Background and aims
Chronic pain including temporomandibular disorder (TMD) pain involves a complex interplay between peripheral and central sensitization, endogenous modulatory pathways, cortical processing and integration and numerous psychological, behavioral and social factors. The aim of this study was to compare spectroscopic patterns of N-Acetyl-aspartate (NAA), total creatine (tCr), choline (Cho), myo-inositol (MI), glutamate (Glu), and the combination of Glu and glutamine in the posterior insula in patients with chronic generalized or regional chronic TMD pain (gTMD and rTMD, respectively) compared to healthy individuals (HI) in relation to clinical findings of TMD pain.
Thirty-six female patients with chronic rTMD or gTMD with at least 3 months duration were included in the study. Ten healthy women were included as controls. All participants completed a questionnaire that comprised assessment of degrees of depression, anxiety, stress, catastrophizing, pain intensity, disability and locations. A clinical Diagnostic Criteria for Temporomandibular Disorders examination that comprised assessment of pain locations, headache, mouth opening capacity, pain on mandibular movement, pain on palpation and temporomandibular joint noises was performed. Pressure-pain threshold (PPT) over the masseter muscle and temporal summation to pressure stimuli were assessed with an algometer. Within a week all participants underwent non-contrast enhanced MRI on a 3T MR scanner assessing T1-w and T2-w fluid attenuation inversion recovery. A single-voxel 1H-MRS examination using point-resolved spectroscopy was performed. The metabolite concentrations of NAA, tCr, Cho, MI, Glu and Glx were analyzed with the LC model. Metabolite levels were calculated as absolute concentrations, normalized to the water signal. Metabolite concentrations were used for statistical analysis from the LC model if the Cramér–Rao bounds were less than 20%. In addition, the ratios NAA/tCr, Cho/tCr, Glu/tCr and MI/tCr were calculated.
The results showed significantly higher tCr levels within the posterior insula in patients with rTMD or gTMD pain than in HI (p=0.029). Cho was negatively correlated to maximum mouth opening capacity with or without pain (rs=−0.42, n=28, p=0.031 and rs=−0.48, n=28, p=0.034, respectively) as well as pressure-pain threshold on the hand (rs=−0.41, n=28, p=0.031). Glu was positively correlated to temporal summation to painful mechanical stimuli (rs=0.42, n=26, p=0.034).
The present study found that increased concentrations of Cho and Glu in the posterior insular cortex is related to clinical characteristics of chronic TMD pain, including generalized pain. These findings provide new evidence about the critical involvement of the posterior insular cortex and the neurobiology underlying TMD pain in both regional and generalized manifestations.
The findings in this study have indirect implications for the diagnosis and management of TMD patients. That said, the findings provide new evidence about the critical involvement of the posterior insular cortex and the neurobiology underlying TMD pain in both regional and generalized manifestations. It is also a further step towards understanding and accepting chronic pain as a disorder in itself.
The authors would like to thank the coordinating MR nurse Anetta Bolejko and the MR staff at Skånes University Hospital, Malmö, Sweden as well as all the participating patients.
Research funding: This study is partly supported by a grant from Region Skåne, Sweden (OFRS).
Conflict of interest: The authors of this work have no conflicts of interest to report.
Informed consent: Written informed consent was obtained from all participants.
Ethical approval: The study was approved by the Regional Ethics Review Board in Lund, Sweden (2016/006) and conducted according to the provisions of the Helsinki Declaration.
