: handGermany12 (2/10)41.2 ± 2.5 (SEM)52.2 ± 32 weeks (SEM)3.9 ± .8 (SEM)12 (2/10)43.2 ± 2.5 (SEM)fMRIFinger tapping taskBOLD at 1.5 T
      Gieteling et al
      • Gieteling E.W.
      • van Rijn M.A.
      • de Jong B.M.
      • Hoogduin J.M.
      • Renken R.
      • van Hilten J.J.
      • Leenders K.L.
      Cerebral activation during motor imagery in complex regional pain syndrome type 1 with dystonia.
      CRPS I: hand with dystoniaNetherlands8 (1/7)46.4 ± 6NANA17 (2/15)42.9 ± 9.2fMRIImagining and performing wrist flexion/extensionBOLD at 3 T
      Kobayashi et al
      • Kobayashi Y.
      • Kurata J.
      • Sekiguchi M.
      • Kokubun M.
      • Akaishizawa T.
      • Chiba Y.
      • Konno S.
      • Kikuchi S.
      Augmented cerebral activation by lumbar mechanical stimulus in chronic low back pain patients: An FMRI study.
      LBPJapan8 (5/3)33 (22–44)>3 MonthsNA8 (8/0)29 (22–42)fMRILumbar mechanical compressionBOLD at 3 T
      Wasan et al
      • Wasan A.D.
      • Loggia M.L.
      • Chen L.Q.
      • Napadow V.
      • Kong J.
      • Gollub R.L.
      Neural correlates of chronic low back pain measured by arterial spin labeling.
      LBPUnited States16 (5/11)47.4 (95% CI = 40–54.8)6.24 years (95% CI = 3.9–11.8)4.8 (95% CI = 3.8–5.9)16 (5/11)46.7 (95% CI = 40.1–53.2)fMRIRest state; clinical maneuver (pain exacerbation); heat pain (affected leg)rCBF at 3 T
      Barke et al
      • Barke A.
      • Baudewig J.
      • Schmidt-Samoa C.
      • Dechent P.
      • Kroner-Herwig B.
      Neural correlates of fear of movement in high and low fear-avoidant chronic low back pain patients: An event-related fMRI study.
      LBPGermany30 (0/30)NANANA30 (0/30)NAfMRIPhotos (aversive and neutral movement/posture; general fear-inducing; neutral; spider)BOLD at 3 T
      Bolwerk et al
      • Bolwerk A.
      • Seifert F.
      • Maihofner C.
      Altered resting-state functional connectivity in complex regional pain syndrome.
      CRPS I and II: hand and footGermany12 (5/7)61.1 ± 11.115.5 (4–406) Weeks5.3 ± 2.112 (5/7)60.9 ± 11fMRIResting stateBOLD at 1.5 T
      Liu et al
      • Liu J.
      • Hao Y.
      • Du M.
      • Wang X.
      • Zhang J.
      • Manor B.
      • Jiang X.
      • Fang W.
      • Wang D.
      Quantitative cerebral blood flow mapping and functional connectivity of postherpetic neuralgia pain: A perfusion fMRI study.
      Postherpetic neuralgiaChina11 (11/0)66.2 ± 5.58.4 ± 6.2 Months8.3 ± 111 (11/0)64 (56–73)fMRIResting staterCBF at 3 T
      Flodin et al
      • Flodin P.
      • Martinsen S.
      • Lofgren M.
      • Bileviciute-Ljungar I.
      • Kosek E.
      • Fransson P.
      Fibromyalgia is associated with decreased connectivity between pain- and sensorimotor brain areas.
      FibromyalgiaSweden16 (0/16)48.3 (25–64)7.6 ± 3.8 YearsNA22 (0/22)45.7 (20–63)fMRIAnkle, knee, and hand tasksBOLD at 3 T
      He et al
      • He S.S.
      • Li F.
      • Song F.
      • Wu S.
      • Chen J.Y.
      • He N.
      • Zou S.J.
      • Huang X.Q.
      • Lui S.
      • Gong Q.Y.
      • Chen S.
      Spontaneous neural activity alterations in temporomandibular disorders: A cross-sectional and longitudinal resting-state functional magnetic resonance imaging study.
      Temporo-mandibular disorderChina23 (9/14)22.4 ± 3.614.8 ± 20.7 MonthsNA20 (9/11)23.1 ± 2.4fMRIResting stateBOLD at 3 T
      Pijnenburg et al
      • Pijnenburg M.
      • Brumagne S.
      • Caeyenberghs K.
      • Janssens L.
      • Goossens N.
      • Marinazzo D.
      • Swinnen S.P.
      • Claeys K.
      • Siugzdaite R.
      Resting-state functional connectivity of the sensorimotor network in individuals with nonspecific low back pain and the association with the sit-to-stand-to-sit task.
      LBPBelgium17 (6/11)33.3 ± 7.99.8 ± 8.2 Years2 ± 217 (5/12)31.8 ± 8.2fMRIResting stateBOLD at 3 T
      Shanahan et al
      • Shanahan C.J.
      • Hodges P.W.
      • Wrigley T.V.
      • Bennell K.L.
      • Farrell M.J.
      Organisation of the motor cortex differs between people with and without knee osteoarthritis.
      OA kneeAustralia11 (6/5)68.9 ± 6.4NA4.3 ± .87 (5/2)64 ± 6.7fMRI15 Pressure stimuli (5 different pressure intensities) on left thumbBOLD at 3 T
      Flodin et al
      • Flodin P.
      • Martinsen S.
      • Altawil R.
      • Waldheim E.
      • Lampa J.
      • Kosek E.
      • Fransson P.
      Intrinsic brain connectivity in chronic pain: A resting-state fMRI study in patients with rheumatoid arthritis.
      Rheumatoid arthritisSweden24 (4/20)53.8 ± 14.866 ± 34 Months3.4 ± 2.919 (3/16)50.4 ± 16.6fMRIResting stateBOLD at 3 T
      Hemington et al
      • Hemington K.S.
      • Wu Q.
      • Kucyi A.
      • Inman R.D.
      • Davis K.D.
      Abnormal cross-network functional connectivity in chronic pain and its association with clinical symptoms.
      Ankylosing spondylitis, back painCanada20 (17/3)39.4 ± 1212.8 ± 10.1 YearsNA20 (17/3)39.7 ± 12fMRIResting stateBOLD at 3 T
      Hotta et al
      • Hotta J.
      • Saari J.
      • Koskinen M.
      • Hlushchuk Y.
      • Forss N.
      • Hari R.
      Abnormal brain responses to action observation in complex regional pain syndrome.
      CRPS I: handFinland13 (0/13)44.7 ± 6.95.2 ± 3.9 Years7.7 ± 1.713 (0/13)44.1 ± 8.6fMRIViewing videos of hand actionsBOLD at 3 T
      Tian et al
      • Tian T.
      • Guo L.
      • Xu J.
      • Zhang S.
      • Shi J.
      • Liu C.
      • Qin Y.
      • Zhu W.
      Brain white matter plasticity and functional reorganization underlying the central pathogenesis of trigeminal neuralgia.
