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

Balance dysfunction is one of the most frequent and disabling symptoms ofrelapsing‐remitting Multiple Sclerosis (RRMS), affecting up to 80% of people with MS(Alayidi et al., 2025). Importantly, subtle impairments in balance and gait emerge evenin the earliest stages of the disease, when clinical disability remains minimal (ExpandedDisability Status Scale [EDSS] ≤ 2.5) (Caronni et al., 2020). Many individuals reportfeelings of instability, dizziness, or unsteadiness despite having a normal neurologicalexamination, while conventional clinical tests often fail to detect these early deficits(Carpinella et al., 2022). Consequently, balance impairment in early RRMS is frequentlyconsidered a "hidden disability," negatively affecting confidence, mobility, and qualityof life long before overt disability develops.Current evidence suggests that early balance dysfunction in MS is primarily driven byimpaired sensory integration rather than muscle weakness. In particular, disruption ofproprioceptive pathways reduces the accuracy of sensory feedback required for posturalcontrol (Fling et al., 2014). To compensate for this deficit, the central nervous systemappears to increase reliance on cortical attentional mechanisms. Functional MRI studiessupport this hypothesis by demonstrating increased activation of the primary sensorimotorcortex 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 reducedbalance confidence and fear of falling despite maintaining relatively normal motorperformance. Patient‐reported outcome measures, such as the Activities‐specific BalanceConfidence (ABC) Scale and the Dizziness Handicap Inventory (DHI), are effective incapturing perceived instability, particularly during static activities. However, thesequestionnaires provide limited information regarding dynamic balance performance.Conversely, objective instrumented assessments have demonstrated that subtleabnormalities in gait are already present during the earliest disease stages, even whenstandard neurological examinations remain normal (Muller et al., 2021).Recent advances in wearable sensor technology have substantially improved the assessmentof gait and balance in MS. Inertial Measurement Units (IMUs) allow precise quantificationof spatiotemporal gait parameters during daily activities and standardized walking tests.Previous studies have shown that individuals with early RRMS exhibit slower walkingspeed, shorter stride length, and prolonged double‐support time compared with healthycontrols, despite having EDSS scores between 1 and 2 (Soyuer et al., 2006; Benedetti etal., 1999; Karst et al., 2005). These alterations correlate with fatigue andself‐perceived disability, suggesting that wearable sensors detect clinically meaningfulimpairments before they become apparent during routine neurological examination.The diagnostic sensitivity of IMU‐based assessments is particularly evident duringpostural control tasks. Carpinella et al. (2022) demonstrated that advanced analysis ofquiet standing using wearable sensors was three to four times more sensitive thanconventional Romberg testing. Specifically, early RRMS participants exhibited reducedsway complexity and increased trunk oscillations, allowing balance impairment to beidentified in 58% of participants compared with only 17% detected using traditionalclinical assessment. These findings strongly support the integration of wearabletechnologies 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 vestibulardysfunction and balance impairment during the early stages of the disease. Task‐basedfMRI consistently demonstrates increased activation of sensorimotor cortical regions,suggesting compensatory recruitment of motor networks, while resting‐state studies revealaltered connectivity within sensorimotor and vestibular circuits. Furthermore, diffusiontensor imaging studies have shown that the structural integrity of proprioceptivepathways predicts balance performance in people with MS (Fling et al., 2014).Nevertheless, to our knowledge, no previous study has combined functional MRI withbalance‐related vestibular stimulation to directly investigate the neural correlates ofearly balance impairment in RRMS. This represents a significant knowledge gap.Immersive virtual reality (VR) offers an innovative approach for investigating balancecontrol under controlled sensory conflict conditions. Beyond its diagnostic potential, VRmay also serve as a rehabilitation tool by repeatedly exposing patients to visual andvestibular challenges that promote sensory reweighting. Recent technological developmentshave led to the creation of MRI‐compatible VR systems capable of presentinggaze‐controlled visual environments