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Relations Between Brain Alterations and Clinical Pain Measures in Chronic Musculoskeletal Pain: A Systematic Review

  • Iris Coppieters
    Correspondence
    Address reprint requests to Iris Coppieters, MSc, PT, Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
    Affiliations
    Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium

    Pain in Motion International Research Group
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  • Mira Meeus
    Affiliations
    Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium

    Pain in Motion International Research Group

    Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
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  • Jeroen Kregel
    Affiliations
    Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium

    Pain in Motion International Research Group

    Departments of Human Physiology and Physiotherapy, Free University of Brussels, Faculty of Physical Education and Physiotherapy, Medical Campus Jette, Brussels, Belgium
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  • Karen Caeyenberghs
    Affiliations
    Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium

    School of Psychology, Faculty of Health Sciences, Australian Catholic University, Sydney, Australia
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  • Robby De Pauw
    Affiliations
    Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
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  • Dorien Goubert
    Affiliations
    Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium

    Pain in Motion International Research Group
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  • Barbara Cagnie
    Affiliations
    Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
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      Highlights

      • Magnetic resonance imaging has shown brain alterations in chronic musculoskeletal pain patients.
      • Brain changes are related to clinical pain measures in chronic musculoskeletal pain.
      • Structural and functional brain alterations are related to clinical pain measures.
      • This systematic review reports preliminary to moderate evidence for these relations.
      • Inconclusive results exist regarding the direction of these relations.

      Abstract

      Compelling evidence has shown chronic widespread and exaggerated pain experience in chronic musculoskeletal pain (MSKP) conditions. In addition, neuroimaging research has revealed morphological and functional brain alterations in these patients. It is hypothesized that brain alterations play a role in the persistent pain complaints of patients with chronic MSKP. Nevertheless, lack of overview exists regarding the relations between brain alterations and clinical measures of pain. The present systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, to investigate the relations between structural or functional brain alterations, using magnetic resonance imaging scans, and clinical pain measures in patients with chronic MSKP. PubMed, Web of Science, Cinahl, and Cochrane databases were searched. First, the obtained articles were screened according to title and abstract. Second, the screening was on the basis of full-text. Risk of bias in included studies was investigated according to the modified Newcastle-Ottawa Scale. Twenty studies met the inclusion criteria. Moderate evidence shows that higher pain intensity and pressure pain sensitivity are related to decreased regional gray matter (GM) volume in brain regions encompassing the cingulate cortex, the insula, and the superior frontal and temporal gyrus. Further, some evidence exists that longer disease duration in fibromyalgia is correlated with decreased total GM volume. Yet, inconclusive evidence exists regarding the association of longer disease duration with decreased or increased regional GM volume in other chronic MSKP conditions. Inconclusive evidence was found regarding the direction of the relation of pain intensity and pressure pain sensitivity with microstructural white matter and functional connectivity alterations. In conclusion, preliminary to moderate evidence demonstrates relations between clinical pain measures, and structural and functional connectivity alterations within brain regions involved in somatosensory, affective, and cognitive processing of pain in chronic MSKP. Nevertheless, inconclusive results exist regarding the direction of these relations. Further research is warranted to unravel whether these brain alterations are positively or negatively correlated to clinical pain measures.

      Perspective

      Structural and functional brain alterations within regions involved in somatosensory, affective, and cognitive pain processing play a crucial role in the persistent pain of chronic MSKP patients. Accordingly, these brain alterations have to be taken into account when assessing and treating patients with chronic MSKP.

      Key words

      Chronic musculoskeletal pain (MSKP) is defined as pain in muscles, tendons, joints, and ligaments for >3 months.
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      Methods

      Research Questions

      This systematic review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines.
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      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred Reporting Items for Systematic reviews and Meta-Analyses: The PRISMA statement.
      The Patient, measurement Instrument, Comparison, Outcome (PICO) approach was applied to formulate the following research questions: 1) ‘What are the relations between structural brain alterations (O = outcome) and clinical pain measures (O) in chronic MSKP patients (P = patient), examined with structural brain MRI techniques (I = measurement instrument)? 2) ‘What are the relations between functional brain alterations (O) and clinical pain measures (O) in chronic MSKP patients (P), examined with functional brain MRI techniques (I)?

      Eligibility Criteria

      Eligibility assessment was performed by screening the obtained articles on the basis of the inclusion and exclusion criteria (Table 1). To be included, articles had to investigate a relation or association between structural or functional brain alterations and clinical measures/correlates of pain (ie, pain duration, pain intensity, pain perception, pressure sensitivity, hyperalgesia, hypersensitivity, allodynia, referred pain) (O) by using brain MRI techniques (I) in patients with chronic MSKP (P).
      Table 1Inclusion and Exclusion Criteria
      InclusionExclusion
      Population
      • Human study
      • Patients with chronic MSKP
      • Adults (≥18 y of age)
      • Animal study
      • Children and adolescents (<18 y of age)
      Instrument
      • At least 1 brain MRI technique is applied:
      • T1 MRI, DTI, DWI, fMRI, rs-fMRI
      • SPECT, PET, EEG, MEG, MR spectroscopy
      Outcome 1
      • At least 1 clinical pain measure was examined:
      • pain intensity, pain perception, pain duration, allodynia, hyperalgesia, referred pain, pressure sensitivity
      • Not examining the relation, association, or correlation between a clinical pain measure and structural or functional brain alterations
      Outcome 2
      • At least 1 type of brain change was examined: structural or functional alterations
      • Not examining the relation, association or correlation between a clinical pain measure and brain alterations
      Type of report
      • Clinical
      • Full-text
      • Nonclinical: review, systematic review, meta-analysis, letter to the editor
      • Full-text not available, abstracts, posters
      Language
      • English, German, Dutch, French
      • All other languages
      Abbreviations: T1 MRI, T1-weighted MRI; DWI, diffusion weighted imaging; rs-fMRI, resting-state fMRI; SPECT, single photon emission computed tomography; PET, photon emission tomography; EEG, electroencephalography; MEG, magnetoencephalography; MR, magnetic resonance.
      Eligibility assessment of the obtained articles was performed by 2 independent researchers (I.C. and B.C.), who have published systematic reviews and were trained in conducting a systematic review by the second author (M.M.). After deduplication, a first screening was performed on the basis of the title and abstract of the remaining articles. If any of the inclusion criteria were not met, the article was excluded. In the second phase, publications were screened on the basis of the full-text and fulfilment of the inclusion criteria was ensured.

      Literature Search Strategy

      A systematic search of relevant literature was conducted by the authors. The electronic databases PubMed (http://www.ncbi.nlm.nih.gov/pubmed), Web of Science (http://isiwebofknowledge.com), Cinahl (https://health.ebsco.com/products/cinahl-complete), and Cochrane (http://onlinelibrary.wiley.com/cochranelibrary/search) were searched through on September 7, 2015 to identify relevant articles. To make the search as complete as possible, reference lists of the included articles were screened. The search strategy consisted of a combination of free text words on the basis of the eligibility criteria. The complete search strategy is shown in Table 2.
      Table 2The Search Terms (Free Text Words) Used for the Literature Review
      PatientsandMeasurement InstrumentandOutcomeandOutcome
      Musculoskeletal pain syndromeBrain imagingWhite matterAllodynia
      Chronic low back painDiffusion tensor imagingCortical thicknessHyperalgesia
      FibromyalgiaDiffusion weighted imagingGray matterHeightened sensitivity
      Chronic fatigue syndromeMagnetization transfer contrastGray matterHypersensitivity
      Temporomandibular disordersMagnetization transfer ratioGray matter volumeReferred pain
      OsteoarthritisT1Gray matter volumePain duration
      Chronic knee painVoxel-based morphometryFunctional connectivityPain severity
      Chronic pelvic pain syndromefMRIStructural connectivityPain intensity
      Chronic ankle painfMRIResting state activity
      Chronic neck painResting-state fMRIResting state connectivity
      Chronic whiplash-associated disorderResting state fMRICortical morphology
      Chronic epicondylalgiaTractography
      Myofacial pain syndrome

      Risk of Bias in Individual Studies

      Methodological quality of all included studies was assessed by 2 independent reviewers (I.C. and J.K.), both PhD candidates working with chronic MSKP patients in the research field of brain MRI. Both reviewers were trained by M.M., a PhD experienced in conducting systematic reviews. Risk of bias was evaluated using the Newcastle-Ottawa Scale (NOS) for case control studies (http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp).

      The Ottawa Hospital. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P: The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed September 15, 2015

      The NOS applies a star rating system to judge methodological quality on the basis of 3 subcategories: selection of groups, comparability, and ascertainment of exposure. This checklist is recommended for case-control studies
      • Zeng X.
      • Zhang Y.
      • Kwong J.S.
      • Zhang C.
      • Li S.
      • Sun F.
      • Niu Y.
      • Du L.
      The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review.
      and has frequently been used by the Cochrane Collaboration (www.cochrane.org). The criterion on response rate could not be scored because this item was not applicable for the articles on the current research topic. Therefore, item 9 was replaced by a self-constructed additional subcategory, ‘MRI data quality and preprocessing’ that includes 2 items, which was chosen specifically for the current systematic review. Item 9 scores whether the researchers performed visual inspection of the MRI data quality (eg, head motion). Item 10 scores whether manual exclusion in case of low data quality and/or data adjustment was included in the preprocessing pipeline. Subsequently, each study could reach a maximum score of 10 on the modified NOS, representing the highest methodological quality. A study earned 1 point when controlling for sex or age in the ‘comparability’ section and an additional point when controlling for another factor (eg, medication use, collecting cardiorespiratory data).
      On the basis of study design and methodological quality, each individual study received a level of evidence, according to the 2005 classification system of the Dutch Institute for Healthcare Improvement (CBO) (Supplementary Table 1). Subsequently, strength of conclusion was determined after clustering studies with comparable experimental methods and research aims, accounting for the study design and the risk of bias (Supplementary Table 2). Strength of conclusion 2 was assigned when there were at least 2 independently conducted studies of evidence level B. Strength of conclusion 3 was assigned when there was at least 1 study of evidence level B. Strength of conclusion 4 was given in case of inconclusive or inconsistent results between various studies.

