BACKGROUND: Functional movement disorders, a common cause of neurological disabilities, can occur with heterogeneous motor manifestations including functional weakness. However, the underlying mechanisms related to brain function and connectivity are unknown. OBJECTIVE: To identify brain connectivity alterations related to functional weakness we assessed network centrality changes in a group of patients with heterogeneous motor manifestations using task-free functional MRI in combination with different network centrality approaches. METHODS: Task-free functional MRI was performed in 48 patients with heterogeneous motor manifestations including 28 patients showing functional weakness and 65 age- and sex-matched healthy controls. Functional connectivity differences were assessed using different network centrality approaches, i.e. global correlation, eigenvector centrality, and intrinsic connectivity. Motor symptom severity was assessed using The Simplified Functional Movement Disorders Rating Scale and correlated with network centrality. RESULTS: Comparing patients with and without functional weakness showed significant network centrality differences in the left temporoparietal junction and precuneus. Patients with functional weakness showed increased centrality in the same anatomical regions when comparing functional weakness with healthy controls. Moreover, in the same regions, patients with functional weakness showed a positive correlation between motor symptom severity and network centrality. This correlation was shown to be specific to functional weakness with an interaction analysis, confirming a significant difference between patients with and without functional weakness. CONCLUSIONS: We identified the temporoparietal junction and precuneus as key regions involved in brain connectivity alterations related to functional weakness. We propose that both regions may be promising targets for phenotype-specific non-invasive brain stimulation.

Department of Neurology and Center of Clinical Neuroscience Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Max Planck Institute for Human Cognitive and Brain Sciences Leipzig Germany

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APA . American Psychiatric Publishing; Arlington, VA: 2013. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®) p. 991.

Ashburner J., Friston K.J. Unified segmentation. Neuroimage. 2005;26:839–851. PubMed

Aybek S., Nicholson T.R., O'Daly O., Zelaya F., Kanaan R.A., David A.S. Emotion-motion interactions in conversion disorder: an FMRI study. PLoS ONE. 2015;10 PubMed PMC

Aybek S., Nicholson T.R., Zelaya F., O'Daly O.G., Craig T.J., David A.S., Kanaan R.A. Neural correlates of recall of life events in conversion disorder. JAMA Psychiatry. 2014;71:52–60. PubMed

Baek K., Donamayor N., Morris L.S., Strelchuk D., Mitchell S., Mikheenko Y., Yeoh S.Y., Phillips W., Zandi M., Jenaway A., Walsh C., Voon V. Impaired awareness of motor intention in functional neurological disorder: implications for voluntary and functional movement. Psychol. Med. 2017;47:1624–1636. PubMed PMC

Baizabal-Carvallo J.F., Hallett M., Jankovic J. Pathogenesis and pathophysiology of functional (psychogenic) movement disorders. Neurobiol. Dis. 2019;127:32–44. PubMed

Bao Z., Howidi B., Burhan A.M., Frewen P. Self-Referential Processing Effects of Non-invasive Brain Stimulation: A Systematic Review. Front. Neurosci. 2021;15 PubMed PMC

Bassett D.S., Bullmore E. Small-world brain networks. Neuroscientist. 2006;12:512–523. PubMed

Beck A.T., Ward C.H., Mendelson M., Mock J., Erbaugh J. An inventory for measuring depression. Arch. Gen. Psychiatry. 1961;4:561–571. PubMed

Biswal B., Yetkin F.Z., Haughton V.M., Hyde J.S. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn. Reson. Med. 1995;34:537–541. PubMed

Buckner R.L., DiNicola L.M. The brain's default network: updated anatomy, physiology and evolving insights. Nat. Rev. Neurosci. 2019;20:593–608. PubMed

Bullmore E., Sporns O. Complex brain networks: graph theoretical analysis of structural and functional systems. Nat. Rev. Neurosci. 2009;10:186–198. PubMed

Canu, E., Agosta, F., Tomic, A., Sarasso, E., Petrovic, I., Piramide, N., Svetel, M., Inuggi, A., N, D.M., Kostic, V.S., Filippi, M., 2020. Breakdown of the affective-cognitive network in functional dystonia. Hum Brain Mapp 41, 3059-3076. PubMed PMC

