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Functional neurological disorder and placebo and nocebo effects: shared mechanisms

Nature Reviews Neurology volume 18, pages 624–635 (2022)Cite this article

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Abstract

Functional neurological disorder (FND) is characterized by neurological symptoms that cannot be explained by a structural neurological cause. Among the different aetiological models that have been proposed for FND, of note is the Bayesian predictive coding model, which posits that perception relies on top-down cortical predictions (priors) to infer the source of incoming sensory information. This model can also apply to non-pathological experiences, such as placebo and nocebo effects, wherein sensory information is shaped by prior expectations and learning. To date, most studies of the relationship between placebo and nocebo effects and FND have focused on the use of placebos for diagnosis and treatment of FND. Here, we propose that this relationship might go beyond diagnosis and therapy. We develop a framework in which shared cognitive, personality and neuroanatomical factors justify the consideration of a deeper link between FND and placebo and nocebo effects. This new perspective might offer guidance for clarification of the pathogenesis of FND and for the identification of potential biomarkers and therapeutic targets.

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Fig. 1: The predictive coding model applied to functional symptoms, placebo and nocebo.
Fig. 2: Schematic representation of the brain areas involved in functional motor and sensory symptoms and nocebo hyperalgesia.
Fig. 3: Overlap between functional neurological disorder (FND) and nocebo effects: key brain regions and mechanisms.

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References

  1. Hallett, M. et al. Functional neurological disorder: new subtypes and shared mechanisms. Lancet Neurol. 21, 537–550 (2022).

    CAS  PubMed  Google Scholar 

  2. Reuber, M. & Brown, R. J. Understanding psychogenic nonepileptic seizures — phenomenology, semiology and the integrative cognitive model. Seizure 44, 199–205 (2017).

    PubMed  Google Scholar 

  3. Edwards, M. J. & Bhatia, K. P. Functional (psychogenic) movement disorders: merging mind and brain. Lancet Neurol. 11, 250–260 (2012).

    PubMed  Google Scholar 

  4. Keynejad, R. C. et al. Stress and functional neurological disorders: mechanistic insights. J. Neurol. Neurosurg. Psychiatry 90, 813–821 (2019).

    PubMed  Google Scholar 

  5. Brown, R. J. Psychological mechanisms of medically unexplained symptoms: an integrative conceptual model. Psychol. Bull. 130, 793–812 (2004).

    PubMed  Google Scholar 

  6. Stone, J. et al. The role of physical injury in motor and sensory conversion symptoms: a systematic and narrative review. J. Psychosom. Res. 66, 383–390 (2009).

    PubMed  Google Scholar 

  7. Edwards, M. J., Adams, R. A., Brown, H., Pareés, I. & Friston, K. J. A Bayesian account of “hysteria”. Brain 135, 3495–3512 (2012).

    PubMed  PubMed Central  Google Scholar 

  8. Friston, K., Kilner, J. & Harrison, L. A free energy principle for the brain. J. Physiol. Paris. 100, 70–87 (2006).

    PubMed  Google Scholar 

  9. Marotta, A. et al. Functional neurological disorders as seen by a cohort of general practitioners in northern Italy: evidence from an online survey. Front. Neurol. 12, 583672 (2021).

    PubMed  PubMed Central  Google Scholar 

  10. Barbey, A. et al. Management of functional neurological disorders (FND): experience from a Swiss FND clinic. Clin. Trans. Neurosci. 6, 2 (2022).

    Google Scholar 

  11. Pick, S. et al. Outcome measurement in functional neurological disorder: a systematic review and recommendations. J. Neurol. Neurosurg. Psychiatry 91, 638–649 (2020).

    PubMed  Google Scholar 

  12. Benedetti, F. Placebo and the new physiology of the doctor–patient relationship. Physiol. Rev. 93, 1207–1246 (2013).

    PubMed  PubMed Central  Google Scholar 

  13. Colloca, L. & Miller, F. G. How placebo responses are formed: a learning perspective. Philos. Trans. R. Soc. B Biol. Sci. 366, 1859–1869 (2011).

    Google Scholar 

  14. Burke, M. J. et al. Leveraging the shared neurobiology of placebo effects and functional neurological disorder: a call for research. J. Neuropsychiatry Clin. Neurosci. 32, 101–104 (2020).

    PubMed  Google Scholar 

  15. Edwards, M. J., Bathia, K. P. & Cordivari, C. Immediate response to botulinum toxin injections in patients with fixed dystonia. Mov. Disord. 26, 917–918 (2011).