      Trigeminal neuropathic painChina20 (8/12)52.6 ± 8.921.1 ± 16.2 Months7.7 ± 1.622 (6/16)52.2 ± 6.1fMRI and MRIResting stateBOLD and DKI analysis at 3 T
      Van Velzen et al
      • van Velzen G.A.
      • Rombouts S.A.
      • van Buchem M.A.
      • Marinus J.
      • van Hilten J.J.
      Is the brain of complex regional pain syndrome patients truly different?.
      CRPS: handNetherland19 (0/19)48.1 ± 11.6110.8 ± 110.5 Years7.1 ± 1.519 (0/19)49.4 ± 11.6fMRI and MRIResting stateBOLD, VBM and DTI analysis at 3 T
      Moayedi et al
      • Moayedi M.
      • Weissman-Fogel I.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      Contribution of chronic pain and neuroticism to abnormal forebrain gray matter in patients with temporomandibular disorder.
      Temporomandibular disorderCanada17 (0/17)33.1 ± 11.99.8 ± 8.2 Years4.3 ± 1.817 (0/17)32.2 ± 10.1MRIResting stateCortical thickness analysis at 3 T
      Desouza et al
      • Desouza D.D.
      • Moayedi M.
      • Chen D.Q.
      • Davis K.D.
      • Hodaie M.
      Sensorimotor and pain modulation brain abnormalities in trigeminal neuralgia: A paroxysmal, sensory-triggered neuropathic pain.
      Trigeminal neuropathic painCanada24 (9/15)48.5 ± 12.76.3 ± 3 YearsNA24 (9/15)47.6 ± 12.3MRIResting stateCortical thickness analysis via 3 T
      Maeda et al
      • Maeda Y.
      • Kettner N.
      • Sheehan J.
      • Kim J.
      • Cina S.
      • Malatesta C.
      • Gerber J.
      • McManus C.
      • Mezzacappa P.
      • Morse L.R.
      • Audette J.
      • Napadow V.
      Altered brain morphometry in carpal tunnel syndrome is associated with median nerve pathology.
      Carpal tunnel syndromeUnited States28 (8/20)48.1 ± 9.68.5 ± 9.1 Years2.5 ± .8 (0–5)28 (11/17)47.3 ± 9.9MRIResting stateDTI analyses at 3 T
      Wu et al
      • Wu Q.
      • Inman R.D.
      • Davis K.D.
      Neuropathic pain in ankylosing spondylitis: A psychophysics and brain imaging study.
      Ankylosing spondylitis, neuropathic painCanada17 (12/5)34.4 ± 12.4NA6.1 ± 1.717 (12/5)34.9 ± 10.1MRIResting stateCortical thickness analysis at 3 T
      Pleger et al
      • Pleger B.
      • Draganski B.
      • Schwenkreis P.
      • Lenz M.
      • Nicolas V.
      • Maier C.
      • Tegenthoff M.
      Complex regional pain syndrome type I affects brain structure in prefrontal and motor cortex.
      CRPS I: handGermany20 (9/11)41.8 ± 9.811.9 ± 14.3 Months5.3 ± 2.420 (9/11)41.6 ± 9.6MRIResting stateVBM analysis (?) at 1.5 T
      Ung et al
      • Ung H.
      • Brown J.E.
      • Johnson K.A.
      • Younger J.
      • Hush J.
      • Mackey S.
      Multivariate classification of structural MRI data detects chronic low back pain.
      LBPUnited States47 (25/22)373. ± 12.28.6 ± 7.8 YearsNA47 (25/22)37.7 ± 7.8MRIResting stateVBM (SVM) analysis at 3 T
      Juottonen et al
      • Juottonen K.
      • Gockel M.
      • Silen T.
      • Hurri H.
      • Hari R.
      • Forss N.
      Altered central sensorimotor processing in patients with complex regional pain syndrome.
      CRPS I: handFinland6 (0/6)44.5 (33–54)42.2 ± 26.2 Months5.6 ± 1.86 (0/6)45.1 (34–55)MEGTactile stimuli to the fingertipsReactivity of 20-Hz motor cortex rhythm
      Shibukawa et al
      • Shibukawa Y.
      • Ishikawa T.
      • Kato Y.
      • Zhang Z.K.
      • Jiang T.
      • Shintani M.
      • Shimono M.
      • Kumai T.
      • Suzuki T.
      • Kato M.
      • Nakamura Y.
      Cerebral cortical dysfunction in patients with temporomandibular disorders in association with jaw movement observation.
      Temporomandibular disorderJapan9 (4/5)32.4NANA8 (4/4)30MEGObservation tasks of jaw- and palm-opening movementsNeuromagnetic signals
      Kirveskari et al
      • Kirveskari E.
      • Vartiainen N.V.
      • Gockel M.
      • Forss N.
      Motor cortex dysfunction in complex regional pain syndrome.
      CRPS I: handFinland8 (0/8)45.5 (26–57)5.5 ± 3.1 Years6.4 ± 1.88 (0/8)46.3 28–57)MEGNoxious thulium laser stimulation of both handsReactivity of 20-Hz motor cortex rhythm
      Grachev et al
      • Grachev I.D.
      • Fredrickson B.E.
      • Apkarian A.V.
      Abnormal brain chemistry in chronic back pain: An in vivo proton magnetic resonance spectroscopy study.
      LBPUnited States9 (7/2)45 ± 69 ± 5 Years6.18 ± 1.7211 (9/2)44 ± 3MRSResting stateRelative concentration of neurochemicals at 1.5 T
      Fayed et al
      • Fayed N.
      • Garcia-Campayo J.
      • Magallon R.
      • Andres-Bergareche H.
      • Luciano J.V.
      • Andres E.
      • Beltran J.
      Localized 1H-NMR spectroscopy in patients with fibromyalgia: A controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate.
      FibromyalgiaSpain10 (2/8)40 ± 6.21.6 ± .3 YearsNA10 (2/8)37.8 ± 8.7MRSResting stateRelative concentration of neurochemicals at 1.5 T
      Sharma et al
      • Sharma N.K.
      • Brooks W.M.
      • Popescu A.E.
      • Vandillen L.
      • George S.Z.
      • McCarson K.E.
      • Gajewski B.J.
      • Gorman P.
      • Cirstea C.M.
      Neurochemical analysis of primary motor cortex in chronic low back pain.
      LBPUnited States19 (4/15)46.1 ± 11.38.8 ± 7.2 Years4.5 ± 1.914 (3/11)44.6 ± 14.7MRSResting stateAbsolute concentration of neurochemicals at 3 T
      Jacobs et al
      • Jacobs J.V.
      • Henry S.M.
      • Nagle K.J.
      Low back pain associates with altered activity of the cerebral cortex prior to arm movements that require postural adjustment.
      LBPUnited States10 (5/5)39.2 ± 6.3

