Resistance Training and Corticospinal Excitability in Multiple Sclerosis (NEXIMS)

Effects of Supervised Progressive Resistance Training on Central Nervous System Functioning (Corticospinal Excitability) and Walking Capacity in Persons With Multiple Sclerosis

The goal of the present study is to investigate effects of progressive resistance training on central nervous system functioning (corticospinal excitability (CSE)) and walking capacity in persons with multiple sclerosis (pwMS). A total of 54 pwMS will be enrolled and randomized into 1 of 3 groups: high dose resistant training (RT), low dose RT, and waitlist control.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Behavioral: Progressive resistance training

Detailed Description

Neurodegeneration is a hallmark of multiple sclerosis (MS), affecting both structure and function of the central nervous system (CNS). Neurodegeneration is the main driver of disability progression in MS, evidenced by studies showing deleterious structural and functional CNS changes, ultimately reducing quality of life. Consequently, the interaction between the nervous system and muscular system undergoes deleterious changes causing reduced neuromuscular function (i.e., ability to develop muscle strength and power) and physical function.

The functional CNS changes have been evidenced by using the non invasive brain stimulation technique Transcranial Magnetic Stimulation, showing decreased corticospinal excitability alongside increased central motor conduction time. Moreover, functional peripheral nervous system (PNS) changes have been evidenced by nerve conduction methods, revealing decreased amplitude of compound muscle action potential and increased latency of nerve signaling. In an ongoing exploratory study (unpublished), the investigators have observed that functional CNS and PNS outcomes deteriorate with disability progression from healthy to mildly to moderately disabled people with MS (PwMS).

Exercise is beneficial from both an individual and a societal perspective, and has proven to be both safe and without any noticeable side effects in PwMS. Resistance training (RT) appears particularly effective in improving neuromuscular function (mainly muscle strength) and physical function (especially walking capacity). Whilst RT and other exercise modalities may elicit positive effects on CNS structure in PwMS, it seems to require a long-term (≥ 6 months) exposure. In contrast, CNS (and potentially PNS) function may adapt much more rapidly, despite a scarcity of studies (and with heterogeneous findings) involving PwMS. Interestingly, an exploratory exercise study (non-controlled, low sample size, 10 weeks treadmill walking intervention) assessed corticospinal excitability in PwMS, and observed substantial improvements after the intervention. Apart from this study, a major knowledge gap exists in terms of elucidating the potential beneficial effects of exercise (RT in particular) on CNS (and PNS) function. Based on evidence from healthy young individuals, substantial improvements in corticospinal excitability have been shown following 2-12 weeks of RT, supporting that RT-induced improvements in corticospinal excitability can also be seen in PwMS. Lastly, as existing exercise guidelines for PwMS fails to refer to evidence on dose-response to exercise, and a recent systematic review on exercise studies found no dose-response studies in PwMS (n=202), this aspect is also of great clinical relevance.

• Study Type: Interventional
• Enrollment (Estimated): 54
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lars Hvid, PhD; Phone Number: 93508717; Email: lhvid@ph.au.dk

Study Locations

• Denmark
  • Central Jutland Region
    • Aarhus, Central Jutland Region, Denmark, 8000
      • Recruiting
      • Department of Public Health
      • Contact: Annette Bachmann; Phone Number: +4587167986; Email: ab@ph.au.dk
  • Copenhagen N
    • Copenhagen, Copenhagen N, Denmark, 2200
      • Recruiting
      • Department of Nutrition, Exercise and sports, University of Copenhagen
      • Contact: Kristian Levring Madsen; Phone Number: +45 3532 0829; Email: nexs@nexs.ku.dk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥ 18 years
• MS diagnosis according to the McDonald diagnostic criteria
• Shows impairments in walking capacity
• Ability to self transport to test and exercise

Exclusion Criteria:

