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

A Window Into the Mind-brain-body Interplay: Development of Diagnostic, Prognostic Biomarkers and Rehabilitation Strategies in Functional Motor Disorders

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.

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.

Experiments 1 and 3

Inclusion Criteria for Patients with FMD:

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

Exclusion Criteria for Patients with FMD:

• 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

Inclusion Criteria for Healthy Controls (HC)

- Age higher or equal to 18 years

Exclusion Criteria for Healthy Controls (HC) 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

Experiment 2

Inclusion criteria

• 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 neurological and/or psychiatric comorbidities
• Contraindications for 3T MRI