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

Exercise Training Effects on Cognition and Brain Function in Multiple Sclerosis: A Systematically-Developed Randomized Controlled Trial

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03677440

Enrollment

Registered

2018-09-19

Start date

2019-02-05

Completion date

2024-12-31

Last updated

2025-06-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cognitive Impairment, Multiple Sclerosis

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.

Interventions

BEHAVIORALTreadmill Walking Exercise Training

12-weeks of supervised, progressive treadmill walking exercise training

BEHAVIORALStretching-and-Toning Exercise Training

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Masking description

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

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

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

Design outcomes

Primary

Measure	Time frame	Description
Cognitive Processing Speed	Baseline, Follow-up (up to 14 weeks)	Raw (Total) Score from the Symbol Digit Modalities Test (0-110; higher scores indicate faster cognitive processing speed)
Thalamocortical Resting-State Functional Connectivity Region 1	Follow-up at 12-weeks minus baseline	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.
Change in Thalamocortical Resting State Functional Connectivity Region 2	Follow-up at 12-weeks minus baseline	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.

Secondary

Measure	Time frame	Description
Community Integration Questionnaire	Baseline, Follow-up (up to 14-weeks)	The Community Integration Questionnaire is a patient-reported measure of community participation. The minimum score is 0 and the maximum score is 31, with higher scores reflecting better community participation.
Lawton-Brody Instrumental Activities of Daily Living	Baseline, Follow-up (up to 14-weeks)	The Lawton-Brody Instrumental Activities of Daily Living is a patient-reported measure of the ability to perform instrumental activities of daily living. The minimum score is 0 and the maximum score is 8, with higher scores reflecting a better ability to complete instrumental activities of daily living.
3-second Paced Auditory Serial Addition Test (PASAT)	Baseline, Follow-up (up to 14-weeks)	The 3-second PASAT is a neuropsychological test of working memory, attention, and cognitive processing speed. The total score is the total number of correct answers provided by the participant. The minimum score is 0 and the maximum score is 60. Higher scores reflect better cognition
Timed 25-foot Walk	Baseline, Follow-up (up to 14-weeks)	The timed 25-foot walk is a neuroperformance outcome where participants are asked to walk as quickly and as safely as possible over a 25-foot course free of debris. The primary outcome is the time to walk 25 feet - averaged across two trials. Higher scores reflect slower walking speed and lower scores reflect faster walking speed.
Multiple Sclerosis Impact Scale-29 Physical Subscale	Baseline, Follow-up (up to 14-weeks)	The Multiple Sclerosis Impact Scale-29 is a patient-reported measure of the impact of multiple sclerosis on physical and mental domains. In this outcome measure, the physical subscale is the component of interest. The minimum score is 0 and the maximum score is 100, with higher scores reflecting greater impact of MS on physical outcomes.
2-second Paced Auditory Serial Addition Test (PASAT)	Baseline, Follow-up (up to 14-weeks)	The 2-second PASAT is a neuropsychological test of working memory, attention, and cognitive processing speed. The raw score is the total number of correct answers provided by the participant. The minimum score is 0 and the maximum score is 60. Higher scores reflect better cognition.
Pattern Comparison Test	Baseline, Follow-up (up to 14-weeks)	The Pattern Comparison Test is a neuropsychological test of cognitive processing speed wherein participants are asked to specify whether or not two patterns are the same or different. The primary outcome is the total number of correct answers provided by the participant across two 20-second trials. The minimum score is 0 and the maximum score is 60. Higher scores reflect better cognitive processing speed.

Countries

United States

Participant flow

Pre-assignment details

N=4 participants who were enrolled into the study subsequently dropped out prior to random assignment. Thus, 43 participants were enrolled into the study and 39 participants were randomly assigned into the study arms.

