This project involves two sub-parts:

Study 1: Effect of lab-based Functional Balance Intervention (FBI) for physical and cognitive symptoms of Multiple Sclerosis.

Study 2: Feasibility of home-based FBI for physical and cognitive symptoms of Multiple Sclerosis.

Each study involves a 2-arm, Phase-1, randomized controlled clinical trial to evaluate the effect of FBI on physical, cognitive function, and daily living among people with MS (PwMS). Study 1 is conducted in a lab setting, while Study 2 is conducted at home with additional safety measures. A total of 150 people with multiple sclerosis will be recruited and telephone screened, with an expected enrollment of 120 (60 per phase). After in-person screening, 96 eligible participants (48 per phase) will undergo pre-training assessment and randomization into FBI or Stretching groups. Training sessions will occur twice a week for four months. Anticipating a 15-17% attrition rate, the target sample size is 80 (40 per phase) for completion of the study. Post-training assessments will be conducted after four months to evaluate FBI's impact on physical and cognitive functions. This evidence-based protocol, previously successful with neurological and older adult populations, intends to provide a low-cost, safe, and effective intervention for PwMS in clinical and community settings, including rural areas.

1.0 BACKGROUND/SCIENTIFIC RATIONALE (Study 1 and 2) Of the 1 million adults living with multiple sclerosis (MS) in the United States, over 80% have physical impairment, an estimated 45-60% have cognitive impairment and 20-30% will develop severe dementia. Physical deficits include muscular weakness, spasticity, sensorimotor dysfunction, and imbalance, which co-occur with cognitive dysfunction and directly impact community mobility and overall quality of life. Cognitive deficits include slowed processing speed and reaction time, poor executive functions like planning and problem-solving, and learning and memory deficits. Physical and cognitive deficits rarely remit after onset and are associated with secondary problems with mobility and balance, resulting in increased fall-risk. Whereas treatments targeting restoration of physical function in PwMS have been established, research informing effective management of cognitive dysfunction is in its early stages. Further, there is limited evidence for pharmacological and rehabilitation approaches that can target both physical and cognitive dysfunction. Yet, there have been recent calls for greater focus on unique modes of exercise training as the most promising approach.

Exercise training interventions have yielded modest, but consistent improvements in physical function, walking ability, and fatigue in PwMS. Whereas there is extensive evidence on exercise training targeting physical function, there is comparatively much less known about exercise training targeting cognitive function in PwMS, and this literature is not yet conclusive. Additionally, previous interventions among PwMS have rarely incorporated components of functional balance for treating physical and cognitive dysfunction. Interventions like aerobic and/or strength training are effective in improving physical function, yet effects on cognitive dysfunction might not be very robust. Indeed, cognitive improvements after protocols of aerobic and/or strength-based exercise training might be limited because these modalities might share limited brain resources with physical domains and cognitive tasks, resulting in only a minor transfer of improvements to physical and cognitive performance. On the other hand, there is more evidence of common neural resources shared between cognitive tasks and balance control (e.g., vestibular, visuospatial processing, executive function, attention). Thus, focusing on functional balance training could have a greater activation of the central nervous system (CNS) integrative frameworks for treating cognitive dysfunction in PwMS. It could further have secondary benefits of improving fall efficacy, physical activity, and community mobility thereby mediating change in measures of quality of life among PwMS. Thus, the investigators propose a novel, multicomponent exercise intervention named Functional Balance Intervention (FBI) for improving physical and cognitive function and other measures of daily living among PwMS. The effects of FBI will be tested in a laboratory setting (Study 1) and then tested in a home-based setting (Study 2) in parallel. For both studies, the FBI will be compared to a control group, who will complete an equivalent dosage of stretching. Results from the proposed Phase-I Randomized Controlled Trial (RCT) will inform the research community to launch a line of larger Phase-II RCT examining the comparative effectiveness of the FBI program among PwMS. The findings from this project can also serve as preliminary groundwork for conducting large-scale clinical trials to assess comparative effectiveness of FBI with other pre-established interventions particularly for individuals with restricted mobility and/or restricted access to onsite healthcare services.

