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Emotion regulation and the salience network: a hypothetical integrative model of fibromyalgia

Abstract

Fibromyalgia is characterized by widespread pain, fatigue, sleep disturbances and other symptoms, and has a substantial socioeconomic impact. Current biomedical and psychosocial treatments are unsatisfactory for many patients, and treatment progress has been hindered by the lack of a clear understanding of the pathogenesis of fibromyalgia. We present here a model of fibromyalgia that integrates current psychosocial and neurophysiological observations. We propose that an imbalance in emotion regulation, reflected by an overactive ‘threat’ system and underactive ‘soothing’ system, might keep the ‘salience network’ (also known as the midcingulo-insular network) in continuous alert mode, and this hyperactivation, in conjunction with other mechanisms, contributes to fibromyalgia. This proposed integrative model, which we term the Fibromyalgia: Imbalance of Threat and Soothing Systems (FITSS) model, should be viewed as a working hypothesis with limited supporting evidence available. We hope, however, that this model will shed new light on existing psychosocial and biological observations, and inspire future research to address the many gaps in our knowledge about fibromyalgia, ultimately stimulating the development of novel therapeutic interventions.

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Fig. 1: Potential pathophysiological processes in fibromyalgia.
Fig. 2: Central sensitivity syndromes and chronic overlapping pain conditions.
Fig. 3: The threat–safeness (im)balance model of fibromyalgia.
Fig. 4: An integrative model of fibromyalgia.
Fig. 5: Development of threat–safeness (im)balance and opportunities for intervention.

References

  1. Harris, R. E. & Clauw, D. J. How do we know that the pain in fibromyalgia is “real”? Curr. Pain. Headache Rep. 10, 403–407 (2006).

    Article  Google Scholar 

  2. Borchers, A. T. & Gershwin, M. E. Fibromyalgia: a critical and comprehensive review. Clin. Rev. Allergy Immunol. 49, 100–151 (2015).

    Article  CAS  Google Scholar 

  3. Häuser, W. et al. Fibromyalgia. Nat. Rev. Dis. Prim. 1, 15022 (2015).

    Article  Google Scholar 

  4. Sarzi-Puttini, P., Giorgi, V., Marotto, D. & Atzeni, F. Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment. Nat. Rev. Rheumatol. 16, 645–660 (2020).

    Article  Google Scholar 

  5. Clauw, D. J., Arnold, L. M. & McCarberg, B. H. The science of fibromyalgia. Mayo Clin. Proc. 86, 907–911 (2011).

    Article  Google Scholar 

  6. Woolf, C. J. Pain amplification — a perspective on the how, why, when, and where of central sensitization. J. Appl. Biobehav. Res. 23, e12124 (2018).

    Article  Google Scholar 

  7. Häuser, W., Walitt, B., Fitzcharles, M. A. & Sommer, C. Review of pharmacological therapies in fibromyalgia syndrome. Arthritis Res. Ther. 16, 201 (2014).

    Article  Google Scholar 

  8. Nüesch, E., Häuser, W., Bernardy, K., Barth, J. & Juni, P. Comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia syndrome: network meta-analysis. Ann. Rheum. Dis. 72, 955–962 (2013).

    Article  Google Scholar 

  9. Gilbert, P. Defence and safety: their function in social behaviour and psychopathology. Br. J. Clin. Psychol. 32, 131–153 (1993).

    Article  CAS  Google Scholar 

  10. Gilbert, P. Compassion: Conceptualisations, Research and Use in Psychotherapy (Routledge, 2005).

  11. Sluka, K. A. & Clauw, D. J. Neurobiology of fibromyalgia and chronic widespread pain. Neuroscience 338, 114–129 (2016).

    Article  CAS  Google Scholar 

  12. Littlejohn, G. Neurogenic neuroinflammation in fibromyalgia and complex regional pain syndrome. Nat. Rev. Rheumatol. 11, 639–648 (2015).

    Article  CAS  Google Scholar 

  13. Harte, S. E., Harris, R. E. & Clauw, D. J. The neurobiology of central sensitization. J. Appl. Biobehav. Res. 23, e12137 (2018).

    Article  Google Scholar 

  14. Pinto, A. M. et al. An updated overview of the neurophysiological and psychosocial dimensions of fibromyalgia — a call for an integrative model. Preprint at https://www.preprints.org/manuscript/202007.0224/v1 (2020).

  15. Kato, K., Sullivan, P. F., Evengård, B. & Pedersen, N. L. Importance of genetic influences on chronic widespread pain. Arthritis Rheum. 54, 1682–1686 (2006).

    Article  CAS  Google Scholar 

  16. Ablin, J. N. & Buskila, D. Update on the genetics of the fibromyalgia syndrome. Best. Pract. Res. Clin. Rheumatol. 29, 20–28 (2015).

    Article  Google Scholar 

  17. Park, D. J. & Lee, S. S. New insights into the genetics of fibromyalgia. Korean J. Intern. Med. 32, 984–995 (2017).

    Article  CAS  Google Scholar 

  18. D’Agnelli, S. et al. Fibromyalgia: genetics and epigenetics insights may provide the basis for the development of diagnostic biomarkers. Mol. Pain. 15, 1744806918819944 (2019).

    Article  Google Scholar 

  19. Veasley, C. et al. Impact of chronic overlapping pain conditions on public health and the urgent need for safe and effective treatment: 2015 analysis and policy recommendations. http://www.chronicpainresearch.org/public/CPRA_WhitePaper_2015-FINAL-Digital.pdf (2015).

  20. Maixner, W., Fillingim, R. B., Williams, D. A., Smith, S. B. & Slade, G. D. Overlapping chronic pain conditions: implications for diagnosis and classification. J. Pain. 17, T93–T107 (2016).

    Article  Google Scholar 

  21. Schrepf, A. et al. ICD-10 codes for the study of chronic overlapping pain conditions in administrative databases. J. Pain. 21, 59–70 (2020).

    Article  Google Scholar 

  22. Veasley, C. in Fibromyalgia Syndrome and Widespread Pain: From Construction to Relevant Recognition (eds Häuser, W. & Perrot, S.) 87–111 (Wolters Kluwer Health, 2018).

  23. Nicholas, M. et al. The IASP classification of chronic pain for ICD-11: chronic primary pain. Pain 160, 28–37 (2019).

    Article  Google Scholar 

  24. Yunus, M. B. Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness. Semin. Arthritis Rheum. 37, 339–352 (2008).

    Article  Google Scholar 

  25. Melzack, R. From the gate to the neuromatrix. Pain Suppl 6, S121–S126 (1999).

    Article  Google Scholar 

  26. Melzack, R. Pain and the neuromatrix in the brain. J. Dent. Educ. 65, 1378–1382 (2001).

    Article  CAS  Google Scholar 

  27. Apkarian, A. V., Bushnell, M. C., Treede, R. D. & Zubieta, J. K. Human brain mechanisms of pain perception and regulation in health and disease. Eur. J. Pain. 9, 463–484 (2005).

    Article  Google Scholar 

  28. Brosschot, J. F., Verkuil, B. & Thayer, J. F. The default response to uncertainty and the importance of perceived safety in anxiety and stress: an evolution-theoretical perspective. J. Anxiety Disord. 41, 22–34 (2016).

    Article  Google Scholar 

  29. Brosschot, J. F., Verkuil, B. & Thayer, J. F. Generalized unsafety theory of stress: unsafe environments and conditions, and the default stress response. Int. J. Environ. Res. Public Health 15, 464 (2018).

    Article  Google Scholar 

  30. Meeus, M. et al. Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: a systematic review. Semin. Arthritis Rheum. 43, 279–287 (2013).

    Article  Google Scholar 

  31. Reyes Del Paso, G. A., Garrido, S., Pulgar, A., Martín-Vázquez, M. & Duschek, S. Aberrances in autonomic cardiovascular regulation in fibromyalgia syndrome and their relevance for clinical pain reports. Psychosom. Med. 72, 462–470 (2010).

