Hostname: page-component-586b7cd67f-vdxz6 Total loading time: 0 Render date: 2024-11-29T00:26:11.410Z Has data issue: false hasContentIssue false
  • English
  • Français

A framework for understanding the pathophysiology of functional neurological disorder

Published online by Cambridge University Press:  04 September 2020

Daniel L. Drane Open the ORCID record for Daniel L. Drane [Opens in a new window] ,
Negar Fani Open the ORCID record for Negar Fani [Opens in a new window] ,
Mark Hallett Open the ORCID record for Mark Hallett [Opens in a new window] ,
Sahib S. Khalsa Open the ORCID record for Sahib S. Khalsa [Opens in a new window] ,
David L. Perez Open the ORCID record for David L. Perez [Opens in a new window]  and
Nicole A. Roberts Open the ORCID record for Nicole A. Roberts [Opens in a new window]
Daniel L. Drane
Affiliation:
Departments of Neurology and Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
Negar Fani
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory School of Medicine, Atlanta, Georgia, USA
Mark Hallett
Affiliation:
Human Motor Control Section, NINDS, National Institutes of Health, Bethesda, Maryland, USA
Sahib S. Khalsa
Affiliation:
Laureate Institute for Brain Research, Tulsa, Oklahoma, USA Oxley College of Health Sciences, The University of Tulsa, Tulsa, Oklahoma, USA
David L. Perez*
Affiliation:
Cognitive Behavioral Neurology and Neuropsychiatry Units, Departments of Neurology and Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
Nicole A. Roberts
Affiliation:
School of Social and Behavioral Sciences, Arizona State University, Phoenix, Arizona, USA
*
*Author for correspondence: David L. Perez MD, MMSc, Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

The symptoms of functional neurological disorder (FND) are a product of its pathophysiology. The pathophysiology of FND is reflective of dysfunction within and across different brain circuits that, in turn, affects specific constructs. In this perspective article, we briefly review five constructs that are affected in FND: emotion processing (including salience), agency, attention, interoception, and predictive processing/inference. Examples of underlying neural circuits include salience, multimodal integration, and attention networks. The symptoms of each patient can be described as a combination of dysfunction in several of these networks and related processes. While we have gained a considerable understanding of FND, there is more work to be done, including determining how pathophysiological abnormalities arise as a consequence of etiologic biopsychosocial factors. To facilitate advances in this underserved and important area, we propose a pathophysiology-focused research agenda to engage government-sponsored funding agencies and foundations.

Keywords

psychogenicconversion disorderemotionagencyattentioninteroception
Type
Perspective
Information
CNS Spectrums , Volume 26 , Issue 6: Special Issue: Functional Neurological Disorder , December 2021 , pp. 555 - 561
Copyright
© The Author(s), 2020. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

All authors contributed equally to this study.