• Pregnancy
• Neurological or other comorbidities that affects the nervous system
• Relapse within the past 2 months
• Pacemaker or metallic implants
• Hypertension (medically unregulated)
• Participation in structured RT over the past 3 months (≥ 2 sessions/week).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: High dose resistance training; 10 weeks intervention with 2.5 weekly supervised resistance training sessions (2 or 3 sessions/week for high dose resistance training; 25 sessions in total).	Behavioral: Progressive resistance training; The RT exercise regime will focus on lower extremity exercises (60-90% of 1 repetition maximum) as well as incorporating functional exercises.
Active Comparator: Low dose resistance training; 10 weeks intervention with 1 weekly supervised resistance training session (low dose resistance training; 10 sessions in total).	Behavioral: Progressive resistance training; The RT exercise regime will focus on lower extremity exercises (60-90% of 1 repetition maximum) as well as incorporating functional exercises.
No Intervention: Waitlist control.; The waitlist control group will initially be instructed to maintain their normal daily activity during the 10 week intervention period. Hereafter, they will be offered a 10 week high dose resistance training intervention that combines supervised and home based exercise sessions .

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MEP/Mmax ratio	Cortical excitability measured as amplitude percentage ratio between MEP (resting) and Mmax (Cmap of TA). Unit (intended): %	Change from Baseline to 10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle strength	Maximal voluntary contraction (MVC) is the maximal force-generating capacity (plantar flexion and dorsal flexion). Unit (intended): N	Change from Baseline to 10 weeks
Voluntary activation I	Assessed by Interpolated Twitch Technique (ITT) (dorsal flexion). Unit (intended): %	Change from Baseline to 10 weeks
Voluntary activation II	EMG amplitude during MVC (plantar flexion and dorsal flexion). Unit (intended): μV	Change from Baseline to 10 weeks
Force Steadiness	A quantitative measure of the ability to control muscle tonus (dorsal flexion). Unit (intended): root-mean-square (RMS) error (Coefficient of Variation (CV))	Change from Baseline to 10 weeks
Rate of Force Developement	This is defined as the speed at which the contractile elements of the muscle can develop force (plantar flexion and dorsal flexion). Unit (intended): N/s	Change from Baseline to 10 weeks
Ultrasound	Measure of muscle thickness of the tibialis anterior. Unit (intended): mm	Change from Baseline to 10 weeks
Resting Motor Threshold (rMT)	The intensity necessary to produce a motor-evoked potential (MEP) that exceeds a defined peak-to-peak amplitude (50 μV) 50% of the time in a finite number of trials. Unit (intended): % Maximum stimulator output (MSO)	Change from Baseline to 10 weeks
Active Motor Threshold (aMT)	The intensity necessary to produce a motor-evoked potential (MEP) that exceeds a defined peak-to-peak amplitude (50 μV) 50% of the time in a finite number of trials during voluntary activation (20% of MVC). Unit (intended): % Maximum stimulator output (MSO)	Change from Baseline to 10 weeks
MEP latency (resting)	The transmission time from stimulating the cortex to the start of the evoked potential in the EMG of the target muscle. Unit (intended): ms	Change from Baseline to 10 weeks
MEP latency (active)	The transmission time from stimulating the cortex to the start of the evoked potential in the EMG of the target muscle. Unit (intended): ms	Change from Baseline to 10 weeks
MEP amplitude (resting)	Peak-to-peak of averaged MEP (20 stimulations of 120% rMT). Unit (intended): mV	Change from Baseline to 10 weeks
MEP amplitude (active)	Peak-to-peak of averaged MEP (20 stimulations of 120% rMT). Unit (intended): mV	Change from Baseline to 10 weeks
Short-interval intracortical Inhibition (SICI)	SICI measures cortical inhibition and is a TMS protocol in which two stimuli are delivered with an interstimulus interval (ISI) of 2.5 ms. Unit (intended): the relative amplitude difference of motor evoked potentials (MEPs) (%).	Change from Baseline to 10 weeks
