Early Symptoms in Multiple Sclerosis: an Investigation Using fMRI and Gait Analysis to Develop Personalized Balance Training for People With Low Disability (EMS_Rehab)

Background

Many people with Multiple Sclerosis (MS) experience a hidden yet clinically significant symptom: impaired balance or a persistent feeling of instability, even during the early stages of the disease (Martin et al., 2006). Although these individuals may appear to walk normally, they often report feeling unsteady, avoiding crowded environments, or fearing falls. In some cases, however, balance deficits become overt and disabling, depending on the location and extent of lesions within the central nervous system. This heterogeneity complicates both the assessment and treatment of balance disorders in MS and highlights the need for personalized evaluation and rehabilitation strategies (Carpinella et al., 2022).

Because early balance impairments are often subtle, they tend to be underestimated in clinical practice and may remain untreated for months or even years. This delay can negatively affect confidence, mobility, safety, and overall quality of life. The present project seeks to address this gap by promoting early identification and intervention before substantial disability develops.

Project Objectives

The objectives of this project are:

To identify the mechanisms underlying early balance impairment in people with MS.

To develop and evaluate an early intervention based on Vestibular Physical Therapy (VPT) that specifically targets sensory reweighting and visuo-vestibular integration. The rehabilitation program is designed to improve gaze stability and saccadic velocity, both of which are essential for maintaining postural control and dynamic balance. In addition, functional magnetic resonance imaging (fMRI) will be used to investigate the neurophysiological mechanisms underlying the intervention, providing insight into how the brain adapts to vestibular stimulation.

If successful, this approach could enable clinicians to detect and treat balance impairments at an earlier stage, using objective and measurable changes in gait and brain function as biomarkers of rehabilitation efficacy.

Methodology

The study will recruit two groups of participants:

Individuals diagnosed with Multiple Sclerosis (Thompson et al., 2018; Wallace et al., 2025) with mild disability (Expanded Disability Status Scale, EDSS ≤ 2.5) who report balance complaints.

Healthy volunteers matched for age and sex.

At baseline (T0), all participants will undergo a comprehensive assessment including:

Structural and functional MRI with vestibular stimulation to investigate the integrity and functional organization of the vestibular network.

Instrumented gait analysis using wearable inertial sensors (Castiglia et al., 2025).

Validated clinical scales and questionnaires assessing objective balance performance, perceived stability, fear of falling, fall risk, and health-related quality of life.

Participants with MS will then be randomly assigned to one of two groups:

Intervention group: Participants will receive a structured Vestibular Physical Therapy (VPT) program consisting of 12 sessions (three sessions per week). Unlike conventional vestibular rehabilitation, this protocol specifically focuses on sensory reweighting and visuo-vestibular integration to enhance gaze stability, saccadic velocity, and postural control.

Control group: Participants will continue receiving standard clinical care for MS without additional vestibular rehabilitation during the initial study phase.

Following completion of the 12-session intervention, all participants will repeat the full assessment battery (T1) to evaluate changes in gait performance, balance, patient-reported outcomes, and brain function.

After a 4-week washout period, a crossover design will be implemented, with participants switching to the alternate treatment arm for an additional 12-session period, followed by a final assessment (T2). Participants initially assigned to the control group will not require a washout period before crossing over to the intervention, as they will not have received VPT during the first phase of the study.

Study Overview

• Status: Not yet recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Other: Vestibular Physical Therapy

Detailed Description

Balance dysfunction is one of the most frequent and disabling symptoms of relapsing-remitting Multiple Sclerosis (RRMS), affecting up to 80% of people with MS (Alayidi et al., 2025). Importantly, subtle impairments in balance and gait emerge even in the earliest stages of the disease, when clinical disability remains minimal (Expanded Disability Status Scale [EDSS] ≤ 2.5) (Caronni et al., 2020). Many individuals report feelings of instability, dizziness, or unsteadiness despite having a normal neurological examination, while conventional clinical tests often fail to detect these early deficits (Carpinella et al., 2022). Consequently, balance impairment in early RRMS is frequently considered a "hidden disability," negatively affecting confidence, mobility, and quality of life long before overt disability develops.

Current evidence suggests that early balance dysfunction in MS is primarily driven by impaired sensory integration rather than muscle weakness. In particular, disruption of proprioceptive pathways reduces the accuracy of sensory feedback required for postural control (Fling et al., 2014). To compensate for this deficit, the central nervous system appears to increase reliance on cortical attentional mechanisms. Functional MRI studies support this hypothesis by demonstrating increased activation of the primary sensorimotor cortex and supplementary motor areas during simple motor tasks in people with early MS, reflecting compensatory neural recruitment (Rocca et al., 2022).

