Home-based Action Observation Treatment With Virtual-reality for Arm Rehabilitation in People With Multiple Sclerosis

Study Overview
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Brief Summary
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Action Observation Treatment (AOT) is a rehabilitative strategy which has been proposed as a promising approach to improve motor performance in neurological conditions, including multiple sclerosis (MS). In this clinical trial, the investigators aim to explore the role of a home-based AOT with virtual reality (VR) in improving upper limb motor function in people with MS (PwMS). The objectives are: To compare the effects of home-based VR-AOT versus VR-landscape observation (LO) on upper limb motor performance; To measure brain network functional changes (functional plasticity) and structural variations of gray matter (GM) and white matter (WM) (structural plasticity) using advanced magnetic resonance imaging (MRI) techniques following VR-AOT and VR-LO; To study the correlations between MRI changes and clinical improvements and the predictors of VR-AOT efficacy. All participants will undergo treatment sessions for 3 weeks (5 consecutive days/week, total=15 sessions lasting 30 minutes each). Those in the VR-AOT group will observe, imagine and execute two upper limb motor tasks in each session. Those in the VR-LO group will perform the same tasks, but they will observe inanimate landscapes beforehand instead.

Official Title
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An Integrated and Home-based Motor Rehabilitation Combining Virtual Reality and Action Observation Treatment in People With Multiple Sclerosis: a Clinical and Neuroimaging Study

