{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:22:05Z","timestamp":1790688125042,"version":"4.1.0"},"reference-count":113,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K09003"],"award-info":[{"award-number":["21K09003"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"award":["21K09003"],"award-info":[{"award-number":["21K09003"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fibromyalgia represents a complex chronic pain condition in which patients experience widespread pain accompanied by fatigue and a broad range of physical and psychological symptoms. Diagnosis relies on symptom-based diagnostic criteria that lack objectivity, making it difficult to properly diagnose and treat. The etiology of fibromyalgia is thought to be multifactorial, including neurobiological, psychological, environmental, and genetic factors. In addition to pain, many patients experience central nervous system-related symptoms, such as fatigue, sleep disturbances, cognitive impairment, anxiety, and depression. Fibromyalgia has recently been recognized as a nociplastic pain disorder. Alterations in sensory processing and pain thresholds in the central nervous system may result in the perception of widespread pain throughout the body. In a recent study, we divided fibromyalgia patients who reported widespread pain into two subgroups based on their pain threshold: a low pain threshold group and a normal pain threshold group. We comparably analyzed these subgroups by using resting-state functional magnetic resonance imaging. This hypothesis article provides an overview of the pathogenesis of fibromyalgia and discusses these two subgroups of nociplastic pain. Recognizing the various pathophysiologies of fibromyalgia will allow us to better understand patients\u2019 conditions and select appropriate treatment options for each patient.<\/jats:p>","DOI":"10.3390\/ijms27114813","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T12:31:56Z","timestamp":1779885116000},"page":"4813","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Fibromyalgia: A Multifactorial Pain Disorder"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2729-9394","authenticated-orcid":false,"given":"Tomohiko","family":"Aoe","sequence":"first","affiliation":[{"name":"Pain Center, Chiba Medical Center, Teikyo University, Ichihara 299-0111, Japan"},{"name":"Pain Clinic, Sanmu Medical Center, Sanmu 289-1326, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1002\/acr.20140","article-title":"The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity","volume":"62","author":"Wolfe","year":"2010","journal-title":"Arthritis Care Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e010364","DOI":"10.1136\/bmjopen-2015-010364","article-title":"Prevalence of chronic pain in the UK: A systematic review and meta-analysis of population studies","volume":"6","author":"Fayaz","year":"2016","journal-title":"BMJ Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1002\/acr.22277","article-title":"An epidemiologic internet survey of fibromyalgia and chronic pain in Japan","volume":"66","author":"Nakamura","year":"2014","journal-title":"Arthritis Care Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1007\/s00296-017-3725-2","article-title":"Prevalence of fibromyalgia in general population and patients, a systematic review and meta-analysis","volume":"37","author":"Heidari","year":"2017","journal-title":"Rheumatol. Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1002\/art.1780330203","article-title":"The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee","volume":"33","author":"Wolfe","year":"1990","journal-title":"Arthritis Rheum."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.semarthrit.2016.08.012","article-title":"2016 Revisions to the 2010\/2011 fibromyalgia diagnostic criteria","volume":"46","author":"Wolfe","year":"2016","journal-title":"Semin Arthritis Rheum."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1002\/acr.24202","article-title":"Modified 2016 American College of Rheumatology Fibromyalgia Criteria, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks-American Pain Society Pain Taxonomy, and the Prevalence of Fibromyalgia","volume":"73","author":"Hauser","year":"2021","journal-title":"Arthritis Care Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1097\/j.pain.0000000000000507","article-title":"Do we need a third mechanistic descriptor for chronic pain states?","volume":"157","author":"Kosek","year":"2016","journal-title":"Pain"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1097\/j.pain.0000000000001939","article-title":"The revised International Association for the Study of Pain definition of pain: Concepts, challenges, and compromises","volume":"161","author":"Raja","year":"2020","journal-title":"Pain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1080\/03007995.2018.1552042","article-title":"Current understanding of the mixed pain concept: A brief narrative review","volume":"35","author":"Freynhagen","year":"2019","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1016\/S0140-6736(21)00392-5","article-title":"Nociplastic pain: Towards an understanding of prevalent pain conditions","volume":"397","author":"Fitzcharles","year":"2021","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1136\/ard-2023-225327","article-title":"From fibrositis to fibromyalgia to nociplastic pain: How rheumatology helped get us here and where do we go from here?","volume":"83","author":"Clauw","year":"2024","journal-title":"Ann. Rheum. Dis."