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

Recruiting

• Conditions: Functional Motor Disorders
• Interventions: Other: Multidisciplinary Rehabilitation Training; Behavioral: Cross-sectional study on patients with FMD and healthy controls (HC); Behavioral: Cross-sectional study on patients with FMD and patients with structural/organic diseases

• Registration Number: NCT06328790
• Lead Sponsor: Michele Tinazzi, MD, PhD

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.

Study Timeline

• Study Start: 2023-05-31
• Status Verified: 2024-03
• Study First Submitted: 2024-03-18
• Study First Submitted QC: 2024-03-18
• Last Update Submitted: 2024-03-23
• Study First Posted: 2024-03-25
• Last Update Posted: 2024-03-26
• Primary Completion: 2025-05
• Study Completion: 2025-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 450

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Functional Motor Disorder rehabilitation group (FMD)	Multidisciplinary Rehabilitation Training	Patients with FMD (subject to current diagnostic criteria) will undergo experiment 3.
Healthy Controls group (HC)	Cross-sectional study on patients with FMD and healthy controls (HC)	Healthy subjects at least 18 years old will undergo experiment 1.
"Organic" Motor Disorders group	Cross-sectional study on patients with FMD and patients with structural/organic diseases	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.
Functional Motor Disorder group (FMD)	Cross-sectional study on patients with FMD and healthy controls (HC)	Patients with FMD (subject to current diagnostic criteria) will undergo experiment 1.

Primary Outcome Measures

Name	Time	Method
Simplified Functional Movement Disorders Rating Scale (S-FMDRS) score	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	Objective-rated validated scale to rate the duration and severity of functional motor symptoms (range: 0-54; higher = worse).
Beck Anxiety Inventory (BAI) score	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	It evaluates anxiety (range: 0-63; higher = worse).
12-item Short-Form Health Survey (SF-12) score	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	The health-Related QoL will be evaluated by the Mental Health and Physical functioning of the 12-item Short-Form Health Survey (SF-12) (range: 0-100; higher = better).
Toronto Alexithymia Scale (TAS-20) score	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	It evaluates the level of alexithymia (range: 20-100; higher = worse).
N2/P2 amplitude	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	Laser evoked potentials (LEP) will be used to collect data
Cortical thickness and gray matter volumes	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	Brain 3 Tesla MRI will be used to collect data
Swing time (%)	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	Gait analysis will be used to collect swing time (%).
Brief Pain Inventory (BPI) score	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	It evaluates pain intensity (range: 0-40; higher = worse) and interference (range: 0-70; higher = worse).
Multidimensional Fatigue Inventory Scale (MFI-20) score	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	It evaluates fatigue differentiating general, physical, reduced-activity, reduced-motivation, and mental fatigue (subscale range: 4-20; higher = worse).
Joint angle at the elbow vibrated and reproduced	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	Tonic vibration reflex (TVR) will be used to collect data
Direct adn indirect index of Sensory Attenuation (SA)	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	Sensory attenuation (SA) will be used to collect data
Clinical Global Impression (CGI) score	After 3 months of the intensive 5-day rehabilitation protocol (T1).	Self-rated perception of change will be assessed with the 7-point Clinical Global Impression (CGI) scale with scores from 1 (very much improved) to 7 (very much worse).
Gait speed (cm/sec)	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	Gait analysis will be used to collect gait speed (cm/s).
Beck Depression Inventory (BDI-II) score	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	It evaluates depression (range: 0-63; higher = worse).
Stance time (sec)	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	An electronic monaxial stabilometric platform will be used to collect stance time (sec).
Velocity of Cop displacement in the anteroposterior directions (mm/s)	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	An electronic monaxial stabilometric platform will be used to collect the velocity of Cop displacement in the anteroposterior directions.
Velocity of Cop displacement in the mediolateral directions (mm/s)	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	An electronic monaxial stabilometric platform will be used to collect the velocity of Cop displacement in the mediolateral directions.
Autism spectrum Quotient (AQ)	Before the intensive 5-day rehabilitation protocol (T0)	It is a 50-item self-report measure used to assess traits of autism in adults and adolescents aged 16 years and over (Total score: 0-50; cut-off: \> 29).
Objective/Subjective heart rate ratio	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	Heartbeat Perception Task (HPT) will be used to collect data
Stride time (s)	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	Gait analysis will be used to collect stride time (s).
Sway area (mm2)	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	An electronic monaxial stabilometric platform will be used to collect sway area (mm2).
Schizotypal Personality Questionnaire (SPQ)	Before the intensive 5-day rehabilitation protocol (T0)	It is a scale for the assessment of schizotypal personality based on DSM-III-R criteria (Total score: 0-74; cut-off: \< 8 \& \> 42).
Stride length (cm)	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	Gait analysis will be used to collect stride length (cm).
Total excursion path (mm)	Before the intensive 5-day rehabilitation protocol (T0) and after 3 months of the intensive 5-day rehabilitation protocol (T1).	An electronic monaxial stabilometric platform will be used to collect total excursion path (mm): area of oscillations of the Center of Pressure (CoP), CoP perimeter length

Trial Locations

Locations (3)

IRCCS Ospedale San Raffaele; 🇮🇹 Milano, Lombardia, Italy

Azienda Ospedaliera OO.RR. S. Giovanni di Dio e Ruggi D'Aragona; 🇮🇹 Salerno, Campania, Italy

Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona; 🇮🇹 Verona, Italy