Exercise With and Without Cognitive Training

The Effect of Exercise With and Without Cognitive Training on Gait in Older Veterans With Multiple Sclerosis

This proposal aims to conduct a 10-week randomized controlled trial comparing walking and resistance training with and without computerized cognitive training in older Veterans with Multiple Sclerosis, followed by 12 months of fall tracking with sensors and fall calendars. The primary objectives of this proposed CDA2 are to provide critical preliminary data on 1) the feasibility of conducting a 10-week RCT, 2) preliminary treatment effects on gait, cognition, and falls, and 3) neuroinflammatory biomarkers. Dr. Katherine Hsieh will receive hands-on training in the design and conduct of clinical trials (Dr. Hackney), mechanisms underlying physical activity, cognitive rehabilitation, and falls (Drs. Twamley, Hackney, & Kesar), fall detection technology (Prof. Sanford), and clinical problems faced by MS participants (Dr. Backus) to achieve her long-term career goal of becoming an independent falls prevention investigator.

Study Overview

• Status: Not yet recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Behavioral: Effect of Exercise with and Without Cognitive Training on Gait

Detailed Description

Significance to VA: A key aim of this proposal is to equip Dr. Katherine Hsieh with the expertise to become an independent VA investigator leading fall prevention trials for older Veterans with Multiple Sclerosis (MS). MS is a chronic, neurodegenerative disease affecting 55,00-70,000 Veterans. Over 28,000 MS cases are reported annually to the VA, and within the Paralyzed Veterans of America, 1 in 4 members have MS. Gait and cognitive impairments are the two of the most common MS symptoms and two of the most important predictors of falls, which lead to fractures, disability, and even death. Adults 55 years and older are the largest group of people living with MS, and the combination of MS symptoms and aging puts older MS Veterans at a high risk of falls. Preventing falls in older Veterans with MS is needed to improve their independence and quality of life. Innovation and Impact: This proposal seeks to utilize an innovative method of combining walking and resistance training with computerized cognitive training on fall risk outcomes. Falls are associated with slower gait speed and declines in processing speed, attention, executive function, and verbal memory. In people with MS, walking and resistance training improves gait function, and computerized cognitive training improves executive functions, processing speed, and attention. Whether combining computerized cognitive training with walking and resistance training provides additional benefits to gait, cognition, and falls remains unclear. Specific Aims: The objectives of this CDA2 proposal are to: 1) determine the feasibility of conducting a 10-week RCT comparing walking and resistance training with and without computerized cognitive training; 2) obtain estimates of intervention effects on gait, cognitive function, and prospective falls; 3) explore neuroinflammatory mechanisms underlying treatment effects. In addition, the PI has established a team of mentors (Drs. Hackney, Twamley, Sanford, Backus, and Kesar) to achieve five career development goals: 1) advance knowledge in the design and conduct of clinical trials; 2) examine mechanisms underlying physical activity, cognitive rehabilitation, and falls in older MS Veterans; 3) develop expertise in the use and implementation of fall detection technology; 4) acquire basic knowledge of clinical problems faced by people with MS; and 5) enhance professional skills including grant writing, scientific communication, and mentorship. Methodology: This trial will enroll 30 older Veterans with MS aged 55 or older randomized to 10 weeks, 3x/week of walking and resistance exercises with computerized cognitive training (n=15) or computer games (n=15). Participants will complete a battery of physical and cognitive tasks at baseline and 10-week follow-up. Following the intervention, the investigators will track falls for 12 months with an Apple watch and fall calendars. Aim 1, feasibility, will be measured with randomization, adherence, retention, and satisfaction to the 10-week trial. Aim 2 will compare gait and mobility, cognition, and future falls between intervention groups. Aim 3 will explore neuroprotective responses using brain-derived neurotrophic factor, interleukin-6, and tumor necrosis alpha to examine group differences and explore subgroup analyses.

Path to Translation/Implementation: Results of this study will provide critical preliminary data on gait, cognition, and falls to power and inform a full-scale RCT as the investigator's next Parent Merit. The investigators will also possess pilot data on biomarkers to identify responders and non-responders and target specific subgroups. Ultimately, this study aims to implement exercise and cognitive training to maximize functional independence for older Veterans with MS. In addition, leading this RCT and longitudinal study, along with taking didactic coursework and training, will help the investigator accomplish her long-term career goal to become an independent falls prevention investigator. By the conclusion of this CDA2, the investigator will possess the knowledge, skills, abilities, and preliminary data necessary to successfully compete for a Parent Merit award and launch her career as a VA falls prevention scientist.