},{"key":"ref_13","first-page":"814","article-title":"Fibrositis (Fibromyalgia) in rheumatoid arthritis","volume":"11","author":"Wolfe","year":"1984","journal-title":"J. Rheumatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.autrev.2008.07.023","article-title":"Etiology of fibromyalgia: The possible role of infection and vaccination","volume":"8","author":"Buskila","year":"2008","journal-title":"Autoimmun. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ryabkova, V.A., Gavrilova, N.Y., Poletaeva, A.A., Pukhalenko, A.I., Koshkina, I.A., Churilov, L.P., and Shoenfeld, Y. (2023). Autoantibody Correlation Signatures in Fibromyalgia and Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: Association with Symptom Severity. Biomedicines, 11.","DOI":"10.3390\/biomedicines11020257"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1097\/j.pain.0000000000003535","article-title":"Autoantibodies in patients with fibromyalgia syndrome","volume":"166","author":"Seefried","year":"2025","journal-title":"Pain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e144201","DOI":"10.1172\/JCI144201","article-title":"Passive transfer of fibromyalgia symptoms from patients to mice","volume":"131","author":"Goebel","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1097\/j.pain.0000000000002881","article-title":"Fibromyalgia patients with elevated levels of anti-satellite glia cell immunoglobulin G antibodies present with more severe symptoms","volume":"164","author":"Krock","year":"2023","journal-title":"Pain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1097\/SPC.0000000000000355","article-title":"Muscle pain syndromes and fibromyalgia: The role of muscle biopsy","volume":"12","author":"Ruggiero","year":"2018","journal-title":"Curr. Opin. Support. Palliat. Care"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gerdle, B., Ghafouri, B., Lund, E., Bengtsson, A., Lundberg, P., Ettinger-Veenstra, H.V., Leinhard, O.D., and Forsgren, M.F. (2020). Evidence of Mitochondrial Dysfunction in Fibromyalgia: Deviating Muscle Energy Metabolism Detected Using Microdialysis and Magnetic Resonance. J. Clin. Med., 9.","DOI":"10.3390\/jcm9113527"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"30247","DOI":"10.1038\/s41598-024-81298-x","article-title":"Mitochondrial function in patients affected with fibromyalgia syndrome is impaired and correlates with disease severity","volume":"14","author":"Macchi","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1002\/art.1780371106","article-title":"Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome","volume":"37","author":"Russell","year":"1994","journal-title":"Arthritis Rheum."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"463","DOI":"10.46497\/ArchRheumatol.2020.7783","article-title":"Serum Calcitonin Gene-Related Peptide and Receptor Protein Levels in Patients With Fibromyalgia Syndrome: A Cross-Sectional Study","volume":"35","author":"Korucu","year":"2020","journal-title":"Arch. Rheumatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s00281-018-0672-2","article-title":"Neurogenic inflammation in fibromyalgia","volume":"40","author":"Littlejohn","year":"2018","journal-title":"Semin. Immunopathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/art.37763","article-title":"Association of fibromyalgia with altered skeletal muscle characteristics which may contribute to postexertional fatigue in postmenopausal women","volume":"65","author":"Srikuea","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Aloisi, A.M., and Casini, I. (2025). Fibromyalgia: Chronic Pain Due to a Blood Dysfunction?. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26094153"},{"key":"ref_27","first-page":"483","article-title":"Is Fibromyalgia a Nociplastic or a Mixed-pain Condition? International, Multidisciplinary Recommendations for Pain Phenotyping in Fibromyalgia Syndrome","volume":"28","author":"Saracoglu","year":"2025","journal-title":"Pain Physician"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/S0049-0172(96)80011-4","article-title":"Familial aggregation in the fibromyalgia syndrome","volume":"26","author":"Buskila","year":"1996","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/art.20042","article-title":"Family study of fibromyalgia","volume":"50","author":"Arnold","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1002\/art.10103","article-title":"Confirmation of an association between fibromyalgia and serotonin transporter promoter region (5- HTTLPR) polymorphism, and relationship to anxiety-related personality traits","volume":"46","author":"Cohen","year":"2002","journal-title":"Arthritis Rheum."},{"key":"ref_31","first-page":"1002","article-title":"Association of catechol-O-methyltransferase Val158Met polymorphism with fibromyalgia risk and FIQ scores: An updated meta-analysis","volume":"43","author":"Lee","year":"2025","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/sj.mp.4001568","article-title":"An association between fibromyalgia and the dopamine D4 receptor exon III repeat polymorphism and relationship to novelty seeking personality traits","volume":"9","author":"Buskila","year":"2004","journal-title":"Mol. