{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T01:20:59Z","timestamp":1791508859445,"version":"4.3.4"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T00:00:00Z","timestamp":1673568000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T00:00:00Z","timestamp":1673568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004756","name":"Emil Aaltosen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004756","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Fibromyalgia (FM) is associated with sympathetically dominant dysautonomia, but the connection between dysautonomia and FM symptoms is unclear. Dysautonomia can be analysed with heart rate variability (HRV) and it has been proposed that FM patients comprise subgroups with differing profiles of symptom severity. In our study, 51 female FM patients aged 18 to 65\u00a0years and 31 age-matched healthy female controls followed a 20-min protocol of alternating relaxation and cognitive stress (mental arithmetic). Heart rates and electrocardiograms were registered. The HRV measures of heart rate (HR), mean interval between heart beats (RR<jats:sub>mean<\/jats:sub>), root mean squared interval differences of successive beats (RMSSD), and the standard deviation of intervals between normal heart beats (SDNN) were analysed with generalized linear modelling. Features in HRV reactivity which differed between FM patients and controls were used to cluster the FM patients and cluster characteristics were analysed. FM patients had higher baseline HR (72.3 [SD 12.7] vs 64.5 [7.80], p\u2009&lt;\u20090.001) and lower RR<jats:sub>mean<\/jats:sub> (0.844 [0.134] vs 0.934 [0.118], p\u2009=\u20090.002), compared with controls. They also reacted to repeated cognitive stress with an attenuated rise in HR (\u2212\u20094.41 [95% CI\u2009\u2212\u20097.88\u00a0to\u2009\u2212\u20090.93], p\u2009=\u20090.013) and attenuated decrease of RR<jats:sub>mean<\/jats:sub> (0.06 [95 CI 0.03 to 0.09], p\u2009&lt;\u20090.001), compared with controls. Clustering of FM patients by HRV reactivity resulted in three clusters characterised by (1) normal levels of HRV and HRV reactivity with low levels of depressive mood and anxiety, (2) reduced levels of HRV and impaired HRV reactivity with increased levels of depressive mood and high levels of anxiety, and (3) lowest HRV and most impaired HRV reactivity with the highest scores for depressive mood and anxiety. Our results show that FM patients have lower HRV than healthy controls and their autonomous reactions to cognitive stress are attenuated. Dysautonomia in FM associates with mood disturbance.\n<\/jats:p><jats:p><jats:bold>Trial registration<\/jats:bold> ClinicalTrials.gov (NCT03300635). Registered October 3 2017\u2014Retrospectively registered, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03300635\">https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03300635<\/jats:ext-link>.<\/jats:p>","DOI":"10.1038\/s41598-023-27581-9","type":"journal-article","created":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T11:10:38Z","timestamp":1673608238000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Heart rate variability responses to cognitive stress in fibromyalgia are characterised by inadequate autonomous system stress responses: a clinical trial"],"prefix":"10.1038","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct03300635","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Teemu","family":"Zetterman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ritva","family":"Markkula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teemu","family":"Miettinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eija","family":"Kalso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,13]]},"reference":[{"issue":"2","key":"27581_CR1","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1002\/art.1780330203","volume":"33","author":"F Wolfe","year":"1990","unstructured":"Wolfe, F. et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 33(2), 160\u201372 (1990).","journal-title":"Arthritis Rheum."