References

Baizabal-Carvallo, JF, Hallett, M, Jankovic, J. Pathogenesis and pathophysiology of functional (psychogenic) movement disorders. Neurobiol Dis. 2019;127:32–44.CrossRefGoogle ScholarPubMed
Begue, I, Adams, C, Stone, J, Perez, DL. Structural alterations in functional neurological disorder and related conditions: a software and hardware problem? Neuroimage Clin. 2019;22:101798.CrossRefGoogle ScholarPubMed
Espay, AJ, Aybek, S, Carson, A, et al. Current concepts in diagnosis and treatment of functional neurological disorders. JAMA Neurol. 2018;75(9):1132–1141.CrossRefGoogle ScholarPubMed
Hallett, M, Stone, J, Carson, AJ. Functional Neurological Disorders. Vol. 139. London: Academic Press; 2016.Google Scholar
McKenzie, PS, Oto, M, Graham, CD, Duncan, R. Do patients whose psychogenic non-epileptic seizures resolve, ‘replace’ them with other medically unexplained symptoms? Medically unexplained symptoms arising after a diagnosis of psychogenic non-epileptic seizures. J Neurol Neurosurg Psychiatry. 2011;82(9):967–969.CrossRefGoogle ScholarPubMed
Espay, AJ, Ries, S, Maloney, T, et al. Clinical and neural responses to cognitive behavioral therapy for functional tremor. Neurology. 2019;93(19):e1787–e1798.CrossRefGoogle ScholarPubMed
Zito, GA, Wiest, R, Aybek, S. Neural correlates of sense of agency in motor control: a neuroimaging meta-analysis. PLoS One. 2020;15(6):e0234321.CrossRefGoogle ScholarPubMed
Pick, S, Goldstein, LH, Perez, DL, Nicholson, TR. Emotional processing in functional neurological disorder: a review, biopsychosocial model and research agenda. J Neurol Neurosurg Psychiatry. 2019;90(6):704–711.CrossRefGoogle ScholarPubMed
Seeley, WW. The salience network: a neural system for perceiving and responding to homeostatic demands. J Neurosci. 2019;39(50):9878–9882.CrossRefGoogle ScholarPubMed
Voon, V, Brezing, C, Gallea, C, et al. Emotional stimuli and motor conversion disorder. Brain. 2010;133(5):1526–1536.CrossRefGoogle ScholarPubMed
Aybek, S, Nicholson, TR, Zelaya, F, et al. Neural correlates of recall of life events in conversion disorder. JAMA Psychiatry. 2014;71(1):52–60.CrossRefGoogle ScholarPubMed
Lanius, RA, Vermetten, E, Loewenstein, RJ, et al. Emotion modulation in PTSD: clinical and neurobiological evidence for a dissociative subtype. Am J Psychiatry. 2010;167(6):640–647.CrossRefGoogle ScholarPubMed
Diez, I, Ortiz-Terán, L, Williams, B, et al. Corticolimbic fast-tracking: enhanced multimodal integration in functional neurological disorder. J Neurology Neurosurg Psychiatry. 2019;90(8):929–938.CrossRefGoogle ScholarPubMed
Li, R, Li, Y, An, D, Gong, Q, Zhou, D, Chen, H. Altered regional activity and inter-regional functional connectivity in psychogenic non-epileptic seizures. Sci Rep. 2015;5:11635.CrossRefGoogle ScholarPubMed
Demartini, B, Petrochilos, P, Ricciardi, L, Price, G, Edwards, MJ, Joyce, E. The role of alexithymia in the development of functional motor symptoms (conversion disorder). J Neurol Neurosurg Psychiatry. 2014;85(10):1132–1137.CrossRefGoogle Scholar
Indranada, AM, Mullen, SA, Duncan, R, Berlowitz, DJ, Kanaan, RAA. The association of panic and hyperventilation with psychogenic non-epileptic seizures: a systematic review and meta-analysis. Seizure. 2018;59:108–115.CrossRefGoogle ScholarPubMed
Craig, AD. How do you feel — now? The anterior insula and human awareness. Nat Rev Neurosci. 2009;10(1):59–70.CrossRefGoogle Scholar
Aybek, S, Nicholson, TR, O’Daly, O, Zelaya, F, Kanaan, RA, David, AS. Emotion-motion interactions in conversion disorder: an FMRI study. PLoS One. 2015;10(4):e0123273.CrossRefGoogle Scholar
Denk, F, McMahon, SB, Tracey, I. Pain vulnerability: a neurobiological perspective. Nat Neurosci. 2014;17(2):192–200.CrossRefGoogle ScholarPubMed
Sepulcre, J, Sabuncu, MR, Yeo, TB, Liu, H, Johnson, KA. Stepwise connectivity of the modal cortex reveals the multimodal organization of the human brain. J Neurosci. 2012;32(31):10649–10661.CrossRefGoogle ScholarPubMed
Hallett, M. Physiology of free will. Ann Neurol. 2016;80(1):5–12.CrossRefGoogle ScholarPubMed