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.pain.2014.02.016","article-title":"Genome-wide analysis of single nucleotide polymorphisms and copy number variants in fibromyalgia suggest a role for the central nervous system","volume":"155","author":"Docampo","year":"2014","journal-title":"Pain"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ovrom, E.A., Mostert, K.A., Khakhkhar, S., McKee, D.P., Yang, P., and Her, Y.F. (2023). A Comprehensive Review of the Genetic and Epigenetic Contributions to the Development of Fibromyalgia. Biomedicines, 11.","DOI":"10.3390\/biomedicines11041119"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1744806918819944","DOI":"10.1177\/1744806918819944","article-title":"Fibromyalgia: Genetics and epigenetics insights may provide the basis for the development of diagnostic biomarkers","volume":"15","author":"Gerra","year":"2019","journal-title":"Mol. Pain"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1097\/j.pain.0000000000000932","article-title":"Epigenetics insights into chronic pain: DNA hypomethylation in fibromyalgia-a controlled pilot-study","volume":"158","author":"Maschietto","year":"2017","journal-title":"Pain"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2978","DOI":"10.1038\/ncomms3978","article-title":"Differential methylation of the TRPA1 promoter in pain sensitivity","volume":"5","author":"Bell","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1016\/j.pain.2013.06.001","article-title":"Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia","volume":"154","author":"Oaklander","year":"2013","journal-title":"Pain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/j.semarthrit.2018.08.003","article-title":"A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: Implications for a new paradigm in fibromyalgia etiopathogenesis","volume":"48","author":"Grayston","year":"2019","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Galosi, E., Truini, A., and Di Stefano, G. (2022). A Systematic Review and Meta-Analysis of the Prevalence of Small Fibre Impairment in Patients with Fibromyalgia. Diagnostics, 12.","DOI":"10.3390\/diagnostics12051135"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e1220","DOI":"10.1097\/PR9.0000000000001220","article-title":"Small fiber pathology in fibromyalgia syndrome","volume":"10","author":"Sommer","year":"2025","journal-title":"Pain Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1093\/brain\/awt053","article-title":"Small fibre pathology in patients with fibromyalgia syndrome","volume":"136","author":"Uceyler","year":"2013","journal-title":"Brain"},{"key":"ref_43","first-page":"1564","article-title":"Increased concentrations of nerve growth factor in cerebrospinal fluid of patients with fibromyalgia","volume":"26","author":"Giovengo","year":"1999","journal-title":"J. Rheumatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.2147\/JPR.S247472","article-title":"Nerve Growth Factor Signaling and Its Contribution to Pain","volume":"13","author":"Barker","year":"2020","journal-title":"J. Pain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1007\/s12035-020-02156-1","article-title":"NGF-Induced Nav1.7 Upregulation Contributes to Chronic Post-surgical Pain by Activating SGK1-Dependent Nedd4-2 Phosphorylation","volume":"58","author":"Liu","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3432","DOI":"10.1021\/acsami.6b14691","article-title":"Sustained Local Release of NGF from a Chitosan-Sericin Composite Scaffold for Treating Chronic Nerve Compression","volume":"9","author":"Zhang","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Favretti, M., Iannuccelli, C., and Di Franco, M. (2023). Pain Biomarkers in Fibromyalgia Syndrome: Current Understanding and Future Directions. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310443"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1056\/NEJMra1507771","article-title":"Opioid Abuse in Chronic Pain--Misconceptions and Mitigation Strategies","volume":"374","author":"Volkow","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1056\/NEJMp1801417","article-title":"Suicide: A Silent Contributor to Opioid-Overdose Deaths","volume":"378","author":"Oquendo","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/S0140-6736(19)30430-1","article-title":"Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia","volume":"393","author":"Colvin","year":"2019","journal-title":"Lancet"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1097\/j.pain.0000000000000633","article-title":"Endogenous opioidergic dysregulation of pain in fibromyalgia: A PET and fMRI study","volume":"157","author":"Schrepf","year":"2016","journal-title":"Pain"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Coulombe, M.A., Lawrence, K.S., Moulin, D.E., Morley-Forster, P., Shokouhi, M., Nielson, W.R., and Davis, K.D. (2017). Lower Functional Connectivity of the Periaqueductal Gray Is Related to Negative Affect and Clinical Manifestations of Fibromyalgia. Front. Neuroanat., 11.","DOI":"10.3389\/fnana.2017.00047"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.bbi.2018.09.018","article-title":"Brain glial activation in fibromyalgia\u2014A multi-site positron emission tomography investigation","volume":"75","author":"Albrecht","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Seo, S., Jung, Y.H., Lee, D., Lee, W.J., Jang, J.H., Lee, J.Y., Choi, S.H., Moon, J.Y., Lee, J.S., and Cheon, G.J. (2021). Abnormal neuroinflammation in fibromyalgia and CRPS using [11C]-(R)-PK11195 PET. