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

Summary

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.

Conditions

• Multiple Sclerosis

Interventions

OTHER

Vestibular Physical Therapy

Vestibular Physical Therapy sessions realized focusing on visuo-vestibular interaction (12 session, 3 x 4 weeks)

Sponsors & Collaborators

• LIFE - Research and Care Institute - Santa Lucia IRCCS

  lead OTHER

Principal Investigators

• Maria Grazia Grasso, MD, PhD · LIFE - Research and Care Institute - Santa Lucia IRCCS

• Diego Piatti, PT, MSc · LIFE - Research and Care Institute - Santa Lucia IRCCS

• Iole Indovina, PhD · LIFE - Research and Care Institute - Santa Lucia IRCCS

• Gianfranco Bosco, MD, PhD · LIFE - Research and Care Institute - Santa Lucia IRCCS

• Giorgia Presicce, MD, PhD · LIFE - Research and Care Institute - Santa Lucia IRCCS

• Gianluca Paolocci, PhD · LIFE - Research and Care Institute - Santa Lucia IRCCS

• Marco Tramontano, PhD · University of Bologna

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2026-10-01

Primary Completion

2028-10-01

Completion

2029-10-01