      (95% CI)
      >12 months1.8 ± .26 (95%CI)10 (5/5)35.4 ± 5.3 (95%CI)EEGArm raiseAlpha event-related desynchronization and Bereitschafts potentials
      Shiraishi et al
      • Shiraishi S.
      • Kobayashi H.
      • Nihashi T.
      • Kato K.
      • Iwano S.
      • Nishino M.
      • Ishigaki T.
      • Ikeda M.
      • Kato T.
      • Ito K.
      • Kimura T.
      Cerebral glucose metabolism change in patients with complex regional pain syndrome: A PET study.
      CRPSJapan18 (10/8)40.7 (21–59)49.8 (6–252) MonthsNA13 (11/2)38.7 (27–58)PETResting stateCerebral glucose metabolism
      Abbreviations: M, male; F, female; NA, not available; SEM, standard error of the mean; DKI, diffusion kurtosis imaging; DTI, diffusion tensor imaging; SVM, support vector machine.
      NOTE. Values are mean ± SD unless otherwise stated.

       Quality and Risk of Bias Within Studies

      The average score for the methodological quality assessment was 3.1 of 5 (range = 1–5; Table 4), with 50 studies presenting a score of ≥3. For the TMS methodology checklist, the average score for the reported items was 64.8% (SD = 13) and for the controlled items 61.1% (SD = 13.8). All studies reported and controlled position and contact of electromyography electrodes and stimulation intensity. All studies that used paired-pulse paradigms (n = 16) reported the intensity of the test and conditioning pulse and the interstimulus interval. Participant age and sex, although reported, were not controlled. Items that were not consistently reported or controlled were: previous motor activity of the muscle to be tested, level of relaxation of the muscles other than those being tested, pulse shape, and participants' prescribed medication.
      Table 4Risk of Bias Assessment for Included Studies
      ReferenceModified STROBE statement itemsTMS methodology checklist
      Source of participantsParticipant selectionMethodologyStatistical analysisFundingTotal scoreReportedControlled
      Salerno et al
      • Salerno A.
      • Thomas E.
      • Olive P.
      • Blotman F.
      • Picot M.C.
      • Georgesco M.
      Motor cortical dysfunction disclosed by single and double magnetic stimulation in patients with fibromyalgia.
      01001241.4%39.3%
      Schwenkreis et al
      • Schwenkreis P.
      • Janssen F.
      • Rommel O.
      • Pleger B.
      • Volker B.
      • Hosbach I.
      • Dertwinkel R.
      • Maier C.
      • Tegenthoff M.
      Bilateral motor cortex disinhibition in complex regional pain syndrome (CRPS) type I of the hand.
      01110364.3%63%
      Strutton et al
      • Strutton P.H.
      • Catley M.
      • McGregor A.H.
      • Davey N.J.
      Corticospinal excitability in patients with unilateral sciatica.
      10011340%41.7%
      On et al
      • On A.Y.
      • Uludag B.
      • Taskiran E.
      • Ertekin C.
      Differential corticomotor control of a muscle adjacent to a painful joint.
      01010253.8%52%
      Eisenberg et al
      • Eisenberg E.
      • Chistyakov A.V.
      • Yudashkin M.
      • Kaplan B.
      • Hafner H.
      • Feinsod M.
      Evidence for cortical hyperexcitability of the affected limb representation area in CRPS: A psychophysical and transcranial magnetic stimulation study.
      11110472.4%71.4%
      Krause et al
      • Krause P.
      • Foerderreuther S.
      • Straube A.
      Effects of conditioning peripheral repetitive magnetic stimulation in patients with complex regional pain syndrome.
      00010161.5%48%
      Strutton et al
      • Strutton P.H.
      • Theodorou S.
      • Catley M.
      • McGregor A.H.
      • Davey N.J.
      Corticospinal excitability in patients with chronic low back pain.
      10011352%45.8%
      Krause et al
      • Krause P.
      • Forderreuther S.
      • Straube A.
      TMS motor cortical brain mapping in patients with complex regional pain syndrome type I.
      10010252%37.5%
      Turton et al
      • Turton A.J.
      • McCabe C.S.
      • Harris N.
      • Filipovic S.R.
      Sensorimotor integration in Complex Regional Pain Syndrome: A transcranial magnetic stimulation study.
      01011346.2%44%
      Tsao et al
      • Tsao H.
      • Galea M.P.
      • Hodges P.W.
      Reorganization of the motor cortex is associated with postural control deficits in recurrent low back pain.
      01111473.1%76%
      Berth et al
      • Berth A.
      • Pap G.
      • Neuman W.
      • Awiszus F.
      Central neuromuscular dysfunction of the deltoid muscle in patients with chronic rotator cuff tears.
      00111377%68%
      Turgut et al
      • Turgut N.
      • Altun B.U.
      Cortical disinhibition in diabetic patients with neuropathic pain.
      01110369.2%64%
      Mhalla et al
      • Mhalla A.
      • de Andrade D.C.
      • Baudic S.
      • Perrot S.
      • Bouhassira D.
      Alteration of cortical excitability in patients with fibromyalgia.
      11010355.2%53.6%
      Schwenkreis et al
      • Schwenkreis P.
      • Scherens A.
      • Ronnau A.K.
      • Hoffken O.
      • Tegenthoff M.
      • Maier C.
      Cortical disinhibition occurs in chronic neuropathic, but not in chronic nociceptive pain.
      01111464.3%66.7%
      Clark et al
      • Clark B.C.
      • Goss D.A.
      • Walkowski S.
      • Hoffman R.L.
      • Ross A.
      • Thomas J.S.
      Neurophysiologic effects of spinal manipulation in patients with chronic low back pain.
      01011354.2%52.2%
      Schwenkreis et al
      • Schwenkreis P.
      • Voigt M.
      • Hasenbring M.
      • Tegenthoff M.
      • Vorgerd M.
      • Kley R.A.
      Central mechanisms during fatiguing muscle exercise in muscular dystrophy and fibromyalgia syndrome: A study with transcranial magnetic stimulation.
      00011264.3%55.6%
      Tsao et al
      • Tsao H.
      • Danneels L.A.
      • Hodges P.W.
      ISSLS prize winner: Smudging the motor brain in young adults with recurrent low back pain.
      00111379.2%82.6%
      Masse-Alarie et al
      • Masse-Alarie H.
      • Flamand V.H.
      • Moffet H.
      • Schneider C.
      Corticomotor control of deep abdominal muscles in chronic low back pain and anticipatory postural adjustments.
      00111369%71.4%
      Vallence et al
      • Vallence A.M.
      • Smith A.
      • Tabor A.
      • Rolan P.E.
      • Ridding M.C.
      Chronic tension-type headache is associated with impaired motor learning.
      00101277%68%
      Kittelson et al
      • Kittelson A.J.
      • Thomas A.C.
      • Kluger B.M.
      • Stevens-Lapsley J.E.
      Corticospinal and intracortical excitability of the quadriceps in patients with knee osteoarthritis.
      01111472.4%71.4%
      Marker et al
      • Marker R.J.
      • Stephenson J.L.
      • Kluger B.M.
      • Curran-Everett D.
      • Maluf K.S.
      Modulation of intracortical inhibition in response to acute psychosocial stress is impaired among individuals with chronic neck pain.
      10111490%82.1%
      Rittig-Rasmussen et al
      • Rittig-Rasmussen B.
      • Kasch H.
      • Fuglsang-Frederiksen A.
      • Svensson P.
      • Jensen T.S.
      Effect of training on corticomotor excitability in clinical neck pain.
      11011457.7%56%
      Bradman et al
      • Bradnam L.
      • Shanahan E.M.
      • Hendy K.
      • Reed A.
      • Skipworth T.
      • Visser A.
      • Lennon S.
      Afferent inhibition and cortical silent periods in shoulder primary motor cortex and effect of a suprascapular nerve block in people experiencing chronic shoulder pain.
      00011261.5%52%
      Schabrun et al
      • Schabrun S.M.
      • Elgueta-Cancino E.L.
      • Hodges P.W.
      Smudging of the motor cortex is related to the severity of low back pain.
      01011343.5%43.5%
      Schabrun et al
      • Schabrun S.M.
      • Hodges P.W.
      • Vicenzino B.
      • Jones E.
      • Chipchase L.S.
      Novel adaptations in motor cortical maps: The relation to persistent elbow pain.
      11111577%76%
      Van Velzen et al
      • van Velzen G.A.
      • Marinus J.
      • van Dijk J.G.
      • van Zwet E.W.
      • Schipper I.B.
      • van Hilten J.J.
      Motor cortical activity during motor tasks is normal in patients with complex regional pain syndrome.
      11001357.7%52%
      Burns et al
      • Burns E.
      • Chipchase L.S.
      • Schabrun S.M.
      Altered function of intracortical networks in chronic lateral epicondylalgia.
      01111479.3%75%
      Caumo et al
      • Caumo W.
      • Deitos A.
      • Carvalho S.
      • Leite J.
      • Carvalho F.
      • Dussan-Sarria J.A.
      • Lopes Tarrago Mda G.
      • Souza A.
      • Torres I.L.
      • Fregni F.
      Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology.
      10011362.1%46.4%
      Masse-Alarie et al
      • Massé-Alarie H.
      • Beaulieu L.D.
      • Preuss R.
      • Schneider C.
      The side of chronic low back pain matters: Evidence from the primary motor cortex excitability and the postural adjustments of multifidi muscles.
      01011362.1%59.3%
      Masse-Alarie et al
      • Masse-Alarie H.
      • Beaulieu L.D.
      • Preuss R.
      • Schneider C.
      Corticomotor control of lumbar multifidus muscles is impaired in chronic low back pain: Concurrent evidence from ultrasound imaging and double-pulse transcranial magnetic stimulation.
      01111469%64.3%
      Rio et al
      • Rio E.
      • Kidgell D.
      • Moseley G.L.
      • Cook J.
      Elevated corticospinal excitability in patellar tendinopathy compared with other anterior knee pain or no pain.
      11010357.7%60%
      Tarrago et al
      • Tarrago Mda G.
      • Deitos A.
      • Brietzke A.P.
      • Vercelino R.
      • Torres I.L.
      • Fregni F.
      • Caumo W.
      Descending control of nociceptive processing in knee osteoarthritis is associated with intracortical disinhibition: An exploratory study.
