Virtual Reality in Physical Therapy in Multiple Sclerosis (VIREMS)

Effect of Neuroproprioceptive "Facilitation, Inhibition" Physical Therapy Using Virtual Reality on Upper Limb Mobility and Postural Stability in Multiple Sclerosis

The randomized controlled trial is aimed to study the efficacy of virtual reality (VR) and its impact on upper limb function and postural stability in people with mild to severe multiple sclerosis (pwMS). The conceptual idea is to compare two kinds of neuroproprioceptive "facilitation and inhibition" physical therapy, first in a real environment and second in virtual reality, in out-patient therapy that will be held in 15 hourly therapies, 2x a week in a period of two months. The efficacy will be assessed by a blinded independent clinical examiner using clinical examination and questionnaire survey before and in a week following the therapeutic intervention. The main focus is on upper limb gross and fine motor skills, trunk stability and stability, and sit to stand stability.

In 60 - 75% of people with multiple sclerosis (MS) an upper limb mobility dysfunction (unilateral or bilateral manual dexterity, sensibility impairment, tremor) is present, resulting in reduced participation in activities of daily living. Physiotherapy has a crucial impact on upper limb mobility, although there are many approaches applied (exercise/strengthening exercise, endurance training, sensory training, constraint-induced movement therapy, robotic rehabilitation therapy, etc.). Virtual reality is an innovative technological concept using game mechanisms that facilitate concentration and motivation in task performance. Current research implies that VR is a safe and effective method in gait and balance//stability rehabilitation therapy and with less evidence, for upper limb mobility improvement. It is expected that a greater therapeutic effect is a result of multifactorial sense stimulation and dopamine centres in the brain. A pilot project showed that virtual reality without the prompt feedback of a physiotherapist is not more effective than standard therapy. A new therapeutic software using virtual reality spontaneously motivating the patient for movement realization was developed in cooperation with the Department of informatics and computer science Faculty of applied sciences University West Bohemia. Accurate execution of neuroproprioceptive "facilitation and inhibition techniques" physical therapy combining key principles from proprioceptive neuromuscular stabilization (PNS) and motor program activating therapy (MPAT), ensures a present physiotherapist. These principles have shown the effect in therapy in pwMS. Participants will be randomized into two arms of the study, both implementing neuroproprioceptive "facilitation and inhibition" physical therapy, first in a real environment and second in VR. The investigators expect that VR intervention shall improve upper limb motor functions, trunk muscles coordination, improve the performance of activities of daily living and quality of life in pwMS more than identical therapy not using VR. The effect of both interventions will be assessed using validated tests for clinical examination- Five times Sit to Stand test (5STS), Nine Hole Peg Test (9HPT), Hand Grip Strength (HGS), Box and Block Test (BNB), accelerometer for tremor examination. Validated questionnaires will be used, specifically the Multiple Sclerosis Impact Scale (MSIS-29), EQ-5D-3L health questionnaire, Visual Analogue Scale, and a questionnaire dealing with individual virtual reality intervention evaluation.

multiple sclerosis, virtual reality, hand dexterity, postural stability, physical therapy, coordination, upper limb fine motor skills, motor programme activating therapy, neuroproprioceptive "facilitation, inhibition", postural control, functional recovery, Demyelinating Autoimmune Disease, Autoimmune Diseases of the Nervous System

A randomized controlled trial. 110 outpatients will be randomized into two interventional groups, one with face-to-face individual neuroproprioceptive "facilitation and inhibition" physical therapy combining key principles of proprioceptive neuromuscular facilitation (PNF) and motor program activating therapy (MPAT). The second arm will place the same therapy, but virtual reality environment. Participants of both groups - active comparator and virtual reality interventional group will undergo 15 hourly therapies, twice a week in a time range of two months. Before and in a week following the last therapy, all participants will be examined by a blinded independent clinician.