Hallett, M. Neurophysiologic studies of functional neurologic disorders. Handb Clin Neurol. 2016;139:61–71.CrossRefGoogle ScholarPubMed
Voon, V, Gallea, C, Hattori, N, Bruno, M, Ekanayake, V, Hallett, M. The involuntary nature of conversion disorder. Neurology. 2010;74(3):223–228.CrossRefGoogle ScholarPubMed
Maurer, CW, LaFaver, K, Ameli, R, et al. Impaired self-agency in functional movement disorders: a resting-state fMRI study. Neurology. 2016;87(6):564–570.Google ScholarPubMed
Perez, DL, Barsky, AJ, Daffner, K, Silbersweig, DA. Motor and somatosensory conversion disorder: a functional unawareness syndrome? J Neuropsychiatry Clin Neurosci. 2012;24(2):141–151.CrossRefGoogle ScholarPubMed
O’Brien, FM, Fortune, GM, Dicker, P, et al. Psychiatric and neuropsychological profiles of people with psychogenic nonepileptic seizures. Epilepsy Behav. 2015;43:39–45.CrossRefGoogle ScholarPubMed
Simani, L, Roozbeh, M, Rostami, M, Pakdaman, H, Ramezani, M, Asadollahi, M. Attention and inhibitory control deficits in patients with genetic generalized epilepsy and psychogenic nonepileptic seizure. Epilepsy Behav. 2020;102:106672.CrossRefGoogle ScholarPubMed
Strutt, AM, Hill, SW, Scott, BM, Uber-Zak, L, Fogel, TG. A comprehensive neuropsychological profile of women with psychogenic nonepileptic seizures. Epilepsy Behav. 2011;20(1):24–28.CrossRefGoogle ScholarPubMed
Alluri, PR, Solit, J, Leveroni, CL, et al. Cognitive complaints in motor functional neurological (conversion) disorders: a focused review and clinical perspective. Cogn Behav Neurol. 2020;33(2):77–89.CrossRefGoogle ScholarPubMed
Bakvis, P, Roelofs, K, Kuyk, J, Edelbroek, PM, Swinkels, WAM, Spinhoven, P. Trauma, stress, and preconscious threat processing in patients with psychogenic nonepileptic seizures. Epilepsia. 2009;50(5):1001–1011.CrossRefGoogle ScholarPubMed
Bakvis, P, Spinhoven, P, Roelofs, K. Basal cortisol is positively correlated to threat vigilance in patients with psychogenic nonepileptic seizures. Epilepsy Behav. 2009;16(3):558–560.CrossRefGoogle ScholarPubMed
Pick, S, Mellers, JDC, Goldstein, LH. Implicit attentional bias for facial emotion in dissociative seizures: additional evidence. Epilepsy Behav. 2018;80:296–302.CrossRefGoogle ScholarPubMed
Roelofs, K, van Galen, GP, Eling, P, GPJ, Keijsers, CAL, Hoogduin. Endogenous and exogenous attention in patients with conversion paresis. Cogn Neuropsychol . 2003;20(8):733–745.CrossRefGoogle ScholarPubMed
Spence, SA, Crimlisk, HL, Cope, H, Ron, MA, Grasby, PM. Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement. Lancet. 2000;355(9211):1243–1244.CrossRefGoogle Scholar
Morris, LS, To B, Baek, K, et al. Disrupted avoidance learning in functional neurological disorder: implications for harm avoidance theories. Neuroimage Clin. 2017;16:286–294.CrossRefGoogle ScholarPubMed
Boeckle, M, Liegl, G, Jank, R, Pieh C. Neural correlates of conversion disorder: overview and meta-analysis of neuroimaging studies on motor conversion disorder. BMC Psychiatry. 2016;16:195.CrossRefGoogle ScholarPubMed
Khalsa, SS, Adolphs, R, Cameron, OG, et al. Interoception and mental health: a roadmap. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3(6):501–513.Google ScholarPubMed
Ricciardi, L, Demartini, B, Crucianelli, L, Krahé, L, Edwards, MJ, Fotopoulou, A. Interoceptive awareness in patients with functional neurological symptoms. Biol Psychol. 2016;113:68–74.CrossRefGoogle ScholarPubMed
Koreki, A, Garfkinel, SN, Mula, M, et al. Trait and state interoceptive abnormalities are associated with dissociation and seizure frequency in patients with functional seizures. Epilepsia. 2020;61(6):1156–1165.CrossRefGoogle ScholarPubMed
Bogaerts, K, Van Eylen, L, Li, W, et al. Distorted symptom perception in patients with medically unexplained symptoms. J Abnorm Psychol. 2010;119(1):226–234.CrossRefGoogle ScholarPubMed
Jungilligens, J, Wellmer, J, Schlegel, U, Kessler, U, Axmacher, N, Popkirov, S. Impaired emotional and behavioural awareness and control in patients with dissociative seizures. Psychol Med. 2019;1–9.Google ScholarPubMed
Brown, RJ, Reuber, M. Towards an integrative theory of psychogenic non-epileptic seizures (PNES). Clin Psychol Rev. 2016;47:55–70.CrossRefGoogle Scholar