From a clinical perspective, individuals with early RRMS frequently report reduced balance confidence and fear of falling despite maintaining relatively normal motor performance. Patient-reported outcome measures, such as the Activities-specific Balance Confidence (ABC) Scale and the Dizziness Handicap Inventory (DHI), are effective in capturing perceived instability, particularly during static activities. However, these questionnaires provide limited information regarding dynamic balance performance. Conversely, objective instrumented assessments have demonstrated that subtle abnormalities in gait are already present during the earliest disease stages, even when standard neurological examinations remain normal (Muller et al., 2021).

Recent advances in wearable sensor technology have substantially improved the assessment of gait and balance in MS. Inertial Measurement Units (IMUs) allow precise quantification of spatiotemporal gait parameters during daily activities and standardized walking tests. Previous studies have shown that individuals with early RRMS exhibit slower walking speed, shorter stride length, and prolonged double-support time compared with healthy controls, despite having EDSS scores between 1 and 2 (Soyuer et al., 2006; Benedetti et al., 1999; Karst et al., 2005). These alterations correlate with fatigue and self-perceived disability, suggesting that wearable sensors detect clinically meaningful impairments before they become apparent during routine neurological examination.

The diagnostic sensitivity of IMU-based assessments is particularly evident during postural control tasks. Carpinella et al. (2022) demonstrated that advanced analysis of quiet standing using wearable sensors was three to four times more sensitive than conventional Romberg testing. Specifically, early RRMS participants exhibited reduced sway complexity and increased trunk oscillations, allowing balance impairment to be identified in 58% of participants compared with only 17% detected using traditional clinical assessment. These findings strongly support the integration of wearable technologies into the early evaluation of balance dysfunction in MS.

Although neuroimaging studies have documented widespread functional reorganization in MS, relatively little is known about the neural mechanisms specifically underlying vestibular dysfunction and balance impairment during the early stages of the disease. Task-based fMRI consistently demonstrates increased activation of sensorimotor cortical regions, suggesting compensatory recruitment of motor networks, while resting-state studies reveal altered connectivity within sensorimotor and vestibular circuits. Furthermore, diffusion tensor imaging studies have shown that the structural integrity of proprioceptive pathways predicts balance performance in people with MS (Fling et al., 2014). Nevertheless, to our knowledge, no previous study has combined functional MRI with balance-related vestibular stimulation to directly investigate the neural correlates of early balance impairment in RRMS. This represents a significant knowledge gap.

Immersive virtual reality (VR) offers an innovative approach for investigating balance control under controlled sensory conflict conditions. Beyond its diagnostic potential, VR may also serve as a rehabilitation tool by repeatedly exposing patients to visual and vestibular challenges that promote sensory reweighting. Recent technological developments have led to the creation of MRI-compatible VR systems capable of presenting gaze-controlled visual environments during brain imaging. Such platforms provide the opportunity to investigate how the brain processes balance-related visual and vestibular stimuli in vivo and may eventually facilitate the development of individualized neurorehabilitation protocols.

Vestibular Physical Therapy (VPT) represents one of the most promising rehabilitation strategies for addressing balance dysfunction in MS. VPT consists of structured exercises involving head and eye movements, gaze stabilization, postural control, and balance tasks designed to promote central vestibular compensation (Tramontano et al., 2025). Although vestibular dysfunction in MS is often central rather than peripheral in origin, growing evidence supports the effectiveness of VPT in improving both dizziness and balance (Tramontano et al., 2021).

A recent meta-analysis demonstrated that vestibular rehabilitation significantly improves balance performance and reduces dizziness compared with no intervention in people with MS, with large clinical effect sizes (García-Muñoz et al., 2020). Although vestibular rehabilitation was not statistically superior to other forms of exercise therapy, it consistently produced greater improvements across studies. Similarly, Smania et al. (2015) showed that sensory integration-based balance training resulted in significantly greater improvements in balance performance, reduced falls, and increased balance confidence compared with conventional rehabilitation.

The beneficial effects of VPT are believed to result from adaptive neuroplastic mechanisms. Vestibular rehabilitation facilitates sensory reweighting by enhancing the integration of visual, vestibular, and proprioceptive information while promoting adaptation of vestibulo-ocular and vestibulo-spinal reflexes. Experimental animal studies further suggest that structured vestibular rehabilitation induces cellular plasticity within vestibular nuclei, accelerating functional recovery through increased microgliogenesis and regulation of neurogenesis (Marouane et al., 2021). In humans, neurorehabilitation studies have similarly reported increased functional connectivity within cerebellar and sensorimotor networks following rehabilitation, supporting the hypothesis that VPT promotes adaptive reorganization of central balance networks.