      11011469%55.6%
      Morgante et al
      • Morgante F.
      • Naro A.
      • Terranova C.
      • Russo M.
      • Rizzo V.
      • Risitano G.
      • Girlanda P.
      • Quartarone A.
      Normal sensorimotor plasticity in complex regional pain syndrome with fixed posture of the hand.
      01111472.4%77.8%
      Parker et al
      • Parker R.S.
      • Lewis G.N.
      • Rice D.A.
      • McNair P.J.
      The association between corticomotor excitability and motor skill learning in people with painful hand arthritis.
      01111496.6%88.9%
      Te et al
      • Te M.
      • Baptista A.F.
      • Chipchase L.S.
      • Schabrun S.M.
      Primary motor cortex organisation is altered in persistent patellofemoral pain.
      11111575%79.2%
      Grachev et al
      • Grachev I.D.
      • Fredrickson B.E.
      • Apkarian A.V.
      Abnormal brain chemistry in chronic back pain: An in vivo proton magnetic resonance spectroscopy study.
      011114NANA
      Juottonen et al
      • Juottonen K.
      • Gockel M.
      • Silen T.
      • Hurri H.
      • Hari R.
      • Forss N.
      Altered central sensorimotor processing in patients with complex regional pain syndrome.
      011013NANA
      Cook et al
      • Cook D.B.
      • Lange G.
      • Ciccone D.S.
      • Liu W.C.
      • Steffener J.
      • Natelson B.H.
      Functional imaging of pain in patients with primary fibromyalgia.
      000011NANA
      Napadow et al
      • Napadow V.
      • Kettner N.
      • Ryan A.
      • Kwong K.K.
      • Audette J.
      • Hui K.K.
      Somatosensory cortical plasticity in carpal tunnel syndrome–a cross-sectional fMRI evaluation.
      011114NANA
      Shiraishi et al
      • Shiraishi S.
      • Kobayashi H.
      • Nihashi T.
      • Kato K.
      • Iwano S.
      • Nishino M.
      • Ishigaki T.
      • Ikeda M.
      • Kato T.
      • Ito K.
      • Kimura T.
      Cerebral glucose metabolism change in patients with complex regional pain syndrome: A PET study.
      011002NANA
      Maihöfner et al
      • Maihofner C.
      • Baron R.
      • DeCol R.
      • Binder A.
      • Birklein F.
      • Deuschl G.
      • Handwerker H.O.
      • Schattschneider J.
      The motor system shows adaptive changes in complex regional pain syndrome.
      011013NANA
      Shibukawa et al
      • Shibukawa Y.
      • Ishikawa T.
      • Kato Y.
      • Zhang Z.K.
      • Jiang T.
      • Shintani M.
      • Shimono M.
      • Kumai T.
      • Suzuki T.
      • Kato M.
      • Nakamura Y.
      Cerebral cortical dysfunction in patients with temporomandibular disorders in association with jaw movement observation.
      011114NANA
      Gieteling et al
      • Gieteling E.W.
      • van Rijn M.A.
      • de Jong B.M.
      • Hoogduin J.M.
      • Renken R.
      • van Hilten J.J.
      • Leenders K.L.
      Cerebral activation during motor imagery in complex regional pain syndrome type 1 with dystonia.
      011013NANA
      Kobayashi et al
      • Kobayashi Y.
      • Kurata J.
      • Sekiguchi M.
      • Kokubun M.
      • Akaishizawa T.
      • Chiba Y.
      • Konno S.
      • Kikuchi S.
      Augmented cerebral activation by lumbar mechanical stimulus in chronic low back pain patients: An FMRI study.
      001012NANA
      Fayed et al
      • Fayed N.
      • Garcia-Campayo J.
      • Magallon R.
      • Andres-Bergareche H.
      • Luciano J.V.
      • Andres E.
      • Beltran J.
      Localized 1H-NMR spectroscopy in patients with fibromyalgia: A controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate.
      100113NANA
      Jacobs et al
      • Jacobs J.V.
      • Henry S.M.
      • Nagle K.J.
      Low back pain associates with altered activity of the cerebral cortex prior to arm movements that require postural adjustment.
      001113NANA
      Kirveskari et al
      • Kirveskari E.
      • Vartiainen N.V.
      • Gockel M.
      • Forss N.
      Motor cortex dysfunction in complex regional pain syndrome.
      001113NANA
      Moayedi et al
      • Moayedi M.
      • Weissman-Fogel I.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      Contribution of chronic pain and neuroticism to abnormal forebrain gray matter in patients with temporomandibular disorder.
      010113NANA
      Wasan et al
      • Wasan A.D.
      • Loggia M.L.
      • Chen L.Q.
      • Napadow V.
      • Kong J.
      • Gollub R.L.
      Neural correlates of chronic low back pain measured by arterial spin labeling.
      010012NANA
      Barke et al
      • Barke A.
      • Baudewig J.
      • Schmidt-Samoa C.
      • Dechent P.
      • Kroner-Herwig B.
      Neural correlates of fear of movement in high and low fear-avoidant chronic low back pain patients: An event-related fMRI study.
      110103NANA
      Sharma et al
      • Sharma N.K.
      • Brooks W.M.
      • Popescu A.E.
      • Vandillen L.
      • George S.Z.
      • McCarson K.E.
      • Gajewski B.J.
      • Gorman P.
      • Cirstea C.M.
      Neurochemical analysis of primary motor cortex in chronic low back pain.
      011114NANA
      Bolwerk et al
      • Bolwerk A.
      • Seifert F.
      • Maihofner C.
      Altered resting-state functional connectivity in complex regional pain syndrome.
      011114NANA
      Desouza et al
      • Desouza D.D.
      • Moayedi M.
      • Chen D.Q.
      • Davis K.D.
      • Hodaie M.
      Sensorimotor and pain modulation brain abnormalities in trigeminal neuralgia: A paroxysmal, sensory-triggered neuropathic pain.
      010113NANA
      Liu et al
      • Liu J.
      • Hao Y.
      • Du M.
      • Wang X.
      • Zhang J.
      • Manor B.
      • Jiang X.
      • Fang W.
      • Wang D.
      Quantitative cerebral blood flow mapping and functional connectivity of postherpetic neuralgia pain: A perfusion fMRI study.
      010012NANA
      Maeda et al
      • Maeda Y.
      • Kettner N.
      • Sheehan J.
      • Kim J.
      • Cina S.
      • Malatesta C.
      • Gerber J.
      • McManus C.
      • Mezzacappa P.
      • Morse L.R.
      • Audette J.
      • Napadow V.
      Altered brain morphometry in carpal tunnel syndrome is associated with median nerve pathology.
      010113NANA
      Wu et al
      • Wu Q.
      • Inman R.D.
      • Davis K.D.
      Neuropathic pain in ankylosing spondylitis: A psychophysics and brain imaging study.
      010113NANA
      Flodin et al
      • Flodin P.
      • Martinsen S.
      • Lofgren M.
      • Bileviciute-Ljungar I.
      • Kosek E.
      • Fransson P.
      Fibromyalgia is associated with decreased connectivity between pain- and sensorimotor brain areas.
      111115NANA
      He et al
      • He S.S.
      • Li F.
      • Song F.
      • Wu S.
      • Chen J.Y.
      • He N.
      • Zou S.J.
      • Huang X.Q.
      • Lui S.
      • Gong Q.Y.
      • Chen S.
      Spontaneous neural activity alterations in temporomandibular disorders: A cross-sectional and longitudinal resting-state functional magnetic resonance imaging study.
      011013NANA
      Pleger et al
      • Pleger B.
      • Draganski B.
      • Schwenkreis P.
      • Lenz M.
      • Nicolas V.
      • Maier C.
      • Tegenthoff M.
      Complex regional pain syndrome type I affects brain structure in prefrontal and motor cortex.
      010012NANA
      Ung et al
      • Ung H.
      • Brown J.E.
      • Johnson K.A.
      • Younger J.
      • Hush J.
      • Mackey S.
      Multivariate classification of structural MRI data detects chronic low back pain.
      010012NANA
      Pijnenburg et al
      • Pijnenburg M.
      • Brumagne S.
      • Caeyenberghs K.
      • Janssens L.
      • Goossens N.
      • Marinazzo D.
      • Swinnen S.P.
      • Claeys K.
      • Siugzdaite R.
      Resting-state functional connectivity of the sensorimotor network in individuals with nonspecific low back pain and the association with the sit-to-stand-to-sit task.
      010012NANA
      Shanahan et al
      • Shanahan C.J.
      • Hodges P.W.
      • Wrigley T.V.
      • Bennell K.L.
      • Farrell M.J.
      Organisation of the motor cortex differs between people with and without knee osteoarthritis.
      010012NANA
      Flodin et al
      • Flodin P.
      • Martinsen S.
      • Altawil R.
      • Waldheim E.
      • Lampa J.
      • Kosek E.
      • Fransson P.
      Intrinsic brain connectivity in chronic pain: A resting-state fMRI study in patients with rheumatoid arthritis.
      111014NANA
      Hemington et al
      • Hemington K.S.
      • Wu Q.
      • Kucyi A.
      • Inman R.D.
      • Davis K.D.
      Abnormal cross-network functional connectivity in chronic pain and its association with clinical symptoms.
      010012NANA
      Hotta et al
      • Hotta J.
      • Saari J.
      • Koskinen M.
      • Hlushchuk Y.
      • Forss N.
      • Hari R.
      Abnormal brain responses to action observation in complex regional pain syndrome.
      110013NANA
      Tian et al
      • Tian T.
      • Guo L.
      • Xu J.
      • Zhang S.
      • Shi J.
      • Liu C.
      • Qin Y.
      • Zhu W.
      Brain white matter plasticity and functional reorganization underlying the central pathogenesis of trigeminal neuralgia.
      101114NANA
      Van Velzen et al
      • van Velzen G.A.
      • Rombouts S.A.
      • van Buchem M.A.
      • Marinus J.
      • van Hilten J.J.
      Is the brain of complex regional pain syndrome patients truly different?.
      010113NANA
      Abbreviations: STROBE, STrengthening the Reporting of OBservational studies in Epidemiology; NA not available.
      NOTE: Each domain would be allocated 1 point if the risk of bias was low and zero point if the risk of bias was considered high. The maximum score possible was five points. NA: not applicable.