    PubMed  Google Scholar 

  16. Huys, A. C. M. L., Haggard, P., Bhatia, K. P. & Edwards, M. J. Misdirected attentional focus in functional tremor. Brain 144, 3436–3450 (2021).

    PubMed  PubMed Central  Google Scholar 

  17. McIntosh, R., McWhriter, L., Ludwig, L., Carson, A. & Stone, J. Attention and sensation in functional motor disorder. Neuropsychologia 106, 207–215 (2017).

    PubMed  Google Scholar 

  18. Roelofs, K., van Galen, G. P., Eling, P., Keijsers, G. P. J. & Hoogduin, C. Endogenous and exogenous attention in patients with conversion paresis. Cogn. Neuropsychol. 20, 733–745 (2003).

    PubMed  Google Scholar 

  19. Edwards, M. J., Fotopoulou, A. & Pareés, I. Neurobiology of functional (psychogenic) movement disorders. Curr. Opin. Neurol. 26, 442–447 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Pareés, I. et al. Failure of explicit movement control in patients with functional motor symptoms. Mov. Disord. 28, 517–523 (2013).

    PubMed  Google Scholar 

  21. Gandolfi, M. et al. Motor dual task with eyes closed improves postural control in patients with functional motor disorders: a posturographic study. Gait Posture 88, 286–291 (2021).

    PubMed  Google Scholar 

  22. Summerfield, C. & Egner, T. Expectation (and attention) in visual cognition. Trends Cogn. Sci. 13, 403–409 (2009).

    PubMed  Google Scholar 

  23. Fiorio, M. et al. Enhancing non-noxious perception: behavioural and neurophysiological correlates of a placebo-like manipulation. Neuroscience 217, 96–104 (2012).

    CAS  PubMed  Google Scholar 

  24. Posner, M. I., Snyder, C. R. & Davidson, B. J. Attention and the detection of signals. J. Exp. Psychol. 109, 160–174 (1980).

    CAS  PubMed  Google Scholar 

  25. Palmer, T. E. The effects of contextual scenes on the identification of objects. Mem. Cogn. 3, 519–526 (1975).

    CAS  Google Scholar 

  26. von Helmholtz, H. V. Treatise on Psychological Optics (trans. Southall, J. P. C.) (Dover, 1962).

  27. Corbetta, M. & Shulman, G. L. Control of goal-directed and stimulus-driven attention in the brain. Nat. Rev. Neurosci. 3, 201–215 (2002).

    CAS  PubMed  Google Scholar 

  28. Mulckhuyse, M. & Dalmaijer, E. S. Distracted by danger: temporal and spatial dynamics of visual selection in the presence of threat. Cogn. Affect. Behav. Neurosci. 16, 315–324 (2016).

    PubMed  Google Scholar 

  29. Bakvis, P., Spinhoven, P. & Roelofs, K. Basal cortisol is positively correlated to threat vigilance in patients with psychogenic nonepileptic seizures. Epilepsy Behav. 16, 558–560 (2009).

    PubMed  Google Scholar 

  30. Reuber, M. The etiology of psychogenic non-epileptic seizures: toward a biopsychosocial model. Neurol. Clin. 27, 909–924 (2009).

    PubMed  Google Scholar 

  31. Beissner, F. et al. Placebo-induced somatic sensations: a multi-modal study of three different placebo interventions. PLoS ONE 10, e0124808 (2015).

    PubMed  PubMed Central  Google Scholar 

  32. Colloca, L., Sigaudo, M. & Benedetti, F. The role of learning in nocebo and placebo effects. Pain 136, 211–218 (2008).

    CAS  PubMed  Google Scholar 

  33. Vellemure, C. & Bushnell, C. M. Cognitive modulation of pain: how do attention and emotion influence pain processing? Pain 95, 195–199 (2002).

    Google Scholar 

  34. Geers, A. L., Helfer, S. G., Weiland, P. E. & Kosbab, K. Expectations and placebo response: a laboratory investigation into the role of somatic focus. J. Behav. Med. 29, 171–178 (2006).

    PubMed  Google Scholar 

  35. Kirmayer, L. J. & Young, A. Culture and somatization: clinical, epidemiological, and ethnographic perspectives. Psychosom. Med. 60, 420–430 (1998).