Despite these advances, important unmet clinical needs remain. First, currently available clinical assessments lack sufficient sensitivity to detect early balance impairment in RRMS. Standard neurological examination and conventional balance tests frequently fail to identify subtle deficits that are readily detected using wearable technologies. Second, the neural mechanisms underlying early balance dysfunction remain poorly understood, particularly regarding the interaction between vestibular, cerebellar, and cortical networks. Finally, vestibular rehabilitation is generally introduced only after moderate disability has developed (EDSS 3-6), despite evidence that many patients experience instability much earlier. This delay represents a missed opportunity for preventive intervention aimed at preserving mobility and reducing long-term disability.

These limitations provide a strong rationale for the proposed study. By combining objective gait analysis using wearable inertial sensors, advanced functional neuroimaging with vestibular stimulation, and an early Vestibular Physical Therapy program specifically targeting visuo-vestibular integration and sensory reweighting, this project seeks to characterize the mechanisms underlying early balance impairment in RRMS and determine whether timely intervention can modify both functional performance and the neural substrates of balance control. Demonstrating the efficacy of early VPT could support a paradigm shift toward proactive rehabilitation in Multiple Sclerosis, enabling clinicians to identify and treat balance dysfunction before irreversible disability develops.

Hypothesis

We hypothesize that individuals with early relapsing-remitting Multiple Sclerosis (RRMS; EDSS ≤ 2.5) exhibit measurable neurophysiological alterations within vestibular and sensorimotor networks despite minimal clinical disability, and that these alterations contribute to the subtle balance impairments commonly reported during the early stages of the disease. We further hypothesize that a targeted Vestibular Physical Therapy (VPT) program, specifically designed to promote sensory reweighting and visuo-vestibular integration, will improve both subjective symptoms and objective balance performance while inducing adaptive neuroplastic changes detectable by functional MRI (fMRI).

Specifically, we propose that the "hidden" imbalance observed in early RRMS reflects compensatory or maladaptive plasticity within vestibular, cerebellar, and sensorimotor circuits. These alterations are expected to manifest as abnormal patterns of functional activation and connectivity on fMRI. By engaging vestibular pathways through a structured rehabilitation program, we anticipate promoting adaptive reorganization of these networks, resulting in improved balance control, enhanced gaze stability, and normalization of functional brain connectivity.

This hypothesis is supported by previous evidence demonstrating increased activation of sensorimotor and vestibular cortical regions during motor tasks in early MS, as well as studies showing that motor rehabilitation modifies functional connectivity in people with MS. Furthermore, vestibular rehabilitation has been shown to induce cerebellar and brainstem plasticity in other neurological populations. However, no previous study has directly investigated these mechanisms in early RRMS using an integrated multimodal approach combining functional neuroimaging, quantitative gait analysis, and vestibular rehabilitation.

Specific Aims Aim 1. Identify the Neuroimaging Correlates of Early Balance Dysfunction

Participants will undergo structural and functional MRI using advanced imaging protocols to characterize the functional organization of vestibular, sensorimotor, cerebellar, and balance-related brain networks. Functional imaging will include vestibular stimulation paradigms, such as controlled acoustic stimulation and, where feasible, visual motion stimuli presented through MRI-compatible immersive virtual reality.

We hypothesize that individuals with RRMS will demonstrate altered functional connectivity among key regions involved in balance control, including the cerebellum, parietal cortex, vestibular brainstem nuclei, and sensorimotor cortex, compared with healthy controls. Furthermore, we expect these neuroimaging abnormalities to correlate with the severity of balance impairment measured through objective gait analysis, providing neurophysiological biomarkers of early balance dysfunction.

Aim 2. Characterize Early Balance Impairment Using Advanced Clinical and Instrumented Measures

Subjective and objective balance performance will be comprehensively evaluated using validated clinical questionnaires, standardized balance assessments, and wearable inertial measurement units (IMUs).

Patient-reported outcomes will include measures of dizziness, balance confidence, and quality of life, while IMUs will quantify gait characteristics-including walking speed, stride length, gait symmetry, smoothness, and postural stability-during standardized walking tasks and quiet standing.

We expect people with early RRMS (EDSS ≤ 2.5) to exhibit measurable impairments in gait and postural control despite minimal disability on conventional neurological examination, confirming the presence of clinically hidden balance dysfunction.