    Article  Google Scholar 

  32. Reyes del Paso, G. A., Garrido, S., Pulgar, Á. & Duschek, S. Autonomic cardiovascular control and responses to experimental pain stimulation in fibromyalgia syndrome. J. Psychosom. Res. 70, 125–134 (2011).

    Article  Google Scholar 

  33. Martinez-Lavin, M. Fibromyalgia as a sympathetically maintained pain syndrome. Curr. Pain. Headache Rep. 8, 385–389 (2004).

    Article  Google Scholar 

  34. Furlan, R. et al. Abnormalities of cardiovascular neural control and reduced orthostatic tolerance in patients with primary fibromyalgia. J. Rheumatol. 32, 1787–1793 (2005).

    Google Scholar 

  35. Reyes Del Paso, G. A. & de la Coba, P. Reduced activity, reactivity and functionality of the sympathetic nervous system in fibromyalgia: an electrodermal study. PLoS One 15, e0241154 (2020).

    Article  CAS  Google Scholar 

  36. Rivat, C. et al. Chronic stress induces transient spinal neuroinflammation, triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia. Pain 150, 358–368 (2010).

    Article  Google Scholar 

  37. Malin, K. & Littlejohn, G. O. Stress modulates key psychological processes and characteristic symptoms in females with fibromyalgia. Clin. Exp. Rheumatol. 31, S64–S71 (2013).

    Google Scholar 

  38. Jennings, E. M., Okine, B. N., Roche, M. & Finn, D. P. Stress-induced hyperalgesia. Prog. Neurobiol. 121, 1–18 (2014).

    Article  Google Scholar 

  39. Critchley, H. D. & Harrison, N. A. Visceral influences on brain and behavior. Neuron 77, 624–638 (2013).

    Article  CAS  Google Scholar 

  40. Critchley, H. D. & Garfinkel, S. N. Interoception and emotion. Curr. Opin. Psychol. 17, 7–14 (2017).

    Article  Google Scholar 

  41. Rost, S., Van Ryckeghem, D. M., Schulz, A., Crombez, G. & Vögele, C. Generalized hypervigilance in fibromyalgia: normal interoceptive accuracy, but reduced self-regulatory capacity. J. Psychosom. Res. 93, 48–54 (2017).

    Article  Google Scholar 

  42. Valenzuela-Moguillansky, C., Reyes-Reyes, A. & Gaete, M. I. Exteroceptive and interoceptive body-self awareness in fibromyalgia patients. Front. Hum. Neurosci. 11, 117 (2017).

    Article  Google Scholar 

  43. Duschek, S., Montoro, C. I. & Reyes Del Paso, G. A. Diminished interoceptive awareness in fibromyalgia syndrome. Behav. Med. 43, 100–107 (2017).

    Article  Google Scholar 

  44. Martínez, E. et al. Embodied pain in fibromyalgia: disturbed somatorepresentations and increased plasticity of the body schema. PLoS One 13, e0194534 (2018).

    Article  Google Scholar 

  45. Kool, M. B. & Geenen, R. Loneliness in patients with rheumatic diseases: the significance of invalidation and lack of social support. J. Psychol. 146, 229–241 (2012).

    Article  Google Scholar 

  46. Kool, M. B., van Middendorp, H., Boeije, H. R. & Geenen, R. Understanding the lack of understanding: invalidation from the perspective of the patient with fibromyalgia. Arthritis Rheum. 61, 1650–1656 (2009).

    Article  Google Scholar 

  47. Kool, M. B. et al. Lack of understanding in fibromyalgia and rheumatoid arthritis: the Illness Invalidation Inventory (3*I). Ann. Rheum. Dis. 69, 1990–1995 (2010).

    Article  CAS  Google Scholar 

  48. Santiago, M. G., Marques, A., Kool, M., Geenen, R. & da Silva, J. A. P. Invalidation in patients with rheumatic diseases: clinical and psychological framework. J. Rheumatol. 44, 512–518 (2017).

    Article  Google Scholar 

  49. Karayannis, N. V., Baumann, I., Sturgeon, J. A., Melloh, M. & Mackey, S. C. The impact of social isolation on pain interference: a longitudinal study. Ann. Behav. Med. 53, 65–74 (2019).

    Article  Google Scholar 

  50. Wolf, L. D., Davis, M. C., Yeung, E. W. & Tennen, H. A. The within-day relation between lonely episodes and subsequent clinical pain in individuals with fibromyalgia: mediating role of pain cognitions. J. Psychosom. Res. 79, 202–206 (2015).

    Article  Google Scholar 

  51. Landa, A. et al. When it hurts even more: the neural dynamics of pain and interpersonal emotions. J. Psychosom. Res. 128, 109881 (2020).

    Article  Google Scholar 

  52. Eisenberger, N. I., Moieni, M., Inagaki, T. K., Muscatell, K. A. & Irwin, M. R. In sickness and in health: the co-regulation of inflammation and social behavior. Neuropsychopharmacology 42, 242–253 (2017).

    Article  CAS  Google Scholar 

  53. Losin, E. A. R. et al. Neural and sociocultural mediators of ethnic differences in pain. Nat. Hum. Behav. 4, 517–530 (2020).

    Article  Google Scholar 

  54. De Ruddere, L., Bosmans, M., Crombez, G. & Goubert, L. Patients are socially excluded when their pain has no medical explanation. J. Pain. 17, 1028–1035 (2016).

    Article  Google Scholar 

  55. De Ruddere, L. & Craig, K. D. Understanding stigma and chronic pain: a-state-of-the-art review. Pain 157, 1607–1610 (2016).

    Article  Google Scholar 

  56. Asbring, P. & Närvänen, A. L. Women’s experiences of stigma in relation to chronic fatigue syndrome and fibromyalgia. Qual. Health Res. 12, 148–160 (2002).

    Google Scholar 

  57. Häuser, W. et al. Self-reported childhood maltreatment, lifelong traumatic events and mental disorders in fibromyalgia syndrome: a comparison of US and German outpatients. Clin. Exp. Rheumatol. 33, S86–S92 (2015).

    Google Scholar 

  58. Yavne, Y., Amital, D., Watad, A., Tiosano, S. & Amital, H. A systematic review of precipitating physical and psychological traumatic events in the development of fibromyalgia. Semin. Arthritis Rheum. 48, 121–133 (2018).

    Article  Google Scholar 

  59. Kivimäki, M. et al. Work stress and incidence of newly diagnosed fibromyalgia: prospective cohort study. J. Psychosom. Res. 57, 417–422 (2004).

    Google Scholar 

  60. Malin, K. & Littlejohn, G. O. Rumination modulates stress and other psychological processes in fibromyalgia. Eur. J. Rheumatol. 2, 143–148 (2015).

    Article  Google Scholar 

  61. Ricci, A. et al. Worry and anger rumination in fibromyalgia syndrome. Reumatismo 68, 195–198 (2016).

    Article  CAS  Google Scholar 

  62. van Houdenhove, B. et al. Daily hassles reported by chronic fatigue syndrome and fibromyalgia patients in tertiary care: a controlled quantitative and qualitative study. Psychother. Psychosom. 71, 207–213 (2002).

    Article  Google Scholar 

  63. Malin, K. & Littlejohn, G. O. Personality and fibromyalgia syndrome. Open Rheumatol. J. 6, 273–285 (2012).

    Article  Google Scholar 

  64. Hassett, A. L., Cone, J. D., Patella, S. J. & Sigal, L. H. The role of catastrophizing in the pain and depression of women with fibromyalgia syndrome. Arthritis Rheum. 43, 2493–2500 (2000).