    CAS  PubMed  Google Scholar 

  36. van den Bergh, O., Witthöft, M., Petersen, S. & Brown, R. J. Symptoms and the body: taking the inferential leap. Neurosci. Biobehav. Rev. 74, 185–203 (2017).

    PubMed  Google Scholar 

  37. Sharpe, D. & Faye, C. Non-epileptic seizures and child sexual abuse: a critical review of the literature. Clin. Psychol. Rev. 26, 1020–1040 (2006).

    PubMed  Google Scholar 

  38. Jungilligens, J., Paredes-Echeverri, S., Popkirov, S., Barrett, L. F. & Perez, D. L. A new science of emotion: implications for functional neurological disorder. Brain https://doi.org/10.1093/brain/awac204 (2022).

    Article  PubMed  Google Scholar 

  39. Goldstein, L. H. & Mellers, J. D. Ictal symptoms of anxiety, avoidance behaviour, and dissociation in patients with dissociative seizures. J. Neurol. Neurosurg. Psychiatry 77, 616–621 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Wessely, S., Sharpe, M. & Hotopf, M. Chronic Fatigue and its Syndromes (Oxford Univ. Press, 1998).

  41. Kirsch, I. Response expectancy as a determinant of experience and behavior. Am. Psychol. 40, 1189–1202 (1985).

    Google Scholar 

  42. Pareés, I. et al. “Jumping to conclusions” bias in functional movement disorders. J. Neurol. Neurosurg. Psychiatry 83, 460–463 (2012).

    PubMed  Google Scholar 

  43. Kaptchuk, T. J., Hemond, C. C. & Miller, F. G. Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice. BMJ 370, m1668 (2020).

    PubMed  Google Scholar 

  44. Büchel, C., Geuter, S., Sprenger, C. & Eippert, F. Placebo analgesia: a predictive coding perspective. Neuron 81, 1223–1239 (2014).

    PubMed  Google Scholar 

  45. Colloca, L., Lopiano, L., Lanotte, M. & Benedetti, F. Overt versus covert treatment for pain, anxiety, and Parkinson’s disease. Lancet Neurol. 3, 679–684 (2004).

    PubMed  Google Scholar 

  46. Pollo, A. et al. Response expectancies in placebo analgesia and their clinical relevance. Pain 93, 77–84 (2001).

    PubMed  Google Scholar 

  47. van Laarhoven, A. I. et al. Induction of nocebo and placebo effects on itch and pain by verbal suggestions. Pain 152, 1486–1494 (2011).

    PubMed  Google Scholar 

  48. Benedetti, F. et al. Open versus hidden medical treatments: the patient’s knowledge about a therapy affects the therapy outcome. Prev. Treat. 6, 1a (2013).

    Google Scholar 

  49. Lidstone, S. C. et al. Effects of expectation on placebo induced dopamine release in Parkinson disease. Arch. Gen. Psychiatry 67, 857–865 (2010).

    CAS  PubMed  Google Scholar 

  50. Kaptchuk, T. J. Open-label placebo: reflections on a research agenda. Perspect. Biol. Med. 61, 311–334 (2018).

    PubMed  Google Scholar 

  51. Carvalho, C. et al. Open-label placebo treatment in chronic low back pain: a randomized controlled trial. Pain 157, 2766–2772 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kaptchuk, T. J. et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS ONE 5, e15591 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ongaro, G. & Kaptchuk, T. J. Symptom perception, placebo effects, and the Bayesian brain. Pain 160, 1–4 (2019).

    PubMed  Google Scholar 

  54. Jensen, K. B. et al. Nonconscious activation of placebo and nocebo pain responses. Proc. Natl Acad. Sci. USA 109, 15959–15964 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Fiorio, M., Emadi Andani, M., Marotta, A., Classen, J. & Tinazzi, M. Placebo-induced changes in excitatory and inhibitory corticospinal circuits during motor performance. J. Neurosci. 34, 3993–4005 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Benedetti, F., Pollo, A. & Colloca, L. Opioid-mediated placebo responses boost pain endurance and physical performance: is it doping in sport competitions? J. Neurosci. 27, 11934–11939 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Pollo, A., Carlino, E. & Benedetti, F. The top‐down influence of ergogenic placebos on muscle work and fatigue. Eur. J. Neurosci. 28, 379–388 (2008).

    PubMed  Google Scholar 

  58. Benedetti, F. et al. Teaching neurons to respond to placebos. J. Physiol. 594, 5647–5660 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Garcin, B. et al. Impact of transcranial magnetic stimulation on functional movement disorders: cortical modulation or a behavioral effect? Front. Neurol. 8, 338 (2017).

