Modulation of Sense of Agency With Non-invasive Brain Stimulation and Mindfulness-based Stress Reduction Therapy

Study Overview
=================
Brief Summary
-----------------
A conversion disorder is a dysfunction of the nervous system in which no structural damage can be demonstrated. However, it must be distinguished from other psychiatric disorders such as psychosis or depression. There are a variety of signs of the disease, such as muscle paralysis, uncontrolled tremors or cramps. In rarer cases, blindness, deafness or numbness may occur. Diagnosing this complex disorder has always been a challenge for neurologists and psychiatrists. This study investigates the effects of transcranial magnetic stimulation (TMS) on the general well-being and symptoms of conversion disorder and other neurological disorders and in comparison to healthy subjects. The TMS method allows to target specific areas of the brain by means of magnetic fields. This technique is not painful and does not have long-lasting effects. In addition, the study investigates the effects of mindfulness-based stress reduction on the general well-being and symptoms of conversion disorder and other neurological disorders and compared to healthy subjects. This technique is not painful and has no long-lasting effects. Furthermore, the study examines movement patterns and symptoms of patients compared to healthy controls while they are in a virtual reality. Finally, the study examines patients' brain activity while playing a game targeting the sense of agency in real time, which is recorded with an MRI scanner. The study includes a maximum of twelve sessions in total (ten sessions of approximately 1.5-2 hours each and two sessions each overnight). The planned study methods include TMS, (real-time and normal) magnetic resonance tomography of the brain (MRI tube), virtual- and augmented reality (AR/VR), questionnaires, blood, saliva, and motion sensors (e.g., fitness bracelet), and participation in the 8-week mindfulness program.

Official Title
-----------------
Modulation of the Sense of Agency Across Different Neurological Disorders Using Non-invasive Brain Stimulation and Mindfulness-based Stress Reduction Therapy

Conditions
-----------------
Functional Neurological Symptom Disorder, Neurological Diseases or Conditions

Intervention / Treatment
-----------------
* Behavioral: Mindfulness-based stress reduction therapy
* Device: Inhibitory TMS
* Behavioral: Psychoeducation
* Device: TMS sham
* Device: Excitatory TMS
* Device: Virtual Reality
* Behavioral: Neurofeedback


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients: A diagnosis of a functional disorder (such as FND, GTS, PPD, anxiety or depression or others) according to DSM-5 diagnostic and ICD-11 criteria, or A diagnosis of an organic neurological disorder such as stroke, multiple sclerosis (MS), neuromuscular, or movement disorder Aged > 16 years old Willing to participate in the study (by signing the ICF) Capable of judgement healthy controls: Aged > 16 years old Willing to participate in the study (by signing the ICF) Capable of judgement Exclusion Criteria: Presence of comorbid psychiatric disorders such as psychosis, current major and severe depression episode, autistic spectrum disorder Past surgery in the brain History of alcohol or drug abuse Botulinum toxin injection in last 3 month Inability to follow the procedure of the study, e.g., due to language problems For organic disorders only: Active severe aphasia, dementia, neglect and acute confusional state, severe pain For female participants: breastfeeding, pregnancy or intention to become pregnant (assessed with standard urine test prior to the enrolment in the experiment and before each visit) For MRI and TMS part only: Past surgery in the brain For MRI and TMS part only: Implanted medical devices not-compatible with MRI or TMS (e.g., cochlear implants, infusion pumps, neurostimulators, cardiac pacemakers) For TMS part only: History of actual or suspected epilepsy For TMS part only: Suspected or diagnosed labile or hypertensive blood pressure For Virtual Reality only: No cybersickness

Ages Eligible for Study
-----------------
Minimum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FND Patients Experimental<br>Group of patients with functional neurological disorders | Behavioral: Mindfulness-based stress reduction therapy<br>* MBSR Therapy is a structured 8-week program that employs mindfulness meditation to alleviate suffering associated with physical, psychosomatic and psychiatric disorders. The program is based upon a systematic procedure to develop enhanced awareness of moment-to-moment experience of perceptible mental processes.<br>Device: Inhibitory TMS<br>* The device will be used to neuromodulate the right TPJ of participants' brain using cTBS stimulation protocol for transcranial magnetic stimulation<br>Device: TMS sham<br>* The device will be used to neuromodulate the right TPJ of participants' brain using transcranial magnetic stimulation over the vertex<br>Device: Excitatory TMS<br>* The device will be used to neuromodulate the right TPJ of participants' brain using iTBS stimulation protocol for transcranial magnetic stimulation<br>Device: Virtual Reality<br>* The device will be used to manipulate the perception of symptoms of patients while they are playing a game in virtual/augmented reality.<br>Behavioral: Neurofeedback<br>* Neurofeedback training will be applied in patients while laying in an MRI scanner. Patients will play a game, which targets the sense of agency, and will receive a real-time feedback about their performance and brain activity. They will learn to self-regulate their performance on the game in order to increase brain activity relevant for the sense of agency.<br>|