    Article  CAS  Google Scholar 

  65. Hassett, A. L. et al. The relationship between affect balance style and clinical outcomes in fibromyalgia. Arthritis Rheum. 59, 833–840 (2008).

    Article  Google Scholar 

  66. Davis, M. C., Zautra, A. J. & Reich, J. W. Vulnerability to stress among women in chronic pain from fibromyalgia and osteoarthritis. Ann. Behav. Med. 23, 215–226 (2001).

    Article  CAS  Google Scholar 

  67. Zautra, A. J. et al. Fibromyalgia: evidence for deficits in positive affect regulation. Psychosom. Med. 67, 147–155 (2005).

    Article  Google Scholar 

  68. van Middendorp, H. et al. Emotions and emotional approach and avoidance strategies in fibromyalgia. J. Psychosom. Res. 64, 159–167 (2008).

    Article  Google Scholar 

  69. González, J. L. et al. Sources of stress and recovery as concurrent predictors of the affect balance of patients with fibromyalgia. Psychol. Rep. 117, 656–673 (2015).

    Article  Google Scholar 

  70. Estévez-López, F. et al. Adaptation profiles comprising objective and subjective measures in fibromyalgia: the al-Ándalus project. Rheumatology 56, 2015–2024 (2017).

    Article  Google Scholar 

  71. Wentz, K. A., Lindberg, C. & Hallberg, L. R. Psychological functioning in women with fibromyalgia: a grounded theory study. Health Care Women Int. 25, 702–729 (2004).

    Article  Google Scholar 

  72. Eisenlohr-Moul, T. A. et al. Parasympathetic reactivity in fibromyalgia and temporomandibular disorder: associations with sleep problems, symptom severity, and functional impairment. J. Pain. 16, 247–257 (2015).

    Article  Google Scholar 

  73. Wolfe, F. Fibromyalgianess. Arthritis Rheum. 61, 715–716 (2009).

    Article  Google Scholar 

  74. Häuser, W., Schmutzer, G., Brähler, E. & Glaesmer, H. A cluster within the continuum of biopsychosocial distress can be labeled “fibromyalgia syndrome” — evidence from a representative German population survey. J. Rheumatol. 36, 2806–2812 (2009).

    Article  Google Scholar 

  75. Wolfe, F., Brähler, E., Hinz, A. & Häuser, W. Fibromyalgia prevalence, somatic symptom reporting, and the dimensionality of polysymptomatic distress: results from a survey of the general population. Arthritis Care Res. 65, 777–785 (2013).

    Article  Google Scholar 

  76. Gilbert, P. Compassion Focused Therapy: Distinctive Features (Routledge, 2010).

  77. Panksepp, J. Affective Neuroscience: The Foundations of Human and Animal Emotions (Oxford University Press, 1998).

  78. LeDoux, J. The Emotional Brain: The Mysterious Underpinnings of Emotional Life (Simon and Schuster, 1998).

  79. LeDoux, J. & Daw, N. D. Surviving threats: neural circuit and computational implications of a new taxonomy of defensive behaviour. Nat. Rev. Neurosci. 19, 269–282 (2018).

    Article  CAS  Google Scholar 

  80. Duarte, J., McEwan, K., Barnes, C., Gilbert, P. & Maratos, F. A. Do therapeutic imagery practices affect physiological and emotional indicators of threat in high self-critics? Psychol. Psychother. 88, 270–284 (2015).

    Article  Google Scholar 

  81. Roelofs, K. Freeze for action: neurobiological mechanisms in animal and human freezing. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 372, 20160206 (2017).

    Article  Google Scholar 

  82. Depue, R. A. & Morrone-Strupinsky, J. V. A neurobehavioral model of affiliative bonding: implications for conceptualizing a human trait of affiliation. Behav. Brain. Sci. 28, 313–350 (2005).

    Article  Google Scholar 

  83. Berridge, K. C. & Kringelbach, M. L. Affective neuroscience of pleasure: reward in humans and animals. Psychopharmacology 199, 457–480 (2008).

    Article  CAS  Google Scholar 

  84. Berridge, K. C. & Kringelbach, M. L. Pleasure systems in the brain. Neuron 86, 646–664 (2015).

    Article  CAS  Google Scholar 

  85. Gilbert, P. Introducing compassion-focused therapy. Adv. Psychiatr. Treat. 15, 199–208 (2009).

    Article  Google Scholar 

  86. Gilbert, P. Compassion: from its evolution to a psychotherapy. Front. Psychol. 11, 586161 (2020).

    Article  Google Scholar 

  87. Eippert, F. et al. Regulation of emotional responses elicited by threat-related stimuli. Hum. Brain Mapp. 28, 409–423 (2007).

    Article  Google Scholar 

  88. Longe, O. et al. Having a word with yourself: neural correlates of self-criticism and self-reassurance. Neuroimage 49, 1849–1856 (2010).

    Article  Google Scholar 

  89. Porges, S. W. The polyvagal perspective. Biol. Psychol. 74, 116–143 (2007).

    Article  Google Scholar 

  90. Gilbert, P. Affiliative and prosocial motives and emotions in mental health. Dialogues Clin. Neurosci. 17, 381–389 (2015).

    Article  Google Scholar 

  91. Taylor, S. E. Tend and befriend: biobehavioral bases of affiliation under stress. Curr. Dir. Psychol. Sci. 15, 273–277 (2006).

    Article  CAS  Google Scholar 

  92. Kirsch, P. et al. Oxytocin modulates neural circuitry for social cognition and fear in humans. J. Neurosci. 25, 11489–11493 (2005).

    Article  CAS  Google Scholar 

  93. Tracy, L. M., Georgiou-Karistianis, N., Gibson, S. J. & Giummarra, M. J. Oxytocin and the modulation of pain experience: implications for chronic pain management. Neurosci. Biobehav. Rev. 55, 53–67 (2015).

    Article  CAS  Google Scholar 

  94. Van Den Houte, M., Van Oudenhove, L., Bogaerts, K., Van Diest, I. & Van den Bergh, O. Endogenous pain modulation: association with resting heart rate variability and negative affectivity. Pain. Med. 19, 1587–1596 (2017).

    Article  Google Scholar 

  95. López-Solà, M., Geuter, S., Koban, L., Coan, J. A. & Wager, T. D. Brain mechanisms of social touch-induced analgesia in females. Pain 160, 2072–2085 (2019).

    Article  Google Scholar 

  96. Staud, R. Heart rate variability as a biomarker of fibromyalgia syndrome. Fut. Rheumatol. 3, 475–483 (2008).

    Article  Google Scholar 

  97. Jenewein, J. et al. Fear-learning deficits in subjects with fibromyalgia syndrome? Eur. J. Pain. 17, 1374–1384 (2013).

    Article  CAS  Google Scholar 

  98. Meulders, A., Jans, A. & Vlaeyen, J. W. S. Differences in pain-related fear acquisition and generalization: an experimental study comparing patients with fibromyalgia and healthy controls. Pain 156, 108–122 (2015).

    Article  Google Scholar 

  99. Meulders, A., Meulders, M., Stouten, I., De Bie, J. & Vlaeyen, J. W. Extinction of fear generalization: a comparison between fibromyalgia patients and healthy control participants. J. Pain. 18, 79–95 (2017).

    Article  Google Scholar 

  100. Sandström, A. et al. Neural correlates of conditioned pain responses in fibromyalgia subjects indicate preferential formation of new pain associations rather than extinction of irrelevant ones. Pain 161, 2079–2088 (2020).

    Article  Google Scholar 

  101. Perry, B. D., Pollard, R. A., Blakley, T. L., Baker, W. L. & Vigilante, D. Childhood trauma, the neurobiology of adaptation, and “use-dependent” development of the brain: how “states” become “traits”. Infant Ment. Health J. 16, 271–291 (1995).

