Study of Biomorkers and Rehabilitation Strategies in Functional Motor Disorders (FMD)

NCT ID: NCT06328790

Last Updated: 2024-03-26

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 450 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2023-05-31
• Study Completion Date: 2025-05-31

Brief Summary

Functional motor disorders (FMD) are prevalent and highly disabling conditions characterized by abnormal movements (functional weakness, tremor, dystonia) significantly altered by distractive manoeuvres and incongruent with movement disorders seen in specific neurological diseases. FMDs are still misunderstood, diagnosed with delay, and not adequately treated, leading to reduced independence and high healthcare costs. Symptoms are physiologically associated with voluntary movement (distractibility, resolution with placebo) but are reported as involuntary. How this happens is yet a matter of debate. Identifying diagnostic and prognostic disease-specific biomarkers is an unmet need. The investigators will investigate motor, exteroceptive and interoceptive domains in a large cohort of FMD patients by a comprehensive set of behavioural, neurophysiological, and MRI tests. Ad-hoc eXplainable Artificial Intelligence (XAI) methods will develop disease-specific diagnostic and prognostic biomarker algorithms.

Detailed Description

Functional motor disorders (FMD) are part of the broad spectrum of functional neurological disorders characterized by abnormal movements (functional limb weakness, tremor, dystonia) significantly altered by distractive manoeuvres and incongruent with movement disorders seen in specific neurological diseases. FMDs have a high prevalence, are still misunderstood, diagnosed with a long delay, and not adequately treated, leading to high degrees of disability and poor quality of life with increasing social and economic costs. The old concept of psychological factors as the primary cause (conversion disorder) has been abandoned due to the lack of evidence about their causal role. According to a predictive coding account, the emerging idea is that symptoms and disability in FMD may depend on dysfunctions of a specific neural system integrating interoception, exteroception, and motor control. The idea underpins the investigator's proposal that FMD symptoms are perceptions of the state of the body. Besides the main pathophysiological features (abnormal attentional focus, beliefs/expectations, and sense of agency), the lived experience of symptoms and their resulting disability may depend on a specific neural system integrating motor, exteroceptive and interoceptive domains. Therefore, dysfunction within this system can cause and sustain motor and non-motor symptoms in FMD. Three-stage research will be conducted. A large cohort of patients with a definite diagnosis of FMD (n=150) and healthy controls (n=150) will be investigated by behavioural, neurophysiological, and MRI tests to collect biomarkers in the motor, exteroceptive and interoceptive domains. Computational modelling of the behavioural, neurophysiological, and MRI biomarkers will be developed through eXplainable Artificial Intelligence (XAI) methods through a data mining approach (machine learning) to implement a diagnostic algorithm biomarker (objective 1). A cohort of patients with "organic" motor disorders (n=75) will undergo the same behavioural, neurophysiological, and MRI tests belonging to the resulting biomarker-based diagnostic algorithm for validation (objective 2). Finally, the modulation of the resulting biomarker-based diagnostic algorithm after rehabilitation and the correlations of motor and non-motor symptoms (NMSs) with clinical improvement will be investigated in a sub-group of patients with FMD to explore the predictive value (objective 3). Our proposal consists of 6 work packages (WP), all integrated to deliver our stated objectives over the project's lifetime to achieve these objectives. Communication and dissemination activities will include the project's visual identity, public website, social media, videos, and press releases. Our proposal will inform the research and clinical community on disease-specific biomarkers for diagnosing and prognosis patients with FMD. The proposed approach has significant potential to disentangle some of the poorly understood features of these disorders, potentially providing a platform for more fundamental insights into brain functioning and the development of precision medicine approaches in their management. The proposed approach can also give the clinicians validated examinations to make a correct early diagnosis. This will improve the management of FMD with a positive impact on the patient's disability and the socio-economic costs of the illness.

Conditions

Functional Motor Disorders

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Functional Motor Disorder rehabilitation group (FMD)

Patients with FMD (subject to current diagnostic criteria) will undergo experiment 3.

Multidisciplinary Rehabilitation Training

Intervention Type: OTHER

34 Patients will attend the in-person 5-day rehabilitation program (2 h/day) followed by a 12-weeks telemedicine program (1 h/week).

Healthy Controls group (HC)

Healthy subjects at least 18 years old will undergo experiment 1.

