Exercise Training Effects on Cognition and Brain Function in Multiple Sclerosis: Project EXACT

NCT03677440 | Completed Results

• 2 other identifiers: IRB-3000001111R01HD091155-01A1
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief Summary

Cognitive impairment is highly prevalent, poorly-managed, and disabling in persons with MS and exercise training might represent a promising approach to manage this symptom of the disease. The proposed study aims to examine the effects of 3-months of supervised, progressive (both intensity and duration) treadmill walking exercise training (designed based on pilot work and American College of Sports Medicine guidelines) compared with an active control condition (i.e., stretching-and-toning activities) on cognitive processing speed and functional MRI outcomes in 88 cognitively-impaired persons with MS. This study is critical for providing evidence supporting treadmill walking exercise training as a behavioral approach for managing slowed cognitive processing speed (i.e., the most common MS-related cognitive impairment) and improving brain health in persons with MS.

Conditions

Multiple Sclerosis; Cognitive Impairment

Outcome Measures

Primary Outcomes (3)

• Cognitive Processing Speed

  Raw (Total) Score from the Symbol Digit Modalities Test (0-110; higher scores indicate faster cognitive processing speed)

  Baseline, Follow-up (up to 14 weeks)

• Thalamocortical Resting-State Functional Connectivity Region 1

  Change in functional connectivity between the thalamus and left superior medial gyrus based on fMRI. As this outcome measure reflects changes in resting-state functional connectivity, positive z-scores indicate increased connectivity and negative z-scores indicate decreased connectivity. A z-score of 0 reflects no change in resting-state functional connectivity.

  Follow-up at 12-weeks minus baseline

• Change in Thalamocortical Resting State Functional Connectivity Region 2

  Resting-state functional connectivity between the thalamus and left putamen based on fMRI. As this outcome measure reflects changes in resting-state functional connectivity, positive z-scores indicate increased connectivity and negative z-scores indicate decreased connectivity. A z-score of 0 reflects no change in resting-state functional connectivity.

  Follow-up at 12-weeks minus baseline

Secondary Outcomes (7)

• 3-second Paced Auditory Serial Addition Test (PASAT)

  Baseline, Follow-up (up to 14-weeks)

• 2-second Paced Auditory Serial Addition Test (PASAT)

  Baseline, Follow-up (up to 14-weeks)

• Pattern Comparison Test

  Baseline, Follow-up (up to 14-weeks)

• Community Integration Questionnaire

  Baseline, Follow-up (up to 14-weeks)

• Lawton-Brody Instrumental Activities of Daily Living

  Baseline, Follow-up (up to 14-weeks)

Study Arms (2)

Treadmill Walking Exercise Training

EXPERIMENTAL

This condition will include 3-months of supervised, progressive light, moderate, and vigorous intensity treadmill walking exercise training based on ACSM guidelines for maximizing adaptations with exercise training. Exercise intensities will be prescribed based on percent oxygen consumption reserve (% VO2R) using values derived from the baseline graded exercise test. The exercise training itself will be led by trained exercise leaders who are not involved in the collection of outcome assessments. At the outset of each session, participants will be fitted with a Polar HR Monitor (Oy, Finland), and HR will be monitored continuously throughout each session. Each session will begin with a 5-10 min warm-up, followed by the exercise; the target heart rate reserve (HRR) range associated with the VO2R range will be maintained for as long as possible during each exercise period. This will be followed by a 5-10 min cool-down.

Behavioral: Treadmill Walking Exercise Training

Stretching-and-Toning Exercise Training

ACTIVE COMPARATOR

The active, non-aerobic exercise condition will involve stretching-and-toning activities using the same frequency and duration of the treadmill walking exercise condition. These activities will be based on a manual provided by the National Multiple Sclerosis Society and sessions will be led by trained exercise leaders who are not involved in the collection of outcome assessments. Activities will target the head/neck, shoulder, elbow/forearm, hand/wrist, trunk/hip, ankle/foot. The progression of activities over the 3-month period will involve performing additional exercises and sets along with using progressively thicker elastic resistance bands that provide minimal resistance. Each session is designed to last up to 60 minutes in total. Each session will begin with a warm-up of up to 10 minutes, followed by stretching-and-toning (following the same duration as the treadmill walking exercise training condition) activities, and a cool-down of up to 10 minutes.

Behavioral: Stretching-and-Toning Exercise Training

Interventions

Treadmill Walking Exercise Training BEHAVIORAL

12-weeks of supervised, progressive treadmill walking exercise training

Treadmill Walking Exercise Training

Stretching-and-Toning Exercise Training BEHAVIORAL

12-weeks of supervised, progressive stretching-and-toning exercise training

Stretching-and-Toning Exercise Training

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

All participants will: * Be between the ages of 18-65 * Have a clinically definite MS diagnosis based on established criteria * Be fully-ambulatory based on Expanded Disability Status Scale (EDSS) scores between 0-4.0 * Demonstrate slowed CPS based on initial SDMT scores at least 1 SD below the regression-based normative score for healthy controls (i.e., 16th percentile) * Be relapse-free and will not have acutely taken corticosteroids for at least 30 days (i.e., relative neurologic stability) * Not have a history of major depressive disorder, schizophrenia, bipolar disorder I or II, or substance-abuse disorders. * Not be taking medications that can affect cognition (e.g., antipsychotics, benzodiazepines). * Be right-handed * Have corrected vision better than 20/80 * Not have known/diagnosed cardiovascular, metabolic, or renal disease. Individuals with known/diagnosed cardiovascular, metabolic, or renal disease who are asymptomatic will be included only with a physician's approval. * Demonstrate scores on the Mini-Mental State Examination (MMSE) of 21 or higher (no decisional impairment) * Be on a stable disease-modifying therapy regimen (i.e., at least 6 months prior to study enrollment). * Have a low risk for contraindications for MRI based on not having metal (e.g., non-MRI compatible aneurysm clips, metal shards in the body or eyes, or recently placed surgical hardware) or electronic devices (e.g., pacemaker, cochlear implant) within the body. * Not be pregnant * Not be engaging in ≥ 150 min of moderate-to-vigorous physical activity (i.e., not meeting public health guidelines for physical activity) per week * Not be actively engaging in cognitive rehabilitation, or participating in regular brain fitness activities * Demonstrate systolic blood pressure values of \< 200 mmHg or diastolic blood pressure values \< 110 mmHg at rest

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Kessler Foundation: lead
• National Institutes of Health (NIH): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Kessler Foundation

West Orange, New Jersey, 07052, United States

Location

MeSH Terms

Conditions

Multiple Sclerosis; Cognitive Dysfunction

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Brian Sandroff, PhD
• Organization: Kessler Foundation

bsandroff@kesslerfoundation.org

973-965-6649

Study Officials

• Brian M Sandroff, PhD

  Kessler Foundation

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants will be unaware if the treadmill walking exercise training or stretching-and-toning conditions represent the experimental or control conditions; outcome assessors will be treatment-blinded; MRI data analysts will be blinded to condition
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 14, 2018
• First Posted: September 19, 2018
• Study Start: February 5, 2019
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2024
• Last Updated: June 5, 2025
• Results First Posted: June 5, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)