    Article  Google Scholar 

  102. Chen, Y. & Baram, T. Z. Toward understanding how early-life stress reprograms cognitive and emotional brain networks. Neuropsychopharmacology 41, 197–206 (2016).

    Article  Google Scholar 

  103. Krugers, H. J. et al. Early life adversity: lasting consequences for emotional learning. Neurobiol. Stress. 6, 14–21 (2017).

    Article  Google Scholar 

  104. Brosschot, J. F., Verkuil, B. & Thayer, J. F. Exposed to events that never happen: generalized unsafety, the default stress response, and prolonged autonomic activity. Neurosci. Biobehav. Rev. 74, 287–296 (2017).

    Article  Google Scholar 

  105. Bowlby, J. in Attachment and Loss: Volume II: Separation, Anxiety and Anger 1–429 (The Hogarth Press and the Institute of Psycho-analysis, 1973).

  106. Mikulincer, M., Shaver, P. R. & Pereg, D. Attachment theory and affect regulation: the dynamics, development, and cognitive consequences of attachment-related strategies. Motiv. Emot. 27, 77–102 (2003).

    Article  Google Scholar 

  107. Schore, A. N. The effects of early relational trauma on right brain development, affect regulation, and infant mental health. Infant. Ment. Health J. 22, 201–269 (2001).

    Article  Google Scholar 

  108. Hornstein, E. A. & Eisenberger, N. I. Unpacking the buffering effect of social support figures: social support attenuates fear acquisition. PLoS ONE 12, e0175891 (2017).

    Article  Google Scholar 

  109. Krahé, C., Springer, A., Weinman, J. A. & Fotopoulou, A. The social modulation of pain: others as predictive signals of salience — a systematic review. Front. Hum. Neurosci. 7, 386 (2013).

    Article  Google Scholar 

  110. Hostinar, C. E. & Gunnar, M. R. Social support can buffer against stress and shape brain activity. AJOB Neurosci. 6, 34–42 (2015).

    Article  Google Scholar 

  111. Pilcher, J. J. & Bryant, S. A. Implications of social support as a self-control resource. Front. Behav. Neurosci. 10, 228 (2016).

    Article  Google Scholar 

  112. Eisenberger, N. I. et al. Attachment figures activate a safety signal-related neural region and reduce pain experience. Proc. Natl Acad. Sci. USA 108, 11721–11726 (2011).

    Article  CAS  Google Scholar 

  113. Younger, J., Aron, A., Parke, S., Chatterjee, N. & Mackey, S. Viewing pictures of a romantic partner reduces experimental pain: involvement of neural reward systems. PLoS One 5, e13309 (2010).

    Article  Google Scholar 

  114. Häuser, W., Kosseva, M., Uceyler, N., Klose, P. & Sommer, C. Emotional, physical, and sexual abuse in fibromyalgia syndrome: a systematic review with meta-analysis. Arthritis Care Res. 63, 808–820 (2011).

    Article  Google Scholar 

  115. Davies, K. A., Macfarlane, G. J., McBeth, J., Morriss, R. & Dickens, C. Insecure attachment style is associated with chronic widespread pain. Pain 143, 200–205 (2009).

    Article  CAS  Google Scholar 

  116. Wang, H., Weber, A., Schiltenwolf, M. & Amelung, D. [Attachment style and cytokine levels in patients with fibromyalgia. A prospective longitudinal study]. Schmerz 28, 504–512 (2014).

    Article  CAS  Google Scholar 

  117. Peñacoba, C., Perez-Calvo, S., Blanco, S. & Sanroman, L. Attachment styles, pain intensity and emotional variables in women with fibromyalgia. Scand. J. Caring Sci. 32, 535–544 (2018).

    Article  Google Scholar 

  118. Jones, G. T. et al. Role of road traffic accidents and other traumatic events in the onset of chronic widespread pain: results from a population-based prospective study. Arthritis Care Res. 63, 696–701 (2011).

    Article  Google Scholar 

  119. Burke, N. N., Finn, D. P., McGuire, B. E. & Roche, M. Psychological stress in early life as a predisposing factor for the development of chronic pain: clinical and preclinical evidence and neurobiological mechanisms. J. Neurosci. Res. 95, 1257–1270 (2017).

    Article  CAS  Google Scholar 

  120. Jones, G. T., Power, C. & Macfarlane, G. J. Adverse events in childhood and chronic widespread pain in adult life: results from the 1958 British Birth Cohort Study. Pain 143, 92–96 (2009).

    Article  Google Scholar 

  121. Jay, M., Bendayan, R., Cooper, R. & Muthuri, S. Lifetime socioeconomic circumstances and chronic pain in later adulthood: findings from a British birth cohort study. BMJ Open 9, e024250 (2019).

    Article  Google Scholar 

  122. Kaleycheva, N. et al. The role of lifetime stressors in adult fibromyalgia: systematic review and meta-analysis of case-control studies. Psychol. Med. 51, 177–193 (2021).

    Article  Google Scholar 

  123. You, D. S. & Meagher, M. W. Childhood adversity and pain sensitization. Psychosom. Med. 78, 1084–1093 (2016).

    Article  CAS  Google Scholar 

  124. Sturycz, C. A. et al. Race/ethnicity does not moderate the relationship between adverse life experiences and temporal summation of the nociceptive flexion reflex and pain: results from the Oklahoma Study of Native American Pain Risk. J. Pain. 20, 941–955 (2019).

    Article  Google Scholar 

  125. Kell, P. A. et al. The relationship between adverse life events and endogenous inhibition of pain and spinal nociception: findings from the Oklahoma Study of Native American Pain Risk (OK-SNAP). J. Pain. 22, 1097–1110 (2021).

    Article  Google Scholar 

  126. Rhudy, J. L. et al. Emotional modulation of pain and spinal nociception in fibromyalgia. Pain 154, 1045–1056 (2013).

    Article  Google Scholar 

  127. Kamping, S., Bomba, I. C., Kanske, P., Diesch, E. & Flor, H. Deficient modulation of pain by a positive emotional context in fibromyalgia patients. Pain 154, 1846–1855 (2013).

    Article  Google Scholar 

  128. Loggia, M. L. et al. Disrupted brain circuitry for pain-related reward/punishment in fibromyalgia. Arthritis Rheumatol. 66, 203–212 (2014).

    Article  Google Scholar 

  129. Siegel, D. J. The Developing Mind: How Relationships and the Brain Interact to Shape Who We Are. 2nd edn. (The Guilford Press, 2012).

  130. Mikulincer, M. & Shaver, P. R. Attachment in Adulthood: Structure, Dynamics, and Change (The Guilford Press, 2016).

  131. Menon, V. in Brain Mapping: an Encyclopedic Reference vol. 2 (ed Toga, A.W) 597–611 (Academic Press, 2015).

  132. Menon, V. Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn. Sci. 15, 483–506 (2011).

    Article  Google Scholar 

  133. Reddan, M. C., Wager, T. D. & Schiller, D. Attenuating neural threat expression with imagination. Neuron 100, 994–1005.e1004 (2018).

    Article  CAS  Google Scholar 

  134. Wager, T. D. et al. An fMRI-based neurologic signature of physical pain. N. Engl. J. Med. 368, 1388–1397 (2013).

    Article  CAS  Google Scholar 

  135. Menon, V. & Uddin, L. Q. Saliency, switching, attention and control: a network model of insula function. Brain Struct. Funct. 214, 655–667 (2010).

    Article  Google Scholar 

  136. Legrain, V., Iannetti, G. D., Plaghki, L. & Mouraux, A. The pain matrix reloaded: a salience detection system for the body. Prog. Neurobiol. 93, 111–124 (2011).

    Article  Google Scholar 

  137. Miller, A. H., Haroon, E., Raison, C. L. & Felger, J. C. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 30, 297–306 (2013).