Cross-sectional study on patients with FMD and healthy controls (HC)

Intervention Type: BEHAVIORAL

Each subject will undergo a set of behavioural, neurophysiological, and Magnetic Resonance Imaging (MRI) tests exploring the motor, exteroceptive and

"Organic" Motor Disorders group

Patients with "organic" motor disorders (weakness due to peripheral neuromuscular disorders, essential tremor, or idiopathic adult-onset dystonia, all according to current diagnostic criteria) will undergo experiment 2.

Cross-sectional study on patients with FMD and patients with structural/organic diseases

Intervention Type: BEHAVIORAL

Each subject will undergo behavioural, neurophysiological, and Magnetic Resonance Imaging (MRI) tests exploring the motor, exteroceptive and interoceptive domains.

Functional Motor Disorder group (FMD)

Patients with FMD (subject to current diagnostic criteria) will undergo experiment 1.

Cross-sectional study on patients with FMD and healthy controls (HC)

Intervention Type: BEHAVIORAL

Each subject will undergo a set of behavioural, neurophysiological, and Magnetic Resonance Imaging (MRI) tests exploring the motor, exteroceptive and

Interventions

Multidisciplinary Rehabilitation Training

34 Patients will attend the in-person 5-day rehabilitation program (2 h/day) followed by a 12-weeks telemedicine program (1 h/week).

Intervention Type: OTHER

Cross-sectional study on patients with FMD and patients with structural/organic diseases

Each subject will undergo behavioural, neurophysiological, and Magnetic Resonance Imaging (MRI) tests exploring the motor, exteroceptive and interoceptive domains.

Intervention Type: BEHAVIORAL

Cross-sectional study on patients with FMD and healthy controls (HC)

Each subject will undergo a set of behavioural, neurophysiological, and Magnetic Resonance Imaging (MRI) tests exploring the motor, exteroceptive and

Intervention Type: BEHAVIORAL

Other Intervention Names

Experiment 3; Experiment 2; Experiment 1

Eligibility Criteria

Inclusion Criteria

• Age higher or equal to 18 years
• Clinically definite diagnosis of FMD

• Age higher or equal to 18 years

• Age higher or equal to 18 years
• Clinically definite diagnosis of "organic" motor disorders: weakness due to peripheral neuromuscular disorders, essential tremor, or idiopathic adult-onset dystonia.
• Score>2 on the Tremor Research Group Essential Tremor Rating Assessment Scale for patients with essential tremor
• Rest tremors and other neurological signs
• Current or past exposure to tremorgenic drugs

Exclusion Criteria

• Mini-Mental State Examination score lower or equal to 24
• Physical impairment precluding signing the informed consent for participation
• Certified other neurological and/or psychiatric comorbidities
• Contraindications for 3T MRI

• Physical impairment precluding signing the informed consent for participation
• Certified neurological and/or psychiatric comorbidities
• Contraindications for 3T MRI

Experiment 2

• Mini-Mental State Examination score lower or equal to 24
• Physical impairment precluding signing the informed consent for participation
• Certified neurological and/or psychiatric comorbidities
• Contraindications for 3T MRI

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

IRCCS Ospedale San Raffaele

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera OO.RR. S. Giovanni di Dio e Ruggi D'Aragona

OTHER

Sponsor Role: collaborator

Michele Tinazzi, MD, PhD

OTHER

Sponsor Role: lead

Responsible Party

Michele Tinazzi, MD, PhD

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Michele Tinazzi, PhD

Role: PRINCIPAL_INVESTIGATOR

Universita di Verona

Locations

Azienda Ospedaliera OO.RR. S. Giovanni di Dio e Ruggi D'Aragona

Salerno, Campania, Italy

Site Status: RECRUITING

IRCCS Ospedale San Raffaele

Milan, Lombardy, Italy

Site Status: RECRUITING

Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona

Verona, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Michele Tinazzi, PhD

Role: CONTACT

michele.tinazzi@univr.it

3480172554 ext. +39

Marialuisa Gandolfi, PhD

Role: CONTACT

marialuisa.gandolfi@univr.it

3491656108 ext. +39

Facility Contacts

Maria Teresa Pellecchia, PhD

Role: primary

mpellecchia@unisa.it

Federica Agosta, PhD

Role: primary

agosta.federica@hsr.it

Elisabetta Sarasso, PhD

Role: backup

sarasso.elisabetta@hsr.it

Michele Tinazzi, PhD

Role: primary

michele.tinazzi@univr.it

0458124768 ext. +39

Marialuisa Gandolfi, PhD

Role: backup

marialuisa.gandolfi@univr.it

3491656108 ext. +39

References

Gupta A, Lang AE. Psychogenic movement disorders. Curr Opin Neurol. 2009 Aug;22(4):430-6. doi: 10.1097/WCO.0b013e32832dc169.