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0246152"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"942","DOI":"10.3899\/jrheum.211170","article-title":"Microstructural Evidence of Neuroinflammation for Psychological Symptoms and Pain in Patients with Fibromyalgia","volume":"49","author":"Lo","year":"2022","journal-title":"J. Rheumatol."},{"key":"ref_56","first-page":"225","article-title":"Cytokine patterns in fibromyalgia and their correlation with clinical manifestations","volume":"25","author":"Bazzichi","year":"2007","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.imlet.2014.01.009","article-title":"Fibromyalgia and cytokines","volume":"161","author":"Howard","year":"2014","journal-title":"Immunol. Lett."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"515","DOI":"10.2147\/JPR.S128508","article-title":"Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma","volume":"10","author":"Backryd","year":"2017","journal-title":"J. Pain Res."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Ryabkova, V.A., Churilov, L.P., and Shoenfeld, Y. (2019). Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination?. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205164"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e2024358118","DOI":"10.1073\/pnas.2024358118","article-title":"Redox imbalance links COVID-19 and myalgic encephalomyelitis\/chronic fatigue syndrome","volume":"118","author":"Paul","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1001\/archinte.159.8.865","article-title":"A prospective study of tender points and fibromyalgia during and after an acute viral infection","volume":"159","author":"Rea","year":"1999","journal-title":"Arch. Intern. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41579-022-00846-2","article-title":"Long COVID: Major findings, mechanisms and recommendations","volume":"21","author":"Davis","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"152455","DOI":"10.1016\/j.semarthrit.2024.152455","article-title":"How to understand the overlap of long COVID, chronic fatigue syndrome\/myalgic encephalomyelitis, fibromyalgia and irritable bowel syndromes","volume":"67","author":"Goldenberg","year":"2024","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Mantle, D., Hargreaves, I.P., Domingo, J.C., and Castro-Marrero, J. (2024). Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010574"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Proal, A.D., and VanElzakker, M.B. (2021). Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.698169"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"(2015). Beyond Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: Redefining an Illness. Mil. Med., 180, 721\u2013723.","DOI":"10.7205\/MILMED-D-15-00085"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.clinthera.2018.12.016","article-title":"Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome and Fibromyalgia: Definitions, Similarities, and Differences","volume":"41","author":"Natelson","year":"2019","journal-title":"Clin. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Wang, E.Y., Mao, T., Klein, J., Dai, Y., Huck, J.D., Liu, F., Zheng, N.S., Zhou, T., Israelow, B., and Wong, P. (2021). Diverse Functional Autoantibodies in Patients with COVID-19. medRxiv.","DOI":"10.1038\/s41586-021-03631-y"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1002\/jmv.26549","article-title":"Human herpesvirus-6, -7, and Epstein-Barr virus reactivation in pityriasis rosea during COVID-19","volume":"93","author":"Drago","year":"2021","journal-title":"J. Med. Virol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Findeisen, K., Guymer, E., and Littlejohn, G. (2025). Neuroinflammatory and Immunological Aspects of Fibromyalgia. Brain Sci., 15.","DOI":"10.3390\/brainsci15020206"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Kawanaka, R., Jin, H., and Aoe, T. (2024). Unraveling the Connection: Pain and Endoplasmic Reticulum Stress. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25094995"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1021\/acschemneuro.0c00793","article-title":"Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis","volume":"12","author":"Yong","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1097\/j.pain.0000000000001480","article-title":"Functional and neurochemical disruptions of brain hub topology in chronic pain","volume":"160","author":"Kaplan","year":"2019","journal-title":"Pain"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"15486","DOI":"10.1038\/s41598-019-51990-4","article-title":"Functional connectivity of music-induced analgesia in fibromyalgia","volume":"9","author":"Barrios","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1002\/art.39043","article-title":"The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical\/autonomic