Chen R., Gerloff C., Classen J., Wassermann E.M., Hallett M., Cohen L.G. Safety of different inter-train intervals for repetitive transcranial magnetic stimulation and recommendations for safe ranges of stimulation parameters. Electroencephalogr. Clin. Neurophysiol. 1997;105:415–421. PubMed

Colenbier N., Van de Steen F., Uddin L.Q., Poldrack R.A., Calhoun V.D., Marinazzo D. Disambiguating the role of blood flow and global signal with partial information decomposition. Neuroimage. 2020;213 PubMed

Corbetta M., Shulman G.L. Control of goal-directed and stimulus-driven attention in the brain. Nat. Rev. Neurosci. 2002;3:201–215. PubMed

Dalong G., Jiyuan L., Yubin Z., Yufei Q., Jinghua Y., Cong W., Hongbo J. Cathodal Transcranial Direct Current Stimulation Over the Right Temporoparietal Junction Suppresses Its Functional Connectivity and Reduces Contralateral Spatial and Temporal Perception. Front. Neurosci. 2021;15 PubMed PMC

Daum C., Hubschmid M., Aybek S. The value of 'positive' clinical signs for weakness, sensory and gait disorders in conversion disorder: a systematic and narrative review. J. Neurol. Neurosurg. Psychiatry. 2014;85:180–190. PubMed

de Lange F.P., Roelofs K., Toni I. Increased self-monitoring during imagined movements in conversion paralysis. Neuropsychologia. 2007;45:2051–2058. PubMed

de Lange F.P., Toni I., Roelofs K. Altered connectivity between prefrontal and sensorimotor cortex in conversion paralysis. Neuropsychologia. 2010;48:1782–1788. PubMed

Dennis E.L., Thompson P.M. Functional brain connectivity using fMRI in aging and Alzheimer's disease. Neuropsychol. Rev. 2014;24:49–62. PubMed PMC

Diez I., Ortiz-Teran L., Williams B., Jalilianhasanpour R., Ospina J.P., Dickerson B.C., Keshavan M.S., LaFrance W.C., Jr., Sepulcre J., Perez D.L. Corticolimbic fast-tracking: enhanced multimodal integration in functional neurological disorder. J. Neurol. Neurosurg. Psychiatry. 2019;90:929–938. PubMed PMC

Donaldson P.H., Rinehart N.J., Enticott P.G. Noninvasive stimulation of the temporoparietal junction: A systematic review. Neurosci. Biobehav. Rev. 2015;55:547–572. PubMed

Edwards M.J., Adams R.A., Brown H., Parees I., Friston K.J. A Bayesian account of 'hysteria'. Brain. 2012;135:3495–3512. PubMed PMC

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

Espay A.J., Aybek S., Carson A., Edwards M.J., Goldstein L.H., Hallett M., LaFaver K., LaFrance W.C., Jr., Lang A.E., Nicholson T., Nielsen G., Reuber M., Voon V., Stone J., Morgante F. Current Concepts in Diagnosis and Treatment of Functional Neurological Disorders. JAMA Neurol. 2018;75:1132–1141. PubMed PMC

Espay A.J., Lang A.E. Phenotype-specific diagnosis of functional (psychogenic) movement disorders. Curr Neurol Neurosci Rep. 2015;15:32. PubMed

Espay A.J., Maloney T., Vannest J., Norris M.M., Eliassen J.C., Neefus E., Allendorfer J.B., Chen R., Szaflarski J.P. Dysfunction in emotion processing underlies functional (psychogenic) dystonia. Mov. Disord. 2018;33:136–145. PubMed PMC

Faul L., Knight L.K., Espay A.J., Depue B.E., LaFaver K. Neural activity in functional movement disorders after inpatient rehabilitation. Psychiatry Res. Neuroimaging. 2020;303 PubMed

Ferreira L.K., Busatto G.F. Resting-state functional connectivity in normal brain aging. Neurosci. Biobehav. Rev. 2013;37:384–400. PubMed