 Branco JC, Bannwarth B, Failde I, Abello Carbonell J, Blotman F, Spaeth M, Saraiva F, Nacci F, Thomas E, Caubère JP, Le Lay K, Taieb C, Matucci-Cerinic M. Prevalence of fibromyalgia: a survey in five European countries. Semin Arthritis Rheum 2010;39:448–53.10.1016/j.semarthrit.2008.12.00319250656 Search in Google Scholar
 Balasubramaniam R, de Leeuw R, Zhu H, Nickerson RB, Okeson JP, Carlson CR. Prevalence of temporomandibular disorders in fibromyalgia and failed back syndrome patients: a blinded prospective comparison study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:204–16.10.1016/j.tripleo.2007.01.01217482850 Search in Google Scholar
 Pimentel MJ, Gui MS, Martins de Aquino LM, Rizzatti-Barbosa CM. Features of temporomandibular disorders in fibromyalgia syndrome. Cranio 2013;31:40–5.10.1179/crn.2013.00623461261 Search in Google Scholar
 Westergren H, Larsson J, Freeman M, Carlsson A, Joud A, Malmstrom EM. Sex-based differences in pain distribution in a cohort of patients with persistent post-traumatic neck pain. Disabil Rehabil 2017;40:1–10. Search in Google Scholar
 Napadow V, LaCount L, Park K, As-Sanie S, Clauw DJ, Harris RE. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum 2010;62:2545–55.2050618110.1002/art.27497 Search in Google Scholar
 Alonso AA, Koutlas IG, Leuthold AC, Lewis SM, Georgopoulos AP. Cortical processing of facial tactile stimuli in temporomandibular disorder as revealed by magnetoencephalography. Exp Brain Res 2010;204:33–45.10.1007/s00221-010-2291-620502887 Search in Google Scholar
 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. J Orofac Pain 2011;25:99–106.21528116 Search in Google Scholar
 Younger JW, Shen YF, Goddard G, Mackey SC. Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems. Pain 2010;149:222–8.10.1016/j.pain.2010.01.00620236763 Search in Google Scholar
 Harris RE, Sundgren PC, Pang Y, Hsu M, Petrou M, Kim SH, McLean SA, Gracely RH, Clauw DJ. Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia. Arthritis Rheum 2008;58:903–7.1831181410.1002/art.23223 Search in Google Scholar
 Harris RE, Sundgren PC, Craig AD, Kirshenbaum E, Sen A, Napadow V, Clauw DJ. Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum 2009;60:3146–52.1979005310.1002/art.24849 Search in Google Scholar
 Feraco P, Bacci A, Pedrabissi F, Passamonti L, Zampogna G, Pedrabissi F, Malavolta N, Leonardi M. Metabolic abnormalities in pain-processing regions of patients with fibromyalgia: a 3T MR spectroscopy study. AJNR Am J Neuroradiol 2011;32:1585–90.2179904210.3174/ajnr.A2550 Search in Google Scholar
 Chang L, Munsaka SM, Kraft-Terry S, Ernst T. Magnetic resonance spectroscopy to assess neuroinflammation and neuropathic pain. J Neuroimmune Pharmacol 2013;8:576–93.10.1007/s11481-013-9460-x23666436 Search in Google Scholar
 Harris RE, Clauw DJ. Imaging central neurochemical alterations in chronic pain with proton magnetic resonance spectroscopy. Neurosci Lett 2012;520:192–6.10.1016/j.neulet.2012.03.04222445845 Search in Google Scholar
 Foerster BR, Petrou M, Edden RA, Sundgren PC, Schmidt-Wilcke T, Lowe SE, Harte SE, Clauw DJ, Harris RE. Reduced insular gamma-aminobutyric acid in fibromyalgia. Arthritis Rheum 2012;64:579–83.10.1002/art.3333921913179 Search in Google Scholar
 Gerstner GE, Gracely RH, Deebajah A, Ichesco E, Quintero A, Clauw DJ, Sundgren PC. Posterior insular molecular changes in myofascial pain. J Dent Res 2012;91:485–90.2245153310.1177/0022034512443366 Search in Google Scholar
 Fayed N, Garcia-Campayo J, Magallon R, Andres-Bergareche H, Luciano JV, Andres E, Beltrán J. Localized 1H-NMR spectroscopy in patients with fibromyalgia: a controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate. Arthritis Res Ther 2010;12:R134.2060922710.1186/ar3072 Search in Google Scholar
 Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet JP, List T, Svensson P, Gonzalez Y, Lobbezoo F, Michelotti A, Brooks SL, Ceusters W, Drangsholt M, Ettlin D, Gaul C, Goldberg LJ, Haythornthwaite JA, Hollender L, Jensen R, et al. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications: recommendations of the International RDC/TMD Consortium Network* and Orofacial Pain Special Interest Group. J Oral Facial Pain Headache 2014;28:6–27.10.11607/jop.115124482784 Search in Google Scholar