dysfunction","volume":"67","author":"Kim","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"10197","DOI":"10.1038\/s41598-024-60993-9","article-title":"Functional connectivity associated with attention networks differs among subgroups of fibromyalgia patients: An observational case-control study","volume":"14","author":"Aoe","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3146","DOI":"10.1002\/art.24849","article-title":"Elevated insular glutamate in fibromyalgia is associated with experimental pain","volume":"60","author":"Harris","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"635.e1","DOI":"10.1016\/j.jpain.2018.01.001","article-title":"Resting Functional Connectivity of the Periaqueductal Gray Is Associated With Normal Inhibition and Pathological Facilitation in Conditioned Pain Modulation","volume":"19","author":"Harper","year":"2018","journal-title":"J. Pain"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Carneiro, B.D., Torres, S., Costa-Pereira, J.T., Pozza, D.H., and Tavares, I. (2025). Descending Pain Modulation in Fibromyalgia: A Short Review of Mechanisms and Biomarkers. Diagnostics, 15.","DOI":"10.3390\/diagnostics15212702"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/art.1780350509","article-title":"Cerebrospinal fluid biogenic amine metabolites in fibromyalgia\/fibrositis syndrome and rheumatoid arthritis","volume":"35","author":"Russell","year":"1992","journal-title":"Arthritis Rheum."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1001\/jama.2014.3266","article-title":"Fibromyalgia: A clinical review","volume":"311","author":"Clauw","year":"2014","journal-title":"JAMA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2974","DOI":"10.1002\/art.20485","article-title":"A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder","volume":"50","author":"Arnold","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"15022","DOI":"10.1038\/nrdp.2015.22","article-title":"Fibromyalgia","volume":"1","author":"Hauser","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1097\/00006842-199711000-00002","article-title":"Psychosocial factors in fibromyalgia compared with rheumatoid arthritis: I. Psychiatric diagnoses and functional disability","volume":"59","author":"Walker","year":"1997","journal-title":"Psychosom. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1002\/acr.23192","article-title":"Clinical Profiles of Young Adults With Juvenile-Onset Fibromyalgia With and Without a History of Trauma","volume":"69","author":"Nelson","year":"2017","journal-title":"Arthritis Care Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e839","DOI":"10.1097\/PR9.0000000000000839","article-title":"Adverse childhood experiences and chronic pain among children and adolescents in the United States","volume":"5","author":"Groenewald","year":"2020","journal-title":"Pain Rep."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Amezqueta, J., and Garcia Gonzalez, J.N. (2025). Anxiety and Depression Scales in Patients with Fibromyalgia: Correlation with Disease Symptomatology. J. Clin. Med., 14.","DOI":"10.3390\/jcm14165867"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Doreste, A., Pujol, J., Penelo, E., Perez, V., Blanco-Hinojo, L., Martinez-Vilavella, G., Pardina-Torner, H., Ojeda, F., Monfort, J., and Deus, J. (2024). Exploring the psychopathological profile of fibromyalgia: Insights from the personality assessment inventory and its association with disease impact. Front. Psychol., 15.","DOI":"10.3389\/fpsyg.2024.1418644"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1002\/ejp.2223","article-title":"A two-component model of hair cortisol concentration in fibromyalgia: Independent effects of pain chronicity and severity","volume":"28","author":"Montoro","year":"2024","journal-title":"Eur. J. Pain"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.pain.2009.05.020","article-title":"Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: A randomized, double-blind, placebo-controlled study","volume":"145","author":"Staud","year":"2009","journal-title":"Pain"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s11926-011-0206-6","article-title":"Evidence for shared pain mechanisms in osteoarthritis, low back pain, and fibromyalgia","volume":"13","author":"Staud","year":"2011","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/BOR.0000000000000929","article-title":"Fibromyalgia and centralized pain in the rheumatoid arthritis patient","volume":"35","author":"Minhas","year":"2023","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Kawanaka, R., Sakuma, S., Kokubun, H., Tetsu, S., Tagaito, Y., Igarashi, T., Liang, S.G., and Aoe, T. (2022). Effects of Intraoperative Opioid Administration on Postoperative Pain and Pain Threshold: A Randomized Controlled Study. J. Clin. Med., 11.","DOI":"10.3390\/jcm11195587"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.pneurobio.2010.10.005","article-title":"The pain matrix reloaded: A salience detection system for the body","volume":"93","author":"Legrain","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1093\/cercor\/bhi105","article-title":"The human parietal operculum. I. Cytoarchitectonic