    PubMed  PubMed Central  Google Scholar 

  60. van den Bergh, O., Winters, W., Devriese, S. & van Diest, I. Learning subjective health complaints. Scand. J. Psychol. 43, 147–152 (2002).

    PubMed  Google Scholar 

  61. Stegen, K., de Bruyne, K., Rasschaert, W., van de Woestijne, K. P. & van den Bergh, O. Fear-relevant images as conditioned stimuli for somatic complaints, respiratory behavior, and reduced end-tidal pCO2. J. Abnorm. Psychol. 108, 143–152 (1999).

    CAS  PubMed  Google Scholar 

  62. Wieder, L., Brown, R., Thompson, T. & Terhune, D. B. Suggestibility in functional neurological disorder: a meta-analysis. J. Neurol. Neurosurg. Psychiatry 92, 150–157 (2021).

    PubMed  Google Scholar 

  63. Eysenck, H. J. Suggestibility and hysteria. J. Neurol. Neurosurg. Psychiatry 6, 22–31 (1943).

    CAS  Google Scholar 

  64. Roelofs, K. et al. Hypnotic susceptibility in patients with conversion disorder. J. Abnorm. Psychol. 111, 390–395 (2002).

    PubMed  Google Scholar 

  65. Deeley, Q. Hypnosis as a model of functional neurologic disorders. Handb. Clin. Neurol. 139, 95–103 (2016).

    CAS  PubMed  Google Scholar 

  66. Phillips, W., Price, J., Molyneux, P. D. & Deeley, Q. Hypnosis. Pract. Neurol. 22, 42–47 (2022).

    PubMed  Google Scholar 

  67. Roelofs, K., Hoogduin, K. A. L. & Keijsers, G. P. J. Motor imagery during hypnotic arm paralysis in high and low hypnotizable subjects. Int. J. Clin. Exp. Hypn. 50, 51–66 (2002).

    PubMed  Google Scholar 

  68. Moene, F. C., Spinhoven, P., Hoogduin, K., Sandyck, P. & Roelofs, K. Hypnotizability, dissociation and trauma in patients with a conversion disorder: an exploratory study. Clin. Psychol. Psychother. 8, 400–410 (2001).

    Google Scholar 

  69. de Pascalis, V., Chiaradia, C. & Carotenuto, E. The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting. Pain 96, 393–402 (2002).

    PubMed  Google Scholar 

  70. de Pascalis, V. & Scacchia, P. Hypnotizability and placebo analgesia in waking and hypnosis as modulators of auditory startle responses in healthy women: an ERP study. PLoS ONE 11, e0159135 (2016).

    PubMed  PubMed Central  Google Scholar 

  71. Huys, A. C. M. L., Beck, B., Haggard, P., Bhatia, K. P. & Edwards, M. J. No increased suggestibility to placebo in functional neurological disorder. Eur. J. Neurol. 28, 2367–2371 (2021).

    PubMed  Google Scholar 

  72. Jalilianhasanpour, R. et al. Resilience linked to personality dimensions, alexithymia and affective symptoms in motor functional neurological disorders. J. Psychosom. Res. 107, 55–61 (2018).

    PubMed  PubMed Central  Google Scholar 

  73. Bokharey, I. Z. Resilience and coping strategies in the patients with conversion disorder and general medical conditions: a comparative study. Malays. J. Psychiatry 22, 39–50 (2013).

    Google Scholar 

  74. Demartini, B. et al. The role of alexithymia in the development of functional motor symptoms (conversion disorder). J. Neurol. Neurosurg. Psychiatry 85, 1132–1137 (2014).

    PubMed  Google Scholar 

  75. Perez, D. L. et al. Corticolimbic structural alterations linked to health status and trait anxiety in functional neurological disorder. J. Neurol. Neurosurg. Psychiatry 88, 1052–1059 (2017).

    PubMed  Google Scholar 

  76. Macchi, Z. A., Kletenik, I., Olvera, C. & Holden, S. K. Psychiatric comorbidities in functional movement disorders: a retrospective cohort study. Mov. Disord. Clin. Pract. 8, 725–732 (2021).

    PubMed  PubMed Central  Google Scholar 

  77. Rady, A., Elfatatry, A., Molokhia, T. & Radwan, A. Psychiatric comorbidities in patients with psychogenic nonepileptic seizures. Epilepsy Behav. 118, 107918 (2021).