Flandin G., Friston K.J. Analysis of family-wise error rates in statistical parametric mapping using random field theory. Hum. Brain Mapp. 2019;40:2052–2054. PubMed PMC

Friston K. The free-energy principle: a unified brain theory? Nat. Rev. Neurosci. 2010;11:127–138. PubMed

Friston K.J., Buechel C., Fink G.R., Morris J., Rolls E., Dolan R.J. Psychophysiological and modulatory interactions in neuroimaging. Neuroimage. 1997;6:218–229. PubMed

Friston K.J., Worsley K.J., Frackowiak R.S., Mazziotta J.C., Evans A.C. Assessing the significance of focal activations using their spatial extent. Hum. Brain Mapp. 1994;1:210–220. PubMed

Geng J.J., Vossel S. Re-evaluating the role of TPJ in attentional control: contextual updating? Neurosci. Biobehav. Rev. 2013;37:2608–2620. PubMed PMC

Gupta A., Lang A.E. Psychogenic movement disorders. Curr. Opin. Neurol. 2009;22:430–436. PubMed

Hallett M. Physiology of psychogenic movement disorders. J. Clin. Neurosci. 2010;17:959–965. PubMed PMC

Hassa T., de Jel E., Tuescher O., Schmidt R., Schoenfeld M.A. Functional networks of motor inhibition in conversion disorder patients and feigning subjects. Neuroimage Clin. 2016;11:719–727. PubMed PMC

Hassa T., Sebastian A., Liepert J., Weiller C., Schmidt R., Tuscher O. Symptom-specific amygdala hyperactivity modulates motor control network in conversion disorder. Neuroimage Clin. 2017;15:143–150. PubMed PMC

Holiga S., Sambataro F., Luzy C., Greig G., Sarkar N., Renken R.J., Marsman J.C., Schobel S.A., Bertolino A., Dukart J. Test-retest reliability of task-based and resting-state blood oxygen level dependence and cerebral blood flow measures. PLoS ONE. 2018;13 PubMed PMC

Igelstrom K.M., Graziano M.S.A. The inferior parietal lobule and temporoparietal junction: A network perspective. Neuropsychologia. 2017;105:70–83. PubMed

Inukai Y., Saito K., Sasaki R., Tsuiki S., Miyaguchi S., Kojima S., Masaki M., Otsuru N., Onishi H. Comparison of Three Non-Invasive Transcranial Electrical Stimulation Methods for Increasing Cortical Excitability. Front. Hum. Neurosci. 2016;10:668. PubMed PMC

Kozlowska K., Griffiths K.R., Foster S.L., Linton J., Williams L.M., Korgaonkar M.S. Grey matter abnormalities in children and adolescents with functional neurological symptom disorder. Neuroimage Clin. 2017;15:306–314. PubMed PMC

Li J.Y., Suo X.L., Li N.N., Lei D., Lu Z.J., Wang L., Peng J.X., Duan L.R., Jing X., Yi J., Gong Q.Y., Peng R. Altered spontaneous brain activity in essential tremor with and without resting tremor: a resting-state fMRI study. MAGMA. 2021;34:201–212. PubMed

Liu T.T., Nalci A., Falahpour M. The global signal in fMRI: Nuisance or Information? Neuroimage. 2017;150:213–229. PubMed PMC

Lohmann, G., Loktyushin, A., Stelzer, J., Scheffler, K., 2018. Eigenvector centrality mapping for ultrahigh resolution fMRI data of the human brain. bioRxiv.

Lohmann G., Margulies D.S., Horstmann A., Pleger B., Lepsien J., Goldhahn D., Schloegl H., Stumvoll M., Villringer A., Turner R. Eigenvector centrality mapping for analyzing connectivity patterns in fMRI data of the human brain. PLoS ONE. 2010;5 PubMed PMC

Lohmann G., Muller K., Bosch V., Mentzel H., Hessler S., Chen L., Zysset S., von Cramon D.Y. LIPSIA–a new software system for the evaluation of functional magnetic resonance images of the human brain. Comput. Med. Imaging Graph. 2001;25:449–457. PubMed