All participants of the study will undergo a clinical examination including a questionnaire survey, led by a blinded independent examiner, who will not have access to intervention documentation. The examiner will see each patient twice, before the first intervention and in follow-up examination in a week following the last therapy. The examiner will be prohibited to talk about the therapy attended. The patients will be informed about the character of the examination and the importance of the most objectivity possible. All therapists can apply both interventions, therefore masking is more efficient.

ARM 1 - Neuroproprioceptive "facilitation and inhibition" physical therapy combining key principles of proprioceptive neuromuscular facilitation (PNF) and motor program activating therapy (MPAT), with former positive probative evidence on MS and are recommended for MS intervention.

ARM 2. Experimental group, neuroproprioceptive "facilitation and inhibition" physical therapy combining key principles of proprioceptive neuromuscular facilitation (PNF) and motor program activating therapy (MPAT) through virtual reality and software inducing and motivating for movement according to principles of proprioceptive neuromuscular facilitation (PNF) and motor program activating therapy (MPAT). We believe that the VR environment might lead to better results due to greater motivation effect, novelty effect, entertainment effect, as well as activating the reward system. We believe the VR might enhance the activation of mirror neurons, it might also activate proprioception. The present physiotherapist is to ensure proper execution of the tasks. The correlation of the two arms of the study should indicate, whether virtual reality and the software used are as effective, or more effective in sustaining the hand motor function and axial stability, than traditionally led therapy.

The 110 outpatients will be randomized into groups: First arm, individual neuroproprioceptive "facilitation and inhibition" physical therapy combining key principles of proprioceptive neuromuscular facilitation (PNF) and motor program activating therapy (MPAT) in a real environment and the second arm, the same therapy in virtual reality environment. All participants will undergo 15 sessions, 60 minutes each, twice a week in a period of two months. The therapy in a second, interventional group, uses virtual reality and new software that was developed specifically for inducing and motivating for movement according to principles of proprioceptive neuromuscular facilitation (PNF) and motor program activating therapy (MPAT). The software allows immediate feedback and moreover, movement is corrected by a present therapist. Evaluation of speed and performance quality might be extracted from the software of virtual reality.

The first arm of the study will consist of a physiotherapeutic approach based on neurophysiological principles using proprioceptive neuromuscular facilitation (PNF) and motor program activating therapy (MPAT) approaches. MPAT makes use of particular motor patterns that evolve in postural control development. The repetition of activated programs, a set of stimuli, applied to change the posture with anatomical centration of the joint under various conditions in leading to better support of postural stabilization while seated, while getting up, stepping forward, and standing, in order to teach the patients to use the acquired motor skills automatically in daily life. PNF is a method used for learning effective movement patterns with high biomechanical effectiveness based on repetitive stimulation of cooperating alfa-motoneurons and proprioceptors in muscle, tendons and joint capsules. Therapy will be individualized and led in the standard face-to-face regiment.

The NHPT requires participants to repeatedly place and then remove nine pegs into nine holes, one at a time, as quickly as possible. Lower number (quicker time) means better result.

Pre-assessment (baseline testing), Post-assessment (immediately in a week following the last procedure)

The Box and Block Test tests gross manual dexterity. This test consists of moving, one by one, the maximum number of blocks from one compartment of a box to another of equal size, originally, within 60 seconds. A lower number (quicker time) means better result.

Pre-assessment (baseline testing), Post-assessment (immediately in a week following the last procedure)

The test assesses time when people stand and sit repeatedly five times. The lower the time to complete the test the better the outcome of the test.

Pre-assessment (baseline testing), Post-assessment (immediately in a week following the last procedure)

Jamar Hydraulic Hand Dynamometer measures isometric grip force and strength. The higher value, the better function (higher strength).

Pre-assessment (baseline testing), Post-assessment (immediately in a week following the last procedure)

The spectral characteristic of postural tremor measured by the 3-axis accelerometer and 3-axis gyroscope chip (Motion Tracking sensor MPU-6050) - lower value, lower tremor.

Pre-assessment (baseline testing), Post-assessment (immediately in a week following the last procedure)

The spectral characteristic of postural tremor measured by the 3-axis accelerometer and 3-axis gyroscope chip (Motion Tracking sensor MPU-6050) - lower value, lower tremor.