    PubMed  Google Scholar 

  78. Anderson, K. E. et al. Impact of psychogenic movement disorders versus Parkinson’s on disability, quality of life, and psychopathology. Mov. Disord. 22, 2204–2209 (2007).

    PubMed  Google Scholar 

  79. Bakvis, P. et al. Trauma, stress, and preconscious threat processing in patients with psychogenic nonepileptic seizures. Epilepsia 50, 1001–1011 (2009).

    PubMed  Google Scholar 

  80. Bakvis, P., Spinhoven, P., Putman, P., Zitman, F. G. & Roelofs, K. The effect of stress induction on working memory in patients with psychogenic nonepileptic seizures. Epilepsy Behav. 19, 448–454 (2010).

    PubMed  Google Scholar 

  81. Kranick, S. et al. Psychopathology and psychogenic movement disorders. Mov. Disord. 26, 1844–1850 (2011).

    PubMed  PubMed Central  Google Scholar 

  82. Baur, V., Hänggi, J. & Jäncke, L. Volumetric associations between uncinate fasciculus, amygdala, and trait anxiety. BMC Neurosci. 13, 4 (2012).

    PubMed  PubMed Central  Google Scholar 

  83. Kuhn, S., Schubert, F. & Gallinat, J. Structural correlates of trait anxiety: reduced thickness in medial orbitofrontal cortex accompanied by volume increase in nucleus accumbens. J. Affect. Disord. 134, 315–319 (2011).

    PubMed  Google Scholar 

  84. Spampinato, M. V., Wood, J. N., de Simone, V. & Grafman, J. Neural correlates of anxiety in healthy volunteers: a voxel-based morphometry study. J. Neuropsychiatry Clin. Neurosci. 21, 199–205 (2009).

    PubMed  Google Scholar 

  85. Blackmon, K. et al. Structural evidence for involvement of a left amygdala–orbitofrontal network in subclinical anxiety. Psychiatry Res. Neuroimaging 194, 296–303 (2011).

    Google Scholar 

  86. Kern, A., Kramm, C., Witt, C. M. & Barth, J. The influence of personality traits on the placebo/nocebo response: a systematic review. J. Psychosom. Res. 128, 109866 (2020).

    PubMed  Google Scholar 

  87. Benedetti, F., Lanotte, M., Lopiano, L. & Colloca, L. When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience 147, 260–271 (2007).

    CAS  PubMed  Google Scholar 

  88. Benedetti, F., Amanzio, M., Vighetti, S. & Asteggiano, G. The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. J. Neurosci. 26, 12014–12022 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Hebb, A. L., Poulin, J. F., Roach, S. P., Zacharko, R. M. & Drolet, G. Cholecystokinin and endogenous opioid peptides: interactive influence on pain, cognition, and emotion. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 1225–1238 (2005).

    CAS  PubMed  Google Scholar 

  90. Bradwejn, J. & Koszycki, D. Cholecystokinin and panic disorder: past and future clinical research strategies. Scand. J. Clin. Lab. Invest. 61, 19–27 (2001).

    CAS  Google Scholar 

  91. Benedetti, F., Amanzio, M., Giovannelli, F., Craigs-Brackhahn, K. & Shaibani, A. Hypothalamic–pituitary–adrenal activity in adverse events reporting after placebo administration. Clin. Pharmacol. Ther. 110, 1349–1357 (2021).

    CAS  PubMed  Google Scholar 

  92. Uhlenhuth, E. H. et al. Medication side effects in anxious patients: negative placebo responses? J. Affect. Disord. 47, 183–190 (1998).

    CAS  PubMed  Google Scholar 

  93. Planès, S., Villier, C. & Mallaret, M. The nocebo effect of drugs. Pharmacol. Res. Perspect. 4, e00208 (2016).

    PubMed  PubMed Central  Google Scholar 

  94. Barsky, A. J., Saintfort, R., Rogers, M. P. & Borus, J. F. Nonspecific medication side effects and the nocebo phenomenon. Jama 287, 622–627 (2002).

    PubMed  Google Scholar 

  95. Bekhuis, E., Boschloo, L., Rosmalen, J. G. & Schoevers, R. A. Differential associations of specific depressive and anxiety disorders with somatic symptoms. J. Psychosom. Res. 78, 116–122 (2015).