    Article  CAS  Google Scholar 

  138. Uddin, L. Q. Salience Network of the Human Brain (Academic Press, 2017).

  139. Uddin, L. Q., Yeo, B. T. T. & Spreng, R. N. Towards a universal taxonomy of macro-scale functional human brain networks. Brain Topogr. 32, 926–942 (2019).

    Article  Google Scholar 

  140. López-Solà, M. et al. Towards a neurophysiological signature for fibromyalgia. Pain 158, 34–47 (2017).

    Article  Google Scholar 

  141. Buckner, R. L., Andrews-Hanna, J. R. & Schacter, D. L. The brain’s default network: anatomy, function, and relevance to disease. Ann. N. Y. Acad. Sci. 1124, 1–38 (2008).

    Article  Google Scholar 

  142. Gracely, R. H., Petzke, F., Wolf, J. M. & Clauw, D. J. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 46, 1333–1343 (2002).

    Article  Google Scholar 

  143. Cook, D. B. et al. Functional imaging of pain in patients with primary fibromyalgia. J. Rheumatol. 31, 364–378 (2004).

    Google Scholar 

  144. Pujol, J. et al. Mapping brain response to pain in fibromyalgia patients using temporal analysis of FMRI. PLoS One 4, e5224 (2009).

    Article  Google Scholar 

  145. López-Solà, M. et al. Altered functional magnetic resonance imaging responses to nonpainful sensory stimulation in fibromyalgia patients. Arthritis Rheumatol. 66, 3200–3209 (2014).

    Article  Google Scholar 

  146. Harte, S. E. et al. Pharmacologic attenuation of cross-modal sensory augmentation within the chronic pain insula. Pain 157, 1933–1945 (2016).

    Article  CAS  Google Scholar 

  147. Harris, R. E. et al. Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum. 60, 3146–3152 (2009).

    Article  CAS  Google Scholar 

  148. Harris, R. E. et al. Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. Anesthesiology 119, 1453–1464 (2013).

    Article  CAS  Google Scholar 

  149. Ichesco, E. et al. Altered resting state connectivity of the insular cortex in individuals with fibromyalgia. J. Pain. 15, 815–826.e1 (2014).

    Article  CAS  Google Scholar 

  150. Napadow, V. et al. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum. 62, 2545–2555 (2010).

    Article  Google Scholar 

  151. Kim, J. Y. et al. Increased power spectral density in resting-state pain-related brain networks in fibromyalgia. Pain 154, 1792–1797 (2013).

    Article  Google Scholar 

  152. Pujol, J. et al. The contribution of sensory system functional connectivity reduction to clinical pain in fibromyalgia. Pain 155, 1492–1503 (2014).

    Article  Google Scholar 

  153. Kaplan, C. M. et al. Functional and neurochemical disruptions of brain hub topology in chronic pain. Pain 160, 973–983 (2019).

    Article  Google Scholar 

  154. Ellingsen, D. M. et al. A picture is worth a thousand words: linking fibromyalgia pain widespreadness from digital pain drawings with pain catastrophizing and brain cross-network connectivity. Pain 162, 1352–1363 (2021).

    Article  CAS  Google Scholar 

  155. Sridharan, D., Levitin, D. J. & Menon, V. A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks. Proc. Natl Acad. Sci. USA 105, 12569–12574 (2008).

    Article  CAS  Google Scholar 

  156. Kennerley, S. W., Behrens, T. E. & Wallis, J. D. Double dissociation of value computations in orbitofrontal and anterior cingulate neurons. Nat. Neurosci. 14, 1581–1589 (2011).

    Article  CAS  Google Scholar 

  157. Wunderlich, K., Dayan, P. & Dolan, R. J. Mapping value based planning and extensively trained choice in the human brain. Nat. Neurosci. 15, 786–791 (2012).

    Article  CAS  Google Scholar 

  158. Margulies, D. S. & Uddin, L. Q. Network convergence zones in the anterior midcingulate cortex. Handb. Clin. Neurol. 166, 103–111 (2019).

    Article  Google Scholar 

  159. Etkin, A. & Wager, T. D. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476–1488 (2007).

    Article  Google Scholar 

  160. Nagai, M., Kishi, K. & Kato, S. Insular cortex and neuropsychiatric disorders: a review of recent literature. Eur. Psychiatry 22, 387–394 (2007).

    Article  CAS  Google Scholar 

  161. Nieuwenhuys, R. The insular cortex: a review. Prog. Brain Res. 195, 123–163 (2012).

    Article  Google Scholar 

  162. Sterzer, P. & Kleinschmidt, A. Anterior insula activations in perceptual paradigms: often observed but barely understood. Brain Struct. Funct. 214, 611–622 (2010).

    Article  Google Scholar 

  163. Travassos, C., Sayal, A., Direito, B., Castelhano, J. & Castelo-Branco, M. Volitional modulation of the left DLPFC neural activity based on a pain empathy paradigm — a potential novel therapeutic target for pain. Front. Neurol. 11, 714 (2020).

    Article  Google Scholar 

  164. Perini, I. et al. The salience of self, not social pain, is encoded by dorsal anterior cingulate and insula. Sci. Rep. 8, 6165 (2018).

    Article  Google Scholar 

  165. Kross, E., Berman, M. G., Mischel, W., Smith, E. E. & Wager, T. D. Social rejection shares somatosensory representations with physical pain. Proc. Natl Acad. Sci. USA 108, 6270–6275 (2011).

    Article  CAS  Google Scholar 

  166. Eisenberger, N. I. Social pain and the brain: controversies, questions, and where to go from here. Annu. Rev. Psychol. 66, 601–629 (2015).

    Article  Google Scholar 

  167. Beissner, F., Meissner, K., Bär, K.-J. & Napadow, V. The autonomic brain: an activation likelihood estimation meta-analysis for central processing of autonomic function. J. Neurosci. 33, 10503–10511 (2013).

    Article  CAS  Google Scholar 

  168. Wager, T. D. et al. Brain mediators of cardiovascular responses to social threat: part I: reciprocal dorsal and ventral sub-regions of the medial prefrontal cortex and heart-rate reactivity. Neuroimage 47, 821–835 (2009).

    Article  Google Scholar 

  169. Wager, T. D. et al. Brain mediators of cardiovascular responses to social threat, part II: prefrontal-subcortical pathways and relationship with anxiety. Neuroimage 47, 836–851 (2009).

    Article  Google Scholar 

  170. Gianaros, P. J. & Wager, T. D. Brain-body pathways linking psychological stress and physical health. Curr. Dir. Psychol. Sci. 24, 313–321 (2015).

    Article  Google Scholar 

  171. Thayer, J. F. & Lane, R. D. A model of neurovisceral integration in emotion regulation and dysregulation. J. Affect. Disord. 61, 201–216 (2000).

    Article  CAS  Google Scholar 

  172. Thayer, J. F. & Lane, R. D. Claude Bernard and the heart-brain connection: further elaboration of a model of neurovisceral integration. Neurosci. Biobehav. Rev. 33, 81–88 (2009).

    Article  Google Scholar 

  173. Thayer, J. F., Ahs, F., Fredrikson, M., Sollers, J. J. & Wager, T. D. A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health. Neurosci. Biobehav. Rev. 36, 747–756 (2012).

    Article  Google Scholar 

  174. Mouraux, A. & Iannetti, G. D. Nociceptive laser-evoked brain potentials do not reflect nociceptive-specific neural activity. J. Neurophysiol. 101, 3258–3269 (2009).

    Article  CAS  Google Scholar 

  175. Baliki, M. N. & Apkarian, A. V. Nociception, pain, negative moods, and behavior selection. Neuron 87, 474–491 (2015).

    Article  CAS  Google Scholar 

  176. Woo, C. W. et al. Separate neural representations for physical pain and social rejection. Nat. Commun. 5, 5380 (2014).