Reference Type: BACKGROUND

PMID: 19542886 (View on PubMed)

Bhatia KP, Bain P, Bajaj N, Elble RJ, Hallett M, Louis ED, Raethjen J, Stamelou M, Testa CM, Deuschl G; Tremor Task Force of the International Parkinson and Movement Disorder Society. Consensus Statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society. Mov Disord. 2018 Jan;33(1):75-87. doi: 10.1002/mds.27121. Epub 2017 Nov 30.

Reference Type: BACKGROUND

PMID: 29193359 (View on PubMed)

Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, Hallett M, Jankovic J, Jinnah HA, Klein C, Lang AE, Mink JW, Teller JK. Phenomenology and classification of dystonia: a consensus update. Mov Disord. 2013 Jun 15;28(7):863-73. doi: 10.1002/mds.25475. Epub 2013 May 6.

Reference Type: BACKGROUND

PMID: 23649720 (View on PubMed)

Engel AG, Myology, vol.II, 3rd ed. New York:McGraw-Hill;2004

Reference Type: BACKGROUND

Piramide N, Agosta F, Sarasso E, Canu E, Volonte MA, Filippi M. Brain activity during lower limb movements in Parkinson's disease patients with and without freezing of gait. J Neurol. 2020 Apr;267(4):1116-1126. doi: 10.1007/s00415-019-09687-1. Epub 2020 Jan 2.

Reference Type: BACKGROUND

PMID: 31897599 (View on PubMed)

Cojan Y, Waber L, Carruzzo A, Vuilleumier P. Motor inhibition in hysterical conversion paralysis. Neuroimage. 2009 Sep;47(3):1026-37. doi: 10.1016/j.neuroimage.2009.05.023. Epub 2009 May 18.

Reference Type: BACKGROUND

PMID: 19450695 (View on PubMed)

Tinazzi M, Morgante F, Marcuzzo E, Erro R, Barone P, Ceravolo R, Mazzucchi S, Pilotto A, Padovani A, Romito LM, Eleopra R, Zappia M, Nicoletti A, Dallocchio C, Arbasino C, Bono F, Pascarella A, Demartini B, Gambini O, Modugno N, Olivola E, Di Stefano V, Albanese A, Ferrazzano G, Tessitore A, Zibetti M, Calandra-Buonaura G, Petracca M, Esposito M, Pisani A, Manganotti P, Stocchi F, Coletti Moja M, Antonini A, Defazio G, Geroin C. Clinical Correlates of Functional Motor Disorders: An Italian Multicenter Study. Mov Disord Clin Pract. 2020 Sep 22;7(8):920-929. doi: 10.1002/mdc3.13077. eCollection 2020 Nov.

Reference Type: BACKGROUND

PMID: 33163563 (View on PubMed)

Gandolfi M, Riello M, Bellamoli V, Bombieri F, Geroin C, Di Vico IA, Tinazzi M. Motor and non-motor outcomes after a rehabilitation program for patients with Functional Motor Disorders: A prospective, observational cohort study. NeuroRehabilitation. 2021;48(3):305-314. doi: 10.3233/NRE-201617.

Reference Type: BACKGROUND

PMID: 33780378 (View on PubMed)

Tomic A, Agosta F, Sarasso E, Petrovic I, Basaia S, Pesic D, Kostic M, Fontana A, Kostic VS, Filippi M. Are there two different forms of functional dystonia? A multimodal brain structural MRI study. Mol Psychiatry. 2020 Dec;25(12):3350-3359. doi: 10.1038/s41380-018-0222-2. Epub 2018 Aug 17.

Reference Type: BACKGROUND

PMID: 30120414 (View on PubMed)

Canu E, Agosta F, Tomic A, Sarasso E, Petrovic I, Piramide N, Svetel M, Inuggi A, D Miskovic N, Kostic VS, Filippi M. Breakdown of the affective-cognitive network in functional dystonia. Hum Brain Mapp. 2020 Aug 1;41(11):3059-3076. doi: 10.1002/hbm.24997. Epub 2020 Apr 3.

Reference Type: BACKGROUND

PMID: 32243055 (View on PubMed)

Piramide N, Sarasso E, Tomic A, Canu E, Petrovic IN, Svetel M, Basaia S, Dragasevic Miskovic N, Kostic VS, Filippi M, Agosta F. Functional MRI connectivity of the primary motor cortex in functional dystonia patients. J Neurol. 2022 Jun;269(6):2961-2971. doi: 10.1007/s00415-021-10879-x. Epub 2021 Nov 12.