    PubMed  Google Scholar 

  96. Agosti, V., Quitkin, F. M., Stewart, J. W. & McGrath, P. J. Somatization as a predictor of medication discontinuation due to adverse events. Int. Clin. Psychopharmacol. 17, 311–314 (2002).

    CAS  PubMed  Google Scholar 

  97. Colagiuri, B. & Quinn, V. F. Autonomic arousal as a mechanism of the persistence of nocebo hyperalgesia. J. Pain. 19, 476–486 (2018).

    PubMed  Google Scholar 

  98. Robbins, N. M., Larimer, P., Bourgeois, J. A. & Lowenstein, D. H. Number of patient-reported allergies helps distinguish epilepsy from psychogenic nonepileptic seizures. Epilepsy Behav. 55, 174–177 (2016).

    PubMed  PubMed Central  Google Scholar 

  99. Aybek, S. et al. Emotion–motion interactions in conversion disorder: an fMRI study. PLoS ONE 10, e0123273 (2015).

    PubMed  PubMed Central  Google Scholar 

  100. Voon, V. et al. Emotional stimuli and motor conversion disorder. Brain 133, 1526–1536 (2010).

    PubMed  PubMed Central  Google Scholar 

  101. Voon, V., Brezing, C., Gallea, C. & Hallett, M. Aberrant supplementary motor complex and limbic activity during motor preparation in motor conversion disorder. Mov. Disord. 26, 2396–2403 (2011).

    PubMed  PubMed Central  Google Scholar 

  102. Apazoglou, K., Mazzola, V., Wegrzyk, J., Polara, G. F. & Aybek, S. Biological and perceived stress in motor functional neurological disorders. Psychoneuroendocrinology 85, 142–150 (2017).

    PubMed  Google Scholar 

  103. Voon, V. et al. Functional neuroanatomy and neurophysiology of functional neurological disorders (conversion disorder). J. Neuropsychiatry Clin. Neurosci. 28, 168–190 (2016).

    PubMed  Google Scholar 

  104. Ashar, Y. K., Chang, L. J. & Wager, T. D. Brain mechanisms of the placebo effect: an affective appraisal account. Annu. Rev. Clin. Psychol. 13, 73–89 (2017).

    PubMed  Google Scholar 

  105. Furmark, T. et al. A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety. J. Neurosci. 28, 13066–13074 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Atlas, L. Y. et al. Dissociable influences of opiates and expectations on pain. J. Neurosci. 32, 8053–8064 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Eippert, F. et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63, 533–543 (2009).

    CAS  PubMed  Google Scholar 

  108. Zhang, W., Qin, S., Guo, J. & Luo, J. A follow-up fMRI study of a transferable placebo anxiolytic effect. Psychophysiol 48, 1119–1128 (2011).

    Google Scholar 

  109. Egorova, N., Benedetti, F., Gollub, R. L. & Kong, J. Between placebo and nocebo: response to control treatment is mediated by amygdala activity and connectivity. Eur. J. Pain. 24, 580–592 (2020).

    PubMed  Google Scholar 

  110. Levy, I. & Schiller, D. Neural computations of threat. Trends Cogn. Sci. 25, 151–171 (2021).

    PubMed  Google Scholar 

  111. Zhang, S., Mano, H., Hanesh, G., Robbins, T. & Seymour, B. Dissociable learning processes underlie human pain conditioning. Curr. Biol. 26, 52–58 (2016).

    PubMed  PubMed Central  Google Scholar 

  112. Rommelfanger, K. S. The role of placebo in the diagnosis and treatment of functional neurologic disorders. Handb. Clin. Neurol. 139, 607–617 (2016).

    CAS  PubMed  Google Scholar 

  113. Devinsky, O. & Fisher, R. Ethical use of placebos and provocative testing in diagnosing nonepileptic seizures. Neurology 47, 866–870 (1996).

    CAS  PubMed  Google Scholar 

  114. Kaas, B. M., Humbyrd, C. J. & Pantelyat, A. Functional movement disorders and placebo: a brief review of the placebo effect in movement disorders and ethical considerations for placebo therapy. Mov. Disord. Clin. Pract. 5, 471–478 (2018).

    PubMed  PubMed Central  Google Scholar 

  115. Bartels, D. J. P. et al. Minimizing nocebo effects by conditioning with verbal suggestion: a randomized clinical trial in healthy humans. PLoS ONE 12, e0182959 (2017).