Participants by arm

Arm	Count
Treadmill Walking Exercise Training 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. Treadmill Walking Exercise Training: 12-weeks of supervised, progressive treadmill walking exercise training	18
Stretching-and-Toning Exercise Training 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. Stretching-and-Toning Exercise Training: 12-weeks of supervised, progressive stretching-and-toning exercise training	19
Total	37

Baseline characteristics

Characteristic	Total	Stretching-and-Toning Exercise Training	Treadmill Walking Exercise Training
Age, Continuous	45.3 Years STANDARD_DEVIATION 9.7	46.1 Years STANDARD_DEVIATION 11.2	44.5 Years STANDARD_DEVIATION 8
Disease Duration	11.8 years STANDARD_DEVIATION 8.5	10.9 years STANDARD_DEVIATION 7.4	13.9 years STANDARD_DEVIATION 9.9
Education	15.6 Years STANDARD_DEVIATION 2.4	15.2 Years STANDARD_DEVIATION 2.2	16.1 Years STANDARD_DEVIATION 2.5
Expanded Disability Status Scale	3.5 units on a scale	3.5 units on a scale	3.0 units on a scale
MS Phenotype Progressive	3 Participants	3 Participants	0 Participants
MS Phenotype Relapsing-Remitting	32 Participants	14 Participants	18 Participants
MS Phenotype Unknown	2 Participants	2 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	15 Participants	9 Participants	6 Participants
Race (NIH/OMB) More than one race	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	21 Participants	9 Participants	12 Participants
Region of Enrollment United States	37 Participants	19 Participants	18 Participants
Sex: Female, Male Female	33 Participants	17 Participants	16 Participants
Sex: Female, Male Male	4 Participants	2 Participants	2 Participants
Symbol Digit Modalities Test z-score	-1.9 z-score STANDARD_DEVIATION 0.6	-1.9 z-score STANDARD_DEVIATION 0.6	-2.0 z-score STANDARD_DEVIATION 0.7

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 19	0 / 20
other Total, other adverse events	8 / 19	1 / 20
serious Total, serious adverse events	0 / 19	0 / 20

Outcome results

Primary

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.

Time frame: Follow-up at 12-weeks minus baseline

Population: N=3 participants did not complete MRI at follow-up (12-weeks)

Arm	Measure	Value (MEAN)	Dispersion
Treadmill Walking Exercise Training	Change in Thalamocortical Resting State Functional Connectivity Region 2	.0193 z-score	Standard Deviation 0.0595
Stretching-and-Toning Exercise Training	Change in Thalamocortical Resting State Functional Connectivity Region 2	-.0414 z-score	Standard Deviation 0.0783

p-value: 0.02t-test, 1 sided

Primary

Cognitive Processing Speed

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

Time frame: Baseline, Follow-up (up to 14 weeks)

Arm	Measure	Group	Value (MEAN)	Dispersion
Treadmill Walking Exercise Training	Cognitive Processing Speed	Baseline	43.5 Raw Score	Standard Deviation 9.6
Treadmill Walking Exercise Training	Cognitive Processing Speed	Follow-up	46.5 Raw Score	Standard Deviation 12.1
Stretching-and-Toning Exercise Training	Cognitive Processing Speed	Baseline	43.7 Raw Score	Standard Deviation 9.2
Stretching-and-Toning Exercise Training	Cognitive Processing Speed	Follow-up	49.1 Raw Score	Standard Deviation 10.7

Comparison: This involves a repeated-measures ANOVA testing a condition (i.e., treadmill walking exercise training vs. stretching-and-toning exercise training)-by-time (i.e., baseline, follow-up) interaction on Symbol Digit Modalities Test scores.p-value: 0.34ANOVA

Primary

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.

Time frame: Follow-up at 12-weeks minus baseline

Population: N=3 participants did not complete MRI at follow-up (12-weeks)

Arm	Measure	Value (MEAN)	Dispersion
Treadmill Walking Exercise Training	Thalamocortical Resting-State Functional Connectivity Region 1	.0334 z-score	Standard Deviation 0.0531
Stretching-and-Toning Exercise Training	Thalamocortical Resting-State Functional Connectivity Region 1	-.0247 z-score	Standard Deviation 0.0605

p-value: 0.01t-test, 1 sided

Secondary

2-second Paced Auditory Serial Addition Test (PASAT)

The 2-second PASAT is a neuropsychological test of working memory, attention, and cognitive processing speed. The raw score is the total number of correct answers provided by the participant. The minimum score is 0 and the maximum score is 60. Higher scores reflect better cognition.