Aim 3. Evaluate the Effects of Targeted Vestibular Physical Therapy

We will conduct a randomized crossover clinical trial in which each participant serves as their own control, thereby maximizing statistical power while minimizing inter-individual variability.

Participants will complete both:

a 4-week Vestibular Physical Therapy (VPT) program consisting of 12 sessions specifically designed to enhance sensory reweighting, visuo-vestibular integration, gaze stability, and saccadic function; and a 4-week control period consisting of standard clinical management without additional vestibular rehabilitation.

Participants initially randomized to the intervention arm will undergo a 4-week washout period before crossing over to the control condition, whereas no washout will be required for participants initially assigned to the control arm.

Clinical assessments, quantitative gait analysis, and functional MRI will be performed before and after each intervention period.

We hypothesize that VPT will produce significantly greater improvements in balance performance, gait parameters, dizziness, and fatigue compared with the control condition. We further expect these functional improvements to be accompanied by adaptive changes in brain connectivity, including normalization of excessive cerebellar-sensorimotor coupling and enhanced integration within vestibular networks.

Importantly, vestibular stimulation delivered during fMRI through controlled acoustic stimuli will provide a direct measure of functional changes within vestibular pathways following rehabilitation, offering mechanistic insight into the neural effects of VPT on postural control and gaze stabilization.

Aim 4. Develop Integrated Biomarkers of Early Balance Dysfunction and Rehabilitation Response

Finally, we will integrate quantitative gait metrics obtained from wearable sensors with functional neuroimaging data to identify multimodal biomarkers of early balance impairment.

Specifically, we will investigate whether individuals exhibiting greater abnormalities in gait and postural control also demonstrate more pronounced alterations in vestibular network connectivity. We will additionally evaluate whether changes in these imaging biomarkers predict clinical improvement following rehabilitation.

The identification of objective biomarkers linking behavior and brain function could facilitate earlier diagnosis, improve patient stratification, and provide sensitive outcome measures for future rehabilitation trials.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• people with Relapsing-Remitting Multiple Sclerosis;
• All participants must be ambulatorial (EDSS ≤2.5);

Exclusion Criteria:

• relapse or medication changes in the prior 6 months;
• people with peripheral vestibular disorders;
• people with contraindications to MRI.

We will also recruit 30 healthy volunteers, matched for age and sex, who will complete the assessment protocol once, to serve as a comparison group for individuals with MS.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VPT; People in this arm will be treated with a vestibular physical therapy programme.	Other: Vestibular Physical Therapy; Vestibular Physical Therapy sessions realized focusing on visuo-vestibular interaction (12 session, 3 x 4 weeks)
No Intervention: No VPT; People in this arm will receive a no-add-on-intervention period
No Intervention: Healty control; A healthy control group is required to enable comparisons between individuals with MS and healthy participants.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mini-BESTest	is a 14-item scale (0-28) measures anticipatory postural adjustments, reactive control, sensory orientation and dynamic gait. It is validated and reliable in people with MS. Test-retest reliability is "good to excellent" in mild/moderate MS. Higher scores indicate better balance stability.	Baseline (T0), after first intervention period (T1; 4 weeks), and after crossover (T2; 8 weeks).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuroimaging (MRI)	Structural and functional MRI on a 3 T scanner will assess brain integrity, connectivity and activity, in particular related to visual optic flow or vestibular stimuli. A 3 T scanner yields high signal-to-noise and improved BOLD sensitivity versus 1.5 T, increasing our ability to detect treatment-related neural changes. Pre/post fMRI (same paradigm each time) will be done at baseline and after each intervention. Imaging data analysis will focus on balance and vestibular networks, comparing activation and connectivity changes with intervention.	Baseline (T0), after first intervention period (T1; 4 weeks), and after crossover (T2; 8 weeks).
Berg Balance Scale (BBS)	Static and dynamic balance assessment (Score range: 0-56, with higher scores indicating better balance performance and lower fall risk).	Baseline (T0), after first intervention period (T1; 4 weeks), and after crossover (T2; 8 weeks).
Dizziness Handicap Inventory (DHI)	The Dizziness Handicap Inventory (DHI) is a validated, self-administered questionnaire consisting of 25 items that assesses the self-perceived impact of dizziness and balance disorders on daily life. The questionnaire evaluates three domains: Functional (9 items), Emotional (9 items), and Physical (7 items). Each item is scored as 0 (No), 2 (Sometimes), or 4 (Yes), yielding a total score ranging from 0 to 100, with higher scores indicating greater perceived disability due to dizziness.	Baseline (T0), after the first intervention period (T1; 4 weeks), and after the crossover intervention (T2; 8 weeks).
Activities-specific Balance Confidence (ABC) Scale	The Activities-specific Balance Confidence (ABC) Scale is a validated self-reported questionnaire that assesses an individual's confidence in maintaining balance while performing 16 common daily activities without becoming unsteady or losing balance. Participants rate their confidence for each activity on a scale from 0 (no confidence) to 100 (complete confidence). The overall score is calculated as the average of all item scores, resulting in a total score ranging from 0 to 100, with higher scores indicating greater balance confidence.	Baseline (T0), after the first intervention period (T1; 4 weeks), and after the crossover intervention (T2; 8 weeks).
Fatigue Severity Scale	The Fatigue Severity Scale (FSS) is a validated self-administered questionnaire used to assess the severity of fatigue and its impact on daily functioning. The scale consists of 9 items, each rated on a 7-point Likert scale, ranging from 1 (strongly disagree) to 7 (strongly agree). The final score is calculated as the mean of the 9 item scores, resulting in a total score ranging from 1 to 7. Higher scores indicate greater fatigue severity. An average score of ≥4 is generally considered indicative of clinically significant fatigue in people with Multiple Sclerosis.	Baseline (T0), after the first intervention period (T1; 4 weeks), and after the crossover intervention (T2; 8 weeks).
Inertial Measurement Unit (IMU)-derived Gait Parameters	Quantitative measures spatiotemporal gait parameters	Baseline (T0), after the first intervention period (T1; 4 weeks), and after the crossover intervention (T2; 8 weeks).
IMU-derived Gait Parameters	Quantitative measures of stability and smoothness of gait	Baseline (T0), after the first intervention period (T1; 4 weeks), and after the crossover intervention (T2; 8 weeks).