       Is There Evidence of Altered M1 Function, Organization, and Structure in Chronic Pain?

      We were unable to conduct meta-analyses of these data because of the heterogeneity of methodology across the included studies. Furthermore, the effect size of the differences between the pain and healthy participants were not reported in these studies.
      In neuropathic pain, 3 studies reported statistically significant (P < .05) increases in M1 activation/connectivity in neuropathic pain populations from regional cerebral blood flow (rCBF)
      • Liu J.
      • Hao Y.
      • Du M.
      • Wang X.
      • Zhang J.
      • Manor B.
      • Jiang X.
      • Fang W.
      • Wang D.
      Quantitative cerebral blood flow mapping and functional connectivity of postherpetic neuralgia pain: A perfusion fMRI study.
      (cluster level corrected P < .05, n = 22 participants, quality score = 2) and blood oxygen level-dependent (BOLD) contrast studies (n = 42 participants, quality score = 4
      • Tian T.
      • Guo L.
      • Xu J.
      • Zhang S.
      • Shi J.
      • Liu C.
      • Qin Y.
      • Zhu W.
      Brain white matter plasticity and functional reorganization underlying the central pathogenesis of trigeminal neuralgia.
      ; n = 19 participants, quality score = 4
      • Napadow V.
      • Kettner N.
      • Ryan A.
      • Kwong K.K.
      • Audette J.
      • Hui K.K.
      Somatosensory cortical plasticity in carpal tunnel syndrome–a cross-sectional fMRI evaluation.
      ). Voxel-based morphometry (VBM) imaging showed 12% to 13% increase in bilateral M1 cortical thickness in trigeminal neuralgia
      • Desouza D.D.
      • Moayedi M.
      • Chen D.Q.
      • Davis K.D.
      • Hodaie M.
      Sensorimotor and pain modulation brain abnormalities in trigeminal neuralgia: A paroxysmal, sensory-triggered neuropathic pain.
      (n = 48 participants, quality score = 3), and larger left M1 cortical thickness that were associated with stronger neuropathic pain symptoms in ankylosing spondylitis
      • Wu Q.
      • Inman R.D.
      • Davis K.D.
      Neuropathic pain in ankylosing spondylitis: A psychophysics and brain imaging study.
      (r = .8, n = 34 participants, quality score = 3). One diffusion tensor imaging study reported that enhanced myelination (lower radial diffusivity) in the microstructure of white matter connecting primary sensory cortex and M1 contralateral to the affected side was correlated with nerve conduction velocity in carpal tunnel syndrome
      • Maeda Y.
      • Kettner N.
      • Sheehan J.
      • Kim J.
      • Cina S.
      • Malatesta C.
      • Gerber J.
      • McManus C.
      • Mezzacappa P.
      • Morse L.R.
      • Audette J.
      • Napadow V.
      Altered brain morphometry in carpal tunnel syndrome is associated with median nerve pathology.
      (r = .72, n = 56 participants, quality score = 3).
      In LBP, 1 MRI study reported increased M1 gray matter (GM) density in people with chronic LBP
      • Ung H.
      • Brown J.E.
      • Johnson K.A.
      • Younger J.
      • Hush J.
      • Mackey S.
      Multivariate classification of structural MRI data detects chronic low back pain.
      (P < .001 uncorrected for multiple comparisons, n = 94 participants, quality score = 2). Although 1 study reported decreased functional connectivity in the left M1, the left supplementary motor area, and the left cerebellum compared with healthy participants
      • Pijnenburg M.
      • Brumagne S.
      • Caeyenberghs K.
      • Janssens L.
      • Goossens N.
      • Marinazzo D.
      • Swinnen S.P.
      • Claeys K.
      • Siugzdaite R.
      Resting-state functional connectivity of the sensorimotor network in individuals with nonspecific low back pain and the association with the sit-to-stand-to-sit task.
      (1.88 ± 0.89 SD vs 2.64 ± 0.8 SD, n = 34 participants, quality score = 2), the other reported increased rCBF in the left M1
      • Wasan A.D.
      • Loggia M.L.
      • Chen L.Q.
      • Napadow V.
      • Kong J.
      • Gollub R.L.
      Neural correlates of chronic low back pain measured by arterial spin labeling.
      (cluster-level P < .01, n = 32 participants, quality score = 2). Two studies reported no change in M1 activation/connectivity using BOLD contrast (n = 45 participants, quality score = 3,
      • Kobayashi Y.
      • Kurata J.
      • Sekiguchi M.
      • Kokubun M.
      • Akaishizawa T.
      • Chiba Y.
      • Konno S.
      • Kikuchi S.
      Augmented cerebral activation by lumbar mechanical stimulus in chronic low back pain patients: An FMRI study.
      and n = 16 participants, quality score = 2
      • Barke A.
      • Baudewig J.
      • Schmidt-Samoa C.
      • Dechent P.
      • Kroner-Herwig B.
      Neural correlates of fear of movement in high and low fear-avoidant chronic low back pain patients: An event-related fMRI study.
      ). One EEG study reported altered cerebrocortical motor activity before an arm raise in chronic LBP participants
      • Jacobs J.V.
      • Henry S.M.
      • Nagle K.J.
      Low back pain associates with altered activity of the cerebral cortex prior to arm movements that require postural adjustment.
      (n = 20 participants, quality score = 3). MRS studies reported conflicting findings for M1 neurochemical metabolism. One study reported no between group difference in sensorimotor cortex
      • Grachev I.D.
      • Fredrickson B.E.
      • Apkarian A.V.
      Abnormal brain chemistry in chronic back pain: An in vivo proton magnetic resonance spectroscopy study.
      (n = 20 participants, quality score = 4), whereas the other reported lower N-acetylasparate concentrations in the right M1 compared with healthy participants
      • Sharma N.K.
      • Brooks W.M.
      • Popescu A.E.
      • Vandillen L.
      • George S.Z.
      • McCarson K.E.
      • Gajewski B.J.
      • Gorman P.
      • Cirstea C.M.
      Neurochemical analysis of primary motor cortex in chronic low back pain.
      (9 ± .9 mM vs 10.2 ± 1.2 mM, n = 33 participants, quality score = 4). For ankylosing spondylitis-related back pain, greater functional impairment was correlated with greater M1–precuneous resting functional connectivity and impaired spinal mobility was associated with weaker M1–rostral ventromedial medulla functional connectivity on BOLD contrast
      • Hemington K.S.
      • Wu Q.
      • Kucyi A.
      • Inman R.D.
      • Davis K.D.
      Abnormal cross-network functional connectivity in chronic pain and its association with clinical symptoms.
      (n = 40 participants, quality score = 2).
      Findings in people with CRPS were inconsistent for M1 structure from VBM studies. One study showed increased M1 GM density
      • Pleger B.
      • Draganski B.
      • Schwenkreis P.
      • Lenz M.
      • Nicolas V.
      • Maier C.
      • Tegenthoff M.
      Complex regional pain syndrome type I affects brain structure in prefrontal and motor cortex.
      (cluster-level P = .042, corrected, n = 40 participants, quality score = 2), whereas the other showed no between group difference in GM volume and white matter connectivity in sensorimotor cortex
      • van Velzen G.A.
      • Rombouts S.A.
      • van Buchem M.A.
      • Marinus J.
      • van Hilten J.J.
      Is the brain of complex regional pain syndrome patients truly different?.
      (n = 38 participants, quality score = 3). Similarly, findings for M1 activation/connectivity from BOLD contrast were inconsistent. Two studies showed increased activation in bilateral M1
      • Maihofner C.
      • Baron R.
      • DeCol R.
      • Binder A.
      • Birklein F.
      • Deuschl G.
      • Handwerker H.O.
      • Schattschneider J.
      The motor system shows adaptive changes in complex regional pain syndrome.
      (cluster-level P < .0001, uncorrected, n = 24 participants, quality score = 3) or connectivity
      • Bolwerk A.
      • Seifert F.
      • Maihofner C.
      Altered resting-state functional connectivity in complex regional pain syndrome.
      (cluster-level P < .01, corrected, n = 24 participants, quality score = 4), whereas 2 showed no changes compared with healthy participants (n = 25 participants, quality score = 3,
      • Gieteling E.W.
      • van Rijn M.A.
      • de Jong B.M.
      • Hoogduin J.M.
      • Renken R.
      • van Hilten J.J.
      • Leenders K.L.
      Cerebral activation during motor imagery in complex regional pain syndrome type 1 with dystonia.
      and n = 38 participants, quality score = 3
      • van Velzen G.A.
      • Rombouts S.A.
      • van Buchem M.A.
      • Marinus J.
      • van Hilten J.J.
      Is the brain of complex regional pain syndrome patients truly different?.
      ). There was a significant between group difference in activation of the sensorimotor cortex
      • Hotta J.
      • Saari J.
      • Koskinen M.
      • Hlushchuk Y.
      • Forss N.
      • Hari R.
      Abnormal brain responses to action observation in complex regional pain syndrome.
      (P < .05, corrected, n = 26 participants, quality score = 3).
      In temporomandibular disorder (TMD), 1 VBM study reported that greater pain severity was associated with smaller GM thickness of the M1 region where the representation of the face was situated
      • Moayedi M.
      • Weissman-Fogel I.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      Contribution of chronic pain and neuroticism to abnormal forebrain gray matter in patients with temporomandibular disorder.
      (r = −.83, n = 34 participants, quality score = 3). BOLD contrast showed decreased intrinsic neural activity in the left M1 in individuals with TMD
      • He S.S.
      • Li F.
      • Song F.
      • Wu S.
      • Chen J.Y.
      • He N.
      • Zou S.J.
      • Huang X.Q.
      • Lui S.
      • Gong Q.Y.
      • Chen S.
      Spontaneous neural activity alterations in temporomandibular disorders: A cross-sectional and longitudinal resting-state functional magnetic resonance imaging study.
      (P < .05, corrected, n = 43 participants, quality score = 3). One MEG study reported that TMD participants had significantly smaller neuromagnetic signals in M1 during observation of jaw-opening movements
      • Shibukawa Y.
      • Ishikawa T.
      • Kato Y.
      • Zhang Z.K.
      • Jiang T.
      • Shintani M.
      • Shimono M.
      • Kumai T.
      • Suzuki T.
      • Kato M.
      • Nakamura Y.
      Cerebral cortical dysfunction in patients with temporomandibular disorders in association with jaw movement observation.
      (1 ± 1 nano amp meter vs 16 ± 3 nano amp meter, n = 17 participants, quality score = 4).
      In fibromyalgia, 1 MRS study showed a lower myoinositol to creatine ratio in the left sensorimotor cortex, indicating possible M1 neuronal metabolic dysfunction
      • Fayed N.
      • Garcia-Campayo J.
      • Magallon R.
      • Andres-Bergareche H.
      • Luciano J.V.
      • Andres E.
      • Beltran J.
      Localized 1H-NMR spectroscopy in patients with fibromyalgia: A controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate.
      (P < .05, n = 20 participants, quality score = 3). Two studies using BOLD contrast reported conflicting findings in M1 activation/connectivity. One reported no between group difference
      • Cook D.B.
      • Lange G.
      • Ciccone D.S.
      • Liu W.C.
      • Steffener J.
      • Natelson B.H.
      Functional imaging of pain in patients with primary fibromyalgia.
      (n = 18 participants, quality score = 3), whereas the other showed decreased sensorimotor cortex connectivity
      • Flodin P.
      • Martinsen S.
      • Lofgren M.
      • Bileviciute-Ljungar I.
      • Kosek E.
      • Fransson P.
      Fibromyalgia is associated with decreased connectivity between pain- and sensorimotor brain areas.
      (P < .00031, corrected, n = 38 participants, quality score = 4).
      One fMRI study in people with knee OA reported that the M1 representation of the affected knee was shifted 4.1 mm anteriorly (SD or CI not reported) and the relative position of the knee and ankle representations were swapped when participants performed ankle and knee tasks
      • Shanahan C.J.
      • Hodges P.W.
      • Wrigley T.V.
      • Bennell K.L.
      • Farrell M.J.
      Organisation of the motor cortex differs between people with and without knee osteoarthritis.
      (n = 18 participants, quality score = 2). In addition, poorer performance of a knee task was associated with more anterior placement of the M1 loci in people with knee OA. In rheumatoid arthritis, 1 study using BOLD contrast reported increased connectivity of bilateral sensorimotor cortex with the supplementary motor and midcingulate cortex
      • Flodin P.
      • Martinsen S.
      • Altawil R.
      • Waldheim E.
      • Lampa J.
      • Kosek E.
      • Fransson P.
      Intrinsic brain connectivity in chronic pain: A resting-state fMRI study in patients with rheumatoid arthritis.
      (P < .00031, corrected, n = 43 participants, quality score = 4).

       Is There Evidence of Altered Corticospinal Excitability in Chronic Pain?