      Data Extraction Process

      The following information was extracted from each included study and is shown in the evidence table (Supplementary Table 3): 1) patients, 2) control group, 3) brain MRI technique, 4) clinical pain measures, 5) correlations, relations, associations, 6) main results, and 7) correlation coefficients, t-scores, Z-scores. The data were obtained by the first author (I.C.) and a second reviewer (R.D.P.) checked the extracted data. Noteworthy, the evidence table only includes the MRI techniques and clinical pain measures, which were used to evaluate possible relations. In addition, the main results regarding relations between clinical pain measures and brain alterations in chronic MSKP patients are summarized whereas the results among the healthy control group are not shown.

      Results

      Study Selection

      The selection process of relevant articles is presented in Figure 1. The initial search resulted in 137 articles. After removing the duplicates, 91 articles remained. Two articles
      • 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.
      • Gerstner G.
      • Ichesco E.
      • Quintero A.
      • Schmidt-Wilcke T.
      Changes in regional gray and white matter volume in patients with myofascial-type temporomandibular disorders: A voxel-based morphometry study.
      were found by manual search: these articles were found in the reference list of included studies. The entire selection process resulted in 20 eligible articles.
      Figure thumbnail gr1
      Figure 1Preferred Reporting Items for Systematic reviews and Meta-Analyses flow diagram of the conducted search.

      Study Characteristics

      All included studies (n = 20) applied a case-control design, comparing chronic MSKP patients with healthy pain-free individuals. The characteristics of each study were extracted and presented in the evidence table (Supplementary Table 3). Articles were divided on the basis of the applied MRI technique. Six articles compared clinical pain measures with GM alterations,
      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      • Gerstner G.
      • Ichesco E.
      • Quintero A.
      • Schmidt-Wilcke T.
      Changes in regional gray and white matter volume in patients with myofascial-type temporomandibular disorders: A voxel-based morphometry study.
      • Kuchinad A.
      • Schweinhardt P.
      • Seminowicz D.A.
      • Wood P.B.
      • Chizh B.A.
      • Bushnell M.C.
      Accelerated brain gray matter loss in fibromyalgia patients: Premature aging of the brain?.
      • 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.
      • Mordasini L.
      • Weisstanner C.
      • Rummel C.
      • Thalmann G.N.
      • Verma R.K.
      • Wiest R.
      • Kessler T.M.
      Chronic pelvic pain syndrome in men is associated with reduction of relative gray matter volume in the anterior cingulate cortex compared to healthy controls.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      4 articles with WM alterations,
      • Kim D.J.
      • Lim M.
      • Kim J.S.
      • Son K.M.
      • Kim H.A.
      • Chung C.K.
      Altered white matter integrity in the corpus callosum in fibromyalgia patients identified by tract-based spatial statistical analysis.
      • Lieberman G.
      • Shpaner M.
      • Watts R.
      • Andrews T.
      • Filippi C.G.
      • Davis M.
      • Naylor M.R.
      White matter involvement in chronic musculoskeletal pain.
      • Lutz J.
      • Jager L.
      • de Quervain D.
      • Krauseneck T.
      • Padberg F.
      • Wichnalek M.
      • Beyer A.
      • Stahl R.
      • Zirngibl B.
      • Morhard D.
      • Reiser M.
      • Schelling G.
      White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion-tensor and volumetric imaging study.
      • Moayedi M.
      • Weissman-Fogel I.
      • Salomons T.V.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.
      and 11 articles observed relations with functional brain alterations.

      Baliki MN, Mansour AR, Baria AT, Apkarian AV: Functional reorganization of the default mode network across chronic pain conditions. PLoS One 9:e106133, 2014

      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      • Farmer M.A.
      • Chanda M.L.
      • Parks E.L.
      • Baliki M.N.
      • Apkarian A.V.
      • Schaeffer A.J.
      Brain functional and anatomical changes in chronic prostatitis/chronic pelvic pain syndrome.
      • 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.
      • Ichesco E.
      • Quintero A.
      • Clauw D.J.
      • Peltier S.
      • Sundgren P.M.
      • Gerstner G.E.
      • Schmidt-Wilcke T.
      Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.
      • Ichesco E.
      • Schmidt-Wilcke T.
      • Bhavsar R.
      • Clauw D.J.
      • Peltier S.J.
      • Kim J.
      • Napadow V.
      • Hampson J.P.
      • Kairys A.E.
      • Williams D.A.
      • Harris R.E.
      Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
      • Kim J.
      • Loggia M.L.
      • Cahalan C.M.
      • Harris R.E.
      • Beissner F.
      • Garcia R.G.
      • Kim H.
      • Barbieri R.
      • Wasan A.D.
      • Edwards R.R.
      • Napadow V.
      The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction.
      • Kong J.
      • Spaeth R.B.
      • Wey H.Y.
      • Cheetham A.
      • Cook A.H.
      • Jensen K.
      • Tan Y.
      • Liu H.
      • Wang D.
      • Loggia M.L.
      • Napadow V.
      • Smoller J.W.
      • Wasan A.D.
      • Gollub R.L.
      S1 is associated with chronic low back pain: A functional and structural MRI study.
      • Lopez-Sola M.
      • Pujol J.
      • Wager T.D.
      • Garcia-Fontanals A.
      • Blanco-Hinojo L.
      • Garcia-Blanco S.
      • Poca-Dias V.
      • Harrison B.J.
      • Contreras-Rodriguez O.
      • Monfort J.
      • Garcia-Fructuoso F.
      • Deus J.
      Altered functional magnetic resonance imaging responses to nonpainful sensory stimulation in fibromyalgia patients.
      • Napadow V.
      • LaCount L.
      • Park K.
      • As-Sanie S.
      • Clauw D.J.
      • Harris R.E.
      Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
      • Yu R.
      • Gollub R.L.
      • Spaeth R.
      • Napadow V.
      • Wasan A.
      • Kong J.
      Disrupted functional connectivity of the periaqueductal gray in chronic low back pain.

      Risk of Bias Within Studies and Level of Evidence

      The risk of bias and level of evidence is shown in Table 3. All studies scored a level of evidence B. Methodological quality was moderate to good, varying between 5 of 10 (50%) and 9 of 10 (90%). Most studies lost points on ‘representativeness of the cases’ (80%), ‘selection of controls’ (85%), and ‘definition of controls’ (60%), either because authors did not mention the required information or the information was not adequate. Nevertheless, most studies were awarded for taking into account confounding factors (eg, matching for age and sex), ascertainment of exposure, and for using the same method of ascertainment for cases and controls. All studies were awarded for manual exclusion in case of low data quality and/or inclusion of automated data adjustment in the preprocessing pipeline.
      Table 3Methodological Quality for Case-Control Studies
      StudySelectionComparabilityExposureMRI Data Quality and PreprocessingTotal Score (%)LOE
      12345678910
      Kim et al
      • Kim D.J.
      • Lim M.
      • Kim J.S.
      • Son K.M.
      • Kim H.A.
      • Chung C.K.
      Altered white matter integrity in the corpus callosum in fibromyalgia patients identified by tract-based spatial statistical analysis.
      +++++++++9/10 (90)B
      Moayedi et al
      • Moayedi M.
      • Weissman-Fogel I.
      • Salomons T.V.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.
      +/+++++++8/10 (80)B
      Ichesco et al
      • Ichesco E.
      • Schmidt-Wilcke T.
      • Bhavsar R.
      • Clauw D.J.
      • Peltier S.J.
      • Kim J.
      • Napadow V.
      • Hampson J.P.
      • Kairys A.E.
      • Williams D.A.
      • Harris R.E.
      Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
      ++++++++8/10 (80)B
      Ichesco et al
      • Ichesco E.
      • Quintero A.
      • Clauw D.J.
      • Peltier S.
      • Sundgren P.M.
      • Gerstner G.E.
      • Schmidt-Wilcke T.
      Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.
      ++++++++8/10 (80)B
      Gerstner et al
      • Gerstner G.
      • Ichesco E.
      • Quintero A.
      • Schmidt-Wilcke T.
      Changes in regional gray and white matter volume in patients with myofascial-type temporomandibular disorders: A voxel-based morphometry study.
      +++++++8/10 (80)B
      Lutz et al
      • Lutz J.
      • Jager L.
      • de Quervain D.
      • Krauseneck T.
      • Padberg F.
      • Wichnalek M.
      • Beyer A.
      • Stahl R.
      • Zirngibl B.
      • Morhard D.
      • Reiser M.
      • Schelling G.
      White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion-tensor and volumetric imaging study.
      +/+++++++8/10 (80)B
      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.
      +++++++7/10 (70)B
      Kim et al
      • Kim J.
      • Loggia M.L.
      • Cahalan C.M.
      • Harris R.E.
      • Beissner F.
      • Garcia R.G.
      • Kim H.
      • Barbieri R.
      • Wasan A.D.
      • Edwards R.R.
      • Napadow V.
      The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction.
      +++++++7/10 (70)B
      Lopez-Sola et al
      • Lopez-Sola M.
      • Pujol J.
      • Wager T.D.
      • Garcia-Fontanals A.
      • Blanco-Hinojo L.
      • Garcia-Blanco S.
      • Poca-Dias V.
      • Harrison B.J.
      • Contreras-Rodriguez O.
      • Monfort J.
      • Garcia-Fructuoso F.
      • Deus J.
      Altered functional magnetic resonance imaging responses to nonpainful sensory stimulation in fibromyalgia patients.
      +/++++++7/10 (70)B
      Baliki et al

      Baliki MN, Mansour AR, Baria AT, Apkarian AV: Functional reorganization of the default mode network across chronic pain conditions. PLoS One 9:e106133, 2014