},{"issue":"1","key":"27581_CR2","doi-asserted-by":"publisher","first-page":"47","DOI":"10.20452\/pamw.3877","volume":"127","author":"W H\u00e4user","year":"2017","unstructured":"H\u00e4user, W., Ablin, J., Perrot, S. & Fitzcharles, M. A. Management of fibromyalgia: Key messages from recent evidence-based guidelines. Polish Arch. Intern. Med. 127(1), 47\u201356 (2017).","journal-title":"Polish Arch. Intern. Med."},{"issue":"11","key":"27581_CR3","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1007\/s00296-007-0403-9","volume":"27","author":"W M\u00fcller","year":"2007","unstructured":"M\u00fcller, W., Schneider, E. M. & Stratz, T. The classification of fibromyalgia syndrome. Rheumatol. Int. 27(11), 1005\u20131010 (2007).","journal-title":"Rheumatol. Int."},{"issue":"11","key":"27581_CR4","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1038\/s41584-020-00506-w","volume":"16","author":"P Sarzi-Puttini","year":"2020","unstructured":"Sarzi-Puttini, P., Giorgi, V., Marotto, D. & Atzeni, F. Fibromyalgia: An update on clinical characteristics, aetiopathogenesis and treatment. Nat. Rev. Rheumatol. 16(11), 645\u2013660 (2020).","journal-title":"Nat. Rev. Rheumatol."},{"issue":"3","key":"27581_CR5","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1097\/RHU.0000000000000089","volume":"20","author":"LA Mart\u00ednez-Mart\u00ednez","year":"2014","unstructured":"Mart\u00ednez-Mart\u00ednez, L. A., Mora, T., Vargas, A., Fuentes-Iniestra, M. & Mart\u00ednez-Lav\u00edn, M. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: A review of case-control studies. J. Clin. Rheumatol. 20(3), 146\u2013150 (2014).","journal-title":"J. Clin. Rheumatol."},{"issue":"9","key":"27581_CR6","first-page":"1787","volume":"32","author":"R Furlan","year":"2005","unstructured":"Furlan, R. et al. Abnormalities of cardiovascular neural control and reduced orthostatic tolerance in patients with primary fibromyalgia. J. Rheumatol. 32(9), 1787\u20131793 (2005).","journal-title":"J. Rheumatol."},{"issue":"579","key":"27581_CR7","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1016\/j.neubiorev.2020.02.007","volume":"112","author":"C Ying-Chih","year":"2020","unstructured":"Ying-Chih, C., Yu-Chen, H. & Wei-Lieh, H. Heart rate variability in patients with somatic symptom disorders and functional somatic syndromes: A systematic review and meta-analysis. Neurosci. Biobehav. Rev. 112(579), 336\u2013344 (2020).","journal-title":"Neurosci. Biobehav. Rev."},{"issue":"1","key":"27581_CR8","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.biopsycho.2013.01.012","volume":"93","author":"AJ Fisher","year":"2013","unstructured":"Fisher, A. J. & Newman, M. G. Heart rate and autonomic response to stress after experimental induction of worry versus relaxation in healthy, high-worry, and generalized anxiety disorder individuals. Biol. Psychol. 93(1), 65\u201374 (2013).","journal-title":"Biol. Psychol."},{"key":"27581_CR9","doi-asserted-by":"publisher","first-page":"258","DOI":"10.3389\/fpubh.2017.00258","volume":"5","author":"F Shaffer","year":"2017","unstructured":"Shaffer, F. & Ginsberg, J. P. An overview of heart rate variability metrics and norms. Front. Public Health 5, 258 (2017).","journal-title":"Front. Public Health"},{"issue":"2","key":"27581_CR10","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.bjpt.2019.02.006","volume":"24","author":"AM Catai","year":"2019","unstructured":"Catai, A. M. et al. Heart rate variability: Are you using it properly? Standardisation checklist of procedures. Braz. J. Phys. Ther. 24(2), 91\u2013102 (2019).","journal-title":"Braz. J. Phys. Ther."},{"issue":"5","key":"27581_CR11","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1097\/PSY.0b013e3181da91f1","volume":"72","author":"GA Reyes Del Paso","year":"2010","unstructured":"Reyes Del Paso, G. A., Garrido, S., Pulgar, \u00c1., Mart\u00edn-V\u00e1zquez, M. & Duschek, S. Aberrances in autonomic cardiovascular regulation in fibromyalgia syndrome and their relevance for clinical pain reports. Psychosom. Med. 72(5), 462\u2013470 (2010).","journal-title":"Psychosom. Med."},{"key":"27581_CR12","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.3389\/fphys.2018.01118","volume":"9","author":"CF Reyes-Manzano","year":"2018","unstructured":"Reyes-Manzano, C. F. et al. Multifractal analysis reveals decreased non-linearity and stronger anticorrelations in heart period fluctuations of fibromyalgia patients. Front. Physiol. 