      Data for resting motor threshold, aMT, MEP amplitude and latency, CSP, and map volume were pooled to perform separate meta-analyses from studies using single-pulse TMS. Pooled effect estimates for all measures revealed no difference between people with and without pain (Table 5; Supplementary Figs 1–6). There was substantial heterogeneity across all measures with the exception of MEP latency and map volume of erector spinae.
      Table 5Effect Sizes for Between Group Differences (People With and Without Pain) From Meta-Analyses of TMS Studies. Pooled Estimates for All Measures Revealed No Difference Between People With and Without Pain, With the Exception of LICI
      Outcome measureNumber of included studiesNumber of participantsQuality score range (maximum score = 5)SMD (95% CI)
      Resting motor threshold196041 to 5.01 (−.29 to .31)
      AMT123573 to 5.11 (−.24 to .46)
      MEP amplitude247881 to 5−.15 (−.38 to .09)
      MEP latency41812 to 4.21 (−.11 to .52)
      Cortical silent period124811 to 4−42 (−.85 to .00)
      Map volume: erector spinae2703−.24 (−.72 to .23)
      Map volume: wrist extensor2462 to 5.35 (−.66 to 1.36)
      SICI155722 to 4.07 (−.36 to .50)
      LICI31022 to 4.78 (.37–1.19)
      ICF72492 to 4−.26 (−.65 to .14)
      SICF31133 to 4.23 (−.24 to .70)
      For comparisons in which significant heterogeneity was observed, we conducted subgroup analysis according to condition. A moderate reduction in aMT in people with chronic knee pain (3 studies, 73 participants, SMD = −.52, 95% CI = −1.02 to −.02, P = .04, χ2 P = .68, I2 = 0%; all studies have quality score >3; Supplementary Fig 2) was detected, indicating increased M1 corticospinal excitability.
      Seven of 35 TMS studies
      • Bradnam L.
      • Shanahan E.M.
      • Hendy K.
      • Reed A.
      • Skipworth T.
      • Visser A.
      • Lennon S.
      Afferent inhibition and cortical silent periods in shoulder primary motor cortex and effect of a suprascapular nerve block in people experiencing chronic shoulder pain.
      • Krause P.
      • Foerderreuther S.
      • Straube A.
      Effects of conditioning peripheral repetitive magnetic stimulation in patients with complex regional pain syndrome.
      • Krause P.
      • Forderreuther S.
      • Straube A.
      TMS motor cortical brain mapping in patients with complex regional pain syndrome type I.
      • On A.Y.
      • Uludag B.
      • Taskiran E.
      • Ertekin C.
      Differential corticomotor control of a muscle adjacent to a painful joint.
      • Salerno A.
      • Thomas E.
      • Olive P.
      • Blotman F.
      • Picot M.C.
      • Georgesco M.
      Motor cortical dysfunction disclosed by single and double magnetic stimulation in patients with fibromyalgia.
      • Schwenkreis P.
      • Voigt M.
      • Hasenbring M.
      • Tegenthoff M.
      • Vorgerd M.
      • Kley R.A.
      Central mechanisms during fatiguing muscle exercise in muscular dystrophy and fibromyalgia syndrome: A study with transcranial magnetic stimulation.
      • Vallence A.M.
      • Smith A.
      • Tabor A.
      • Rolan P.E.
      • Ridding M.C.
      Chronic tension-type headache is associated with impaired motor learning.
      scored lower than 3 (median value) on the modified STROBE statement and were categorized as high risk of bias. Meta-analyses rerun after removing the high risk of bias TMS studies detected a large reduction in the CSP for CRPS but left only a single small study (n = 20 participants) in that subgroup.

       Is There Evidence for Altered Intra-Cortical Facilitation and/or Inhibition in Chronic Pain?

      Sixteen studies investigated intracortical inhibitory and facilitatory networks using paired-pulse TMS paradigms with several different measures. A moderate increase in long-interval intracortical inhibition (LICI) was detected in people with pain (3 studies, 102 participants, SMD = .78, 95% CI = .37–1.19, P < .001, χ2 P = .84, I2 = 0%; Fig 2), indicating increased M1 intracortical inhibition. No difference between people with and without pain was found for short-interval intracortical inhibition (SICI), intra-cortical facilitation (ICF) or short-interval ICF (SICF; Table 5, Supplementary Figs 7–9). One study appeared to mislabel ICF as SICF on the basis of the experimental protocol and was not included in the meta-analysis.
      • Caumo W.
      • Deitos A.
      • Carvalho S.
      • Leite J.
      • Carvalho F.
      • Dussan-Sarria J.A.
      • Lopes Tarrago Mda G.
      • Souza A.
      • Torres I.L.
      • Fregni F.
      Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology.
      There was substantial heterogeneity in the pooled effect estimates for SICI (χ2 P <.01, I2 = 80%) and ICF (χ2 P = .04, I2 = 51%). The subgroup analysis showed a moderate reduction in SICI in people with CRPS (4 studies, 100 participants, SMD = −.77, 95% CI = −1.21 to −.34, P < .01, χ2 P = .72, I2 = 0%; Supplementary Fig 7), indicating reduced M1 intracortical inhibition, and a moderate reduction in ICF in people with non-neuropathic pain (6 studies, 151 participants, SMD = −.53, 95% CI = −.94 to −.13, P = .01, χ2 P = .24, I2 = 26%; Supplementary Fig 8), indicating reduced M1 ICF.
      Figure 2
      Figure 2Meta-analysis forest plot for LICI.
      Evidence of reduced M1 intracortical inhibition in people with CRPS is complemented by the findings of attenuated activities of the 20-Hz cortical rhythm (which reflects decreased M1 cortical inhibition) from 2 MEG studies. The 20-Hz rebound duration in the right hemisphere was significantly shorter
      • Juottonen K.
      • Gockel M.
      • Silen T.
      • Hurri H.
      • Hari R.
      • Forss N.
      Altered central sensorimotor processing in patients with complex regional pain syndrome.
      (357 vs 458 ms, P < .03, n = 18 participants, quality score = 3), and the rebound amplitude (1 ± 1 SD vs 7 ± 3 SD femtotesla/cm, P = .05) and the reactivity (4 ± 2 SD vs 16 ± 5 SD femtotesla/cm, P = .03) to painful hand stimuli were significantly smaller
      • Kirveskari E.
      • Vartiainen N.V.
      • Gockel M.
      • Forss N.
      Motor cortex dysfunction in complex regional pain syndrome.
      (n = 18 participants, quality score = 3) compared with healthy participants. One PET study (n = 31 participants, quality score = 2) showed reduced glucose metabolism in the contralateral M1 in CRPS
      • Shiraishi S.
      • Kobayashi H.
      • Nihashi T.
      • Kato K.
      • Iwano S.
      • Nishino M.
      • Ishigaki T.
      • Ikeda M.
      • Kato T.
      • Ito K.
      • Kimura T.
      Cerebral glucose metabolism change in patients with complex regional pain syndrome: A PET study.
      (P < .005, uncorrected), suggesting possible M1 inhibition.

      Discussion

      To our knowledge, this systematic review is the first to provide a comprehensive and critical review of studies investigating M1 structure, organization, and function in people with chronic pain. For a range of neurophysiological parameters, published studies provided conflicting evidence. Meta-analyses identified a moderate increase in M1 LICI in people with chronic pain. Our findings suggest that the evidence for M1 changes in chronic pain populations is inconclusive for most measures.