Edwards, MJ, Adams, RA, Brown, H, Pareés, I, Friston, KJ. A Bayesian account of ‘hysteria’. Brain. 2012;135(11):3495–3512.CrossRefGoogle Scholar
Perez, DL, Barsky, AJ, Vago, DR, Baslet, G, Silbersweig, DA. A neural circuit framework for somatosensory amplification in somatoform disorders. J Neuropsychiatry Clin Neurosci. 2015;27(1):e40–e50.CrossRefGoogle ScholarPubMed
Teufel, C, Fletcher, PC. Forms of prediction in the nervous system. Nat Rev Neurosci. 2020;21(4):231–242.CrossRefGoogle ScholarPubMed
Keller, GB, Mrsic-Flogel, TD. Predictive processing: a canonical cortical computation. Neuron. 2018;100(2):424–435.CrossRefGoogle ScholarPubMed
Walsh, KS, McGovern, DP, Clark, A, O’Connell, RG. Evaluating the neurophysiological evidence for predictive processing as a model of perception. Ann N Y Acad Sci. 2020;1464(1):242–268.CrossRefGoogle Scholar
Fleming, SM. Awareness as inference in a higher-order state space. Neurosci Conscious. 2020;2020(1):niz020CrossRefGoogle Scholar
Bègue, I, Blakemore, R, Klug, J, et al. Metacognition of visuomotor decisions in conversion disorder. Neuropsychologia. 2018;114:251–265.CrossRefGoogle ScholarPubMed
Sadnicka, A, Daum, C, Meppelink, AM, Manohar S, Edwards M. Reduced drift rate: a biomarker of impaired information processing in functional movement disorders. Brain. 2020;143(2):674–683.CrossRefGoogle ScholarPubMed
Burleson, MH, Quigley, KS. Social interoception and social allostasis through touch: legacy of the somatovisceral afference model of emotion. Soc Neurosci. 2019;1–11.Google ScholarPubMed
Ludwig, L, Pasman, JA, Nicholson, T, et al. Stressful life events and maltreatment in conversion (functional neurological) disorder: systematic review and meta-analysis of case-control studies. Lancet Psychiatry. 2018;5(4):307–320.CrossRefGoogle ScholarPubMed
Teicher, MH, Samson, JA, Anderson, CM, Ohashi, K. The effects of childhood maltreatment on brain structure, function and connectivity. Nat Rev Neurosci. 2016;17(10):652–666.CrossRefGoogle ScholarPubMed
Spagnolo, PA, Norato, G, Maurer, CW, et al. Effects of TPH2 gene variation and childhood trauma on the clinical and circuit-level phenotype of functional movement disorders. J Neurol Neurosurg Psychiatry. 2020;91(8):814–821.CrossRefGoogle ScholarPubMed
Roelofs, K, Keijsers, GP, Hoogduin, KA, Näring, GWB, Moene, FC. Childhood abuse in patients with conversion disorder. Am J Psychiatry. 2002;159(11):1908–1913.CrossRefGoogle ScholarPubMed
Williams, B, Ospina, JP, Jalilianhasanpour, R, Fricchione, GL, Perez, DL. Fearful attachment linked to childhood abuse, alexithymia, and depression in motor functional neurological disorders. J Neuropsychiatry Clin Neurosci. 2019;31(1):65–69.CrossRefGoogle ScholarPubMed
Hailes, HP, Yu, R, Danese, A, Fazel, S. Long-term outcomes of childhood sexual abuse: an umbrella review. Lancet Psychiatry. 2019;6(10):830–839.CrossRefGoogle Scholar
Diez, I, Larson, AG, Nakhate, V, et al. Early-life trauma endophenotypes and brain circuit-gene expression relationships in functional neurological (conversion) disorder. Mol Psychiatry. 2020;Google ScholarPubMed
Godlewska, BR, Norbury, R, Selvaraj, S, Cowen, PJ, Harmer, CJ. Short-term SSRI treatment normalises amygdala hyperactivity in depressed patients. Psychol Med. 2012;42(12):2609–2617.CrossRefGoogle ScholarPubMed
Allendorfer, JB, Nenert, R, Hernando, KA, et al. FMRI response to acute psychological stress differentiates patients with psychogenic non-epileptic seizures from healthy controls — a biochemical and neuroimaging biomarker study. Neuroimage Clin. 2019;24:101967.CrossRefGoogle ScholarPubMed
Perez, DL, Matin, N, Barsky, A, et al. Cingulo-insular structural alterations associated with psychogenic symptoms, childhood abuse and PTSD in functional neurological disorders. J Neurol Neurosurg Psychiatry. 2017;88(6):491–497.CrossRefGoogle ScholarPubMed
Kozlowska, K, Griffiths, KR, Foster, SL, Linton, J, Williams, LM, Korgaonkar, MS. Grey matter abnormalities in children and adolescents with functional neurological symptom disorder. NeuroImage Clin. 2017;15:306–314.CrossRefGoogle ScholarPubMed