9, 1118 (2018).","journal-title":"Front. Physiol."},{"issue":"2","key":"27581_CR13","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.semarthrit.2013.03.004","volume":"43","author":"M Meeus","year":"2013","unstructured":"Meeus, M. et al. Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: A systematic review. Semin. Arthritis Rheum. 43(2), 279\u2013287 (2013).","journal-title":"Semin. Arthritis Rheum."},{"issue":"1","key":"27581_CR14","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1097\/j.pain.0000000000000360","volume":"157","author":"LM Tracy","year":"2016","unstructured":"Tracy, L. M. et al. Meta-analytic evidence for decreased heart rate variability in chronic pain implicating parasympathetic nervous system dysregulation. Pain 157(1), 7\u201329 (2016).","journal-title":"Pain"},{"issue":"2","key":"27581_CR15","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.jpain.2014.11.009","volume":"16","author":"K Thieme","year":"2015","unstructured":"Thieme, K., Turk, D. C., Gracely, R. H., Maixner, W. & Flor, H. The relationship among psychological and psychophysiological characteristics of fibromyalgia patients. J. Pain 16(2), 186\u2013196 (2015).","journal-title":"J. Pain"},{"issue":"1","key":"27581_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12891-021-04013-1","volume":"22","author":"T Zetterman","year":"2021","unstructured":"Zetterman, T. et al. Muscle activity and acute stress in fibromyalgia. BMC Musculoskelet. Disord. 22(1), 1\u201313 (2021).","journal-title":"BMC Musculoskelet. Disord."},{"issue":"5","key":"27581_CR17","first-page":"728","volume":"18","author":"CS Burckhardt","year":"1991","unstructured":"Burckhardt, C. S. & Clark, S. R. B. R. The fibromyalgia impact questionnaire: Development and validation. J. Rheumatol. 18(5), 728\u2013733 (1991).","journal-title":"J. Rheumatol."},{"issue":"1","key":"27581_CR18","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.sjpain.2011.10.004","volume":"3","author":"J Gauffin","year":"2012","unstructured":"Gauffin, J. et al. Validation of a finnish version of the fibromyalgia impact questionnaire (Finn-FIQ). Scand. J. Pain 3(1), 15\u201320 (2012).","journal-title":"Scand. J. Pain"},{"issue":"4","key":"27581_CR19","doi-asserted-by":"publisher","first-page":"385","DOI":"10.2307\/2136404","volume":"24","author":"S Cohen","year":"1983","unstructured":"Cohen, S., Kamarck, T. & Mermelstein, R. A global measure of perceived stress. J. Health Soc. Behav. 24(4), 385\u2013396 (1983).","journal-title":"J. Health Soc. Behav."},{"issue":"5","key":"27581_CR20","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.jpsychores.2006.07.004","volume":"61","author":"K Thieme","year":"2006","unstructured":"Thieme, K. et al. Psychophysiological responses in patients with fibromyalgia syndrome. J. Psychosom. Res. 61(5), 671\u2013679 (2006).","journal-title":"J. Psychosom. Res."},{"issue":"2","key":"27581_CR21","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1007\/s00357-006-0018-y","volume":"23","author":"W Qiu","year":"2006","unstructured":"Qiu, W. & Joe, H. Generation of random clusters with specified degree of separation. J. Classif. 23(2), 315\u2013334 (2006).","journal-title":"J. Classif."},{"key":"27581_CR22","unstructured":"Pinheiro, J., Bates, D., DebRoy, S., Sarkar, D. & Team RC. nlme: Linear and Nonlinear Mixed Effects Models. R Package Version 3.1-147. https:\/\/CRAN.R-project.org\/package=nlme (2021)."},{"key":"27581_CR23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphys.2019.00505","volume":"10","author":"T Adjei","year":"2019","unstructured":"Adjei, T., Von Rosenberg, W., Nakamura, T., Chanwimalueang, T. & Mandic, D. P. The ClassA framework: HRV based assessment of SNS and PNS dynamics without LF-HF controversies. Front. Physiol. 10, 1\u201315 (2019).","journal-title":"Front. Physiol."},{"key":"27581_CR24","volume-title":"Autonomic Nervous System Monitoring\u2014Heart Rate Variability","author":"G Minarini","year":"2020","unstructured":"Minarini, G. Root mean square of the successive differences as marker of the parasympathetic system and difference in the outcome after ANS stimulation. In Autonomic Nervous System Monitoring\u2014Heart Rate Variability (ed. Aslanidis, T.) (IntechOpen, 2020)."