      +++++++7/10 (70)B
      Mordasini et al
      • Mordasini L.
      • Weisstanner C.
      • Rummel C.
      • Thalmann G.N.
      • Verma R.K.
      • Wiest R.
      • Kessler T.M.
      Chronic pelvic pain syndrome in men is associated with reduction of relative gray matter volume in the anterior cingulate cortex compared to healthy controls.
      +++++++7/10 (70)B
      Yu et al
      • Yu R.
      • Gollub R.L.
      • Spaeth R.
      • Napadow V.
      • Wasan A.
      • Kong J.
      Disrupted functional connectivity of the periaqueductal gray in chronic low back pain.
      ++++++7/10 (60)B
      Ceko et al
      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      ++++++7/10 (70)B
      Kong et al
      • Kong J.
      • Spaeth R.B.
      • Wey H.Y.
      • Cheetham A.
      • Cook A.H.
      • Jensen K.
      • Tan Y.
      • Liu H.
      • Wang D.
      • Loggia M.L.
      • Napadow V.
      • Smoller J.W.
      • Wasan A.D.
      • Gollub R.L.
      S1 is associated with chronic low back pain: A functional and structural MRI study.
      +++++++7/10 (70)B
      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.
      ++++++6/10 (60)B
      Farmer et al
      • Farmer M.A.
      • Chanda M.L.
      • Parks E.L.
      • Baliki M.N.
      • Apkarian A.V.
      • Schaeffer A.J.
      Brain functional and anatomical changes in chronic prostatitis/chronic pelvic pain syndrome.
      +++++++6/10 (60)B
      Lieberman et al
      • Lieberman G.
      • Shpaner M.
      • Watts R.
      • Andrews T.
      • Filippi C.G.
      • Davis M.
      • Naylor M.R.
      White matter involvement in chronic musculoskeletal pain.
      ++++++6/10 (60)B
      Younger et al
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      +++/++5/10 (50)B
      Napadow et al
      • Napadow V.
      • LaCount L.
      • Park K.
      • As-Sanie S.
      • Clauw D.J.
      • Harris R.E.
      Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
      +++++5/10 (50)B
      Kuchinad et al
      • Kuchinad A.
      • Schweinhardt P.
      • Seminowicz D.A.
      • Wood P.B.
      • Chizh B.A.
      • Bushnell M.C.
      Accelerated brain gray matter loss in fibromyalgia patients: Premature aging of the brain?.
      +++++5/10 (50)B
      Abbreviations: LOE, level of evidence; −, score not fulfilled; +, score fulfilled; /, answer is unclear.
      NOTE. Newcastle-Ottawa Quality Assessment Scale: case-control studies: 1 = Is the case definition adequate?; 2 = Representativeness of the cases; 3 = Selection of controls; 4 = Definition of controls; 5 = Study controls for age or sex; 6 = Study controls for any additional factor; 7 = Ascertainment of exposure; 8 = Same method of ascertainment for cases and controls; 9 = Visual inspection of the MRI data quality; 10 = Manual exclusion in case of low data quality and/or automated data adjustment included in preprocessing pipeline.
      In most cases (90.5% or 181 of the 200 items), the 2 reviewers (I.C. and J.K.) agreed. After a second review and a comparison of the 19 differences, the reviewers reached a consensus for 197 items. For the 3 remaining items, a third investigator was consulted (R.D.P.). The final score of each study is presented in Table 3.

      Syntheses of Results

      Structural Brain MRI

      Overall, 10 studies investigated the relationship between structural brain alterations and clinical pain measures in chronic MSKP patients.
      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      • Gerstner G.
      • Ichesco E.
      • Quintero A.
      • Schmidt-Wilcke T.
      Changes in regional gray and white matter volume in patients with myofascial-type temporomandibular disorders: A voxel-based morphometry study.
      • Kim D.J.
      • Lim M.
      • Kim J.S.
      • Son K.M.
      • Kim H.A.
      • Chung C.K.
      Altered white matter integrity in the corpus callosum in fibromyalgia patients identified by tract-based spatial statistical analysis.
      • Kuchinad A.
      • Schweinhardt P.
      • Seminowicz D.A.
      • Wood P.B.
      • Chizh B.A.
      • Bushnell M.C.
      Accelerated brain gray matter loss in fibromyalgia patients: Premature aging of the brain?.
      • Lieberman G.
      • Shpaner M.
      • Watts R.
      • Andrews T.
      • Filippi C.G.
      • Davis M.
      • Naylor M.R.
      White matter involvement in chronic musculoskeletal pain.
      • Lutz J.
      • Jager L.
      • de Quervain D.
      • Krauseneck T.
      • Padberg F.
      • Wichnalek M.
      • Beyer A.
      • Stahl R.
      • Zirngibl B.
      • Morhard D.
      • Reiser M.
      • Schelling G.
      White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion-tensor and volumetric imaging study.
      • 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.
      • Moayedi M.
      • Weissman-Fogel I.
      • Salomons T.V.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.
      • Mordasini L.
      • Weisstanner C.
      • Rummel C.
      • Thalmann G.N.
      • Verma R.K.
      • Wiest R.
      • Kessler T.M.
      Chronic pelvic pain syndrome in men is associated with reduction of relative gray matter volume in the anterior cingulate cortex compared to healthy controls.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      Six of 10 articles used voxel-based morphometry,
      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      • Gerstner G.
      • Ichesco E.
      • Quintero A.
      • Schmidt-Wilcke T.
      Changes in regional gray and white matter volume in patients with myofascial-type temporomandibular disorders: A voxel-based morphometry study.
      • Kuchinad A.
      • Schweinhardt P.
      • Seminowicz D.A.
      • Wood P.B.
      • Chizh B.A.
      • Bushnell M.C.
      Accelerated brain gray matter loss in fibromyalgia patients: Premature aging of the brain?.
      • 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.
      • Mordasini L.
      • Weisstanner C.
      • Rummel C.
      • Thalmann G.N.
      • Verma R.K.
      • Wiest R.
      • Kessler T.M.
      Chronic pelvic pain syndrome in men is associated with reduction of relative gray matter volume in the anterior cingulate cortex compared to healthy controls.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      1 article performed cortical thickness analysis,
      • 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.
      and 4 articles applied DTI.
      • Kim D.J.
      • Lim M.
      • Kim J.S.
      • Son K.M.
      • Kim H.A.
      • Chung C.K.
      Altered white matter integrity in the corpus callosum in fibromyalgia patients identified by tract-based spatial statistical analysis.
      • Lieberman G.
      • Shpaner M.
      • Watts R.
      • Andrews T.
      • Filippi C.G.
      • Davis M.
      • Naylor M.R.
      White matter involvement in chronic musculoskeletal pain.
      • Lutz J.
      • Jager L.
      • de Quervain D.
      • Krauseneck T.
      • Padberg F.
      • Wichnalek M.
      • Beyer A.
      • Stahl R.
      • Zirngibl B.
      • Morhard D.
      • Reiser M.
      • Schelling G.
      White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion-tensor and volumetric imaging study.
      • Moayedi M.
      • Weissman-Fogel I.
      • Salomons T.V.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.

      GM Alterations Related to Clinical Pain Measures

      Pain Intensity

      Three studies examined the relation between clinical pain intensity and alterations in regional GM volume.
      • 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.
      • Mordasini L.
      • Weisstanner C.
      • Rummel C.
      • Thalmann G.N.
      • Verma R.K.
      • Wiest R.
      • Kessler T.M.
      Chronic pelvic pain syndrome in men is associated with reduction of relative gray matter volume in the anterior cingulate cortex compared to healthy controls.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      Mordasini et al
      • Mordasini L.
      • Weisstanner C.
      • Rummel C.
      • Thalmann G.N.
      • Verma R.K.
      • Wiest R.
      • Kessler T.M.
      Chronic pelvic pain syndrome in men is associated with reduction of relative gray matter volume in the anterior cingulate cortex compared to healthy controls.
      and Younger et al
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      reported a significant relation between pain intensity and regional GM volume. Increased pain intensity in patients with chronic temporomandibular disorders was associated with decreased GM volume in the right rostral ACC, right PCC, precuneus, and superior frontal and superior temporal gyrus.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      Mordasini et al
      • Mordasini L.
      • Weisstanner C.
      • Rummel C.
      • Thalmann G.N.
      • Verma R.K.
      • Wiest R.
      • Kessler T.M.
      Chronic pelvic pain syndrome in men is associated with reduction of relative gray matter volume in the anterior cingulate cortex compared to healthy controls.
      reported correlations between higher chronic pelvic pain intensity and decreased GM volume in the left ACC.
      In conclusion, there is moderate evidence that higher clinical pain intensity in chronic MSKP patients is related to decreased GM volume in pain processing regions such as the ACC
      • Mordasini L.
      • Weisstanner C.
      • Rummel C.
      • Thalmann G.N.
      • Verma R.K.
      • Wiest R.
      • Kessler T.M.
      Chronic pelvic pain syndrome in men is associated with reduction of relative gray matter volume in the anterior cingulate cortex compared to healthy controls.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      (strength of conclusion 2).
      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.
      reported a negative correlation between pain intensity in temporomandibular disorders patients and GM thickness in the anterior midcingulate cortex and the ventrolateral aspect of the primary motor cortex. Furthermore, they reported that increased pain unpleasantness was associated with decreased GM thickness in the lateral orbitofrontal cortex.
      In conclusion, there is some evidence that increased pain intensity and pain unpleasantness in chronic temporomandibular disorders patients is correlated with decreased GM thickness in pain, motor, and cognitive processing regions of the brain (strength of conclusion 3).

      Pressure Pain Sensitivity

      Two studies reported an association between pressure pain sensitivity and regional GM volume alterations.
      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      Younger et al
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      reported a negative association between pressure pain sensitivity and GM volume in the trigeminal nuclei in chronic temporomandibular disorders patients. Furthermore, Ceko and colleagues
      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      observed significant relations between increased pressure pain sensitivity and decreased GM volume in the left anterior insula and PCC in fibromyalgia patients.
      In conclusion, there is moderate evidence that increased pressure pain sensitivity in chronic MSKP patients is associated with decreased GM volume in somatosensory, pain, and affect-cognitive processing brain regions (strength of conclusion 2).