| Active Comparator: Organic controls<br>Group of patients with organic neurological disorders | Device: Inhibitory TMS<br>* The device will be used to neuromodulate the right TPJ of participants' brain using cTBS stimulation protocol for transcranial magnetic stimulation<br>Device: TMS sham<br>* The device will be used to neuromodulate the right TPJ of participants' brain using transcranial magnetic stimulation over the vertex<br>Device: Excitatory TMS<br>* The device will be used to neuromodulate the right TPJ of participants' brain using iTBS stimulation protocol for transcranial magnetic stimulation<br>|
| Active Comparator: Healthy controls<br>Group of healthy controls | Device: Inhibitory TMS<br>* The device will be used to neuromodulate the right TPJ of participants' brain using cTBS stimulation protocol for transcranial magnetic stimulation<br>Device: TMS sham<br>* The device will be used to neuromodulate the right TPJ of participants' brain using transcranial magnetic stimulation over the vertex<br>Device: Excitatory TMS<br>* The device will be used to neuromodulate the right TPJ of participants' brain using iTBS stimulation protocol for transcranial magnetic stimulation<br>Device: Virtual Reality<br>* The device will be used to manipulate the perception of symptoms of patients while they are playing a game in virtual/augmented reality.<br>|
| Active Comparator: FND Patients Comparator<br>Group of patients with functional neurological disorders | Device: Inhibitory TMS<br>* The device will be used to neuromodulate the right TPJ of participants' brain using cTBS stimulation protocol for transcranial magnetic stimulation<br>Behavioral: Psychoeducation<br>* Participants will learn about the symptoms and how to cope with the symptoms<br>Device: TMS sham<br>* The device will be used to neuromodulate the right TPJ of participants' brain using transcranial magnetic stimulation over the vertex<br>Device: Excitatory TMS<br>* The device will be used to neuromodulate the right TPJ of participants' brain using iTBS stimulation protocol for transcranial magnetic stimulation<br>Behavioral: Neurofeedback<br>* Neurofeedback training will be applied in patients while laying in an MRI scanner. Patients will play a game, which targets the sense of agency, and will receive a real-time feedback about their performance and brain activity. They will learn to self-regulate their performance on the game in order to increase brain activity relevant for the sense of agency.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in objective Performance Agency Task (TMS) | The changes in objective performance on the behavioural tasks targeting the sense of agency using the score of an agency task played in the Magnetic Resonance Imaging (MRI) scanner, on a computer or in Virtual Reality before and after brain stimulation (transcranial magnetic stimulation, TMS). The performance is measured by counting the number of targets hit minus the number of obstacles hit during the computer game [-]. | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline), visit 7 to 11 (12 - 16 weeks) | 
| Change in subjective Performance Agency Task (TMS) | The changes in objective and subjective performance on the behavioural tasks targeting the sense of agency using questionnaires before and after brain stimulation. Participants rate their performance on a visual analog scale (VAS) from 0 to 10 [-]. | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline), visit 7 to 11 (12 - 16 weeks) | 
| Change in objective Performance Agency Task (MBSR) | The objective performance on the behavioural tasks targeting the sense of agency using the score of an agency task played in the MRI scanner, on a computer or in Virtual Reality before and after a therapeutic intervention (mindfulness-based stress reduction, MBSR).The performance is measured by counting the number of targets hit minus the number of obstacles hit during the computer game [-]. | Visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4), visit 7 to 11 (12 - 16 weeks) | 
| Change in subjective Performance Agency Task (MBSR) | The subjective performance on the behavioural tasks targeting the sense of agency using questionnaires before and after a therapeutic intervention (MBSR). Participants rate their performance on a visual analog scale (VAS) from 0 to 10 [-]. | Visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4), visit 7 to 11 (12 - 16 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| task-based fMRI measures TMS | The functional magnetic resonance imaging (fMRI) measures of blood oxygenation signal (BOLD) in the whole brain during the behavioural task before and after excitatory, inhibitory or sham rTMS, in patients affected by a functional neuropsychiatric disorder (e.g., FND, Gilles de la Tourette Syndrome (GTS), Psychosomatic Pain Disorder (PPD)), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke) and healthy subjects. BOLD is measured in change in intensity between conditions with conditions being before and after rTMS [-]. | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline) | 