},{"issue":"19","key":"27581_CR25","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1177\/2047487319872567","volume":"27","author":"BS Tegegne","year":"2020","unstructured":"Tegegne, B. S., Man, T., van Roon, A. M., Snieder, H. & Riese, H. Reference values of heart rate variability from 10-second resting electrocardiograms: The lifelines cohort study. Eur. J. Prev. Cardiol. 27(19), 2191\u20132194 (2020).","journal-title":"Eur. J. Prev. Cardiol."},{"issue":"2","key":"27581_CR26","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1037\/a0035747","volume":"69","author":"DM Ehde","year":"2014","unstructured":"Ehde, D. M., Dillworth, T. M. & Turner, J. A. Cognitive-behavioral therapy for individuals with chronic pain: Efficacy, innovations, and directions for research. Am. Psychol. 69(2), 153\u2013166 (2014).","journal-title":"Am. Psychol."},{"issue":"9","key":"27581_CR27","doi-asserted-by":"publisher","first-page":"T1","DOI":"10.1016\/j.jpain.2016.02.010","volume":"17","author":"RH Dworkin","year":"2016","unstructured":"Dworkin, R. H. et al. Multidimensional diagnostic criteria for chronic pain: Introduction to the ACTTION\u2013American Pain Society Pain Taxonomy (AAPT). J. Pain 17(9), T1-9 (2016).","journal-title":"J. Pain"},{"issue":"12","key":"27581_CR28","doi-asserted-by":"publisher","first-page":"1948","DOI":"10.1017\/S0033291719001351","volume":"49","author":"C Koch","year":"2019","unstructured":"Koch, C., Wilhelm, M., Salzmann, S., Rief, W. & Euteneuer, F. A meta-Analysis of heart rate variability in major depression. Psychol. Med. 49(12), 1948\u20131957 (2019).","journal-title":"Psychol. Med."},{"issue":"9","key":"27581_CR29","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1111\/psyp.12455","volume":"52","author":"GF Lewis","year":"2015","unstructured":"Lewis, G. F. et al. Relaxation training assisted by heart rate variability biofeedback: Implication for a military predeployment stress inoculation protocol. Psychophysiology 52(9), 1167\u20131174 (2015).","journal-title":"Psychophysiology"},{"issue":"3\u20134","key":"27581_CR30","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.jpain.2019.07.003","volume":"21","author":"AL Adler-Neal","year":"2020","unstructured":"Adler-Neal, A. L. et al. The role of heart rate variability in mindfulness-based pain relief. J. Pain 21(3\u20134), 306\u2013323 (2020).","journal-title":"J. Pain"},{"key":"27581_CR31","doi-asserted-by":"publisher","first-page":"2072","DOI":"10.1097\/j.pain.0000000000000273","volume":"156","author":"CB Meloto","year":"2015","unstructured":"Meloto, C. B. et al. COMT gene locus: New functional variants. Pain 156, 2072\u20132083 (2015).","journal-title":"Pain"},{"issue":"5","key":"27581_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/ar2316","volume":"9","author":"G Vargas-Alarc\u00f3n","year":"2007","unstructured":"Vargas-Alarc\u00f3n, G. et al. Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia. Arthritis Res. Ther. 9(5), 1\u20137 (2007).","journal-title":"Arthritis Res. Ther."},{"key":"27581_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphys.2018.01616","volume":"9","author":"T Adjei","year":"2018","unstructured":"Adjei, T., Xue, J. & Mandic, D. P. The female heart: Sex differences in the dynamics of ECG in response to stress. Front. Physiol. 9, 1\u20138 (2018).","journal-title":"Front. Physiol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-27581-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-27581-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-27581-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T11:19:46Z","timestamp":1673608786000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-27581-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,13]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["27581"],"URL":"https:\/\/doi.org\/10.1038\/s41598-023-27581-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,13]]},"assertion":[{"value":"15 January 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 January 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 January 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Eija Kalso has served on the advisory boards of Orion Pharma and Pfizer. The other authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"700"}}