during brain imaging. Such platforms provide theopportunity to investigate how the brain processes balance‐related visual and vestibularstimuli in vivo and may eventually facilitate the development of individualizedneurorehabilitation protocols.Vestibular Physical Therapy (VPT) represents one of the most promising rehabilitationstrategies for addressing balance dysfunction in MS. VPT consists of structured exercisesinvolving head and eye movements, gaze stabilization, postural control, and balance tasksdesigned to promote central vestibular compensation (Tramontano et al., 2025). Althoughvestibular dysfunction in MS is often central rather than peripheral in origin, growingevidence supports the effectiveness of VPT in improving both dizziness and balance(Tramontano et al., 2021).A recent meta‐analysis demonstrated that vestibular rehabilitation significantly improvesbalance performance and reduces dizziness compared with no intervention in people withMS, with large clinical effect sizes (García‐Muñoz et al., 2020). Although vestibularrehabilitation was not statistically superior to other forms of exercise therapy, itconsistently produced greater improvements across studies. Similarly, Smania et al.(2015) showed that sensory integration‐based balance training resulted in significantlygreater improvements in balance performance, reduced falls, and increased balanceconfidence compared with conventional rehabilitation.The beneficial effects of VPT are believed to result from adaptive neuroplasticmechanisms. Vestibular rehabilitation facilitates sensory reweighting by enhancing theintegration of visual, vestibular, and proprioceptive information while promotingadaptation of vestibulo‐ocular and vestibulo‐spinal reflexes. Experimental animal studiesfurther suggest that structured vestibular rehabilitation induces cellular plasticitywithin vestibular nuclei, accelerating functional recovery through increasedmicrogliogenesis and regulation of neurogenesis (Marouane et al., 2021). In humans,neurorehabilitation studies have similarly reported increased functional connectivitywithin cerebellar and sensorimotor networks following rehabilitation, supporting thehypothesis that VPT promotes adaptive reorganization of central balance networks.Despite these advances, important unmet clinical needs remain. First, currently availableclinical assessments lack sufficient sensitivity to detect early balance impairment inRRMS. Standard neurological examination and conventional balance tests frequently fail toidentify 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 corticalnetworks. Finally, vestibular rehabilitation is generally introduced only after moderatedisability has developed (EDSS 3‐6), despite evidence that many patients experienceinstability much earlier. This delay represents a missed opportunity for preventiveintervention aimed at preserving mobility and reducing long‐term disability.These limitations provide a strong rationale for the proposed study. By combiningobjective gait analysis using wearable inertial sensors, advanced functional neuroimagingwith vestibular stimulation, and an early Vestibular Physical Therapy programspecifically targeting visuo‐vestibular integration and sensory reweighting, this projectseeks to characterize the mechanisms underlying early balance impairment in RRMS anddetermine whether timely intervention can modify both functional performance and theneural substrates of balance control. Demonstrating the efficacy of early VPT couldsupport a paradigm shift toward proactive rehabilitation in Multiple Sclerosis, enablingclinicians to identify and treat balance dysfunction before irreversible disabilitydevelops.HypothesisWe hypothesize that individuals with early relapsing‐remitting Multiple Sclerosis (RRMS;EDSS ≤ 2.5) exhibit measurable neurophysiological alterations within vestibular andsensorimotor networks despite minimal clinical disability, and that these alterationscontribute to the subtle balance impairments commonly reported during the early stages ofthe disease. We further hypothesize that a targeted Vestibular Physical Therapy (VPT)program, specifically designed to promote sensory reweighting and visuo‐vestibularintegration, will improve both subjective symptoms and objective balance performancewhile inducing adaptive neuroplastic changes detectable by functional MRI (fMRI).Specifically, we propose that the "hidden" imbalance observed in early RRMS reflectscompensatory or maladaptive plasticity within vestibular, cerebellar, and sensorimotorcircuits. These alterations are expected to manifest as abnormal patterns of functionalactivation and connectivity on fMRI. By engaging vestibular pathways through a structuredrehabilitation program, we