2.0 OBJECTIVES (Study 1 and 2) The two-study project is an alternative, non-pharmacological intervention, which represents an important avenue for treating physical and cognitive symptoms of MS and aims to impact measures of mobility and quality of life. Through this project, the investigators will simultaneously examine the effects of FBI compared to stretching among PwMS in a lab-based setting (Study 1) and home-based setting (Study 2). Study 1 and 2 will run in parallel i.e., all data collection, analysis, and dissemination activities will occur simultaneously. For both studies, the investigators first postulate that a Functional Balance Intervention (FBI) can result in immediate improvements in physical function, possibly mediated via improvements in secondary endpoints of dual-task balance, functional mobility, and gait. Secondly, the investigators postulate the possibility that cognition shares more similar neural processes with balance control than with other functional domains, such that CNS adaptations induced by functional balance training could translate into immediate in cognition40. The improvements in physical and cognitive function will mediate improvements in other measures of daily living.

Below are the combined specific aims for Study 1 and 2:

Aim 1: Examine the effect of the FBI (Intervention Group) on physical function in PwMS compared to a stretching program (Control Group).

Hypothesis 1: After 4 months of training, the FBI will show significantly higher improvements in physical function compared to the stretching.

Aim 2: Examine the effect of a multicomponent FBI on cognitive function compared to PwMS in the stretching program.

Hypothesis 2: After 4 months of training, the FBI will show significantly higher improvements in cognitive function compared to the stretching.

Aim 3: Examine the effects of the multicomponent FBI compared to the control group among PwMS on measures of daily living (dual task performance, balance confidence community mobility, and quality of life).

Hypothesis 3: After 4 months of training, the FBI will show significantly higher improvements in measures of daily living compared to stretching.

3.0 Research Design Both sub-studies included in this project (i.e., Study 1 and 2) involve a randomized controlled trial design to establish the feasibility and initial effect of a multicomponent, Functional Balance Intervention (FBI) for immediate improvements in physical and cognitive function, and measures of daily living among persons with multiple sclerosis (PwMS). Study 1 will include training sessions in the lab, and Study 2 will include training sessions at home. Data collection procedures for Study 1 and 2 will run in parallel.

A total sample of 120 participants with Multiple Sclerosis (60 in each study) will be enrolled in this project. The investigators expect ~20% in-person screening failures. Hence, the investigators expect that ~96 PwMS will be eligible to be included in the study, undergo pre-training assessment, and then randomized into 2 groups. The Interventional Group (n=24 for Study 1 and n=24 for Study 2) will undergo a multi component Functional Balance Intervention for 4 months, whereas in the Control Group (n=24 for Study 1 and n=24 for Study 2) will receive a stretching intervention for 4 months.

Study overview (Study 1 and 2) All participants will undergo the following procedures.

• Week 1: Recruitment and phone screening
• Week 2: In-person screening (2 hours)
• Week 3: Pre-training assessment (2 hours)
• Week 4: Random Assignment
• Week 5-20: Training sessions (1 hour/day, 2 times per week for 4 months)
• Week 21: Post-training assessment (2 hours)

Inclusion criteria:

Telephone screening (for Study 1 and 2):

• Age group: Adults between 55-80 years of age
• Self-reported diagnosis of Multiple Sclerosis
• Be on stable disease modifying therapy (DMT) for ≥6 months.
• Has not received physical therapy or occupational therapy services for ≥6 months.
• Able to stand up from a chair independently with or without use of handrails.
• Score between 25-75% on the 12-item Multiple Sclerosis walking scale, which indicates that they have mobility disability or walking dysfunction.
• Absence of any other acute or chronic neurological (Stroke, Parkinson's disease), cardiopulmonary, musculoskeletal (injuries like fractures or dislocations or pathologies like Rheumatoid arthritis) or systemic diagnosis, all conditions that except Multiple Sclerosis that can directly impact individual's ability to stand and walk.
• Can understand and communicate in English because the protocol will only be delivered in English.
• Be willing to complete all aspects of the study protocol (outcome assessments, 4-month training, accelerometer wear, etc.).
• Individuals who give a positive response (Yes) to the question of whether the participants feel that their memory or thinking skills worsened lately?" will be marked as potential individuals with mild cognitive impairment.
• Must be willing to come to the lab for 2 times a week for four months for training sessions (for Study 1 participants only).
• Must have access to the internet and must be willing to attend weekly zoom calls and undergo monthly tests on zoom (for Study 2 participants only).
• Must be living with a family member (for Study 2 participants only).
• Must have a helper buddy to be present during the home exercise sessions and monthly progression evaluation Zoom calls with the researcher (for Study 2 participants only).