    Article  Google Scholar 

  177. Kragel, P. A. et al. Generalizable representations of pain, cognitive control, and negative emotion in medial frontal cortex. Nat. Neurosci. 21, 283–289 (2018).

    Article  CAS  Google Scholar 

  178. Krishnan, A. et al. Somatic and vicarious pain are represented by dissociable multivariate brain patterns. Elife 5, e15166 (2016).

    Article  Google Scholar 

  179. Uddin, L. Q., Iacoboni, M., Lange, C. & Keenan, J. P. The self and social cognition: the role of cortical midline structures and mirror neurons. Trends Cogn. Sci. 11, 153–157 (2007).

    Article  Google Scholar 

  180. Goulden, N. et al. The salience network is responsible for switching between the default mode network and the central executive network: replication from DCM. Neuroimage 99, 180–190 (2014).

    Article  Google Scholar 

  181. Uddin, L. Q. Salience processing and insular cortical function and dysfunction. Nat. Rev. Neurosci. 16, 55–61 (2015).

    Article  CAS  Google Scholar 

  182. Schiller, D., Levy, I., Niv, Y., LeDoux, J. E. & Phelps, E. A. From fear to safety and back: reversal of fear in the human brain. J. Neurosci. 28, 11517–11525 (2008).

    Article  CAS  Google Scholar 

  183. Woo, C. W. et al. Quantifying cerebral contributions to pain beyond nociception. Nat. Commun. 8, 14211 (2017).

    Article  CAS  Google Scholar 

  184. Baliki, M. N. et al. Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J. Neurosci. 26, 12165–12173 (2006).

    Article  CAS  Google Scholar 

  185. Vachon-Presseau, E. et al. The emotional brain as a predictor and amplifier of chronic pain. J. Dent. Res. 95, 605–612 (2016).

    Article  CAS  Google Scholar 

  186. Wiech, K. et al. Anterior insula integrates information about salience into perceptual decisions about pain. J. Neurosci. 30, 16324–16331 (2010).

    Article  CAS  Google Scholar 

  187. Peyron, R. & Faillenot, I. [Functional brain mapping of pain perception]. Med. Sci. 27, 82–87 (2011).

    Google Scholar 

  188. Liu, C. H. et al. Increased salience network activity in patients with insomnia complaints in major depressive disorder. Front. Psychiatry 9, 93 (2018).

    Article  Google Scholar 

  189. Marques, D. R., Gomes, A. A., Caetano, G. & Castelo-Branco, M. Insomnia disorder and brain’s default-mode network. Curr. Neurol. Neurosci. Rep. 18, 45 (2018).

    Article  Google Scholar 

  190. Cooney, R. E., Joormann, J., Eugène, F., Dennis, E. L. & Gotlib, I. H. Neural correlates of rumination in depression. Cogn. Affect. Behav. Neurosci. 10, 470–478 (2010).

    Article  Google Scholar 

  191. Kucyi, A. et al. Enhanced medial prefrontal-default mode network functional connectivity in chronic pain and its association with pain rumination. J. Neurosci. 34, 3969–3975 (2014).

    Article  CAS  Google Scholar 

  192. Servaas, M. N. et al. Connectomics and neuroticism: an altered functional network organization. Neuropsychopharmacology 40, 296–304 (2015).

    Article  Google Scholar 

  193. Schrepf, A. et al. Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study. Pain 157, 2217–2225 (2016).

    Article  CAS  Google Scholar 

  194. Rocchi, G. et al. Opioidergic system and functional architecture of intrinsic brain activity: implications for psychiatric disorders. Neuroscientist 26, 343–358 (2020).

    Article  Google Scholar 

  195. Ballantyne, J. C. & Sullivan, M. D. Discovery of endogenous opioid systems: what it has meant for the clinician’s understanding of pain and its treatment. Pain 158, 2290–2300 (2017).

    Article  CAS  Google Scholar 

  196. Jensen, K. B. et al. Evidence of dysfunctional pain inhibition in fibromyalgia reflected in rACC during provoked pain. Pain 144, 95–100 (2009).

    Article  Google Scholar 

  197. Jensen, K. B. et al. Patients with fibromyalgia display less functional connectivity in the brain’s pain inhibitory network. Mol. Pain. 8, 32 (2012).

    Article  Google Scholar 

  198. Jensen, K. B. et al. Overlapping structural and functional brain changes in patients with long-term exposure to fibromyalgia pain. Arthritis Rheum. 65, 3293–3303 (2013).

    Article  Google Scholar 

  199. Baraniuk, J. N. et al. A chronic fatigue syndrome-related proteome in human cerebrospinal fluid. BMC Neurol. 5, 22 (2005).

    Article  Google Scholar 

  200. Macfarlane, G. J. et al. EULAR revised recommendations for the management of fibromyalgia. Ann. Rheum. Dis. 76, 318–328 (2017).

    Article  CAS  Google Scholar 

  201. Grayston, R. et al. A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: implications for a new paradigm in fibromyalgia etiopathogenesis. Semin. Arthritis Rheum. 48, 933–940 (2018).

    Article  Google Scholar 

  202. Harte, S. E. et al. Reduced intraepidermal nerve fiber density after a sustained increase in insular glutamate: a proof-of-concept study examining the pathogenesis of small fiber pathology in fibromyalgia. Pain. Rep. 2, e590 (2017).

    Article  Google Scholar 

  203. Van Houdenhove, B. & Egle, U. T. Fibromyalgia: a stress disorder? Piecing the biopsychosocial puzzle together. Psychother. Psychosom. 73, 267–275 (2004).

    Article  Google Scholar 

  204. Martinez-Lavin, M. Fibromyalgia: when distress becomes (un)sympathetic pain. Pain. Res. Treat. 2012, 981565 (2012).

    Google Scholar 

  205. Lyon, P., Cohen, M. & Quintner, J. An evolutionary stress-response hypothesis for chronic widespread pain (fibromyalgia syndrome). Pain. Med. 12, 1167–1178 (2011).

    Article  Google Scholar 

  206. Van Houdenhove, B. & Luyten, P. Central sensitivity syndromes: stress system failure may explain the whole picture. Semin. Arthritis Rheum. 39, 218–219 (2009).

    Article  Google Scholar 

  207. Eccleston, C. Chronic pain as embodied defence: implications for current and future psychological treatments. Pain 159, S17–S23 (2018).

    Article  Google Scholar 

  208. Hill, P. Chronic pain: a consequence of dysregulated protective action. Br. J. Pain. 13, 13–21 (2019).

    Article  Google Scholar 

  209. Penlington, C. Exploring a compassion-focused intervention for persistent pain in a group setting. Br. J. Pain. 13, 59–66 (2019).

    Article  Google Scholar 

  210. Gooding, H., Stedmon, J. & Crix, D. ‘All these things don’t take the pain away but they do help you to accept it’: making the case for compassion-focused therapy in the management of persistent pain. Br. J. Pain. 14, 31–41 (2020).

    Article  Google Scholar 

  211. Kolacz, J. & Porges, S. W. Chronic diffuse pain and functional gastrointestinal disorders after traumatic stress: pathophysiology through a polyvagal perspective. Front. Med. 5, 145 (2018).

    Article  Google Scholar 

  212. De Paepe, B., Smet, J., Baeken, C., Van Oosterwijck, J. & Meeus, M. A capital role for the brain’s insula in the diverse fibromyalgia-associated symptoms. Med. Hypotheses 143, 110077 (2020).

    Article  Google Scholar 

  213. Akiki, T. J., Averill, C. L. & Abdallah, C. G. A network-based neurobiological model of PTSD: evidence from structural and functional neuroimaging studies. Curr. Psychiatry Rep. 19, 81 (2017).

    Article  Google Scholar 

  214. Häuser, W. et al. Posttraumatic stress disorder in fibromyalgia syndrome: prevalence, temporal relationship between posttraumatic stress and fibromyalgia symptoms, and impact on clinical outcome. Pain 154, 1216–1223 (2013).

