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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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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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Nature Reviews Neurology thanks Gaston Baslet, Matthew Burke and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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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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