      Pain Duration

      Four articles
      • Gerstner G.
      • Ichesco E.
      • Quintero A.
      • Schmidt-Wilcke T.
      Changes in regional gray and white matter volume in patients with myofascial-type temporomandibular disorders: A voxel-based morphometry study.
      • Kuchinad A.
      • Schweinhardt P.
      • Seminowicz D.A.
      • Wood P.B.
      • Chizh B.A.
      • Bushnell M.C.
      Accelerated brain gray matter loss in fibromyalgia patients: Premature aging of the brain?.
      • 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.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      reported an association between the duration of chronic MSKP and GM volume alterations. Three articles described a relation with regional GM volume
      • Gerstner G.
      • Ichesco E.
      • Quintero A.
      • Schmidt-Wilcke T.
      Changes in regional gray and white matter volume in patients with myofascial-type temporomandibular disorders: A voxel-based morphometry study.
      • 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.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      and 1 article showed a relation with total GM volume.
      • Kuchinad A.
      • Schweinhardt P.
      • Seminowicz D.A.
      • Wood P.B.
      • Chizh B.A.
      • Bushnell M.C.
      Accelerated brain gray matter loss in fibromyalgia patients: Premature aging of the brain?.
      A negative correlation was reported by Gerstner et al,
      • Gerstner G.
      • Ichesco E.
      • Quintero A.
      • Schmidt-Wilcke T.
      Changes in regional gray and white matter volume in patients with myofascial-type temporomandibular disorders: A voxel-based morphometry study.
      who observed that longer pain duration in chronic temporomandibular disorders patients was correlated with decreased GM volume in the right superior and middle temporal gyrus. Kuchinad et al
      • Kuchinad A.
      • Schweinhardt P.
      • Seminowicz D.A.
      • Wood P.B.
      • Chizh B.A.
      • Bushnell M.C.
      Accelerated brain gray matter loss in fibromyalgia patients: Premature aging of the brain?.
      reported that longer disease duration in fibromyalgia patients was correlated with decreased total GM volume. In contrast, Younger et al
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      and 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.
      described a positive relation between duration of temporomandibular disorders and regional GM volume. Increased GM volume was found in the PCC and midbrain bilaterally, in the right hippocampus and in the right middle cerebellar peduncle.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      Further, longer temporomandibular disorders disease duration was correlated with increased GM volume in the sensory thalamus.
      • 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.
      In conclusion, there is moderate evidence that regional GM volume alterations are correlated with chronic MSKP duration (strength of conclusion 2). However, inconclusive evidence exists regarding the relation between longer disease duration and decreased or increased regional GM volume (strength of conclusion 4).
      Additionally, there is some evidence that longer disease duration in fibromyalgia patients is correlated with decreased total GM volume (strength of conclusion 3).

      WM Alterations Related to Clinical Pain Measures

      Pain Intensity

      Four studies
      • Kim D.J.
      • Lim M.
      • Kim J.S.
      • Son K.M.
      • Kim H.A.
      • Chung C.K.
      Altered white matter integrity in the corpus callosum in fibromyalgia patients identified by tract-based spatial statistical analysis.
      • Lieberman G.
      • Shpaner M.
      • Watts R.
      • Andrews T.
      • Filippi C.G.
      • Davis M.
      • Naylor M.R.
      White matter involvement in chronic musculoskeletal pain.
      • Lutz J.
      • Jager L.
      • de Quervain D.
      • Krauseneck T.
      • Padberg F.
      • Wichnalek M.
      • Beyer A.
      • Stahl R.
      • Zirngibl B.
      • Morhard D.
      • Reiser M.
      • Schelling G.
      White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion-tensor and volumetric imaging study.
      • Moayedi M.
      • Weissman-Fogel I.
      • Salomons T.V.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.
      investigated the relationship between clinical pain correlates and structural alterations in WM using DTI as an MRI technique. Kim and colleagues
      • Kim D.J.
      • Lim M.
      • Kim J.S.
      • Son K.M.
      • Kim H.A.
      • Chung C.K.
      Altered white matter integrity in the corpus callosum in fibromyalgia patients identified by tract-based spatial statistical analysis.
      and Moayedi and colleagues
      • Moayedi M.
      • Weissman-Fogel I.
      • Salomons T.V.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.
      reported a correlation between higher pain intensity and lower FA in the corpus callosum,
      • Kim D.J.
      • Lim M.
      • Kim J.S.
      • Son K.M.
      • Kim H.A.
      • Chung C.K.
      Altered white matter integrity in the corpus callosum in fibromyalgia patients identified by tract-based spatial statistical analysis.
      internal, external and extreme capsules,
      • Moayedi M.
      • Weissman-Fogel I.
      • Salomons T.V.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.
      and the thalamus.
      • Moayedi M.
      • Weissman-Fogel I.
      • Salomons T.V.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.
      Moayedi et al
      • Moayedi M.
      • Weissman-Fogel I.
      • Salomons T.V.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.
      also detected a negative correlation between pain unpleasantness and FA in the right internal capsule. In contrast, Lutz et al
      • Lutz J.
      • Jager L.
      • de Quervain D.
      • Krauseneck T.
      • Padberg F.
      • Wichnalek M.
      • Beyer A.
      • Stahl R.
      • Zirngibl B.
      • Morhard D.
      • Reiser M.
      • Schelling G.
      White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion-tensor and volumetric imaging study.
      and Lieberman et al
      • Lieberman G.
      • Shpaner M.
      • Watts R.
      • Andrews T.
      • Filippi C.G.
      • Davis M.
      • Naylor M.R.
      White matter involvement in chronic musculoskeletal pain.
      have reported positive correlations between higher pain intensity and increased FA values in the WM of the right superior frontal gyrus
      • Lutz J.
      • Jager L.
      • de Quervain D.
      • Krauseneck T.
      • Padberg F.
      • Wichnalek M.
      • Beyer A.
      • Stahl R.
      • Zirngibl B.
      • Morhard D.
      • Reiser M.
      • Schelling G.
      White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion-tensor and volumetric imaging study.
      and between higher total pain experience score and increased FA in the left uncinate fasciculus.
      • Lieberman G.
      • Shpaner M.
      • Watts R.
      • Andrews T.
      • Filippi C.G.
      • Davis M.
      • Naylor M.R.
      White matter involvement in chronic musculoskeletal pain.
      In conclusion, there is moderate evidence that higher pain intensity is correlated with FA alterations in regional WM tracts involved in transmission of somatosensory, pain, and affective and cognitive information (strength of conclusion 2). However, there is inconclusive evidence as to whether greater pain intensity is related to decreased or increased FA values in these WM tracts (strength of conclusion 4).

      Subjective Pain Scores

      Lieberman et al
      • Lieberman G.
      • Shpaner M.
      • Watts R.
      • Andrews T.
      • Filippi C.G.
      • Davis M.
      • Naylor M.R.
      White matter involvement in chronic musculoskeletal pain.
      reported positive correlations in chronic MSKP patients between higher total pain experience scores and increased AD in the left anterior and posterior limb of the internal capsule. Additionally, increased typical pain scores on the McGill pain questionnaire were positively correlated with increased AD in the left anterior limb.
      In conclusion, there is some evidence that increased subjective pain scores in chronic MSKP patients are correlated with increased AD in WM tracts involved in transmission of information through the anterior and posterior limb of the internal capsule (strength of conclusion 3).

      Functional Brain MRI

      Overall, 11 articles described interrelations between clinical pain correlates and functional brain alterations using fMRI and/or resting-state fMRI in chronic MSKP patients.

      Baliki MN, Mansour AR, Baria AT, Apkarian AV: Functional reorganization of the default mode network across chronic pain conditions. PLoS One 9:e106133, 2014

      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      • Farmer M.A.
      • Chanda M.L.
      • Parks E.L.
      • Baliki M.N.
      • Apkarian A.V.
      • Schaeffer A.J.
      Brain functional and anatomical changes in chronic prostatitis/chronic pelvic pain syndrome.
      • 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.
      • Ichesco E.
      • Quintero A.
      • Clauw D.J.
      • Peltier S.
      • Sundgren P.M.
      • Gerstner G.E.
      • Schmidt-Wilcke T.
      Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.
      • Ichesco E.
      • Schmidt-Wilcke T.
      • Bhavsar R.
      • Clauw D.J.
      • Peltier S.J.
      • Kim J.
      • Napadow V.
      • Hampson J.P.
      • Kairys A.E.
      • Williams D.A.
      • Harris R.E.
      Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
      • Kim J.
      • Loggia M.L.
      • Cahalan C.M.
      • Harris R.E.
      • Beissner F.
      • Garcia R.G.
      • Kim H.
      • Barbieri R.
      • Wasan A.D.
      • Edwards R.R.
      • Napadow V.
      The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction.
      • Kong J.
      • Spaeth R.B.
      • Wey H.Y.
      • Cheetham A.
      • Cook A.H.
      • Jensen K.
      • Tan Y.
      • Liu H.
      • Wang D.
      • Loggia M.L.
      • Napadow V.
      • Smoller J.W.
      • Wasan A.D.
      • Gollub R.L.
      S1 is associated with chronic low back pain: A functional and structural MRI study.
      • Lopez-Sola M.
      • Pujol J.
      • Wager T.D.
      • Garcia-Fontanals A.
      • Blanco-Hinojo L.
      • Garcia-Blanco S.
      • Poca-Dias V.
      • Harrison B.J.
      • Contreras-Rodriguez O.
      • Monfort J.
      • Garcia-Fructuoso F.
      • Deus J.
      Altered functional magnetic resonance imaging responses to nonpainful sensory stimulation in fibromyalgia patients.
      • Napadow V.
      • LaCount L.
      • Park K.
      • As-Sanie S.
      • Clauw D.J.
      • Harris R.E.
      Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
      • Yu R.
      • Gollub R.L.
      • Spaeth R.
      • Napadow V.
      • Wasan A.
      • Kong J.
      Disrupted functional connectivity of the periaqueductal gray in chronic low back pain.
      Six studies examined fibromyalgia patients, 1 article included chronic pelvic pain patients, 3 articles assessed chronic low back pain patients, 1 article investigated osteoarthritis patients, and 1 article included patients with temporomandibular disorders.

