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

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

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.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Behavioral: Aerobic Exercise

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Hamburg, Germany, 20241
    • University Hospital Hamburg-Eppendorf

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aerobic Exercise (12 Weeks); 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; 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
No Intervention: Waitlist Control Group; 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?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Patient-Reported Outcomes	Patient-reported outcomes will be assessed for depressive symptoms (IDS-30SR), fatigue (FSMC), quality of life (HAQUAMS), and walking (MSWS-12)	Baseline and at Month 3 (end of intervention)
Change in Walking Ability	Walking ability will be assessed using the six-minute-walk test (6MWT) as well as Actibelt accelerometry	Baseline and at Month 3 (end of intervention)

Collaborators and Investigators

• Sponsor: Universitätsklinikum Hamburg-Eppendorf
• Collaborators: German Federal Ministry of Education and Research
• Investigators: Principal Investigator: Stefan M Gold, PhD, Center for Molecular Neurobiology, University Hospital Hamburg Eppendorf; Principal Investigator: Andreas K Engel, MD, Dept Neurophysiology, University Hospital Hamburg Eppendorf; Principal Investigator: Christoph Heesen, MD, Dept Neurology, University Hospital Hamburg Eppendorf; Principal Investigator: Guido Nolte, PhD, Dept Neurophysiology, University Hospital Hamburg Eppendorf; Principal Investigator: Karl-Heinz Schulz, MD, PhD, Dept Sports Medicine, University Hospital Hamburg Eppendorf

Publications and helpful links

General Publications

• Baquet L, Hasselmann H, Patra S, Stellmann JP, Vettorazzi E, Engel AK, Rosenkranz SC, Poettgen J, Gold SM, Schulz KH, Heesen C. Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial. PeerJ. 2018 Dec 12;6:e6037. doi: 10.7717/peerj.6037. eCollection 2018.

Study record dates

Study Major Dates

• Study Start: December 1, 2013
• Primary Completion (Actual): May 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: December 3, 2013
• First Submitted That Met QC Criteria: December 3, 2013
• First Posted (Estimate): December 9, 2013

Study Record Updates

• Last Update Posted (Actual): June 26, 2017
• Last Update Submitted That Met QC Criteria: June 23, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Rehabilitation; Exercise; Cognition; Neuroimaging; Connectivity
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis
• Other Study ID Numbers: AERCONN; 031A130 (Other Grant/Funding Number: BMBF)