anticipate promoting adaptive reorganization of thesenetworks, resulting in improved balance control, enhanced gaze stability, andnormalization of functional brain connectivity.This hypothesis is supported by previous evidence demonstrating increased activation ofsensorimotor and vestibular cortical regions during motor tasks in early MS, as well asstudies showing that motor rehabilitation modifies functional connectivity in people withMS. Furthermore, vestibular rehabilitation has been shown to induce cerebellar andbrainstem plasticity in other neurological populations. However, no previous study hasdirectly investigated these mechanisms in early RRMS using an integrated multimodalapproach combining functional neuroimaging, quantitative gait analysis, and vestibularrehabilitation.Specific Aims Aim 1. Identify the Neuroimaging Correlates of Early Balance DysfunctionParticipants will undergo structural and functional MRI using advanced imaging protocolsto characterize the functional organization of vestibular, sensorimotor, cerebellar, andbalance‐related brain networks. Functional imaging will include vestibular stimulationparadigms, such as controlled acoustic stimulation and, where feasible, visual motionstimuli presented through MRI‐compatible immersive virtual reality.We hypothesize that individuals with RRMS will demonstrate altered functionalconnectivity among key regions involved in balance control, including the cerebellum,parietal cortex, vestibular brainstem nuclei, and sensorimotor cortex, compared withhealthy controls. Furthermore, we expect these neuroimaging abnormalities to correlatewith 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 InstrumentedMeasuresSubjective and objective balance performance will be comprehensively evaluated usingvalidated clinical questionnaires, standardized balance assessments, and wearableinertial measurement units (IMUs).Patient‐reported outcomes will include measures of dizziness, balance confidence, andquality of life, while IMUs will quantify gait characteristics‐including walking speed,stride length, gait symmetry, smoothness, and postural stability‐during standardizedwalking tasks and quiet standing.We expect people with early RRMS (EDSS ≤ 2.5) to exhibit measurable impairments in gaitand 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 TherapyWe will conduct a randomized crossover clinical trial in which each participant serves astheir own control, thereby maximizing statistical power while minimizing inter‐individualvariability.Participants will complete both:a 4‐week Vestibular Physical Therapy (VPT) program consisting of 12 sessions specificallydesigned to enhance sensory reweighting, visuo‐vestibular integration, gaze stability,and saccadic function; and a 4‐week control period consisting of standard clinicalmanagement without additional vestibular rehabilitation.Participants initially randomized to the intervention arm will undergo a 4‐week washoutperiod before crossing over to the control condition, whereas no washout will be requiredfor participants initially assigned to the control arm.Clinical assessments, quantitative gait analysis, and functional MRI will be performedbefore and after each intervention period.We hypothesize that VPT will produce significantly greater improvements in balanceperformance, gait parameters, dizziness, and fatigue compared with the control condition.We further expect these functional improvements to be accompanied by adaptive changes inbrain connectivity, including normalization of excessive cerebellar‐sensorimotor couplingand enhanced integration within vestibular networks.Importantly, vestibular stimulation delivered during fMRI through controlled acousticstimuli will provide a direct measure of functional changes within vestibular pathwaysfollowing rehabilitation, offering mechanistic insight into the neural effects of VPT onpostural control and gaze stabilization.Aim 4. Develop Integrated Biomarkers of Early Balance Dysfunction and RehabilitationResponseFinally, we will integrate quantitative gait metrics obtained from wearable sensors withfunctional neuroimaging data to identify multimodal biomarkers of early balanceimpairment.Specifically, we will investigate whether individuals exhibiting greater abnormalities ingait and postural control also demonstrate more pronounced alterations in vestibularnetwork connectivity. We will additionally evaluate whether changes in these imagingbiomarkers predict clinical improvement following rehabilitation.The identification of objective biomarkers linking behavior and brain function couldfacilitate earlier diagnosis, improve patient stratification, and provide sensitiveoutcome measures for future rehabilitation trials.