Lou Y., Huang P., Li D., Cen Z., Wang B., Gao J., Xuan M., Yu H., Zhang M., Luo W. Altered brain network centrality in depressed Parkinson's disease patients. Mov. Disord. 2015;30:1777–1784. PubMed

Marapin R.S., Gelauff J.M., Marsman J.B.C., de Jong B.M., Dreissen Y.E.M., Koelman J., van der Horn H.J., Tijssen M.A.J. Altered Posterior Midline Activity in Patients with Jerky and Tremulous Functional Movement Disorders. Brain Connect. 2021;11:584–593. PubMed

Marapin R.S., van der Stouwe A.M.M., de Jong B.M., Gelauff J.M., Vergara V.M., Calhoun V.D., Dalenberg J.R., Dreissen Y.E.M., Koelman J., Tijssen M.A.J., van der Horn H.J. The chronnectome as a model for Charcot's 'dynamic lesion' in functional movement disorders. Neuroimage Clin. 2020;28 PubMed PMC

Margulies D.S., Bottger J., Long X., Lv Y., Kelly C., Schafer A., Goldhahn D., Abbushi A., Milham M.P., Lohmann G., Villringer A. Resting developments: a review of fMRI post-processing methodologies for spontaneous brain activity. MAGMA. 2010;23:289–307. PubMed

Martuzzi R., Ramani R., Qiu M., Shen X., Papademetris X., Constable R.T. A whole-brain voxel based measure of intrinsic connectivity contrast reveals local changes in tissue connectivity with anesthetic without a priori assumptions on thresholds or regions of interest. Neuroimage. 2011;58:1044–1050. PubMed PMC

Maurer C.W., LaFaver K., Ameli R., Epstein S.A., Hallett M., Horovitz S.G. Impaired self-agency in functional movement disorders: A resting-state fMRI study. Neurology. 2016;87:564–570. PubMed PMC

McCabe C., Mishor Z. Antidepressant medications reduce subcortical-cortical resting-state functional connectivity in healthy volunteers. Neuroimage. 2011;57:1317–1323. PubMed PMC

Mengotti P., Kasbauer A.S., Fink G.R., Vossel S. Lateralization, functional specialization, and dysfunction of attentional networks. Cortex. 2020;132:206–222. PubMed

Monsa R., Peer M., Arzy S. Self-reference, emotion inhibition and somatosensory disturbance: preliminary investigation of network perturbations in conversion disorder. Eur. J. Neurol. 2018;25:888–e862. PubMed

Mueller K., Jech R., Ballarini T., Holiga S., Ruzicka F., Piecha F.A., Moller H.E., Vymazal J., Ruzicka E., Schroeter M.L. Modulatory Effects of Levodopa on Cerebellar Connectivity in Parkinson's Disease. Cerebellum. 2019;18:212–224. PubMed PMC

Mueller K., Jech R., Hoskovcova M., Ulmanova O., Urgosik D., Vymazal J., Ruzicka E. General and selective brain connectivity alterations in essential tremor: A resting state fMRI study. Neuroimage Clin. 2017;16:468–476. PubMed PMC

Mueller K., Jech R., Ruzicka F., Holiga S., Ballarini T., Bezdicek O., Moller H.E., Vymazal J., Ruzicka E., Schroeter M.L., Urgosik D. Brain connectivity changes when comparing effects of subthalamic deep brain stimulation with levodopa treatment in Parkinson's disease. Neuroimage. Clin. 2018;19:1025–1035. PubMed PMC

Mueller K., Ruzicka F., Slovak M., Forejtova Z., Dusek P., Dusek P., Jech R., Serranova T. Centrality and seed-based correlation maps obtained with functional MRI. Mendeley Data. 2022;V1 doi: 10.17632/w35fvmtnf2.1. DOI

Nahab F.B., Kundu P., Gallea C., Kakareka J., Pursley R., Pohida T., Miletta N., Friedman J., Hallett M. The neural processes underlying self-agency. Cereb. Cortex. 2011;21:48–55. PubMed PMC

Nahab F.B., Kundu P., Maurer C., Shen Q., Hallett M. Impaired sense of agency in functional movement disorders: An fMRI study. PLoS ONE. 2017;12 PubMed PMC

Nair, V., Hinton, G., 2010. Rectified Linear Units improve Restricted Boltzmann Machines. International Conference on Machine Learning (ICML), Haifa, Israel, pp. 807-814.