| resting-state fMRI measures TMS | The fMRI measures of blood oxygenation in the whole brain at rest, before and after excitatory, inhibitory or sham rTMS, in patients affected by a functional neuropsychiatric disorder (e.g., FND, GTS, PPD), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke) and healthy subjects. BOLD is measured in change in functional connectivity between conditions with conditions being before and after rTMS. Functional connectivity is calculated using Pearson's correlation coefficient between pairs of brain regions [-]. | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline) | 
| DTI measures TMS | The fMRI measures of blood oxygenation in the whole brain using diffusion tensor imaging (DTI), before and after excitatory, inhibitory or sham rTMS, in patients affected by a functional neuropsychiatric disorder (e.g., FND, GTS, PPD), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke) and healthy subjects. DTI measures the direction and strengths of white matter fibre tracts by measuring the diffusion of water molecules. The measured quantity is the diffusivity or diffusion coefficient, a proportionality constant that relates diffusive flux to a concentration gradient [mm2/s]. | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline) | 
| task-based fMRI measures MBSR | The fMRI measures of blood oxygenation in the whole brain during the behavioural task, before and after MBSR or psychoeducation, in patients affected by a functional neuropsychiatric disorder (e.g., FND, GTS, PPD), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke). BOLD is measured in change in intensity between conditions with conditions being before and after rTMS [-]. | Visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) | 
| resting-state fMRI measures MBSR | The fMRI measures of blood oxygenation in the whole brain at rest before and after MBSR or psychoeducation, in patients affected by a functional neuropsychiatric disorder (e.g., FND, GTS, PPD), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke). BOLD is measured in change in functional connectivity between conditions with conditions being before and after rTMS. Functional connectivity is calculated using Pearson's correlation coefficient between pairs of brain regions [-]. | Visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) | 
| DTI measures MBSR | The fMRI measures of blood oxygenation in the whole brain during DTI, before and after MBSR or psychoeducation, in patients affected by a functional neuropsychiatric disorder (e.g., FND, GTS, PPD), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke). DTI measures the direction and strengths of white matter fibre tracts by measuring the diffusion of water molecules. The measured quantity is the diffusivity or diffusion coefficient, a proportionality constant that relates diffusive flux to a concentration gradient [mm2/s]. | Visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) | 
| Subjective Agency TMS | Subjective assessment of own agency during a behavioural task, before and after excitatory, inhibitory or sham rTMS, in patients affected by a functional neuropsychiatric disorder (e.g., FND, Gilles de la Tourette Syndrome (GTS), Psychosomatic Pain Disorder (PPD)), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke) and healthy subjects. Participants rate their performance on a visual analog scale (VAS) from 0 to 10 [-]. | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline) | 
| Subjective Agency MBSR | Subjective assessment of own agency during a behavioural task, before and after MBSR or psychoeducation, in patients affected by a functional neuropsychiatric disorder (e.g., FND, GTS, PPD), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke). Participants rate their performance on a visual analog scale (VAS) from 0 to 10 [-]. | Visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) | 
| Neurological Examination TMS | The performance on an objective neurological examination, before and after excitatory, inhibitory or sham rTMS, in patients affected by a functional neuropsychiatric disorder (e.g., FND, Gilles de la Tourette Syndrome (GTS), Psychosomatic Pain Disorder (PPD)), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke). Patients will be examined according to standardized medical examination tests (e.g., positive signs & A Simplified Version of the Psychogenic Movement Disorders Scale (S-FMDRS) for FND). | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline) | 
| Neurological Examination MBSR | The performance on an objective neurological examination, before and after MBSR or psychoeducation in patients affected by a functional neuropsychiatric disorder (e.g., FND, GTS, PPD), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke). Patients will be examined according to standardized medical examination tests (e.g., positive signs & A Simplified Version of the Psychogenic Movement Disorders Scale (S-FMDRS) for FND). | Visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) | 
| Objective stress parameters pre/post | The stress parameters assessed using salivary cortisol before and after MBSR Therapy compared to psychoeducation, in patients affected by a functional neuropsychiatric disorder, an organic condition or in healthy subjects. Cortisol levels are measured using Enzyme-linked Immunosorbent Assay (ELISA) [ng/ul]. | Visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) | 
| Subjective stress parameters pre/post | Subjective stress before and after MBSR Therapy compared to psychoeducation, in patients affected by a functional neuropsychiatric disorder, an organic condition or in healthy subjects. Subjective stress is measured using a VAS from 0-100. | Visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) | 