mapping of subdivisions","volume":"16","author":"Eickhoff","year":"2006","journal-title":"Cereb. Cortex"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.neulet.2018.11.042","article-title":"The posterior insular-opercular cortex: An access to the brain networks of thermosensory and nociceptive processes?","volume":"702","author":"Peyron","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nrn755","article-title":"Control of goal-directed and stimulus-driven attention in the brain","volume":"3","author":"Corbetta","year":"2002","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.neuron.2008.04.017","article-title":"The reorienting system of the human brain: From environment to theory of mind","volume":"58","author":"Corbetta","year":"2008","journal-title":"Neuron"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.pain.2009.03.020","article-title":"A neurocognitive model of attention to pain: Behavioral and neuroimaging evidence","volume":"144","author":"Legrain","year":"2009","journal-title":"Pain"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.cortex.2017.01.010","article-title":"Attention to pain! A neurocognitive perspective on attentional modulation of pain in neuroimaging studies","volume":"89","author":"Torta","year":"2017","journal-title":"Cortex"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"136967","DOI":"10.1016\/j.neulet.2022.136967","article-title":"Functional connectivity across dorsal and ventral attention networks in response to task difficulty and experimental pain","volume":"793","author":"Fairclough","year":"2023","journal-title":"Neurosci. Lett."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1097\/01.NAJ.0000476162.13177.ae","article-title":"Fibromyalgia Syndrome: Current Considerations in Symptom Management","volume":"116","author":"Menzies","year":"2016","journal-title":"Am. J. Nurs."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"101416","DOI":"10.1016\/j.berh.2019.05.001","article-title":"Psychological therapies for chronic widespread pain and fibromyalgia syndrome","volume":"33","author":"Hauser","year":"2019","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Jones, E.A., Asaad, F., Patel, N., Jain, E., and Abd-Elsayed, A. (2024). Management of Fibromyalgia: An Update. Biomedicines, 12.","DOI":"10.3390\/biomedicines12061266"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Carneiro, B.D., Pozza, D.H., and Tavares, I. (2025). Can Gratitude Ease the Burden of Fibromyalgia? A Systematic Review. Behav. Sci., 15.","DOI":"10.3390\/bs15081079"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Taylor, T.L., Dodds, F., Tharpe, M., Zumbro, E.L., Hankes, M., Jones, R., Rumble, D., Antoine, L., Allen-Watts, K., and Sims, A. (2024). The potential impact of exercise on affect and neuroinflammation in older adults living with fibromyalgia: A scoping review. Front. Hum. Neurosci., 18.","DOI":"10.3389\/fnhum.2024.1463935"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"76","DOI":"10.23736\/S1973-9087.21.06432-7","article-title":"Multidisciplinary rehabilitation treatments for patients with fibromyalgia: A systematic review","volume":"58","author":"Lladser","year":"2022","journal-title":"Eur. J. Phys. Rehabil. Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/biof.1293","article-title":"Ubiquinol-10 supplementation improves autonomic nervous function and cognitive function in chronic fatigue syndrome","volume":"42","author":"Fukuda","year":"2016","journal-title":"Biofactors"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1089\/ars.2013.5260","article-title":"Can coenzyme q10 improve clinical and molecular parameters in fibromyalgia?","volume":"19","author":"Cordero","year":"2013","journal-title":"Antioxid. Redox Signal"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/j.1600-079X.2010.00836.x","article-title":"Adjuvant use of melatonin for treatment of fibromyalgia","volume":"50","author":"Hussain","year":"2011","journal-title":"J. Pineal Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1080\/17512433.2022.2081151","article-title":"The efficacy of vitamin D in treatment of fibromyalgia: A meta-analysis of randomized controlled studies and systematic review","volume":"15","author":"Qu","year":"2022","journal-title":"Expert. Rev. Clin. Pharmacol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1007\/s11916-024-01277-9","article-title":"Pharmacological Treatment of Fibromyalgia Syndrome: A Practice-Based Review","volume":"28","author":"Giorgi","year":"2024","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Wolfe, F., Walitt, B., Perrot, S., Rasker, J.J., and Hauser, W. (2018). Fibromyalgia diagnosis and biased assessment: Sex, prevalence and bias. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203755"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4813\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T12:35:52Z","timestamp":1779885352000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4813"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,27]]},"references-count":113,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27114813"],"URL":"https:\/\/doi.org\/10.3390\/ijms27114813","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,27]]}}}