    Article  Google Scholar 

  215. Häuser, W., Ablin, J. & Walitt, B. in Comprehensive Guide to Post-Traumatic Stress Disorders (eds Colin, R. M., Victor, R. P., & Vinood, B. P.) 563–577 (Springer International Publishing, 2016).

  216. Crettaz, B. et al. Stress-induced allodynia — evidence of increased pain sensitivity in healthy humans and patients with chronic pain after experimentally induced psychosocial stress. PLoS One 8, e69460 (2013).

    Article  CAS  Google Scholar 

  217. Krusemark, E. A., Novak, L. R., Gitelman, D. R. & Li, W. When the sense of smell meets emotion: anxiety-state-dependent olfactory processing and neural circuitry adaptation. J. Neurosci. 33, 15324–15332 (2013).

    Article  CAS  Google Scholar 

  218. Martinez-Lavin, M. & Hermosillo, A. G. Autonomic nervous system dysfunction may explain the multisystem features of fibromyalgia. Semin. Arthritis Rheum. 29, 197–199 (2000).

    Article  CAS  Google Scholar 

  219. Kadetoff, D., Lampa, J., Westman, M., Andersson, M. & Kosek, E. Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels. J. Neuroimmunol. 242, 33–38 (2012).

    Article  CAS  Google Scholar 

  220. Albrecht, D. S. et al. Brain glial activation in fibromyalgia — a multi-site positron emission tomography investigation. Brain Behav. Immun. 75, 72–83 (2018).

    Article  Google Scholar 

  221. Liu, Y. Z., Wang, Y. X. & Jiang, C. L. Inflammation: the common pathway of stress-related diseases. Front. Hum. Neurosci. 11, 316 (2017).

    Article  Google Scholar 

  222. Michopoulos, V., Powers, A., Gillespie, C. F., Ressler, K. J. & Jovanovic, T. Inflammation in fear- and anxiety-based disorders: PTSD, GAD, and beyond. Neuropsychopharmacology 42, 254–270 (2017).

    Article  CAS  Google Scholar 

  223. Troubat, R. et al. Neuroinflammation and depression: a review. Eur. J. Neurosci. 53, 151–171 (2021).

    Article  CAS  Google Scholar 

  224. Forseth, K. O., Førre, O. & Gran, J. T. A 5.5 year prospective study of self-reported musculoskeletal pain and of fibromyalgia in a female population: significance and natural history. Clin. Rheumatol. 18, 114–121 (1999).

    Article  CAS  Google Scholar 

  225. Holm, L. W., Carroll, L. J., Cassidy, J. D., Skillgate, E. & Ahlbom, A. Widespread pain following whiplash-associated disorders: incidence, course, and risk factors. J. Rheumatol. 34, 193–200 (2007).

    Google Scholar 

  226. McBeth, J. et al. Moderation of psychosocial risk factors through dysfunction of the hypothalamic-pituitary-adrenal stress axis in the onset of chronic widespread musculoskeletal pain: findings of a population-based prospective cohort study. Arthritis Rheum. 56, 360–371 (2007).

    Article  CAS  Google Scholar 

  227. Tak, L. M., Bakker, S. J. & Rosmalen, J. G. Dysfunction of the hypothalamic-pituitary-adrenal axis and functional somatic symptoms: a longitudinal cohort study in the general population. Psychoneuroendocrinology 34, 869–877 (2009).

    Article  CAS  Google Scholar 

  228. Generaal, E. et al. Biological stress systems, adverse life events and the onset of chronic multisite musculoskeletal pain: a 6-year cohort study. Ann. Rheum. Dis. 75, 847–854 (2016).

    Article  CAS  Google Scholar 

  229. Hung, C. H. et al. Activation of acid-sensing ion channel 3 by lysophosphatidylcholine 16:0 mediates psychological stress-induced fibromyalgia-like pain. Ann. Rheum. Dis. 79, 1644–1656 (2020).

    Article  CAS  Google Scholar 

  230. Suarez-Roca, H. et al. Role of mu-opioid and NMDA receptors in the development and maintenance of repeated swim stress-induced thermal hyperalgesia. Behav. Brain Res. 167, 205–211 (2006).

    Article  CAS  Google Scholar 

  231. Pierce, A. N. & Christianson, J. A. Stress and chronic pelvic pain. Prog. Mol. Biol. Transl. Sci. 131, 509–535 (2015).

    Article  Google Scholar 

  232. Kaplan, C. M. et al. Neurobiological antecedents of multisite pain in children. Pain 163, e596–e603 (2021).

    Article  Google Scholar 

  233. Calhoon, G. G. & Tye, K. M. Resolving the neural circuits of anxiety. Nat. Neurosci. 18, 1394–1404 (2015).

    Article  CAS  Google Scholar 

  234. Xie, S., Zhang, X., Cheng, W. & Yang, Z. Adolescent anxiety disorders and the developing brain: comparing neuroimaging findings in adolescents and adults. Gen. Psychiatr. 34, e100411 (2021).

    Article  Google Scholar 

  235. Abend, R. et al. Threat imminence reveals links among unfolding of anticipatory physiological response, cortical-subcortical intrinsic functional connectivity, and anxiety. Neurobiol. Stress. 16, 100428 (2022).

    Article  Google Scholar 

  236. Clemens, B. et al. Alerted default mode: functional connectivity changes in the aftermath of social stress. Sci. Rep. 7, 40180 (2017).

    Article  CAS  Google Scholar 

  237. Abdallah, C. G. et al. Salience network disruption in U.S. Army soldiers with posttraumatic stress disorder. Chronic Stress 3, 2470547019850467 (2019).

    Article  Google Scholar 

  238. Banks, S. M. & Kerns, R. D. Explaining high rates of depression in chronic pain: a diathesis-stress framework. Psychol. Bull. 119, 95–110 (1996).

    Article  Google Scholar 

  239. Geenen, R., Newman, S., Bossema, E. R., Vriezekolk, J. E. & Boelen, P. A. Psychological interventions for patients with rheumatic diseases and anxiety or depression. Best. Pract. Res. Clin. Rheumatol. 26, 305–319 (2012).

    Article  Google Scholar 

  240. Choy, E. H. The role of sleep in pain and fibromyalgia. Nat. Rev. Rheumatol. 11, 513–520 (2015).

    Article  Google Scholar 

  241. Creed, F. A review of the incidence and risk factors for fibromyalgia and chronic widespread pain in population-based studies. Pain 161, 1169–1176 (2020).

    Article  Google Scholar 

  242. Karcher, N. R. & Barch, D. M. The ABCD study: understanding the development of risk for mental and physical health outcomes. Neuropsychopharmacology 46, 131–142 (2021).

    Article  Google Scholar 

  243. Houtveen, J. H., van Eck van der Sluijs, J., Thorsell, S., van Broeckhuysen-Kloth, S. & Geenen, R. Changed dynamic symptom networks after a self-compassion training in patients with somatic symptom disorder: a multiple single-case pilot project. J. Psychosom. Res. 154, 110724 (2022).

    Article  Google Scholar 

  244. Vachon-Presseau, E. et al. Identification of traits and functional connectivity-based neurotraits of chronic pain. PLoS Biol. 17, e3000349 (2019).

    Article  CAS  Google Scholar 

  245. Pace, T. W. et al. Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to psychosocial stress. Psychoneuroendocrinology 34, 87–98 (2009).

    Article  CAS  Google Scholar 

  246. Arch, J. J. et al. Self-compassion training modulates alpha-amylase, heart rate variability, and subjective responses to social evaluative threat in women. Psychoneuroendocrinology 42, 49–58 (2014).

    Article  CAS  Google Scholar 

  247. Andrés-Rodríguez, L. et al. Immune-inflammatory pathways and clinical changes in fibromyalgia patients treated with Mindfulness-Based Stress Reduction (MBSR): a randomized, controlled clinical trial. Brain Behav. Immun. 80, 109–119 (2019).