| Sleep | The outcomes of ambient sensors (i.e., actigraphs) monitor non-invasively everyday life activity (ELA), including sleep, in patients affected by a functional neuropsychiatric disorder, an organic condition or in healthy subjects. Actigraphs measure light input and motion. A variety of outcome measures can be calculated such as Time in Bed, Time asleep, | Visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) | 
| Neurofeedback | The real-time measures of blood oxygenation in the target areas (e.g., TPJ) in patients affected by a functional neuropsychiatric disorder (e.g., FND, GTS, PPD), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke) and healthy subjects. Participants will receive direct feedback on their performance in the scanner. | Visit 7 to 11 (12 - 16 weeks) | 
| Long-term effects on task-based fMRI measures MBSR | To measure the long-term (six months) effect of MBSR Therapy, the fMRI measures of blood oxygenation signal (BOLD) is measured in the whole brain during the behavioural task, in patients affected by a functional neuropsychiatric disorder (e.g., FND, Gilles de la Tourette Syndrome (GTS), Psychosomatic Pain Disorder (PPD)), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke) and healthy subjects. BOLD is measured in change in intensity between conditions with conditions being at follow-up compared to Visit 5 (after MBSR therapy)[-]. | At follow-up (6 month after visit 5) | 
| Long-term effects on resting-state fMRI measures MBSR | To measure the long-term (six months) effect of MBSR Therapy, the fMRI measures of blood oxygenation signal (BOLD) is measured in the whole brain at rest, in patients affected by a functional neuropsychiatric disorder (e.g., FND, GTS, PPD), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke) and healthy subjects. BOLD is measured in change in functional connectivity between conditions with conditions being at follow-up compared to Visit 5 (after MBSR therapy). Functional connectivity is calculated using Pearson's correlation coefficient between pairs of brain regions [-]. . | At follow-up (6 month after visit 5) | 
| Long-term effects on DTI measures MBSR | To measure the long-term (six months) effect of MBSR Therapy, the fMRI measures of blood oxygenation signal (BOLD) is measured in the whole brain during DTI, in patients affected by a functional neuropsychiatric disorder (e.g., FND, GTS, PPD), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke) and healthy subjects. DTI measures the direction and strengths of white matter fibre tracts by measuring the diffusion of water molecules. The measured quantity is the diffusivity or diffusion coefficient, a proportionality constant that relates diffusive flux to a concentration gradient [mm2/s]. | At follow-up (6 month after visit 5) | 
| Long-term effects on subjective agency MBSR | To measure the long-term (six months) effect of MBSR therapy, the subjective performance on the behavioural tasks targeting the sense of agency is used. Participants rate their agency on a visual analog scale (VAS) from 0 to 10 [-]. Subjective agency at follow-up will be compared to subjective agency at Visit 5 (after MBSR). | At follow-up (6 month after visit 5) | 
| Long-term effects on neurological examination MBSR | To measure the long-term (six months) effect of MBSR therapy, the performance on an objective neurological examination will be assessed, in patients affected by a functional neuropsychiatric disorder (e.g., FND, GTS, PPD), in comparison to patients affected by an organic condition (e.g., Dystonia, Stroke). Patients will be examined according to standardized medical examination tests (e.g., positive signs & A Simplified Version of the Psychogenic Movement Disorders Scale (S-FMDRS) for FND). Outcome of neurological assessment at follow-up will be compared to outcome of neurological assessment at Visit 5 (after MBSR). | At follow-up (6 month after visit 5) | 
| Long-term effects on objective performance | To measure the long-term (six months) effect of MBSR therapy, the objective performance on the behavioural tasks targeting the sense of agency is used. The performance is measured by counting the number of targets hit minus the number of obstacles hit during the computer game [-]. Objective performance at follow-up will be compared to objective performance at Visit 5 (after MBSR). | At follow-up (6 month after visit 5) | 
| Long-term effects on subjective performance | To measure the long-term (six months) effect of MBSR therapy, the subjective performance on the behavioural tasks targeting the sense of agency is used. Participants rate their performance on a visual analog scale (VAS) from 0 to 10 [-]. Objective performance at follow-up will be compared to objective performance at Visit 5 (after MBSR). | At follow-up (6 month after visit 5) | 
| Neurophysiological measures: MEP | Motor evoked potential (MEP) is measured by eliciting an action potential using non-invasive brain stimulation (TMS) over the motor cortex through the scalp [% TMS - max. intensity output]. Neurophysiological measures will be used to characterise movement disorders. We will compare MEPs in patients with a functional, or organic condition, to healthy subjects. | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline), visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) and follow up (6 month after visit 5) | 