Pre-assessment (baseline testing), Post-assessment (immediately in a week following the last procedure)

A 29-item self-report measure with 20 items associated with a physical scale and 9 items with a psychological scale. Items ask about the impact of MS on a day-to-day life in the past two weeks. All items have 5 response options: 1 "not at all" to 5" extremely". Each of the two scales is scored by summing the responses across items, then converting to a 0-100 scale where 100 indicates the greater impact of the disease on daily function (worse health).

Pre-assessment (baseline testing), Post-assessment (immediately in a week following the last procedure)

Descriptive system for health-related quality of life states in adults, consisting of five dimensions (Mobility, Self-care, Usual activities, Pain & discomfort, Anxiety & depression), each of which has three severity levels that are described by statements appropriate to that dimension. A higher number means a worse quality of life.

Pre-assessment (baseline testing), Post-assessment (immediately in a week following the last procedure)

The fMRI examinations shall be performed in the MR system Siemens Vida 3T located in IKEM using a 64-channel RF head coil. Examination protocol will include essential structural imaging (3D SPACE FLAIR sequence with an isotropic spatial resolution of 1 mm3), measurement of functional connectivity using resting-state fMRI, and measurement of structural connectivity utilising the evaluation of the spatial distribution of molecular diffusion (generalised DTI - diffusion tensor imaging, with 108 spatial directions and 3b-factors allowing the reconstruction not only of fractional anisotropy but also the diffusion kurtosis imaging). The resting of 30 seconds will be followed by a 30-second unilateral hand active movement-driven stimulation interval, repeated eight times.

Pre-assessment (baseline testing), Post-assessment (immediately in a week following the last procedure)]

The study will include an analysis of long non-coding RNA (lncRNA), the subtypes, and the activation of dendritic cells. The dynamic of the studied parameters might bring essential knowledge on the biological effect of rehabilitation intervention in people with multiple sclerosis. These parameters will be studied and correlated concerning individual MS treatment.

Pre-assessment (baseline testing), Post-assessment (immediately in a week following the last procedure)]

For more systematic patient population characteristics and monitoring of individual levels of functioning, disability and health, we will obtain information from the Brief ICF core set for Multiple Sclerosis, the official core set by the ICF Research Branch.

Pre-assessment (baseline testing), Post-assessment (immediately in a week following the last procedure)]

Inclusion Criteria: The inclusion criteria comprise of a definite diagnosis of multiple sclerosis, EDSS score ≥ 2 a ≤ 7 ((10); determined by neurologist), no history of relapse, no history of change in disease-modifying treatment, no history of corticosteroid therapy in the past three months prior to recruitment. Exclusion Criteria: The exclusion criteria include other factors influencing mobility (history of stroke, pregnancy, traumatic injury of limb/s. Severe cardiovascular or orthopedic dysfunction, impaired cognitive functions in the course of examination and/or consecutive therapy.

All data sharing terms and conditions and the nature of the relationship between the study and new user will be contained in a Data-sharing Agreement that will be issued and sighed before any data are handed out. The de-identification process for each patient is to ensure anonymization of individual patient's data, in order to be able to share IPD within the terms of participant's consent and ethics committee approval. The study policy on sharing defines the terms of privileged use by the study team. The research team requires to be appropriately notified and acknowledged in publications and other outputs of the transferred data (or analyses conducted by the study on the new users' behalf). The Data-sharing agreement will comprehend arrangements for data destruction or secure archiving. It is planned that the data will be placed into an online repository (to be specified later).

The IPD will be made available from 3-months months following the first publication of findings based on the data until 3 years following the first publication.

The datasets will be prepared and might be reachable on a request. The study team formally reviews access requests for proposals. The data on an exclusive basis will be made available for third party use/ the new user, which can range from direct provision of data, data analysis collaboration, and/or scientific collaboration. Also, the requester is to state the purpose for which the data are to be used.