Intracortical facilitation (ICF)	ICF measures cortical facilitation and is a TMS protocol in which two stimuli are delivered with an interstimulus interval (ISI) of 10 ms. Unit (intended): the relative amplitude reduction of motor evoked potentials (MEPs) (%).	Change from Baseline to 10 weeks
Cortical Silent Period (CSP)	The temporary interruption of electromyographic signal from a muscle following a motor-evoked potential (MEP) triggered by transcranial magnetic stimulation (TMS). Unit (intended): ms	Change from Baseline to 10 weeks
Central Motor Conduction Time (CMCT)	The time it takes for the fastest action potentials to travel from the site of cortical stimulation to the spinal motoneuron. It is calculated by subtracting the peripheral motor conduction time (PMCT) from the MEP latency or by the F-wave method. Unit (intended): ms	Change from Baseline to 10 weeks
EEG-EMG coherence (0-1)	Synchronization between brain activity (EEG) and muscle activity (EMG) over a specific frequency range. Unit (intended): ranging from 0 to 1, where 0 is no coherence and 1 is perfect coherence.	Change from Baseline to 10 weeks
Timed 25 feet walk test (T25FWT)	Objective test that measures walking speed. Unit (intended): seconds.	Change from Baseline to 10 weeks
6-minute walk test (6MWT)	Objective test that measures walking endurance. Unit (intended): meters.	Change from Baseline to 10 weeks
Six spot step test (SSST)	Objective test that measures walking coordination and balance. Unit (intended): seconds.	Change from Baseline to 10 weeks
5 sit-to-stand (5STS)	Objective test that measures functional lower limb muscle strength and power. Unit (intended): seconds.	Change from Baseline to 10 weeks
9-step stair ascend (9SSA)	Objective test that measures functional lower limb muscle strength and power. Unit (intended): seconds.	Change from Baseline to 10 weeks
Patient determined disease steps (PDDS)	A patient-reported measure of disability. Unit (intended): score (0-8; 0 is normal).	Change from Baseline to 10 weeks
Multiple Sclerosis Walking Scale (MSWS)	Questionnaire that measures quality of life. Unit (intended): score (0-100; 0 is better).	Change from Baseline to 10 weeks
Modified fatigue impact scale (MFIS)	Questionnaire that measures the impact fatigue has on daily life. Unit (intended): score (0-84; 0 is better)	Change from Baseline to 10 weeks
MS impact scale (MSIS)	Questionnaire that measures the impact MS has on daily life. Unit (intended): score (29-145; 29 is better)	Change from Baseline to 10 weeks
Falls-efficacy scale - international (FES-1)	Questionnaire that measures concerns about falling. Unit (intended): score (16-64; 16 is better)	Change from Baseline to 10 weeks
The Physical Activity Enjoyment Scale (PACES)	Questionnaire that measures enjoyment for physical activity. Unit (intended): score (8-56; Higher score reflect greater level of enjoyment)	Change from Baseline to 10 weeks
Brief pain inventory (BPI)	Questionnaire that measures pain severity and pain interference. Unit (intended): No scoring algorithm, but "worst pain" or the arithmetic mean of the four severity items can be used as measures of pain severity; the arithmetic mean of the seven interference items can be used as a measure of pain interference.	Change from Baseline to 10 weeks
Accelerometry	Method used to measures and analyze movement and acceleration in three dimensions of a person (physical activity). Unit (intended): g (m/s^2)	Change from Baseline to 10 weeks
Baecke physical activity	Questionnaire (patient-reported outcome) assessing patient-reported participation in physical activities. Unit (intended): Score range is continuous (0-xx). Higher is better.	Change from Baseline to 10 weeks

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital; University of Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): May 31, 2026

Study Registration Dates

• First Submitted: April 16, 2024
• First Submitted That Met QC Criteria: April 16, 2024
• First Posted (Actual): April 18, 2024

Study Record Updates

• Last Update Posted (Estimated): December 11, 2024
• Last Update Submitted That Met QC Criteria: December 6, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis; Sclerosis
• Other Study ID Numbers: Neuro_Exercise

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No