Nielsen G., Ricciardi L., Meppelink A.M., Holt K., Teodoro T., Edwards M. A Simplified Version of the Psychogenic Movement Disorders Rating Scale: The Simplified Functional Movement Disorders Rating Scale (S-FMDRS) Movement Disorders Clinical Practice. 2017;4:710–716. PubMed PMC

Parkes L., Fulcher B., Yucel M., Fornito A. An evaluation of the efficacy, reliability, and sensitivity of motion correction strategies for resting-state functional MRI. Neuroimage. 2018;171:415–436. PubMed

Perez D.L., Matin N., Barsky A., Costumero-Ramos V., Makaretz S.J., Young S.S., Sepulcre J., LaFrance W.C., Jr., Keshavan M.S., Dickerson B.C. Cingulo-insular structural alterations associated with psychogenic symptoms, childhood abuse and PTSD in functional neurological disorders. J. Neurol. Neurosurg. Psychiatry. 2017;88:491–497. PubMed PMC

Perez D.L., Nicholson T.R., Asadi-Pooya A.A., Begue I., Butler M., Carson A.J., David A.S., Deeley Q., Diez I., Edwards M.J., Espay A.J., Gelauff J.M., Hallett M., Horovitz S.G., Jungilligens J., Kanaan R.A.A., Tijssen M.A.J., Kozlowska K., LaFaver K., LaFrance W.C., Jr., Lidstone S.C., Marapin R.S., Maurer C.W., Modirrousta M., Reinders A., Sojka P., Staab J.P., Stone J., Szaflarski J.P., Aybek S. Neuroimaging in Functional Neurological Disorder: State of the Field and Research Agenda. Neuroimage Clin. 2021;30 PubMed PMC

Pezzulo G., Zorzi M., Corbetta M. The secret life of predictive brains: what's spontaneous activity for? Trends Cogn. Sci. 2021;25:730–743. PubMed PMC

Power J.D., Barnes K.A., Snyder A.Z., Schlaggar B.L., Petersen S.E. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage. 2012;59:2142–2154. PubMed PMC

Satterthwaite T.D., Wolf D.H., Loughead J., Ruparel K., Elliott M.A., Hakonarson H., Gur R.C., Gur R.E. Impact of in-scanner head motion on multiple measures of functional connectivity: relevance for studies of neurodevelopment in youth. Neuroimage. 2012;60:623–632. PubMed PMC

Schrag A.E., Mehta A.R., Bhatia K.P., Brown R.J., Frackowiak R.S., Trimble M.R., Ward N.S., Rowe J.B. The functional neuroimaging correlates of psychogenic versus organic dystonia. Brain. 2013;136:770–781. PubMed PMC

Sojka P., Diez I., Bares M., Perez D.L. Individual differences in interoceptive accuracy and prediction error in motor functional neurological disorders: A DTI study. Hum. Brain Mapp. 2021;42:1434–1445. PubMed PMC

Sojka P., Losak J., Lamos M., Bares M., Kasparek T., Brazdil M., Balaz M., Svetlak M., Kocvarova J., Fialova J. Processing of Emotions in Functional Movement Disorder: An Exploratory fMRI Study. Front. Neurol. 2019;10:861. PubMed PMC

Spielberger C.D. Consulting Psychologists Press; Palo Alto: 1983. STAI: Manual for the Stait-Trait Anxiety Inventory.