| Neurophysiological measures: MT | Motor threshold (MT) measures the intensity of a pulse which elicits a predefined MEP. Neurophysiological measures will be used to characterise movement disorders. We will compare MTs in patients with a functional, or organic condition, to healthy subjects. | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline), visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) and follow up (6 month after visit 5) | 
| Neurophysiological measures: SICI | Short IntraCortical Inhibition (SICI) measures the reduction of the MEP occurring after weak (subthreshold) conditioning pulse followed by a supra-threshold test pulse at short interstimulus intervals (approximately 2 msec). Neurophysiological measures will be used to characterise movement disorders. We will compare SICIs in patients with a functional, or organic condition, to healthy subjects. | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline), visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) and follow up (6 month after visit 5) | 
| Neurophysiological measures: LICI | Long IntraCortical Inhibition (LICI) measures the reduction of MEP, as described in Outcome 28, at long interstimulus intervals (between 50 and 200 msec), using supra-threshold paired stimulation. Neurophysiological measures will be used to characterise movement disorders. We will compare LICIs in patients with a functional, or organic condition, to healthy subjects. | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline), visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) and follow up (6 month after visit 5) | 
| Neurophysiological measures CSP | Cortical Silent Period (CSP) measures the period of electromyography (EMG) silence before activity resumes baseline, following the MEP elicited by a pulse to the motor cortex during tonic contraction of a target muscle. Neurophysiological measures will be used to characterise movement disorders. We will compare CSPs in patients with a functional, or organic condition, to healthy subjects. | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline), visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) and follow up (6 month after visit 5) | 
| Neurophysiological measures: PAS | Paired Associative Stimulation (PAS) measures the increase in the MEP amplitude following lowfrequency stimulation over the median nerve of the hand, paired with TMS over the motor cortex. This is an index for plasticity. Neurophysiological measures will be used to characterise movement disorders. We will compare CSPs in patients with a functional, or organic condition, to healthy subjects. | Visit 1 (at baseline), visit 2 (one week after baseline), visit 3 (two weeks after baseline), visit 4 (at least 1 week after visit 3), visit 5 (8 weeks after visit 4) and follow up (6 month after visit 5) | 
| Epigenetic profile | Mean methylation rates of genes involved in the stress-pathway (i.e., Oxytocin, Serotonine, Dopamine, Glucocorticoid receptor) will be assessed in patients affected by a functional or organic disorder and healthy subjects using blood samples. Methylation profiles will be determined using the bisulfite - treatment method. | 1st visit (baseline) | 
| Long-term fluctuations of objective stress parameters | To assess the long-term (six months) fluctuations of stress, salivary cortisol will be measured at follow-up in patients affected by a functional neuropsychiatric disorder, an organic condition or in healthy subjects. Cortisol levels are measured using Enzyme-linked Immunosorbent Assay (ELISA) [ng/ul]. | at follow-up (6 month after visit 5) | 
| Long-term fluctuations of subjective stress parameters | To assess the long-term (six months) fluctuations of stress, subjective stress levels will be measured at follow-up in patients affected by a functional neuropsychiatric disorder, an organic condition or in healthy subjects. Subjective stress is measured using a VAS from 0-100. | at follow-up (6 month after visit 5) | 
| Position of focus of attention | To assess the position of focus of attention we will use eye tracking while participants play a game in virtual reality. We assess where participants focus their attention while moving their limbs | at visit 6 (at least one week after visit 5) | 
| Kinematics of limb movements | To assess the kinematics of movements of participants, we apply motion tracking systems with which we measure movement translation and rotation in space. | at visit 6 (at least one week after visit 5) | 
| Stability | The objective and subjective sway in functional patients, organic control patients and healthy subjects will be assessed using posturography, which includes diverse balance exercises on a force plate (e.g. with eyes open / with eyes closed). | Visit 1 (at baseline), and follow up (8 month after visit 1) | 
| Cognition | Outcomes of neuropsychiatric test battery will be compared in functional patients, organic control patients and healthy subjects (e.g. attention, working memory), and further correlated with the fMRI BOLD signal in e.g., the multimodal vestibular network. | Visit 1 (at baseline), and follow up (8 month after visit 1) | 
| Pain processing | Pain processing and perception of pain will be studied in functional patients, organic patients and healthy subjects by using a standardized tool (i.e. Algopeg). Scores from Algopeg will be associated with neural correlates (e.g., resting state fMRI). | Visit 1 (at baseline), and follow up (8 month after visit 1) |