      FC Alterations Related to Clinical Pain Measures

      Pain Intensity

      Most studies investigated relations between clinical pain measures and FC alterations.

      Baliki MN, Mansour AR, Baria AT, Apkarian AV: Functional reorganization of the default mode network across chronic pain conditions. PLoS One 9:e106133, 2014

      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      • 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.
      • Ichesco E.
      • Quintero A.
      • Clauw D.J.
      • Peltier S.
      • Sundgren P.M.
      • Gerstner G.E.
      • Schmidt-Wilcke T.
      Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.
      • Ichesco E.
      • Schmidt-Wilcke T.
      • Bhavsar R.
      • Clauw D.J.
      • Peltier S.J.
      • Kim J.
      • Napadow V.
      • Hampson J.P.
      • Kairys A.E.
      • Williams D.A.
      • Harris R.E.
      Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
      • Kim J.
      • Loggia M.L.
      • Cahalan C.M.
      • Harris R.E.
      • Beissner F.
      • Garcia R.G.
      • Kim H.
      • Barbieri R.
      • Wasan A.D.
      • Edwards R.R.
      • Napadow V.
      The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction.
      • Kong J.
      • Spaeth R.B.
      • Wey H.Y.
      • Cheetham A.
      • Cook A.H.
      • Jensen K.
      • Tan Y.
      • Liu H.
      • Wang D.
      • Loggia M.L.
      • Napadow V.
      • Smoller J.W.
      • Wasan A.D.
      • Gollub R.L.
      S1 is associated with chronic low back pain: A functional and structural MRI study.
      • Napadow V.
      • Kim J.
      • Clauw D.J.
      • Harris R.E.
      Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.
      • Napadow V.
      • LaCount L.
      • Park K.
      • As-Sanie S.
      • Clauw D.J.
      • Harris R.E.
      Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
      • Yu R.
      • Gollub R.L.
      • Spaeth R.
      • Napadow V.
      • Wasan A.
      • Kong J.
      Disrupted functional connectivity of the periaqueductal gray in chronic low back pain.
      Napadow et al
      • Napadow V.
      • LaCount L.
      • Park K.
      • As-Sanie S.
      • Clauw D.J.
      • Harris R.E.
      Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
      reported in fibromyalgia patients a positive association between higher current pain intensity and increased FC between the DMN and right middle and anterior insula, cerebellum, dorsolateral prefrontal cortex, and subgenual ACC. Further, a positive covariation was reported between higher current pain intensity and increased FC between the right executive attention network and right anterior, left middle, and posterior insula and putamen.
      In contrast, Napadow et al
      • Napadow V.
      • LaCount L.
      • Park K.
      • As-Sanie S.
      • Clauw D.J.
      • Harris R.E.
      Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
      reported higher current pain intensity to be related to decreased FC between the right executive attention network and the hippocampus, periaqueductal gray, nucleus cuneiformis, and the pontine raphe. A negative relation was shown in temporomandibular disorders patients between pain intensity and FC between the left anterior insula and rostral ACC during resting-state fMRI by Ichesco et al.
      • Ichesco E.
      • Quintero A.
      • Clauw D.J.
      • Peltier S.
      • Sundgren P.M.
      • Gerstner G.E.
      • Schmidt-Wilcke T.
      Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.
      Ichesco et al,
      • Ichesco E.
      • Schmidt-Wilcke T.
      • Bhavsar R.
      • Clauw D.J.
      • Peltier S.J.
      • Kim J.
      • Napadow V.
      • Hampson J.P.
      • Kairys A.E.
      • Williams D.A.
      • Harris R.E.
      Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
      reported in fibromyalgia patients higher pain intensity to be related to increased FC between the right anterior insula and superior temporal gyrus. Kong et al
      • Kong J.
      • Spaeth R.B.
      • Wey H.Y.
      • Cheetham A.
      • Cook A.H.
      • Jensen K.
      • Tan Y.
      • Liu H.
      • Wang D.
      • Loggia M.L.
      • Napadow V.
      • Smoller J.W.
      • Wasan A.D.
      • Gollub R.L.
      S1 is associated with chronic low back pain: A functional and structural MRI study.
      reported positive relations between pain intensity changes after exercises and FC at the left insula, precuneus, amygdala, and fusiform in chronic low back pain patients.
      Baliki et al

      Baliki MN, Mansour AR, Baria AT, Apkarian AV: Functional reorganization of the default mode network across chronic pain conditions. PLoS One 9:e106133, 2014

      reported in chronic low back pain and osteoarthritis patients positive correlations between current pain intensity and medial prefrontal cortex/insula FC. Further, Ceko et al
      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      reported in fibromyalgia positive relations between current pain intensity and FC of the left anterior insula to the primary somatosensory cortex (S1) and primary motor cortex. In addition, Kim et al
      • Kim J.
      • Loggia M.L.
      • Cahalan C.M.
      • Harris R.E.
      • Beissner F.
      • Garcia R.G.
      • Kim H.
      • Barbieri R.
      • Wasan A.D.
      • Edwards R.R.
      • Napadow V.
      The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction.
      reported a correlation between higher pain intensity and increased changes (from the pain phase through the rest phase) in S1 leg connectivity to the anterior insula in fibromyalgia patients. Additionally, increased temporal summation of pain was correlated with increased changes in S1 leg connectivity to the right anterior/middle insula in fibromyalgia patients. In contrast, higher clinical pain intensity was related to decreased resting-state FC within S1.
      Ichesco et al
      • Ichesco E.
      • Schmidt-Wilcke T.
      • Bhavsar R.
      • Clauw D.J.
      • Peltier S.J.
      • Kim J.
      • Napadow V.
      • Hampson J.P.
      • Kairys A.E.
      • Williams D.A.
      • Harris R.E.
      Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
      examined associations between pain rating index scores and FC in fibromyalgia patients. Higher FC, between insula and superior temporal gyrus, was associated with higher affective scores. Higher sensory scores were correlated with greater FC between the right middle insula and bilateral precuneus. In contrast, Yu et al
      • Yu R.
      • Gollub R.L.
      • Spaeth R.
      • Napadow V.
      • Wasan A.
      • Kong J.
      Disrupted functional connectivity of the periaqueductal gray in chronic low back pain.
      observed in chronic low back pain patients a negative relationship between increased low back pain ratings and FC between periaqueductal gray and left ventromedial prefrontal cortex/rostral ACC after a pain-inducing maneuver.
      In conclusion, there is moderate evidence that greater clinical pain intensity is related to alterations in FC in chronic MSKP patients (strength of conclusion 2). However, inconclusive evidence exists regarding the direction of the relation within somatosensory, pain, and affect-cognitive processing regions/networks in chronic MSKP patients. Positive

      Baliki MN, Mansour AR, Baria AT, Apkarian AV: Functional reorganization of the default mode network across chronic pain conditions. PLoS One 9:e106133, 2014

      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      • 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.
      • Ichesco E.
      • Schmidt-Wilcke T.
      • Bhavsar R.
      • Clauw D.J.
      • Peltier S.J.
      • Kim J.
      • Napadow V.
      • Hampson J.P.
      • Kairys A.E.
      • Williams D.A.
      • Harris R.E.
      Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
      • Kong J.
      • Spaeth R.B.
      • Wey H.Y.
      • Cheetham A.
      • Cook A.H.
      • Jensen K.
      • Tan Y.
      • Liu H.
      • Wang D.
      • Loggia M.L.
      • Napadow V.
      • Smoller J.W.
      • Wasan A.D.
      • Gollub R.L.
      S1 is associated with chronic low back pain: A functional and structural MRI study.
      • Napadow V.
      • Kim J.
      • Clauw D.J.
      • Harris R.E.
      Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.
      • Napadow V.
      • LaCount L.
      • Park K.
      • As-Sanie S.
      • Clauw D.J.
      • Harris R.E.
      Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
      and negative
      • 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.
      • Ichesco E.
      • Quintero A.
      • Clauw D.J.
      • Peltier S.
      • Sundgren P.M.
      • Gerstner G.E.
      • Schmidt-Wilcke T.
      Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.
      • Kim J.
      • Loggia M.L.
      • Cahalan C.M.
      • Harris R.E.
      • Beissner F.
      • Garcia R.G.
      • Kim H.
      • Barbieri R.
      • Wasan A.D.
      • Edwards R.R.
      • Napadow V.
      The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction.
      • Napadow V.
      • Kim J.
      • Clauw D.J.
      • Harris R.E.
      Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.
      • Napadow V.
      • LaCount L.
      • Park K.
      • As-Sanie S.
      • Clauw D.J.
      • Harris R.E.
      Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
      • Yu R.
      • Gollub R.L.
      • Spaeth R.
      • Napadow V.
      • Wasan A.
      • Kong J.
      Disrupted functional connectivity of the periaqueductal gray in chronic low back pain.
      relations between pain intensity and FC alterations were found (strength of conclusion 4).