Reference Type: BACKGROUND

PMID: 34773159 (View on PubMed)

Landolfi A, Ricciardi C, Donisi L, Cesarelli G, Troisi J, Vitale C, Barone P, Amboni M. Machine Learning Approaches in Parkinson's Disease. Curr Med Chem. 2021;28(32):6548-6568. doi: 10.2174/0929867328999210111211420.

Reference Type: BACKGROUND

PMID: 33430721 (View on PubMed)

Teodoro T, Koreki A, Meppelink AM, Little S, Nielsen G, Macerollo A, Ferreira JJ, Parees I, Lang A, Edwards MJ. Contingent negative variation: a biomarker of abnormal attention in functional movement disorders. Eur J Neurol. 2020 Jun;27(6):985-994. doi: 10.1111/ene.14189. Epub 2020 Apr 14.

Reference Type: BACKGROUND

PMID: 32096289 (View on PubMed)

Lorenz J, Garcia-Larrea L. Contribution of attentional and cognitive factors to laser evoked brain potentials. Neurophysiol Clin. 2003 Dec;33(6):293-301. doi: 10.1016/j.neucli.2003.10.004.

Reference Type: BACKGROUND

PMID: 14678843 (View on PubMed)

Hanzlikova Z, Kofler M, Slovak M, Vechetova G, Fecikova A, Kemlink D, Sieger T, Ruzicka E, Valls-Sole J, Edwards MJ, Serranova T. Prepulse inhibition of the blink reflex is abnormal in functional movement disorders. Mov Disord. 2019 Jul;34(7):1022-1030. doi: 10.1002/mds.27706. Epub 2019 May 2.

Reference Type: BACKGROUND

PMID: 31046188 (View on PubMed)

Gandolfi M, Fiorio M, Geroin C, Prior M, De Marchi S, Amboni M, Smania N, Tinazzi M. Motor dual task with eyes closed improves postural control in patients with functional motor disorders: A posturographic study. Gait Posture. 2021 Jul;88:286-291. doi: 10.1016/j.gaitpost.2021.06.011. Epub 2021 Jun 11.

Reference Type: BACKGROUND

PMID: 34153806 (View on PubMed)

Parees I, Brown H, Nuruki A, Adams RA, Davare M, Bhatia KP, Friston K, Edwards MJ. Loss of sensory attenuation in patients with functional (psychogenic) movement disorders. Brain. 2014 Nov;137(Pt 11):2916-21. doi: 10.1093/brain/awu237. Epub 2014 Aug 26.

Reference Type: BACKGROUND

PMID: 25161293 (View on PubMed)

Tinazzi M, Marotta A, Zenorini M, Riello M, Antonini A, Fiorio M. Movement perception of the tonic vibration reflex is abnormal in functional limb weakness. Parkinsonism Relat Disord. 2021 Jun;87:1-6. doi: 10.1016/j.parkreldis.2021.04.011. Epub 2021 Apr 20.

Reference Type: BACKGROUND

PMID: 33895678 (View on PubMed)

Grunewald RA, Yoneda Y, Shipman JM, Sagar HJ. Idiopathic focal dystonia: a disorder of muscle spindle afferent processing? Brain. 1997 Dec;120 ( Pt 12):2179-85. doi: 10.1093/brain/120.12.2179.

Reference Type: BACKGROUND

PMID: 9448573 (View on PubMed)

Fiorio M, Recchia S, Corra F, Simonetto S, Garcia-Larrea L, Tinazzi M. Enhancing non-noxious perception: behavioural and neurophysiological correlates of a placebo-like manipulation. Neuroscience. 2012 Aug 16;217:96-104. doi: 10.1016/j.neuroscience.2012.04.066. Epub 2012 May 6.

Reference Type: BACKGROUND

PMID: 22569155 (View on PubMed)

Morgante F, Matinella A, Andrenelli E, Ricciardi L, Allegra C, Terranova C, Girlanda P, Tinazzi M. Pain processing in functional and idiopathic dystonia: An exploratory study. Mov Disord. 2018 Aug;33(8):1340-1348. doi: 10.1002/mds.27402. Epub 2018 May 8.

Reference Type: BACKGROUND

PMID: 29737565 (View on PubMed)

Schandry R. Heart beat perception and emotional experience. Psychophysiology. 1981 Jul;18(4):483-8. doi: 10.1111/j.1469-8986.1981.tb02486.x. No abstract available.