 List T, Helkimo M, Falk G. Reliability and validity of a pressure threshold meter in recording tenderness in the masseter muscle and the anterior temporalis muscle. Cranio 1989;7:223–9.263821110.1080/08869634.1989.11678288 Search in Google Scholar
 Grachev ID, Fredrickson BE, Apkarian AV. Abnormal brain chemistry in chronic back pain: an in vivo proton magnetic resonance spectroscopy study. Pain 2000;89:7–18.10.1016/S0304-3959(00)00340-7 Search in Google Scholar
 Blaes F, Schmitz K, Tschernatsch M, Kaps M, Krasenbrink I, Hempelmann G, Bräu ME. Autoimmune etiology of complex regional pain syndrome (M. Sudeck). Neurology 2004;63:1734–6.1553427110.1212/01.WNL.0000143066.58498.BA Search in Google Scholar
 Alexander GM, Perreault MJ, Reichenberger ER, Schwartzman RJ. Changes in immune and glial markers in the CSF of patients with Complex Regional Pain Syndrome. Brain Behav Immun 2007;21:668–76.10.1016/j.bbi.2006.10.00917129705 Search in Google Scholar
 Brand A, Richter-Landsberg C, Leibfritz D. Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 1993;15:289–98.10.1159/0001113477805581 Search in Google Scholar
 Widerstrom-Noga E, Pattany PM, Cruz-Almeida Y, Felix ER, Perez S, Cardenas DD, Martinez-Arizala A. Metabolite concentrations in the anterior cingulate cortex predict high neuropathic pain impact after spinal cord injury. Pain 2013;154:204–12.10.1016/j.pain.2012.07.02223141478 Search in Google Scholar
 Pattany PM, Yezierski RP, Widerstrom-Noga EG, Bowen BC, Martinez-Arizala A, Garcia BR, Quencer RM. Proton magnetic resonance spectroscopy of the thalamus in patients with chronic neuropathic pain after spinal cord injury. AJNR Am J Neuroradiol 2002;23:901–5.12063213 Search in Google Scholar
 Sartorius A, Vollmayr B, Neumann-Haefelin C, Ende G, Hoehn M, Henn FA. Specific creatine rise in learned helplessness induced by electroconvulsive shock treatment. Neuroreport 2003;14:2199–201.10.1097/00001756-200312020-0001314625447 Search in Google Scholar
 Ende G, Braus DF, Walter S, Weber-Fahr W, Henn FA. The hippocampus in patients treated with electroconvulsive therapy: a proton magnetic resonance spectroscopic imaging study. Arch Gen Psychiatry 2000;57:937–43.1101581110.1001/archpsyc.57.10.937 Search in Google Scholar
 Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 2009;10:895–926.10.1016/j.jpain.2009.06.01219712899 Search in Google Scholar
 Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, Fam AG, Farber SJ, Fiechtner JJ, Franklin CM, Gatter RA, Hamaty D, Lessard J, Lichtbroun AS, Masi AT, Mccain GA, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160–72.10.1002/art.17803302032306288 Search in Google Scholar
 Staud R, Cannon RC, Mauderli AP, Robinson ME, Price DD, Vierck CJ, Jr. Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome. Pain 2003;102:87–95.10.1016/s0304-3959(02)00344-512620600 Search in Google Scholar
 Cathcart S, Winefield AH, Rolan P, Lushington K. Reliability of temporal summation and diffuse noxious inhibitory control. Pain Res Manag 2009;14:433–8.2001171310.1155/2009/523098 Search in Google Scholar
 Lin CS. Brain signature of chronic orofacial pain: a systematic review and meta-analysis on neuroimaging research of trigeminal neuropathic pain and temporomandibular joint disorders. PLoS One 2014;9:e94300.2475979810.1371/journal.pone.0094300 Search in Google Scholar
 Raphael KG, Marbach JJ, Klausner J. Myofascial face pain. Clinical characteristics of those with regional vs. widespread pain. J Am Dent Assoc 2000;131:161–71.10680383 Search in Google Scholar
 Chen H, Slade G, Lim PF, Miller V, Maixner W, Diatchenko L. Relationship between temporomandibular disorders, widespread palpation tenderness, and multiple pain conditions: a case-control study. J Pain 2012;13: 1016–27.2303140110.1016/j.jpain.2012.07.011 Search in Google Scholar
 Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB, Yunus MB. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res 2010;62:600–10.10.1002/acr.20140 Search in Google Scholar
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