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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Maria A Rocca, MD; Phone Number: 0039 0226433019; Email: rocca.mara@hsr.it
• Study Contact Backup: Name: Paola Valsasina, MSc; Phone Number: 0039 0226433944; Email: valsasina.paola@hsr.it

Study Locations

• Italy
  • Milan
    • Milan, Milan, Italy, 20132
      • Recruiting
      • IRCCS San Raffaele
      • Contact: Massimo Filippi, MD; Phone Number: 00390226433054; Email: filippi.massimo@hsr.it
      • Contact: Maria A. Rocca, MD; Phone Number: 00390226433019; Email: rocca.mara@hsr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VR-AOT; 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; 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).
Active Comparator: VR-LO; Home-based landscape observation with virtual-reality for upper limb rehabilitation	Other: Home-based landscape observation with virtual-reality for upper limb rehabilitation; 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).

What is the study measuring?

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 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
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

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele
• Collaborators: Istituto di Neuroscienze Consiglio Nazionale delle Ricerche
• Investigators: Principal Investigator: Maria A Rocca, MD, IRCCS Ospedale San Raffaele

Publications and helpful links

General Publications

• Rocca MA, Tortorella P, Ceccarelli A, Falini A, Tango D, Scotti G, Comi G, Filippi M. The "mirror-neuron system" in MS: A 3 tesla fMRI study. Neurology. 2008 Jan 22;70(4):255-62. doi: 10.1212/01.wnl.0000284667.29375.7e. Epub 2007 Dec 12.
• Rocca MA, Meani A, Fumagalli S, Pagani E, Gatti R, Martinelli-Boneschi F, Esposito F, Preziosa P, Cordani C, Comi G, Filippi M. Functional and structural plasticity following action observation training in multiple sclerosis. Mult Scler. 2019 Oct;25(11):1472-1487. doi: 10.1177/1352458518792771. Epub 2018 Aug 7.
• Rizzolatti G, Fabbri-Destro M, Nuara A, Gatti R, Avanzini P. The role of mirror mechanism in the recovery, maintenance, and acquisition of motor abilities. Neurosci Biobehav Rev. 2021 Aug;127:404-423. doi: 10.1016/j.neubiorev.2021.04.024. Epub 2021 Apr 25.
• Nuara A, Avanzini P, Rizzolatti G, Fabbri-Destro M. Efficacy of a home-based platform for child-to-child interaction on hand motor function in unilateral cerebral palsy. Dev Med Child Neurol. 2019 Nov;61(11):1314-1322. doi: 10.1111/dmcn.14262. Epub 2019 May 21.
• De Marco D, Scalona E, Bazzini MC, Nuara A, Taglione E, Lopomo NF, Rizzolatti G, Fabbri-Destro M, Avanzini P. Observation of others' actions during limb immobilization prevents the subsequent decay of motor performance. Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):e2025979118. doi: 10.1073/pnas.2025979118.
• Jonsdottir J, Perini G, Ascolese A, Bowman T, Montesano A, Lawo M, Bertoni R. Unilateral arm rehabilitation for persons with multiple sclerosis using serious games in a virtual reality approach: Bilateral treatment effect? Mult Scler Relat Disord. 2019 Oct;35:76-82. doi: 10.1016/j.msard.2019.07.010. Epub 2019 Jul 20.

Study record dates

Study Major Dates

• Study Start (Actual): November 2, 2023
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: January 26, 2023
• First Submitted That Met QC Criteria: January 26, 2023
• First Posted (Actual): February 6, 2023

Study Record Updates

• Last Update Posted (Estimated): December 9, 2025
• Last Update Submitted That Met QC Criteria: December 2, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis
• Other Study ID Numbers: RF-2021-12374941

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The dataset including all the data obtained from this study will be available from the Principal Investigator upon reasonable request.
• IPD Sharing Time Frame: The dataset including all the data obtained from this study will be available 6 months after the publication of the results.
• IPD Sharing Access Criteria: The dataset including all the data obtained from this study will be available from the Principal Investigator upon reasonable request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No