    PubMed  PubMed Central  Google Scholar 

  116. Darragh, M., Booth, R. J. & Consedine, N. S. Who responds to placebos? Considering the “placebo personality” via a transactional model. Psychol. Health Med. 20, 287–295 (2015).

    PubMed  Google Scholar 

  117. Lorber, W., Mazzoni, G. & Kirsch, I. Illness by suggestion: expectancy, modeling, and gender in the production of psychosomatic symptoms. Ann. Behav. Med. 33, 112–116 (2007).

    PubMed  Google Scholar 

  118. Benedetti, F., Durando, J. & Vighetti, S. Nocebo and placebo modulation of hypobaric hypoxia headache involves the cyclooxygenase–prostaglandins pathway. Pain 155, 921–928 (2014).

    CAS  PubMed  Google Scholar 

  119. di Blasi, Z., Harkness, E., Ernst, E., Georgiou, A. & Kleijnen, J. Influence of context effect on health outcomes: a systematic review. Lancet 357, 757–762 (2001).

    PubMed  Google Scholar 

  120. Howe, L. C., Goyer, J. P. & Crum, A. J. Harnessing the placebo effect: exploring the influence of physician characteristics on placebo response. Health Psychol. 36, 1074–1082 (2017).

    PubMed  PubMed Central  Google Scholar 

  121. Nielsen, G., Buszewicz, M., Edwards, M. J. & Stevenson, F. A qualitative study of the experiences and perceptions of patients with functional motor disorder. Disab. Rehab. 42, 2043–2048 (2020).

    Google Scholar 

  122. Espay, A. J. et al. Current concepts in diagnosis and treatment of functional neurological disorders. JAMA Neurol. 75, 1132–1141 (2018).

    PubMed  PubMed Central  Google Scholar 

  123. Stone, J. & Vermeulen, M. Functional sensory symptoms. Handb. Clin. Neurol. 139, 271–281 (2016).

    CAS  PubMed  Google Scholar 

  124. Bell, H. A. et al. Functional cognitive disorder: dementia’s blind spot. Brain 143, 2895–2903 (2020).

    Google Scholar 

  125. Yon, D. & Frith, C. D. Precision and the Bayesian brain. Curr. Biol. 31, R1026–R1032 (2021).

    CAS  PubMed  Google Scholar 

  126. Friston, K. J., Parr, T. & de Vries, B. The graphical brain: belief propagation and active inference. Netw. Neurosci. 1, 381–414 (2017).

    PubMed  PubMed Central  Google Scholar 

  127. Rommelfanger, K. S. Opinion: a role for placebo therapy in psychogenic movement disorders. Nat. Rev. Neurol. 9, 351–356 (2013).

    PubMed  Google Scholar 

  128. Fahn, S. & Williams, D. T. Psychogenic dystonia. Adv. Neurol. 50, 431–455 (1988).

    CAS  PubMed  Google Scholar 

  129. Factor, S. A., Podskalny, G. D. & Molho, E. S. Psychogenic movement disorders: frequency, clinical profile, and characteristics. J. Neurol. Neurosurg. Psychiatry 59, 406–412 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Baik, J. S. Attention in Parkinson’s disease mimicking suggestion in psychogenic movement disorder. J. Mov. Disord. 5, 53 (2012).

    PubMed  PubMed Central  Google Scholar 

  131. Hall-Patch, L. et al. Acceptability and effectiveness of a strategy for the communication of the diagnosis of psychogenic nonepileptic seizures. Epilepsia 51, 70–78 (2010).

    PubMed  Google Scholar 

  132. Carson, A., Ludwig, L. & Welch, K. Psychologic theories in functional neurologic disorders. Handb. Clin. Neurol. 139, 105–120 (2016).

    CAS  PubMed  Google Scholar 

  133. Baslet, G., Ehlert, A., Oser, M. & Dworetzky, B. A. Mindfulness-based therapy for psychogenic nonepileptic seizures. Epilepsy Behav. 103, 106534 (2020).

    PubMed  Google Scholar 

  134. Larsson, M. J., Steffen, P. R. & Primosch, M. The impact of a brief mindfulness meditation intervention on cognitive control and error-related performance monitoring. Front. Hum. Neurosci. 7, 308 (2013).

    Google Scholar 

  135. Howlett, S. & Reuber, M. An augmented model of brief psychodynamic interpersonal therapy for patients with nonepileptic seizures. Psychotherapy 46, 125–138 (2009).