      Pressure Pain Sensitivity

      Three studies investigated the relation between pressure pain sensitivity and FC alterations.
      • 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.
      • Ichesco E.
      • Quintero A.
      • Clauw D.J.
      • Peltier S.
      • Sundgren P.M.
      • Gerstner G.E.
      • Schmidt-Wilcke T.
      Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.
      • Ichesco E.
      • Schmidt-Wilcke T.
      • Bhavsar R.
      • Clauw D.J.
      • Peltier S.J.
      • Kim J.
      • Napadow V.
      • Hampson J.P.
      • Kairys A.E.
      • Williams D.A.
      • Harris R.E.
      Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
      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.
      reported that increased pressure pain sensitivity in fibromyalgia was correlated with decreased FC between the right inferior orbitofrontal regions and right associative visual cortex. In contrast, they also reported a relation between increased pressure pain sensitivity and increased FC between pain-related regions (ie, the left insula and dorsal PCC, the left Rolandic operculum, left parahippocampal gyrus, and thalamus and prefrontal cortex).
      Ichesco et al
      • Ichesco E.
      • Schmidt-Wilcke T.
      • Bhavsar R.
      • Clauw D.J.
      • Peltier S.J.
      • Kim J.
      • Napadow V.
      • Hampson J.P.
      • Kairys A.E.
      • Williams D.A.
      • Harris R.E.
      Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
      investigated correlations between FC and pressure pain thresholds at different intensities. In fibromyalgia patients, a negative correlation was detected between lower pressure pain thresholds, hence increased pressure pain sensitivity and higher FC. Higher FC was reported between the right posterior insula and PCC during a faint, mild, and slightly intense stimulus. A slightly intense stimulus correlated with FC between the left middle insula and left middle cingulate cortex. When a faint stimulus was given, higher FC was reported between the left middle insula and right middle cingulate cortex and between the right posterior insula and left middle ACC. Ichesco et al
      • Ichesco E.
      • Quintero A.
      • Clauw D.J.
      • Peltier S.
      • Sundgren P.M.
      • Gerstner G.E.
      • Schmidt-Wilcke T.
      Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.
      reported that increased pressure pain sensitivity was related to decreased FC between the left anterior insula and the right ACC and medial frontal gyrus in chronic temporomandibular disorders patients.
      In conclusion, there is moderate evidence that pressure pain sensitivity is related to alterations in FC within somatosensory, pain, and affect-cognitive processing brain regions/networks in chronic MSKP patients (strength of conclusion 2). However, inconclusive evidence exists regarding the direction of the relation between increased pressure pain sensitivity and FC alterations in chronic MSKP patients. Positive
      • 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.
      • Ichesco E.
      • Quintero A.
      • Clauw D.J.
      • Peltier S.
      • Sundgren P.M.
      • Gerstner G.E.
      • Schmidt-Wilcke T.
      Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.
      and negative
      • 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.
      • Ichesco E.
      • Schmidt-Wilcke T.
      • Bhavsar R.
      • Clauw D.J.
      • Peltier S.J.
      • Kim J.
      • Napadow V.
      • Hampson J.P.
      • Kairys A.E.
      • Williams D.A.
      • Harris R.E.
      Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
      relations between pressure pain sensitivity and FC alterations were found (strength of conclusion 4).

      Functional Activity Alterations Related to Clinical Pain Measures

      Pain Intensity

      Farmer et al
      • Farmer M.A.
      • Chanda M.L.
      • Parks E.L.
      • Baliki M.N.
      • Apkarian A.V.
      • Schaeffer A.J.
      Brain functional and anatomical changes in chronic prostatitis/chronic pelvic pain syndrome.
      reported a positive correlation between pain intensity and activity in the anterior insula in men with chronic pelvic pain. Lopez-Sola et al
      • Lopez-Sola M.
      • Pujol J.
      • Wager T.D.
      • Garcia-Fontanals A.
      • Blanco-Hinojo L.
      • Garcia-Blanco S.
      • Poca-Dias V.
      • Harrison B.J.
      • Contreras-Rodriguez O.
      • Monfort J.
      • Garcia-Fructuoso F.
      • Deus J.
      Altered functional magnetic resonance imaging responses to nonpainful sensory stimulation in fibromyalgia patients.
      observed negative correlations between pain intensity in fibromyalgia patients and activation in primary and secondary visual cortical areas. Furthermore, hypersensitivity to tactile stimulation (ie, allodynia) was related to decreased activation in the superior middle temporal gyri.
      In conclusion, there is some evidence that higher pain intensity and allodynia are associated with decreased functional brain activation in fibromyalgia patients (strength of conclusion 3). Further, there is some evidence that greater pain intensity is related to increased functional activity in the anterior insula in men with chronic pelvic pain (strength of conclusion 3).

      Discussion

      The purpose of this systematic review was to summarize the evidence regarding relations between structural and functional brain alterations and clinical pain measures in chronic MSKP patients, examined with brain MRI techniques. Most studies reported significant relations between structural and functional alterations in the brain and various clinical pain correlates such as pain intensity, pain duration, and pressure pain sensitivity. Overall, the included studies examined a wide range of brain regions involved in somatosensory, cognitive, and affective processing of pain. Remarkably, the direction of the relations (eg, increased or decreased GM volume related to higher pain measures) often differed between and within various studies. This might be due to a variety of conditions that are classified as chronic MSKP, together with the multiple MRI acquisition and analytical techniques that have been applied to measure alterations in the brain. Furthermore, the different standardized scales and questionnaires that have been used to measure clinical features of pain could have influenced the direction and nature of the observed relations as well as the specific brain regions that were investigated. Nevertheless, several conclusions can be made and are summarized in Table 4. In addition, a glossary of important terms regarding MRI analysis of brain alterations is presented in Table 5.
      Table 4Summary of Evidence Regarding Interrelations Between Brain Alterations and Clinical Pain Measures
      Brain Structural and Functional Alterations, Clinical Pain MeasuresStrength of ConclusionReference
      Interrelations between GM alterations and clinical pain measures in chronic MSKP
       ↘ GM volume (ACC), ↗ clinical pain intensityModerate evidence (2)
      • Litcher-Kelly L.
      • Martino S.A.
      • Broderick J.E.
      • Stone A.A.
      A systematic review of measures used to assess chronic musculoskeletal pain in clinical and randomized controlled clinical trials.
      • Nijs J.
      • Van Houdenhove B.
      • Oostendorp R.A.
      Recognition of central sensitization in patients with musculoskeletal pain: Application of pain neurophysiology in manual therapy practice.
       ↘ GM volume (pain processing regions), ↗ pressure pain sensitivityModerate evidence (2)
      • Buckner R.L.
      • Krienen F.M.
      • Yeo B.T.
      Opportunities and limitations of intrinsic functional connectivity MRI.
      • Nijs J.
      • Van Houdenhove B.
      • Oostendorp R.A.
      Recognition of central sensitization in patients with musculoskeletal pain: Application of pain neurophysiology in manual therapy practice.
       Δ in regional GM volume (pain processing regions), ↗ pain durationModerate evidence (2)
      • Fischl B.
      FreeSurfer.
      • Kuchinad A.
      • Schweinhardt P.
      • Seminowicz D.A.
      • Wood P.B.
      • Chizh B.A.
      • Bushnell M.C.
      Accelerated brain gray matter loss in fibromyalgia patients: Premature aging of the brain?.
      • Nijs J.
      • Van Houdenhove B.
      • Oostendorp R.A.
      Recognition of central sensitization in patients with musculoskeletal pain: Application of pain neurophysiology in manual therapy practice.
       ↘ Total GM volume, ↗ pain duration in FMPreliminary evidence (3)
      • Ichesco E.
      • Quintero A.
      • Clauw D.J.
      • Peltier S.
      • Sundgren P.M.
      • Gerstner G.E.
      • Schmidt-Wilcke T.
      Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.
       ↘ GM thickness (pain processing regions), ↗ pain intensity and unpleasantnessPreliminary evidence (3)
      • Kuchinad A.
      • Schweinhardt P.
      • Seminowicz D.A.
      • Wood P.B.
      • Chizh B.A.
      • Bushnell M.C.
      Accelerated brain gray matter loss in fibromyalgia patients: Premature aging of the brain?.
      Interrelations between WM alterations and clinical pain measures in chronic MSKP
       Δ in FA (WM tracts involved in transmission of somatosensory, pain, affective, and cognitive information), ↗ clinical pain intensityModerate evidence (2)
      • Jones D.K.
      • Cercignani M.
      Twenty-five pitfalls in the analysis of diffusion MRI data.
      • 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.
      • Kim J.
      • Loggia M.L.
      • Cahalan C.M.
      • Harris R.E.
      • Beissner F.
      • Garcia R.G.
      • Kim H.
      • Barbieri R.
      • Wasan A.D.
      • Edwards R.R.
      • Napadow V.
      The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction.
      • Kucyi A.
      • Davis K.D.
      The dynamic pain connectome.
       ↗ AD (WM tracts involved in transmission of information through the basal ganglia), ↗ subjective pain scoresPreliminary evidence (3)
      • Jones D.K.
      • Cercignani M.
      Twenty-five pitfalls in the analysis of diffusion MRI data.
      Interrelations between FC alterations and clinical pain measures in chronic MSKP
       Δ in FC (brain regions/networks involved in somatosensory, pain, and affect-cognitive processing of pain), ↗ clinical pain intensityModerate evidence (2)

      Baliki MN, Schnitzer TJ, Bauer WR, Apkarian AV: Brain morphological signatures for chronic pain. PLoS One 6:e26010, 2011