       Evidence for Altered ICF and/or Inhibition in Chronic Pain

      Pooled data from 3 studies investigating non-neuropathic pain provided evidence of increased LICI, indicating increased M1 intracortical inhibition. Increased LICI reflects upregulated γ-aminobutyric acid (GABA)B-mediated intracortical inhibition.
      • McDonnell M.N.
      • Orekhov Y.
      • Ziemann U.
      The role of GABA(B) receptors in intracortical inhibition in the human motor cortex.
      Subgroup analyses showed reduced ICF in non-neuropathic pain, suggesting decreased ICF of glutamatergic interneurons through N-methyl-D-aspartate receptors,
      • Ziemann U.
      • Chen R.
      • Cohen L.G.
      • Hallett M.
      Dextromethorphan decreases the excitability of the human motor cortex.
      and reduced SICI in CRPS, suggesting M1 intracortical disinhibition driven by downregulated GABAA-receptors.
      • McDonnell M.N.
      • Orekhov Y.
      • Ziemann U.
      The role of GABA(B) receptors in intracortical inhibition in the human motor cortex.
      • Werhahn K.J.
      • Kunesch E.
      • Noachtar S.
      • Benecke R.
      • Classen J.
      Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans.
      However, although our subgroup analyses were preplanned, interpretation of these findings requires caution because there are no overall effects in the pooled estimates for SICI and ICF.
      Consistent with a previous review of CRPS,
      • Di Pietro F.
      • McAuley J.H.
      • Parkitny L.
      • Lotze M.
      • Wand B.M.
      • Moseley G.L.
      • Stanton T.R.
      Primary motor cortex function in complex regional pain syndrome: A systematic review and meta-analysis.
      our review also found M1 disinhibition on the basis of MEG outcomes from 2 studies. The 20-Hz cortical rhythm measured in MEG is initially decreased (suppression; reflecting an activated M1) and subsequently increased (rebound; reflecting inhibited M1) and represents the functional state of M1.
      • Parkkonen E.
      • Laaksonen K.
      • Piitulainen H.
      • Parkkonen L.
      • Forss N.
      Modulation of the ~20-Hz motor-cortex rhythm to passive movement and tactile stimulation.
      • Salmelin R.
      • Hari R.
      Spatiotemporal characteristics of sensorimotor neuromagnetic rhythms related to thumb movement.
      Combined MEG and MRS showed a positive correlation between 20-Hz rebound amplitude and the concentration of the inhibitory neurotransmitter GABA, indicating the rebound period represents GABAergic inhibition in M1.
      • Gaetz W.
      • Edgar J.C.
      • Roberts D.J.
      Relating MEG measured motor cortical oscillations to resting γ-Aminobutyric acid (GABA) concentration.
      MEG studies reported a significantly shorter rebound duration of 20-Hz rhythm in both hemispheres,
      • Juottonen K.
      • Gockel M.
      • Silen T.
      • Hurri H.
      • Hari R.
      • Forss N.
      Altered central sensorimotor processing in patients with complex regional pain syndrome.
      and weaker rebound amplitude and reactivity of 20-Hz rhythm in the hemisphere contralateral to the affected side,
      • Kirveskari E.
      • Vartiainen N.V.
      • Gockel M.
      • Forss N.
      Motor cortex dysfunction in complex regional pain syndrome.
      indicating M1 disinhibition in CRPS. These findings suggest M1 disinhibition in CRPS, reflecting downregulated GABAergic inhibition. The MEG findings of reduced M1 inhibition in CRPS are inconsistent with the findings of increased LICI in chronic pain from TMS studies. These inconsistencies could be explained because none of these TMS studies investigated CRPS. Although 1 PET study reported reduced glucose metabolism in the contralateral M1 for CRPS in the group analysis, indicating possible M1 inhibition, only 3 (of 18) CRPS participants showed this finding in the individual analysis.
      • Shiraishi S.
      • Kobayashi H.
      • Nihashi T.
      • Kato K.
      • Iwano S.
      • Nishino M.
      • Ishigaki T.
      • Ikeda M.
      • Kato T.
      • Ito K.
      • Kimura T.
      Cerebral glucose metabolism change in patients with complex regional pain syndrome: A PET study.
      Future larger trials are needed to elucidate M1 glucose metabolism in CRPS.

       Evidence of Altered M1 Structure, Organization, and Function in Chronic Pain

      There is conflicting evidence for M1 changes in chronic pain, which may be explained by the heterogeneity of the underlying neurophysiological mechanisms, methodological differences, internal study biases, reporting biases, and the random play of chance, because of the small sample sizes of the included studies. For example, heterogeneity of underlying neurophysiological mechanisms in nonspecific chronic LBP has been reported.
      • Smart K.M.
      • Blake C.
      • Staines A.
      • Doody C.
      The Discriminative validity of "nociceptive," "peripheral neuropathic," and "central sensitization" as mechanisms-based classifications of musculoskeletal pain.
      A mixture of neuropathic and non-neuropathic pain components were identified not only in chronic nonspecific LBP,
      • Spahr N.
      • Hodkinson D.
      • Jolly K.
      • Williams S.
      • Howard M.
      • Thacker M.
      Distinguishing between nociceptive and neuropathic components in chronic low back pain using behavioural evaluation and sensory examination.
      but ankylosing spondylitis back pain,
      • Wu Q.
      • Inman R.D.
      • Davis K.D.
      Neuropathic pain in ankylosing spondylitis: A psychophysics and brain imaging study.
      and knee and hip OA.
      • French H.P.
      • Smart K.M.
      • Doyle F.
      Prevalence of neuropathic pain in knee or hip osteoarthritis: A systematic review and meta-analysis.
      • Hochman J.R.
      • Davis A.M.
      • Elkayam J.
      • Gagliese L.
      • Hawker G.A.
      Neuropathic pain symptoms on the modified painDETECT correlate with signs of central sensitization in knee osteoarthritis.
      • Moreton B.J.
      • Tew V.
      • das Nair R.
      • Wheeler M.
      • Walsh D.A.
      • Lincoln N.B.
      Pain phenotype in patients with knee osteoarthritis: Classification and measurement properties of painDETECT and self-report Leeds assessment of neuropathic symptoms and signs scale in a cross-sectional study.
      • Moss P.
      • Benson H.A.
      • Will R.
      • Wright A.
      Patients with knee osteoarthritis who score highly on the PainDETECT questionnaire present with multimodality hyperalgesia, increased pain, and impaired physical function.
      However, it is unclear whether a neuropathic pain subgroup exists in other pain conditions. Future studies should investigate whether distinct pain subgroups exist within chronic pain conditions and whether these subgroups present with different M1 changes.
      Evidence from several different measures suggests increased M1 activation/connectivity in neuropathic pain. M1 disinhibition has been attributed to increased M1 activation (carpal tunnel syndrome), increased M1 rCBF (postherpic neuralgia), and increased M1 functional connectivity (trigeminal neuralgia)
      • Liu J.
      • Hao Y.
      • Du M.
      • Wang X.
      • Zhang J.
      • Manor B.
      • Jiang X.
      • Fang W.
      • Wang D.
      Quantitative cerebral blood flow mapping and functional connectivity of postherpetic neuralgia pain: A perfusion fMRI study.
      • Napadow V.
      • Kettner N.
      • Ryan A.
      • Kwong K.K.
      • Audette J.
      • Hui K.K.
      Somatosensory cortical plasticity in carpal tunnel syndrome–a cross-sectional fMRI evaluation.
      • Tian T.
      • Guo L.
      • Xu J.
      • Zhang S.
      • Shi J.
      • Liu C.
      • Qin Y.
      • Zhu W.
      Brain white matter plasticity and functional reorganization underlying the central pathogenesis of trigeminal neuralgia.
      though M1 disinhibition in neuropathic pain was not supported by the finding of a reduction in MEP amplitude from a single study in people with diabetic neuropathy
      • Turgut N.
      • Altun B.U.
      Cortical disinhibition in diabetic patients with neuropathic pain.
      (Supplementary Fig 3). More research is needed to elucidate the neurophysiological mechanisms driving M1 functional changes in neuropathic pain populations.
      Several studies reported that impaired motor control in chronic pain was associated with M1 reorganization or altered corticomotor physiology.
      • Jacobs J.V.
      • Henry S.M.
      • Nagle K.J.
      Low back pain associates with altered activity of the cerebral cortex prior to arm movements that require postural adjustment.
      • Shanahan C.J.
      • Hodges P.W.
      • Wrigley T.V.
      • Bennell K.L.
      • Farrell M.J.
      Organisation of the motor cortex differs between people with and without knee osteoarthritis.
      • Tsao H.
      • Galea M.P.
      • Hodges P.W.
      Reorganization of the motor cortex is associated with postural control deficits in recurrent low back pain.
      For example, delayed activation of the trunk muscles when performing an arm raise in chronic LBP patients was associated with smaller amplitudes of Bereitschafts potential, an EEG potential generated by M1 and the supplementary motor cortex representing movement preparation,
      • Jacobs J.V.
      • Henry S.M.
      • Nagle K.J.
      Low back pain associates with altered activity of the cerebral cortex prior to arm movements that require postural adjustment.
      and with increased map volume and the posterolaterally shifted M1 representation of transversus abdominis.
      • Tsao H.
      • Galea M.P.
      • Hodges P.W.
      Reorganization of the motor cortex is associated with postural control deficits in recurrent low back pain.
      This supports the role of altered M1 in motor control impairment in musculoskeletal disorders. However, the causal relationship and the interaction between M1 changes, motor control impairment, and symptom persistence in chronic pain requires further investigation.
      A previous review on M1 function in CRPS could not draw a definite conclusion on M1 functional changes.
      • Di Pietro F.
      • McAuley J.H.
      • Parkitny L.
      • Lotze M.
      • Wand B.M.
      • Moseley G.L.
      • Stanton T.R.
      Primary motor cortex function in complex regional pain syndrome: A systematic review and meta-analysis.
      Two recent MRI studies investigating M1 function and structure for CRPS were included in this review, which reported conflicting findings, likely because of different experimental protocols (resting state vs observational tasks).
      • Hotta J.
      • Saari J.
      • Koskinen M.
      • Hlushchuk Y.
      • Forss N.
      • Hari R.
      Abnormal brain responses to action observation in complex regional pain syndrome.
      • van Velzen G.A.
      • Rombouts S.A.
      • van Buchem M.A.
      • Marinus J.
      • van Hilten J.J.
      Is the brain of complex regional pain syndrome patients truly different?.
      Taken together with the other neurophysiological evidence, no conclusion on M1 changes in CRPS can be drawn from our findings.