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Other: Home-based Action Observation Treatment with virtual-reality for upper limb rehabilitation
* Other: Home-based landscape observation with virtual-reality for upper limb rehabilitation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-65 years; Diagnosis of MS according to 2017 revised McDonald criteria; Ability to understand the purpose and risks of the study and provide signed informed consent; Ability to remotely perform VR-AOT; Right pre-morbid handedness (EHI>50); Muscle strength deficit involving the right upper limb (≥1 point decrease of MRC scale); Presence of activity limitation of the right hand (need of adaptations, supervision or help by another person for the execution of daily living activities according to items 1-6 of the FIM); EDSS score 2.0-7.0 (inclusive); Cerebellar functional system score of the EDSS ≤1; Baseline 9HPT score >21 seconds and <180 seconds. Exclusion Criteria: MRI contraindications; Significant visual deficits not allowing to observe VR stimuli; Moderate to severe pain disturbances (VAS≥4); Concomitant neuro-psychiatric or systemic diseases (other than MS); Clinical relapses or steroid treatment in the past 3 months; Modification of symptomatic treatment or botulin toxin injection in the upper limb in the past 3 months; Stable disease-modifying treatment for MS for ≤6 months; Rehabilitation treatment in the past 3 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized, controlled, single-blinded, parallel study. A total sample size of 60 PwMS is planned, with 30 participants randomly assigned to each of the treatment arms (ratio 1:1) through a computer-generated list managed by a physician external to the study.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VR-AOT<br>Home-based Action Observation Treatment with virtual-reality for upper limb rehabilitation | Other: Home-based Action Observation Treatment with virtual-reality for upper limb rehabilitation<br>* Observation of a VR scenario depicting multiple repetitions of a specific upper limb motor task belonging to typical activities of daily living, followed by mental imagination of the action observed and then by the execution of the same task, using objects provided in a kit. In each session, patients will watch 2 different videos and will perform the two corresponding actions. The time scheduled for observation, imagery and execution of each action will be of 5, 3, and 7 minutes, respectively, so that each session will last about 30 minutes. New actions, chosen from a dataset of 50 stimuli showing progressively increasing levels of difficulty, will be weekly administered on the basis of patient's degree of motor impairment, to involve different manual skills. 30 minutes sessions, 5 times a week for 3 consecutive weeks (15 sessions in total).<br>|
| Active Comparator: VR-LO<br>Home-based landscape observation with virtual-reality for upper limb rehabilitation | Other: Home-based landscape observation with virtual-reality for upper limb rehabilitation<br>* Observation of virtually explorable landscapes followed by rest with eyes closed without focusing on any thought in particular and then execution of the same actions requested to VR-AOT-group. In each session, patients will explore 2 different landscapes and perform 2 different actions. The time scheduled for observation, rest and action execution will be of 5, 3, and 7 minutes, respectively, so that each session will last about 30 minutes.New actions, chosen from a dataset of 50 stimuli showing progressively increasing levels of difficulty, will be weekly administered on the basis of patient's degree of motor impairment, to involve different manual skills. 30 minutes sessions, 5 times a week for 3 consecutive weeks (15 sessions in total).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in right hand Nine-hole peg test (9HPT) | Time required to complete the 9HPT, a measure of hand dexterity, with the right hand (average of two tests). | Baseline, after 3 weeks of training and after a 3-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in left hand Nine-hole peg test (9HPT) | Time required to complete the 9HPT, a measure of hand dexterity, with the left hand (average of two tests). | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in hand grip strength | Hand grip strength measured with the Jamar handheld dynamometer. Measured for left and right hand separately. | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in finger tapping frequency | Number of taps performed with the index finger in 30 seconds (average of two trials). Measured for left and right hand separately. | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in Medical Research Council (MRC) scale | Segmental upper limb strength measured using the MRC scale. Scores on this scale range from 0 (no visible contraction) to 5 (normal strength). Measured for left and right upper limb separately. | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in Modified Ashworth Scale (MAS) | Upper limb spasticity (shoulder adductors, elbow flexors, wrist flexors and pronators) measured using the MAS. Scores in this scale range from 0 (no increase in muscle tone) to 4 (affected part rigid in flexion or extension). Measured for left and right upper limb separately. | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in items 1-6 of the Functional Independence Measure (FIM) | Autonomy in upper limb-related activities of daily living measured with items 1-6 of the FIM. Each item's score ranges from 1 (total assistance needed) to 7 (complete independence). | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in Expanded Disability Status Scale (EDSS) | Multiple sclerosis-related global disability and functional systems subscores. Scores in this scale range from 0 (normal neurological function) to 10 (death due to multiple sclerosis). | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in Paced Auditory Serial Addition Test (PASAT) | A cognitive task that measures sustained attention and working memory. The scores of this test, ranging from 0 to 60, are corrected for age, sex and years of education. Higher scores reflect a better performance in the test. | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in Symbol-Digit Modalities Test (SDMT) | A cognitive task that measures information processing speed. The scores of this test, ranging from 0 to 110, are corrected for age, sex and years of education. Higher scores reflect a better performance in the test. | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) | An instrument that rates the severity of depressive symptoms. It is administered by a clinician through an interview. It is composed by 10 items, each with a score ranging from 0 to 6. The overall score ranges from 0 to 60, with higher scores reflecting greater severity of depressive symptoms. | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in Modified Fatigue Impact Scale (MFIS) | A 21-item scale where patients rate their perceived feeling of fatigue in three subscales (physical, cognitive and psychosocial). The total score of this scale ranges from 0 to 84, with higher scores reflecting more impact of fatigue in everyday life. | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in Arm Function in Multiple Sclerosis Questionnaire (AMSQ) | A self-reported measure of upper limb function containing 31 items. The score of this scale ranges from 31 to 186, with higher scores indicating more limitation in hand and arm function. | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in Multiple Sclerosis Quality of Life-54 (MSQOL-54) | A health-related measure of quality of life in people with MS. It contains 54 items grouped in 12 subscales. Two summary scores can be extracted from this scale: the physical health and mental health composite scores. These scores can be derived from a weighted combination of scale scores (scale scores range from 0 to 100 and a higher scale score indicates better quality of life). | Baseline, after 3 weeks of training and after a 3-month follow-up | 
| Change in global brain volume | Normalized volumes of the brain, GM and WM will be extracted from 3D T1 MRI sequences. | Baseline and after 3 weeks of training | 
| Changes in regional gray matter volumes | Tensor-based morphometry (TBM) will be used to map and compare longitudinal changes of regional GM volumes between groups | Baseline and after 3 weeks of training | 
| Changes in white matter microstructural architecture | Tract-based spatial statistics (TBSS) will be used to map training-related changes of WM architecture. | Baseline and after 3 weeks of training | 
| Changes in resting state functional connectivity | Independent Component Analysis will be used to decompose resting state functional MRI data into spatially independent maps and time courses, and to select the main sensory and motor functional networks of interest, as well as the Mirror Neuron System network. | Baseline and after 3 weeks of training | 
| Changes in brain activation during an object manipulation task | Statistical Parametric Mapping (SPM) 12 will be applied to functional MRI sequences acquired during the object manipulation task to evaluate the modifications of functional activations during this task. | Baseline and after 3 weeks of training |