Stone J., Aybek S. Functional limb weakness and paralysis. Handb Clin Neurol. 2016;139:213–228. PubMed

Stone J., Warlow C., Sharpe M. The symptom of functional weakness: a controlled study of 107 patients. Brain. 2010;133:1537–1551. PubMed

Stone J., Zeman A., Simonotto E., Meyer M., Azuma R., Flett S., Sharpe M. FMRI in patients with motor conversion symptoms and controls with simulated weakness. Psychosom. Med. 2007;69:961–969. PubMed

Tahmasian M., Bettray L.M., van Eimeren T., Drzezga A., Timmermann L., Eickhoff C.R., Eickhoff S.B., Eggers C. A systematic review on the applications of resting-state fMRI in Parkinson's disease: Does dopamine replacement therapy play a role? Cortex. 2015;73:80–105. PubMed

Tomic A., Agosta F., Sarasso E., Petrovic I., Basaia S., Pesic D., Kostic M., Fontana A., Kostic V.S., Filippi M. Are there two different forms of functional dystonia? A multimodal brain structural MRI study. Mol. Psychiatry. 2020;25:3350–3359. PubMed

van Beilen M., de Jong B.M., Gieteling E.W., Renken R., Leenders K.L. Abnormal parietal function in conversion paresis. PLoS ONE. 2011;6 PubMed PMC

van Beilen M., Vogt B.A., Leenders K.L. Increased activation in cingulate cortex in conversion disorder: what does it mean? J. Neurol. Sci. 2010;289:155–158. PubMed

Van den Bergh O., Witthoft M., Petersen S., Brown R.J. Symptoms and the body: Taking the inferential leap. Neurosci. Biobehav. Rev. 2017;74:185–203. PubMed

van der Kruijs S.J., Bodde N.M., Vaessen M.J., Lazeron R.H., Vonck K., Boon P., Hofman P.A., Backes W.H., Aldenkamp A.P., Jansen J.F. Functional connectivity of dissociation in patients with psychogenic non-epileptic seizures. J. Neurol. Neurosurg. Psychiatry. 2012;83:239–247. PubMed

Voon V., Brezing C., Gallea C., Ameli R., Roelofs K., LaFrance W.C., Jr., Hallett M. Emotional stimuli and motor conversion disorder. Brain. 2010;133:1526–1536. PubMed PMC

Voon V., Brezing C., Gallea C., Hallett M. Aberrant supplementary motor complex and limbic activity during motor preparation in motor conversion disorder. Mov. Disord. 2011;26:2396–2403. PubMed PMC

Voon V., Gallea C., Hattori N., Bruno M., Ekanayake V., Hallett M. The involuntary nature of conversion disorder. Neurology. 2010;74:223–228. PubMed PMC

Wang P., Luo X., Zhong C., Yang L., Guo F., Yu N. Resting state fMRI reveals the altered synchronization of BOLD signals in essential tremor. J. Neurol. Sci. 2018;392:69–76. PubMed

Wegrzyk J., Kebets V., Richiardi J., Galli S., de Ville D.V., Aybek S. Identifying motor functional neurological disorder using resting-state functional connectivity. Neuroimage Clin. 2018;17:163–168. PubMed PMC

Whitfield-Gabrieli S., Nieto-Castanon A. Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect. 2012;2:125–141. PubMed

Wink A.M., de Munck J.C., van der Werf Y.D., van den Heuvel O.A., Barkhof F. Fast eigenvector centrality mapping of voxel-wise connectivity in functional magnetic resonance imaging: implementation, validation, and interpretation. Brain Connect. 2012;2:265–274. PubMed

Wolters A.F., van de Weijer S.C.F., Leentjens A.F.G., Duits A.A., Jacobs H.I.L., Kuijf M.L. Resting-state fMRI in Parkinson's disease patients with cognitive impairment: A meta-analysis. Parkinsonism Relat Disord. 2019;62:16–27. PubMed

Worsley K.J., Marrett S., Neelin P., Vandal A.C., Friston K.J., Evans A.C. A unified statistical approach for determining significant signals in images of cerebral activation. Hum. Brain Mapp. 1996;4:58–73. PubMed

Yeshurun Y., Nguyen M., Hasson U. The default mode network: where the idiosyncratic self meets the shared social world. Nat. Rev. Neurosci. 2021;22:181–192. PubMed PMC

Zito G.A., Anderegg L.B., Apazoglou K., Muri R.M., Wiest R., Holtforth M.G., Aybek S. Transcranial magnetic stimulation over the right temporoparietal junction influences the sense of agency in healthy humans. J. Psychiatry Neurosci. 2020;45:271–278. PubMed PMC

Multi-centre classification of functional neurological disorders based on resting-state functional connectivity