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 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.