      • Buckner R.L.
      • Krienen F.M.
      • Yeo B.T.
      Opportunities and limitations of intrinsic functional connectivity MRI.
      • Denk F.
      • McMahon S.B.
      • Tracey I.
      Pain vulnerability: A neurobiological perspective.
      • Geha P.Y.
      • Baliki M.N.
      • Harden R.N.
      • Bauer W.R.
      • Parrish T.B.
      • Apkarian A.V.
      The brain in chronic CRPS pain: Abnormal gray-white matter interactions in emotional and autonomic regions.
      • Geisser M.E.
      • Gracely R.H.
      • Giesecke T.
      • Petzke F.W.
      • Williams D.A.
      • Clauw D.J.
      The association between experimental and clinical pain measures among persons with fibromyalgia and chronic fatigue syndrome.
      • Henderson L.A.
      • Gandevia S.C.
      • Macefield V.G.
      Gender differences in brain activity evoked by muscle and cutaneous pain: A retrospective study of single-trial fMRI data.
      • Herbst M.
      • Maclaren J.
      • Lovell-Smith C.
      • Sostheim R.
      • Egger K.
      • Harloff A.
      • Korvink J.
      • Hennig J.
      • Zaitsev M.
      Reproduction of motion artifacts for performance analysis of prospective motion correction in MRI.
      • Logothetis N.K.
      What we can do and what we cannot do with fMRI.
      • Lopez-Sola M.
      • Pujol J.
      • Wager T.D.
      • Garcia-Fontanals A.
      • Blanco-Hinojo L.
      • Garcia-Blanco S.
      • Poca-Dias V.
      • Harrison B.J.
      • Contreras-Rodriguez O.
      • Monfort J.
      • Garcia-Fructuoso F.
      • Deus J.
      Altered functional magnetic resonance imaging responses to nonpainful sensory stimulation in fibromyalgia patients.
      • Nijs J.
      • Meeus M.
      • Van Oosterwijck J.
      • Ickmans K.
      • Moorkens G.
      • Hans G.
      • De Clerck L.S.
      In the mind or in the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome.
       Δ in FC (brain regions/networks involved in somatosensory, pain, and affect-cognitive processing of pain), ↗ pressure pain sensitivityModerate evidence (2)
      • Denk F.
      • McMahon S.B.
      • Tracey I.
      Pain vulnerability: A neurobiological perspective.
      • Geha P.Y.
      • Baliki M.N.
      • Harden R.N.
      • Bauer W.R.
      • Parrish T.B.
      • Apkarian A.V.
      The brain in chronic CRPS pain: Abnormal gray-white matter interactions in emotional and autonomic regions.
      • Geisser M.E.
      • Gracely R.H.
      • Giesecke T.
      • Petzke F.W.
      • Williams D.A.
      • Clauw D.J.
      The association between experimental and clinical pain measures among persons with fibromyalgia and chronic fatigue syndrome.
      Interrelations between functional activity alterations and clinical pain measures in chronic MSKP
       ↘ Functional activity (temporal, occipital regions), ↗ clinical pain intensity and allodyniaPreliminary evidence (3)
      • Kim D.J.
      • Lim M.
      • Kim J.S.
      • Son K.M.
      • Kim H.A.
      • Chung C.K.
      Altered white matter integrity in the corpus callosum in fibromyalgia patients identified by tract-based spatial statistical analysis.
       ↗ Functional activity in anterior insula, ↗ clinical pain intensityPreliminary evidence (3)
      • Ceko M.
      • Shir Y.
      • Ouellet J.A.
      • Ware M.A.
      • Stone L.S.
      • Seminowicz D.A.
      Partial recovery of abnormal insula and dorsolateral prefrontal connectivity to cognitive networks in chronic low back pain after treatment.
      Abbreviations: ↘, decreased; ↗, increased; FM, fibromyalgia.
      Table 5Glossary of Important Terms Regarding MRI Analysis of Brain Alterations
      DMNA constellation of brain regions thought to be involved in self-referential thinking.
      • Buckner R.L.
      • Krienen F.M.
      • Yeo B.T.
      Opportunities and limitations of intrinsic functional connectivity MRI.
      • 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.
      The DMN is deactivated during various externally focused task conditions.
      ICATechnique to analyze resting state fMRI data, which allows for the estimation of resting state or FC networks.
      EANThe frontoparietal EAN is a brain network involved in cognitive processing of working memory and attention.
      • Ceko M.
      • Shir Y.
      • Ouellet J.A.
      • Ware M.A.
      • Stone L.S.
      • Seminowicz D.A.
      Partial recovery of abnormal insula and dorsolateral prefrontal connectivity to cognitive networks in chronic low back pain after treatment.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred Reporting Items for Systematic reviews and Meta-Analyses: The PRISMA statement.
      FAFA is a measure of the degree of diffusion anisotropy. The FA is normalized so that it ranges from 0 (diffusion is isotropic) to 1 (diffusion is constrained along 1 axis only). FA is typically much higher in WM structures than in CSF and GM, because of the highly organized and tightly packed myelinated axons in WM. Because of this, FA is often used as a surrogate marker for WM ‘integrity.’
      • Barsky A.J.
      • Borus J.F.
      Functional somatic syndromes.
      ADAD is a measure of diffusion along the first eigenvector. Decreased AD but unchanged radial diffusivity is typically assumed to indicate axonal damage or a lower axonal density.
      • Barsky A.J.
      • Borus J.F.
      Functional somatic syndromes.
      As such, AD leads to a more specific interpretation of the concept of WM ‘integrity’ associated with FA.
      Z-scoreA Z-score is a way of standardizing the scale of 2 distributions. When the scales have been standardized, it is easier to compare scores on one distribution with scores on the other distribution. The mean of a distribution of Z-scores is always 0. The SD of a distribution of Z-scores is always 1.
      t-scoreThe t-score is a measure not of the strength of the association but the confidence with which we can assert that there is an association.

      A t-score is a standard score Z-shifted and scaled to have a mean of 50 and an SD of 10.
      Abbreviations: ICA, independent components analysis; EAN, executive attention network; CSF, cerebrospinal fluid.
      Twenty case-control studies met the inclusion criteria. All studies scored a level of evidence B. Methodological quality was moderate to good, varying between 5 of 10 (50%) and 9 of 10 (90%). Moderate evidence shows that higher pain intensity and pressure pain sensitivity are related to decreased regional GM volume in brain regions encompassing the cingulate cortex, the insula, and the superior frontal and temporal gyrus.
      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      • Mordasini L.
      • Weisstanner C.
      • Rummel C.
      • Thalmann G.N.
      • Verma R.K.
      • Wiest R.
      • Kessler T.M.
      Chronic pelvic pain syndrome in men is associated with reduction of relative gray matter volume in the anterior cingulate cortex compared to healthy controls.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      Further, some evidence exists that longer disease duration in fibromyalgia patients is correlated with decreased total GM volume. Yet, inconclusive evidence exists regarding the association of longer disease duration with decreased or increased regional GM volume in other chronic MSKP conditions.
      • Gerstner G.
      • Ichesco E.
      • Quintero A.
      • Schmidt-Wilcke T.
      Changes in regional gray and white matter volume in patients with myofascial-type temporomandibular disorders: A voxel-based morphometry study.
      • 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.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      Moreover, moderate evidence is present for a correlation between higher pain intensity and FA alterations in regional WM tracts
      • Kim D.J.
      • Lim M.
      • Kim J.S.
      • Son K.M.
      • Kim H.A.
      • Chung C.K.
      Altered white matter integrity in the corpus callosum in fibromyalgia patients identified by tract-based spatial statistical analysis.
      • Lieberman G.
      • Shpaner M.
      • Watts R.
      • Andrews T.
      • Filippi C.G.
      • Davis M.
      • Naylor M.R.
      White matter involvement in chronic musculoskeletal pain.
      • Lutz J.
      • Jager L.
      • de Quervain D.
      • Krauseneck T.
      • Padberg F.
      • Wichnalek M.
      • Beyer A.
      • Stahl R.
      • Zirngibl B.
      • Morhard D.
      • Reiser M.
      • Schelling G.
      White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion-tensor and volumetric imaging study.
      • Moayedi M.
      • Weissman-Fogel I.
      • Salomons T.V.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.
      and FC alterations.

      Baliki MN, Mansour AR, Baria AT, Apkarian AV: Functional reorganization of the default mode network across chronic pain conditions. PLoS One 9:e106133, 2014

      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      • 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.
      • Ichesco E.
      • Quintero A.
      • Clauw D.J.
      • Peltier S.
      • Sundgren P.M.
      • Gerstner G.E.
      • Schmidt-Wilcke T.
      Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.
      • Ichesco E.
      • Schmidt-Wilcke T.
      • Bhavsar R.
      • Clauw D.J.
      • Peltier S.J.
      • Kim J.
      • Napadow V.
      • Hampson J.P.
      • Kairys A.E.
      • Williams D.A.
      • Harris R.E.
      Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
      • Kim J.
      • Loggia M.L.
      • Cahalan C.M.
      • Harris R.E.
      • Beissner F.
      • Garcia R.G.
      • Kim H.
      • Barbieri R.
      • Wasan A.D.
      • Edwards R.R.
      • Napadow V.
      The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction.
      • Kong J.
      • Spaeth R.B.
      • Wey H.Y.
      • Cheetham A.
      • Cook A.H.
      • Jensen K.
      • Tan Y.
      • Liu H.
      • Wang D.
      • Loggia M.L.
      • Napadow V.
      • Smoller J.W.
      • Wasan A.D.
      • Gollub R.L.
      S1 is associated with chronic low back pain: A functional and structural MRI study.
      • Napadow V.
      • Kim J.
      • Clauw D.J.
      • Harris R.E.
      Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.
      • Napadow V.
      • LaCount L.
      • Park K.
      • As-Sanie S.
      • Clauw D.J.
      • Harris R.E.
      Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
      • Yu R.
      • Gollub R.L.
      • Spaeth R.
      • Napadow V.
      • Wasan A.
      • Kong J.
      Disrupted functional connectivity of the periaqueductal gray in chronic low back pain.
      However, inconclusive evidence was found regarding the direction of the relation of pain intensity and pressure pain sensitivity with microstructural WM
      • Kim D.J.
      • Lim M.
      • Kim J.S.
      • Son K.M.
      • Kim H.A.
      • Chung C.K.
      Altered white matter integrity in the corpus callosum in fibromyalgia patients identified by tract-based spatial statistical analysis.
      • Lieberman G.
      • Shpaner M.
      • Watts R.
      • Andrews T.
      • Filippi C.G.
      • Davis M.
      • Naylor M.R.
      White matter involvement in chronic musculoskeletal pain.
      • Lutz J.
      • Jager L.
      • de Quervain D.
      • Krauseneck T.
      • Padberg F.
      • Wichnalek M.
      • Beyer A.
      • Stahl R.
      • Zirngibl B.
      • Morhard D.
      • Reiser M.
      • Schelling G.
      White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion-tensor and volumetric imaging study.
      • Moayedi M.
      • Weissman-Fogel I.
      • Salomons T.V.
      • Crawley A.P.
      • Goldberg M.B.
      • Freeman B.V.
      • Tenenbaum H.C.
      • Davis K.D.
      White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.
      and FC

      Baliki MN, Mansour AR, Baria AT, Apkarian AV: Functional reorganization of the default mode network across chronic pain conditions. PLoS One 9:e106133, 2014