Collaborators and Investigators

• Sponsor: LIFE - Research and Care Institute - Santa Lucia IRCCS
• Investigators: Principal Investigator: Maria Grazia Grasso, MD, PhD, LIFE - Research and Care Institute - Santa Lucia IRCCS; Study Director: Diego Piatti, PT, MSc, LIFE - Research and Care Institute - Santa Lucia IRCCS; Study Chair: Iole Indovina, PhD, LIFE - Research and Care Institute - Santa Lucia IRCCS; Study Chair: Gianfranco Bosco, MD, PhD, LIFE - Research and Care Institute - Santa Lucia IRCCS; Study Chair: Giorgia Presicce, MD, PhD, LIFE - Research and Care Institute - Santa Lucia IRCCS; Study Chair: Gianluca Paolocci, PhD, LIFE - Research and Care Institute - Santa Lucia IRCCS; Study Chair: Marco Tramontano, PhD, University of Bologna

Publications and helpful links

General Publications

• Caronni A, Gervasoni E, Ferrarin M, Anastasi D, Brichetto G, Confalonieri P, Di Giovanni R, Prosperini L, Tacchino A, Solaro C, Rovaris M, Cattaneo D, Carpinella I. Local Dynamic Stability of Gait in People With Early Multiple Sclerosis and No-to-Mild Neurological Impairment. IEEE Trans Neural Syst Rehabil Eng. 2020 Jun;28(6):1389-1396. doi: 10.1109/TNSRE.2020.2991636. Epub 2020 Apr 30.
• Tramontano M, Paolocci G, Piatti D, Attanasio G, Casagrande Conti L, Bergamini E, Manzari L, Lacquaniti F, Staab JP, Bosco G, Indovina I. Dynamic postural stability, symmetry, and smoothness of gait in patients with persistent postural-perceptual dizziness. J Vestib Res. 2025 Mar;35(2):82-90. doi: 10.1177/09574271241295615. Epub 2024 Nov 6.
• Piatti D, Paolocci G, Verdecchia DH, Grasso MG, Bosco G, Indovina I, Tramontano M. Effectiveness of vestibular physical therapy on balance and dizziness in people with multiple sclerosis: A systematic review and meta-analysis. J Vestib Res. 2026 May 5:9574271261444952. doi: 10.1177/09574271261444952. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 1, 2029

Study Registration Dates

• First Submitted: September 1, 2026
• First Submitted That Met QC Criteria: September 1, 2026
• First Posted (Actual): September 4, 2026

Study Record Updates

• Last Update Posted (Actual): September 4, 2026
• Last Update Submitted That Met QC Criteria: September 1, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; fMRI; Gait Analysis; Vestibular Physical Therapy
• 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: 538/SL/26

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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