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

Contacts and Locations

• Study Contact: Name: Madeleine E Hackney, PhD; Phone Number: 5006 (404) 321-6111; Email: mehackn@emory.edu
• Study Contact Backup: Name: Katherine Hsieh, PhD; Phone Number: (404) 321-6111; Email: khsieh5@gsu.edu

Study Locations

• United States
  • Georgia
    • Decatur, Georgia, United States, 30033-4004
      • Atlanta VA Medical and Rehab Center, Decatur, GA
      • Contact: Joe R Nocera, PhD; Phone Number: 6354 404-321-6111; Email: joenocera@emory.edu
      • Principal Investigator: Katherine Hsieh, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• US Veteran
• Diagnosis of Multiple Sclerosis
• Relapse free in the last 30 days
• Capable of standing unaided for at least 1 minute
• Expanded Disability Status Scale <6.5
• Ability to speak and understand English

Exclusion Criteria:

• Any neurological disorder other than MS
• Modified Telephone Interview for Cognitive Status <20
• Current participation in an exercise or cognitive rehabilitation study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Computerized Cognitive Training; This group will complete 75 minutes of walking and resistance exercises followed by computerized cognitive training. Exercises will include treadmill walking and resistance training using bodyweight, dumbbells, and/or bands, following guidelines from the National MS Society. Progression and intensity will be individualized and gradual over time. Sessions are 3x per week for 10 weeks. After a cool-down, participants will use RehaCom for 30 minutes. Cognitive modules will progress in difficulty and tailored. Modules will target attention, executive function, logical reasoning, and memory.	Behavioral: Effect of Exercise with and Without Cognitive Training on Gait; This behavioral trial aims to determine the effect of exercise with and without computerized cognitive training on gait in older Veterans with Multiple Sclerosis.
Active Comparator: Active Control; This group will complete the same exercises as the experimental group. After their cool-down, they will use a computer for 30 minutes to play puzzle games. These games were not developed to provide cognitive rehabilitation. Games will vary each session.	Behavioral: Effect of Exercise with and Without Cognitive Training on Gait; This behavioral trial aims to determine the effect of exercise with and without computerized cognitive training on gait in older Veterans with Multiple Sclerosis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gait speed	Participants will walk 10m at their usual and fast speeds to measure gait speed in meters/second.	Baseline & 10-week Follow-up
Exit questionnaire	Satisfaction will be examined with an exit questionnaire that uses a Likert questionnaire (5 point scale) to assay enjoyment of the intervention, willingness to continue with the intervention should participants have the opportunity and whether the participants noted improvement in aspects of well being, e.g., mood, quality of life, mental activity, physical activity, and whether the participants noted improvement in motor function, eg gait, balance, strength, etc.	10-week Follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Static Postural Control	Participants will stand for 30 seconds in challenging balance conditions. Time (in seconds) before needing to take a recovery step will be measured.	Baseline & 10-week Follow-up
Symbol Digit Modality Test	This is a test of processing speed. Participants are asked to match symbols with corresponding numbers. The score is the number of correctly matched symbols within two minutes.	Baseline & 10-week Follow-up
California Verbal Learning Test	This is a test of memory. Participants are read a list of words and asked to memorize them over the course of 5 trials. The scale ranges from 1-15 with higher scores being better.	Baseline & 10-week Follow-up
Falls efficacy scale (FES)	This is a 16-item questionnaire to measure fear of falling when doing different activities. Scale ranges from 16-64.	Baseline & 10-week Follow-up
Number of falls per month	Number of falls will be tracked via fall calendars or sensors for 12 months following the intervention.	1 year follow up after intervention, e.g., at 15 months.
Brain-derived neurotrophic factor	BDNF will be measured in picograms/mL to determine neurotrophic effects from the intervention	Baseline & 10-week Follow-up
Tumor necrosis alpha	TNF-alpha will be measured in picograms/mL to determine inflammatory effects from the intervention	Baseline & 10-week Follow-up
Interleukin-6	IL-6 will be measured to determine inflammatory effects from the intervention	Baseline & 10-week Follow-up
Time to complete the Timed Up and Go	Begin sitting in a chair, walk 3 meters, turn around a cone, and walk back and sit in the chair. The time to complete the TUG is measured in seconds.	Baseline & 10-week Follow-up
Brief Visuospatial Memory Test	Participants are presented an image for 10 seconds and asked to reproduce the image.	Baseline & 10-week Follow-up

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Katherine Hsieh, PhD, Atlanta VA Medical and Rehab Center, Decatur, GA

Study record dates

Study Major Dates

• Study Start (Estimated): January 4, 2027
• Primary Completion (Estimated): January 4, 2028
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: February 25, 2026
• First Submitted That Met QC Criteria: February 25, 2026
• First Posted (Actual): March 3, 2026

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 25, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Rehabilitation; Multiple Sclerosis; Aging; Cognition; Walking; Mobility; Falls
• 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: RRD9-014-25M; 1IK2RD000353-01A1 (Other Grant/Funding Number: Department of VA)

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
• product manufactured in and exported from the U.S.: No