Reference Type: BACKGROUND

PMID: 7267933 (View on PubMed)

Nielsen G, Ricciardi L, Demartini B, Hunter R, Joyce E, Edwards MJ. Outcomes of a 5-day physiotherapy programme for functional (psychogenic) motor disorders. J Neurol. 2015 Mar;262(3):674-81. doi: 10.1007/s00415-014-7631-1. Epub 2015 Jan 4.

Reference Type: BACKGROUND

PMID: 25557282 (View on PubMed)

Nielsen G, Buszewicz M, Stevenson F, Hunter R, Holt K, Dudziec M, Ricciardi L, Marsden J, Joyce E, Edwards MJ. Randomised feasibility study of physiotherapy for patients with functional motor symptoms. J Neurol Neurosurg Psychiatry. 2017 Jun;88(6):484-490. doi: 10.1136/jnnp-2016-314408. Epub 2016 Sep 30.

Reference Type: BACKGROUND

PMID: 27694498 (View on PubMed)

Demartini B, Bombieri F, Goeta D, Gambini O, Ricciardi L, Tinazzi M. A physical therapy programme for functional motor symptoms: A telemedicine pilot study. Parkinsonism Relat Disord. 2020 Jul;76:108-111. doi: 10.1016/j.parkreldis.2019.05.004. Epub 2019 May 3.

Reference Type: BACKGROUND

PMID: 31078400 (View on PubMed)

Guo Y, Graber A, McBurney RN, Balasubramanian R. Sample size and statistical power considerations in high-dimensionality data settings: a comparative study of classification algorithms. BMC Bioinformatics. 2010 Sep 3;11:447. doi: 10.1186/1471-2105-11-447.

Reference Type: BACKGROUND

PMID: 20815881 (View on PubMed)

Boscolo Galazzo I, Cruciani F, Brusini L, Salih A, Radeva P, Storti SF, Menegaz G. Explainable Artificial Intelligence for Magnetic Resonance Imaging Aging Brainprints: Grounds and challenges. IEEE Signal Processing Magazine, vol. 39, no. 2, pp. 99-116. 2022 March. doi: 10.1109/MSP.2021.3126573.

Reference Type: BACKGROUND

Cruciani F, Brusini L, Zucchelli M, Retuci Pinheiro G, Setti F, Boscolo Galazzo I, Deriche R, Rittner L, Calabrese M, Menegaz G. Interpretable deep learning as a means for decrypting disease signature in multiple sclerosis. J Neural Eng. 2021 Jul 19;18(4). doi: 10.1088/1741-2552/ac0f4b.

Reference Type: BACKGROUND

PMID: 34181581 (View on PubMed)

Salih A, Boscolo Galazzo I, Raisi-Estabragh Z, Petersen SE, Gkontra P, Lekadir K, Menegaz G, Radeva P. A new scheme for the assessment of the robustness of Explainable Methods Applied to Brain Age estimation. IEEE 34th International Symposium on Computer-Based Medical Systems (CBMS), Aveiro, Portugal, 2021, pp. 492-497. doi: 10.1109/CBMS52027.2021.00098.

Reference Type: BACKGROUND

Karch JD, Brandmaier AM, Voelkle MC. Gaussian Process Panel Modeling-Machine Learning Inspired Analysis of Longitudinal Panel Data. Front Psychol. 2020 Mar 19;11:351. doi: 10.3389/fpsyg.2020.00351. eCollection 2020.

Reference Type: BACKGROUND

PMID: 32265770 (View on PubMed)

Gandolfi M, Sandri A, Mariotto S, Tamburin S, Paolicelli A, Fiorio M, Pedrotti G, Barone P, Pellecchia MT, Erro R, Cuoco S, Carotenuto I, Vinciguerra C, Botto A, Zenere L, Canu E, Sibilla E, Filippi M, Sarasso E, Agosta F, Tinazzi M; Group Collaborators Consortium. A window into the mind-brain-body interplay: Development of diagnostic, prognostic biomarkers, and rehabilitation strategies in functional motor disorders. PLoS One. 2024 Sep 26;19(9):e0309408. doi: 10.1371/journal.pone.0309408. eCollection 2024.

Reference Type: DERIVED

PMID: 39325803 (View on PubMed)

Other Identifiers

PNRR-MAD-2022-12376826

Identifier Type: -

Identifier Source: org_study_id