In-person Screening (for Study 1 and 2):

• Must have mobility Disability, a score of 4.0-6.5 on the Expanded Disability Status Scale (EDSS).
• Must have mild cognitive impairment, a score of 18-25 on the Montreal Cognitive Assessment (MoCA) and score >1 but less than 2.5 standard deviations on 2 or more measures within at least 1 domain (e.g., memory, language, attention/processing speed, executive function, visuospatial abilities) on the established criteria named "Jak / Bondi" criteria.
• Must be physically inactive, a score <14 on the questionnaire named "Godin leisure time" questionnaire.

Exclusion Criteria:

Telephone Screening (for Study 1 and 2):

• MS Relapse or exacerbation ≤3 months
• Recent major surgery (< 6 months) or hospitalization (< 3 months) that might interfere with testing/training.
• Complaints of shortness of breath or uncontrolled pain (>3/10 on visual analogue scale (VAS)) at rest to avoid complications/injuries during testing/training.
• Uncontrolled/untreated hypertension or diabetes to avoid cardiovascular complications during testing/training.
• Self-reported history of bone fracture in the last six months to avoid complications/injuries during testing/training.
• Self-reported disability in performing activities of daily living (with or without assistive device).
• Self-reported diagnosis of epilepsy or uncontrolled seizures in the past year.
• Intake of sedative drugs (diazepam, lorazepam, midazolam, propofol, dexmedetomidine, thiopental) that might interfere with testing/training.
• Intake of any Alzheimer's Disease (AD) or dementia modifying medications (donepezil, rivastigmine, galantamine, aducanumab) as well as other anticipated FDA approved drugs that may be approved during the next 5 years. Individuals who are enrolled in any AD disease modifying drugs trials that might interfere with testing/training or affect the ability to understand instructions will also be excluded.
• Intake of anti-depressants or anxiety drugs.
• Moderate or high risk for possible injury or death when undertaking strenuous or maximal exercise as indicated by reporting a 'YES' on any of the seven items on the Physical Activity Readiness Questionnaire. These participants will be excluded from participation, and further advised to seek medical guidance from their physician.
• People with severe cognitive impairment will be excluded, indicated by a score of 18 or higher on the Telephone Interview for Cognitive status (TICS-M). These participants will be advised to seek medical guidance from the physician.
• Currently undergoing any cognitive rehabilitation for higher brain functions or physical rehabilitation.
• Pacemaker users

In-person Screening (for Study 1 and 2):

• Cardiovascular abnormalities: Heart Rate > 85% of age-predicted maximal heart rate, systolic blood pressure (SBP) > 165 millimetre of mercury (mmHg), diastolic blood pressure > 110 mmHg during rest OR systolic blood pressure < 90 mmHg and/or mean arterial blood pressure < 65 mmHg OR oxygen saturation < 95% during rest.
• Osteopenia (a T - Score of ≤-2.5 on heel ultrasound). Participants with a score ≤ -2.5 will be advised to seek medical guidance from their physician.
• Loss of protective peripheral sensations (inability to perceive 5.07/10 g on the Semmes Monofilament testing).
• Global aphasia (A score of <71% on the Mississippi Aphasia Scoring test)
• Peripheral nerve injuries (traumatic nerve lacerations, pathological nerve damage).
• High fall-risk, <40/56 on Berg Balance Scale (for Study 2 participants only)
• Inability to walk 1 block with or without an assistive device (for Study 2 participants only)

Subjects will be blinded to group existence and assignment and outcome assessors will be blinded to group assignment