Exercise in Multiple Sclerosis: Effects on Cognitive Function and Brain Connectivity

Study Overview
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Brief Summary
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Cognitive dysfunction is frequent in patients with multiple sclerosis (MS) and to date, there are no available treatments to improve cognition in this patient population. Some evidence from animal studies and small clinical trials suggest that aerobic exercise might beneficially affect cognitive function in MS. The aim of this randomized-controlled trial is to explore if an aerobic exercise training program can enhance cognition in MS. In addition, we will employ neuroimaging markers to determine if exercise alters measures of brain structure and function. Patients will be randomly assigned to either a 3-months exercise program (bicycle ergometry, 2-3 session per week) or a waitlist control group. The primary endpoint of the study is a test of verbal learning and memory. Secondary endpoints include neuroimaging markers of functional and structural connectivity in the brain. We hypothesize that exercise will improve verbal learning and memory and beneficially affect measures of brain connectivity.

Detailed Description
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Background: Cognitive dysfunction is frequent in patients with multiple sclerosis (MS) and to date, there are no available treatments to improve cognition in this patient population. Some evidence from animal studies and small clinical trials suggest that aerobic exercise might beneficially affect cognitive function in MS. Aims: This study aims to explore the potential of an aerobic exercise program on brain structure and function in MS in a single-blind, randomized controlled phase IIa trial. We hypothesize that exercise will improve verbal learning and memory (primary endpoint) as well as induce changes in neuroimaging markers of structural and functional central nervous system (CNS) connectivity (secondary endpoints). Tertiary outcomes will include walking ability, motor function and coordination, as well as patient-based outcomes (depression, fatigue, and health-related quality of life). Design: This is a single-blind, randomized, controlled phase IIa trial with a parallel group design comparing 3 months of standardized aerobic exercise training (bicycle ergometry) to a waitlist control group (superiority framework). The allocation ratio of exercise to waitlist control is 1:1 with a sample size of n=60.

Official Title
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Randomized Controlled Trial Investigating the Effects of a Standardized Aerobic Exercise Intervention on Cognitive Function and Brain Connectivity in Relapsing-remitting Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Behavioral: Aerobic Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsing-remitting multiple sclerosis according to McDonald criteria Currently in remission Disease duration < 10 years Low to moderate physical disability (EDSS 0-3.5) On stable immunotherapy (>3 months) or without any planned treatment for the next year Exclusion Criteria: Patients who are not able to understand the study concept due to severe cognitive deficits or psychiatric comorbidity Patients currently taking psychoactive drugs Patients unable to undergo aerobic exercise training for medical reasons Patients with active disease or uncertain stability under current immunomodulatory therapy (as judged by the treating neurologist) Patients with implants or body modifications (e.g. dental implants, piercings, tattoos, pacemakers etc.) which might interfere with MEG and MRI assessments Patients unable to travel to the study center 2-3 times a week for the duration of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aerobic Exercise (12 Weeks)<br>Aerobic exercise on a bicycle ergometer, tailored to the individual's level of fitness. Duration: 12 weeks with 2-3 sessions per week. | Behavioral: Aerobic Exercise<br>* 3-months exercise program tailored to the individual level of aerobic fitness. Patients will exercise on a bicycle ergometer (2-3 session per week) according to a predefined training plan with increasing duration and intensity<br>|
| No Intervention: Waitlist Control Group<br>No intervention (patients randomized to this group will be offered access to the training program after completion of the trial) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Verbal Learning and Memory | Verbal Learning and Memory will be assessed with the Verbal Learning and Memory Test (VLMT) | Baseline and at Month 3 (end of intervention) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Functional Connectivity | Functional connectivity of CNS networks will be assessed by resting-state functional magnetic resonance imaging (rs fMRI) and resting-state magnetoencephalography (rs MEG) | Baseline and at Month 3 (end of intervention) | 
| Change in Structural Connectivity | Structural connectivity and integrity of CNS networks will be assessed by diffusion tensor imaging (DTI) as well as measures of gray matter density using magnetic resonance imaging (MRI) | Baseline and at Month 3 (end of intervention) | 
| Change in Neuropsychological Function | Neuropsychological function will be assessed using a standardized battery covering the following domains: visuospatial learning and memory, attention, processing speed, working memory, and social cognition | Baseline and at Month 3 (end of intervention) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise, Cognition, Neuroimaging, Rehabilitation, Connectivity