      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      • 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.
      • Ichesco E.
      • Quintero A.
      • Clauw D.J.
      • Peltier S.
      • Sundgren P.M.
      • Gerstner G.E.
      • Schmidt-Wilcke T.
      Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.
      • Ichesco E.
      • Schmidt-Wilcke T.
      • Bhavsar R.
      • Clauw D.J.
      • Peltier S.J.
      • Kim J.
      • Napadow V.
      • Hampson J.P.
      • Kairys A.E.
      • Williams D.A.
      • Harris R.E.
      Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
      • Kim J.
      • Loggia M.L.
      • Cahalan C.M.
      • Harris R.E.
      • Beissner F.
      • Garcia R.G.
      • Kim H.
      • Barbieri R.
      • Wasan A.D.
      • Edwards R.R.
      • Napadow V.
      The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction.
      • Kong J.
      • Spaeth R.B.
      • Wey H.Y.
      • Cheetham A.
      • Cook A.H.
      • Jensen K.
      • Tan Y.
      • Liu H.
      • Wang D.
      • Loggia M.L.
      • Napadow V.
      • Smoller J.W.
      • Wasan A.D.
      • Gollub R.L.
      S1 is associated with chronic low back pain: A functional and structural MRI study.
      • Napadow V.
      • Kim J.
      • Clauw D.J.
      • Harris R.E.
      Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.
      • Napadow V.
      • LaCount L.
      • Park K.
      • As-Sanie S.
      • Clauw D.J.
      • Harris R.E.
      Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
      • Yu R.
      • Gollub R.L.
      • Spaeth R.
      • Napadow V.
      • Wasan A.
      • Kong J.
      Disrupted functional connectivity of the periaqueductal gray in chronic low back pain.
      alterations in chronic MSKP.
      It can be summarized that different chronic MSKP syndromes, which seem to be a heterogeneous group, expose unique (specific for each chronic MSKP condition) anatomical ‘brain signatures’ and functional reorganization. However, among all included chronic MSKP conditions it seems that brain regions involved in the limbic-affective and cognitive component of pain processing are involved in the observed neuroplastic brain remodeling. On the basis of this compelling evidence it can be stated that chronic MSKP is not only involved with somatosensory processing but also critically involves cognitive and affective-limbic processing in regions such as the ACC, insula, prefrontal cortex, and amygdala.
      Important to discuss is that the observed relations (eg, extent and direction) between clinical pain characteristics and brain alterations can be influenced by multiple factors. Research has shown in chronic MSKP and non-MSKP patients the influence on pain and neuroplasticity of sex, age, genetics, environment, preexisting vulnerabilities, previous experiences, medication, culture, and psychosocial factors.
      • Baliki M.N.
      • Apkarian A.V.
      Nociception, pain, negative moods, and behavior selection.
      • Blankstein U.
      • Chen J.
      • Diamant N.E.
      • Davis K.D.
      Altered brain structure in irritable bowel syndrome: Potential contributions of pre-existing and disease-driven factors.
      • Ceko M.
      • Bushnell M.C.
      • Fitzcharles M.A.
      • Schweinhardt P.
      Fibromyalgia interacts with age to change the brain.
      • Geha P.Y.
      • Baliki M.N.
      • Harden R.N.
      • Bauer W.R.
      • Parrish T.B.
      • Apkarian A.V.
      The brain in chronic CRPS pain: Abnormal gray-white matter interactions in emotional and autonomic regions.
      • Henderson L.A.
      • Gandevia S.C.
      • Macefield V.G.
      Gender differences in brain activity evoked by muscle and cutaneous pain: A retrospective study of single-trial fMRI data.
      • Loggia M.L.
      • Berna C.
      • Kim J.
      • Cahalan C.M.
      • Martel M.O.
      • Gollub R.L.
      • Wasan A.D.
      • Napadow V.
      • Edwards R.R.
      The lateral prefrontal cortex mediates the hyperalgesic effects of negative cognitions in chronic pain patients.
      • Martinez-Jauand M.
      • Sitges C.
      • Rodriguez V.
      • Picornell A.
      • Ramon M.
      • Buskila D.
      • Montoya P.
      Pain sensitivity in fibromyalgia is associated with catechol-O-methyltransferase (COMT) gene.
      • Matsuzawa-Yanagida K.
      • Narita M.
      • Nakajima M.
      • Kuzumaki N.
      • Niikura K.
      • Nozaki H.
      • Takagi T.
      • Tamai E.
      • Hareyama N.
      • Terada M.
      • Yamazaki M.
      • Suzuki T.
      Usefulness of antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites.
      • Mogil J.S.
      • Bailey A.L.
      Sex and gender differences in pain and analgesia.
      • Tsang A.
      • Von Korff M.
      • Lee S.
      • Alonso J.
      • Karam E.
      • Angermeyer M.C.
      • Borges G.L.
      • Bromet E.J.
      • Demytteneare K.
      • de Girolamo G.
      • de Graaf R.
      • Gureje O.
      • Lepine J.P.
      • Haro J.M.
      • Levinson D.
      • Oakley Browne M.A.
      • Posada-Villa J.
      • Seedat S.
      • Watanabe M.
      Common chronic pain conditions in developed and developing countries: Gender and age differences and comorbidity with depression-anxiety disorders.
      • Younger J.W.
      • Chu L.F.
      • D’Arcy N.T.
      • Trott K.E.
      • Jastrzab L.E.
      • Mackey S.C.
      Prescription opioid analgesics rapidly change the human brain.
      Accordingly, all of these variables could interfere with the observed relations between brain alterations and clinical pain measures and therefore may explain the incongruence found in this systematic review.
      Various hypotheses can be made to explain the relation between clinical pain measures and GM decreases. It has been suggested that GM decrease is associated with long-term nociceptive input and neuroplastic changes.
      • Apkarian A.V.
      • Sosa Y.
      • Sonty S.
      • Levy R.M.
      • Harden R.N.
      • Parrish T.B.
      • Gitelman D.R.
      Chronic back pain is associated with decreased prefrontal and thalamic gray matter density.
      • Kim J.H.
      • Suh S.I.
      • Seol H.Y.
      • Oh K.
      • Seo W.K.
      • Yu S.W.
      • Park K.W.
      • Koh S.B.
      Regional grey matter changes in patients with migraine: A voxel-based morphometry study.
      • Schmidt-Wilcke T.
      • Leinisch E.
      • Straube A.
      • Kampfe N.
      • Draganski B.
      • Diener H.C.
      • Bogdahn U.
      • May A.
      Gray matter decrease in patients with chronic tension type headache.
      Furthermore, increased cortical thickness for example in frontal brain regions could be the consequence of increased cognitive load in chronic pain conditions.
      • 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.
      The frontal pole may process the cognitive dimension of pain, which suggests that pain has a cognitive load and this may require continuous engagement of regions in the frontal cortex and subsequently may lead to cortical thickness. The same theories could be hypothesized for alterations in limbic-affective brain regions.
      To put the results of the current systematic review into a broader perspective, scientific studies regarding the relations between brain alterations and clinical pain measures in chronic non-MSKP patients should be reported. Research in other chronic pain syndromes such as irritable bowel syndrome and complex regional pain syndrome has also investigated the relationship between structural and functional brain alterations, and clinical pain measures such as pain intensity, pain inhibition, and pain duration.
      • Barad M.J.
      • Ueno T.
      • Younger J.
      • Chatterjee N.
      • Mackey S.
      Complex regional pain syndrome is associated with structural abnormalities in pain-related regions of the human brain.
      • Piche M.
      • Chen J.I.
      • Roy M.
      • Poitras P.
      • Bouin M.
      • Rainville P.
      Thicker posterior insula is associated with disease duration in women with irritable bowel syndrome (IBS) whereas thicker orbitofrontal cortex predicts reduced pain inhibition in both IBS patients and controls.
      • Valet M.
      • Gundel H.
      • Sprenger T.
      • Sorg C.
      • Muhlau M.
      • Zimmer C.
      • Henningsen P.
      • Tolle T.R.
      Patients with pain disorder show gray-matter loss in pain-processing structures: A voxel-based morphometric study.
      • Wilder-Smith C.H.
      • Schindler D.
      • Lovblad K.
      • Redmond S.M.
      • Nirkko A.
      Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controls.
      Positive and negative correlations between clinical pain measures and GM morphology alterations have been reported in chronic non-MSKP patients in similar regions involved in somatosensory, affective, and cognitive components of pain processing, as reported in chronic MSKP patients.
      • Barad M.J.
      • Ueno T.
      • Younger J.
      • Chatterjee N.
      • Mackey S.
      Complex regional pain syndrome is associated with structural abnormalities in pain-related regions of the human brain.
      • Piche M.
      • Chen J.I.
      • Roy M.
      • Poitras P.
      • Bouin M.
      • Rainville P.
      Thicker posterior insula is associated with disease duration in women with irritable bowel syndrome (IBS) whereas thicker orbitofrontal cortex predicts reduced pain inhibition in both IBS patients and controls.
      • Valet M.
      • Gundel H.
      • Sprenger T.
      • Sorg C.
      • Muhlau M.
      • Zimmer C.
      • Henningsen P.
      • Tolle T.R.
      Patients with pain disorder show gray-matter loss in pain-processing structures: A voxel-based morphometric study.
      The observed relations between brain alterations and clinical pain measures in chronic non-MSKP patients are in accordance with the results of our systematic review, but the direction of the relation was often conflicting.

      Clinical Relevance and Implications

      To our knowledge, this is the first systematic review summarizing the current evidence regarding relations between brain alterations explored with MRI, and clinical pain correlates (ie, pain duration, pain intensity, pain perception, pressure sensitivity, hyperalgesia, hypersensitivity, allodynia, and referred pain) in patients with chronic MSKP. Regarding the results, it can be stated that structural and functional brain alterations are closely related to clinical aspects of pain perception, modulation, and duration. Increased pain intensity and pressure pain sensitivity seem to be related to decreased GM volume in regions involved in somatosensory, affective, and cognitive processing of pain. In contrast, inconclusive evidence was found regarding the direction of the relation between WM and FC alterations, and increased pain intensity or pressure pain sensitivity.
      On the basis of the summarized evidence, we can presume that central pain