    Article  Google Scholar 

  248. Matthewson, G. M., Woo, C. W., Reddan, M. C. & Wager, T. D. Cognitive self-regulation influences pain-related physiology. Pain 160, 2338–2349 (2019).

    Article  Google Scholar 

  249. Montero-Marin, J. et al. Effects of attachment-based compassion therapy (ABCT) on brain-derived neurotrophic factor and low-grade inflammation among fibromyalgia patients: a randomized controlled trial. Sci. Rep. 9, 15639 (2019).

    Article  Google Scholar 

  250. Maratos, F. A. & Sheffield, D. Brief compassion-focused imagery dampens physiological pain responses. Mindfulness 11, 2730–2740 (2020).

    Article  Google Scholar 

  251. Doll, A., Hölzel, B. K., Boucard, C. C., Wohlschläger, A. M. & Sorg, C. Mindfulness is associated with intrinsic functional connectivity between default mode and salience networks. Front. Hum. Neurosci. 9, 461 (2015).

    Article  Google Scholar 

  252. Cunningham, N. R., Kashikar-Zuck, S. & Coghill, R. C. Brain mechanisms impacted by psychological therapies for pain: identifying targets for optimization of treatment effects. Pain. Rep. 4, e767 (2019).

    Article  Google Scholar 

  253. Kober, H., Buhle, J., Weber, J., Ochsner, K. N. & Wager, T. D. Let it be: mindful acceptance down-regulates pain and negative emotion. Soc. Cogn. Affect. Neurosci. 14, 1147–1158 (2019).

    Article  Google Scholar 

  254. Scult, M. A. et al. Changes in functional connectivity following treatment with emotion regulation therapy. Front. Behav. Neurosci. 13, 10 (2019).

    Article  Google Scholar 

  255. Reddan, M. C. & Wager, T. D. Brain systems at the intersection of chronic pain and self-regulation. Neurosci. Lett. 702, 24–33 (2019).

    Article  CAS  Google Scholar 

  256. Zeidan, F., Baumgartner, J. N. & Coghill, R. C. The neural mechanisms of mindfulness-based pain relief: a functional magnetic resonance imaging-based review and primer. Pain. Rep. 4, e759 (2019).

    Article  Google Scholar 

  257. Jinich-Diamant, A. et al. Neurophysiological mechanisms supporting mindfulness meditation-based pain relief: an updated review. Curr. Pain. Headache Rep. 24, 56 (2020).

    Article  Google Scholar 

  258. Gentili, C. et al. Psychological flexibility as a resilience factor in individuals with chronic pain. Front. Psychol. 10, 2016 (2019).

    Article  Google Scholar 

  259. Conversano, C. et al. Optimism and its impact on mental and physical well-being. Clin. Pract. Epidemiol. Ment. Health 6, 25–29 (2010).

    Article  Google Scholar 

  260. Purdie, F. & Morley, S. Compassion and chronic pain. Pain 157, 2625–2627 (2016).

    Article  Google Scholar 

  261. Vallejo, M. A. et al. Self-forgiveness in fibromyalgia patients and its relationship with acceptance, catastrophising and coping. Clin. Exp. Rheumatol. 38, 79–85 (2020).

    Google Scholar 

  262. Adler-Neal, A. L. & Zeidan, F. Mindfulness meditation for fibromyalgia: mechanistic and clinical considerations. Curr. Rheumatol. Rep. 19, 59 (2017).

    Article  Google Scholar 

  263. Pinto, A. M., Geenen, R., Castilho, P. & da Silva, J. A. P. Progress towards improved non-pharmacological management of fibromyalgia. Jt. Bone Spine 87, 377–379 (2020).

    Article  Google Scholar 

  264. Perrot, S. & Russell, I. J. More ubiquitous effects from non-pharmacologic than from pharmacologic treatments for fibromyalgia syndrome: a meta-analysis examining six core symptoms. Eur. J. Pain. 18, 1067–1080 (2014).

    Article  CAS  Google Scholar 

  265. Veehof, M. M., Trompetter, H. R., Bohlmeijer, E. T. & Schreurs, K. M. Acceptance- and mindfulness-based interventions for the treatment of chronic pain: a meta-analytic review. Cogn. Behav. Ther. 45, 5–31 (2016).

    Article  CAS  Google Scholar 

  266. Haugmark, T., Hagen, K. B., Smedslund, G. & Zangi, H. A. Mindfulness- and acceptance-based interventions for patients with fibromyalgia — a systematic review and meta-analyses. PLoS One 14, e0221897 (2019).

    Article  CAS  Google Scholar 

  267. Montero-Marin, J. et al. Efficacy of “Attachment-Based Compassion Therapy” in the treatment of fibromyalgia: a randomized controlled trial. Front. Psychiatry 8, 307 (2017).

    Article  Google Scholar 

  268. Austin, J. et al. Compassion-based interventions for people with long-term physical conditions: a mixed methods systematic review. Psychol. Health 36, 16–42 (2021).

    Article  CAS  Google Scholar 

  269. Lumley, M. A. et al. Emotional awareness and expression therapy, cognitive behavioral therapy, and education for fibromyalgia: a cluster-randomized controlled trial. Pain 158, 2354–2363 (2017).

    Article  Google Scholar 

  270. Trindade, I. A., Ferreira, C. & Pinto-Gouveia, J. Acceptability and preliminary test of efficacy of the mind programme in women with breast cancer: an acceptance, mindfulness, and compassion-based intervention. J. Context. Behav. Sci. 15, 162–171 (2020).

    Article  Google Scholar 

  271. Carvalho, S. A. et al. Self-compassion in acceptance and commitment therapy for chronic pain: a pilot study. Scand. J. Pain. 22, 631–638 (2021).

    Article  Google Scholar 

  272. Bernardy, K., Klose, P., Welsch, P. & Häuser, W. Efficacy, acceptability and safety of Internet-delivered psychological therapies for fibromyalgia syndrome: a systematic review and meta-analysis of randomized controlled trials. Eur. J. Pain. 23, 3–14 (2019).

    Article  CAS  Google Scholar 

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Acknowledgements

A.M.P. is the holder of a PhD Grant (SFRH/BD/145954/2019), sponsored by the Portuguese Foundation for Science and Technology (FCT), the Human Capital Operational Programme (POCH) and the European Union (EU), and was financially supported (through a stipend) for this work by the Coimbra Rheumatology Association (ARCo) and the Portuguese Society of Rheumatology (SPR). M.L.-S. is a Serra Hunter Lecturer Professor at the School of Medicine, University of Barcelona.

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A.M.P., F.P., M.L. and R.G. researched data for the article. J.A.P.S., A.M.P., R.G., E.K. and M.L. wrote the article. J.A.P.S., A.M.P., R.G., T.D.W., M.A.L., W.H., E.K., M.L.-S., J.L.R. and J.W.G.J. made a substantial contribution to discussion of the content. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to José A. P. da Silva.

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E.K. reports personal fees from Eli Lilly, Sandoz and UCB Pharma, outside the submitted work. T.R.M. reports personal fees from Lundbeck, Astellas, Janssen and Angelini outside the submitted work. R.G., T.D.W., M.A.L., W.H., J.N.A., K.A., J.B., D.B., J.C., M.C.-B., L.J.C., M.-A.F., M.L.-S., M.L., P.J.M., F.P., J.L.R., L.Q.U., P.C., J.W.G.J. and J.A.P.S. declare no competing interests.

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Pinto, A.M., Geenen, R., Wager, T.D. et al. Emotion regulation and the salience network: a hypothetical integrative model of fibromyalgia. Nat Rev Rheumatol 19, 44–60 (2023). https://doi.org/10.1038/s41584-022-00873-6

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