    PubMed  Google Scholar 

  136. Mogg, K. & Bradley, B. P. Anxiety and attention to threat: cognitive mechanisms and treatment with attention bias modification. Behav. Res. Ther. 87, 76–108 (2016).

    PubMed  Google Scholar 

  137. Richardson, M., Isbister, G. & Nicholson, B. A novel treatment protocol (Nocebo Hypothesis Cognitive Behavioural Therapy; NH-CBT) for functional neurological symptom disorder/conversion disorder: a retrospective consecutive case series. Behav. Cogn. Psychother. 46, 497–503 (2018).

    PubMed  Google Scholar 

  138. Richardson, M., Kleinstäuber, M. & Wong, D. Nocebo-Hypothesis Cognitive Behavioral Therapy (NH-CBT) for persons with functional neurological symptoms (motor type): design and implementation of a randomized active-controlled trial. Front. Neurol. 11, 586359 (2020).

    PubMed  PubMed Central  Google Scholar 

  139. Moene, F. C., Spinhoven, P., Hoogduin, K. A. L. & van Dyck, R. A randomized controlled clinical trial of a hypnosis-based treatment for patients with conversion disorder, motor type. Int. J. Clin. Exp. Hypn. 51, 29–50 (2003).

    PubMed  Google Scholar 

Download references

Acknowledgements

The work of M.B. and A.M. is partially supported by Italian Ministry of Research and University (MIUR) 5-year special funding to strengthen and enhance excellence in research and teaching (https://www.miur.gov.it/dipartimenti-di-eccellenza).

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Author notes

  1. These authors contributed equally: Mark J. Edwards and Michele Tinazzi.

Authors and Affiliations

  1. Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

    Mirta Fiorio, Miriam Braga, Angela Marotta, Michele Tinazzi & Diletta Barbiani

  2. Center for Mind/Brain Sciences (CIMeC), University of Trento, Rovereto, Italy

    Bernardo Villa-Sánchez

  3. Institute of Molecular and Clinical Sciences, St George’s University of London, London, UK

    Mark J. Edwards

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Contributions

M.F. developed the idea of the article. D.B., M.F. and M.B. researched data for the article. M.B wrote the first draft of the manuscript. M.F., D.B., M.T., M.J.E., A.M. and B.V.-S. reviewed and critically edited the manuscript. All authors contributed substantially to discussions of the article content and to the review or editing of the manuscript before submission.

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Correspondence to Mirta Fiorio.

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Competing interests

M.J.E. has received honoraria for speaking from Merz Pharma and UCB, and royalties from Oxford University Press, and provides expert witness opinions in clinical negligence and personal injury cases. All other authors declare no competing interests.

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Glossary

Classical conditioning

A type of associative learning in which repeated pairings of a neutral stimulus (for example, an inert pill) with an unconditioned stimulus (for example, an active drug) lead to a conditioned response (for example, symptom improvement) when the originally neutral — now conditioned — stimulus is presented.

Cueing effect

A phenomenon whereby the processing of specific targets is facilitated when they are preceded by a cue that reliably indicates the location in which they will occur.

Environmental contingencies

Interplay between different contextual factors which synergistically produce an effect on behaviour.

Physiological arousal

An individual’s state of activation that involves different physiological responses (for example, increase in blood pressure and rate of respiration).

Precipitating factors

Biological, psychological and/or social factors that can occur from some months to a few days before the first symptom manifestation and cause the onset of functional neurological disorder (FND) (for example, physical injury and psychological stress).

Predisposing factors

Biological, psychological and/or social factors that increase vulnerability to develop functional neurological disorder (FND) (for example, genetic factors, illness exposure and psychosocial adversity).

Priors

Conscious or unconscious predictions/expectations through which the brain anticipates and explains physical sensations or external sensory information.

Response expectancies

Predictions of one’s own non-volitional responses (for example, automatic reactions) to specific events.

Trait anxiety

An individual’s stable tendency to experience feelings of apprehension and nervousness.

Triggering events

Events that trigger the recurrent manifestation of symptoms in functional neurological disorder (FND).

Somatization

A psychological mechanism in which psychological distress is expressed through bodily symptoms.

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Fiorio, M., Braga, M., Marotta, A. et al. Functional neurological disorder and placebo and nocebo effects: shared mechanisms. Nat Rev Neurol 18, 624–635 (2022). https://doi.org/10.1038/s41582-022-00711-z

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