       Evidence of Altered Corticospinal Excitability in Chronic Pain

      Meta-analyses of TMS data revealed no significant change in any measure of corticospinal excitability in people with chronic pain. Although subgroup analysis found a reduction in aMT in chronic knee pain, suggesting increased excitability in the motor system particularly in relation to neuronal and interneuronal membrane excitability,
      • Ziemann U.
      • Lonnecker S.
      • Steinhoff B.J.
      • Paulus W.
      Effects of antiepileptic drugs on motor cortex excitability in humans: A transcranial magnetic stimulation study.
      interpretation of this finding requires caution because there is no overall effect in the pooled estimate for aMT.
      A previous review on corticomotor excitability in chronic pain reported evidence of M1 disinhibition that was more prominent in neuropathic pain populations.
      • Parker R.S.
      • Lewis G.N.
      • Rice D.A.
      • McNair P.J.
      Is motor cortical excitability altered in people with chronic pain? A systematic review and meta-analysis.
      However, our review did not find compelling evidence of M1 disinhibition when people with and without pain were compared. This discrepancy is likely because of our inclusion of more recent studies
      • Bradnam L.
      • Shanahan E.M.
      • Hendy K.
      • Reed A.
      • Skipworth T.
      • Visser A.
      • Lennon S.
      Afferent inhibition and cortical silent periods in shoulder primary motor cortex and effect of a suprascapular nerve block in people experiencing chronic shoulder pain.
      • Caumo W.
      • Deitos A.
      • Carvalho S.
      • Leite J.
      • Carvalho F.
      • Dussan-Sarria J.A.
      • Lopes Tarrago Mda G.
      • Souza A.
      • Torres I.L.
      • Fregni F.
      Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology.
      • Massé-Alarie H.
      • Beaulieu L.D.
      • Preuss R.
      • Schneider C.
      The side of chronic low back pain matters: Evidence from the primary motor cortex excitability and the postural adjustments of multifidi muscles.
      • Masse-Alarie H.
      • Beaulieu L.D.
      • Preuss R.
      • Schneider C.
      Corticomotor control of lumbar multifidus muscles is impaired in chronic low back pain: Concurrent evidence from ultrasound imaging and double-pulse transcranial magnetic stimulation.
      • Morgante F.
      • Naro A.
      • Terranova C.
      • Russo M.
      • Rizzo V.
      • Risitano G.
      • Girlanda P.
      • Quartarone A.
      Normal sensorimotor plasticity in complex regional pain syndrome with fixed posture of the hand.
      • Parker R.S.
      • Lewis G.N.
      • Rice D.A.
      • McNair P.J.
      The association between corticomotor excitability and motor skill learning in people with painful hand arthritis.
      • Rio E.
      • Kidgell D.
      • Moseley G.L.
      • Cook J.
      Elevated corticospinal excitability in patellar tendinopathy compared with other anterior knee pain or no pain.
      • Schabrun S.M.
      • Hodges P.W.
      • Vicenzino B.
      • Jones E.
      • Chipchase L.S.
      Novel adaptations in motor cortical maps: The relation to persistent elbow pain.
      • Shanahan C.J.
      • Hodges P.W.
      • Wrigley T.V.
      • Bennell K.L.
      • Farrell M.J.
      Organisation of the motor cortex differs between people with and without knee osteoarthritis.
      • Tarrago Mda G.
      • Deitos A.
      • Brietzke A.P.
      • Vercelino R.
      • Torres I.L.
      • Fregni F.
      • Caumo W.
      Descending control of nociceptive processing in knee osteoarthritis is associated with intracortical disinhibition: An exploratory study.
      • Te M.
      • Baptista A.F.
      • Chipchase L.S.
      • Schabrun S.M.
      Primary motor cortex organisation is altered in persistent patellofemoral pain.
      and exclusion of studies containing neurological populations.
      • Lefaucheur J.P.
      • Drouot X.
      • Menard-Lefaucheur I.
      • Keravel Y.
      • Nguyen J.P.
      Motor cortex rTMS restores defective intracortical inhibition in chronic neuropathic pain.
      Also, CRPS studies were separated from neuropathic pain in our subgroup analyses because they have different diagnostic criteria and pathophysiology.
      Altered M1 representation of erector spinae muscles (reduced map volume) in chronic LBP has been reported,
      • Tsao H.
      • Danneels L.A.
      • Hodges P.W.
      ISSLS prize winner: Smudging the motor brain in young adults with recurrent low back pain.
      but not supported by a larger study.
      • Schabrun S.M.
      • Elgueta-Cancino E.L.
      • Hodges P.W.
      Smudging of the motor cortex is related to the severity of low back pain.
      Pooled map volume data from these studies found no significant difference between LBP and healthy participants. The differences between the studies in sample size and methodology such as different electromyography electrodes (fine wire needle vs superficial, surface electrodes), the sizes of grid used to measure the map (5 × 7 cm versus 6 × 7 cm), and different coils used to deliver TMS could contribute to the contradictory findings of M1 reorganization of erector spinae in LBP. Although some small single studies reported increased map volume of the wrist extensor (lateral epicondylalgia) and transversus abdominis (LBP) muscles, and decreased map volume of quadriceps (patellofemoral pain; Supplementary Fig 5), meta-analyses do not support the changes in M1 representations.

       Limitations and Recommendations

      Several limitations should be considered when interpreting the findings of this review. First, most included studies were small, and may be affected by low statistical power as well as conversely, the propensity for small published studies to return positive and often inflated effect sizes.
      • Button K.S.
      • Ioannidis J.P.
      • Mokrysz C.
      • Nosek B.A.
      • Flint J.
      • Robinson E.S.
      • Munafo M.R.
      Power failure: Why small sample size undermines the reliability of neuroscience.
      Additionally, subgroup analyses are regarded as exploratory and interpretation of these findings requires caution, particularly when there is no overall effect in the pooled estimates. False positive significance tests also increase in likelihood rapidly as more subgroup analyses are performed.
      TMS studies investigating M1 representations of the affected muscles in chronic pain reported the center of gravity (CoG) as the location of M1 representation. Smudged M1 representations of affected muscles (measured by the distance between the CoG of neighboring muscles) has been reported in chronic LBP and lateral epicondylalgia, suggesting M1 reorganization.
      • Schabrun S.M.
      • Elgueta-Cancino E.L.
      • Hodges P.W.
      Smudging of the motor cortex is related to the severity of low back pain.
      • Schabrun S.M.
      • Hodges P.W.
      • Vicenzino B.
      • Jones E.
      • Chipchase L.S.
      Novel adaptations in motor cortical maps: The relation to persistent elbow pain.
      • Tsao H.
      • Danneels L.A.
      • Hodges P.W.
      ISSLS prize winner: Smudging the motor brain in young adults with recurrent low back pain.
      However, we were unable to meta-analyze CoG data because studies reported either the coordinates of the CoG or the absolute distance between the averaged CoG for each group. Future research using TMS to investigate M1 representation of the affected muscles should report the coordinates of CoG for meta-analysis of the data. We also acknowledge that 4 included TMS studies were published by 1 of the coauthors of this review.
      • Burns E.
      • Chipchase L.S.
      • Schabrun S.M.
      Altered function of intracortical networks in chronic lateral epicondylalgia.
      • Schabrun S.M.
      • Elgueta-Cancino E.L.
      • Hodges P.W.
      Smudging of the motor cortex is related to the severity of low back pain.
      • Schabrun S.M.
      • Hodges P.W.
      • Vicenzino B.
      • Jones E.
      • Chipchase L.S.
      Novel adaptations in motor cortical maps: The relation to persistent elbow pain.
      • Te M.
      • Baptista A.F.
      • Chipchase L.S.
      • Schabrun S.M.
      Primary motor cortex organisation is altered in persistent patellofemoral pain.
      To minimize the bias, reviewers who were not involved in these studies performed the risk of bias assessment.
      A recent study reported that the errors of software commonly used for data analysis in fMRI studies may result in a false positive rate of up to 70% and questioned the validity of some fMRI studies.
      • Eklund A.
      • Nichols T.E.
      • Knutsson H.
      Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates.
      It is beyond the scope of this review to discuss how these statistical issues may influence the findings of this review. However, the fMRI findings of M1 activation/connectivity and organization for chronic pain in this review should be interpreted with caution. Several studies included in this review investigated the sensorimotor cortex rather than the M1.
      • Fayed N.
      • Garcia-Campayo J.
      • Magallon R.
      • Andres-Bergareche H.
      • Luciano J.V.
      • Andres E.
      • Beltran J.
      Localized 1H-NMR spectroscopy in patients with fibromyalgia: A controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate.
      • Flodin P.
      • Martinsen S.
      • Altawil R.
      • Waldheim E.
      • Lampa J.
      • Kosek E.
      • Fransson P.
      Intrinsic brain connectivity in chronic pain: A resting-state fMRI study in patients with rheumatoid arthritis.
      • Flodin P.
      • Martinsen S.
      • Lofgren M.
      • Bileviciute-Ljungar I.
      • Kosek E.
      • Fransson P.
      Fibromyalgia is associated with decreased connectivity between pain- and sensorimotor brain areas.
      • Hotta J.
      • Saari J.
      • Koskinen M.
      • Hlushchuk Y.
      • Forss N.
      • Hari R.
      Abnormal brain responses to action observation in complex regional pain syndrome.
      • van Velzen G.A.
      • Rombouts S.A.
      • van Buchem M.A.
      • Marinus J.
      • van Hilten J.J.
      Is the brain of complex regional pain syndrome patients truly different?.
      It is possible that heterogeneity in the brain region being investigated (ie, sensorimotor vs M1) contributed to the inconclusive findings of this review.

      Conclusions

      This review provides the current evidence on M1 structure, organization, and function in chronic pain and identifies areas where further research is required. EEG, MEG, MRS, and PET techniques have been rarely used to investigate M1 function in chronic pain. Data pertaining to M1 changes for conditions such as TMD, rheumatoid arthritis, neck, shoulder, and neuropathic pain are still lacking. Additionally, more research using paired-pulse TMS paradigms to investigate M1 ICF/and inhibition in chronic pain is required because data are still lacking for measures of LICI and SICF. Future studies with larger sample sizes are warranted to elucidate M1 changes in chronic pain conditions and to inform treatments targeting M1.

      Supplementary Data

      The following is the supplementary data to this article:

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