Resistance Training and Corticospinal Excitability in Multiple Sclerosis

Multiple Sclerosis Clinical Trial

— NEXIMS  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06374108
• Other study ID #: Neuro_Exercise
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 1, 2024
• Est. completion date: May 31, 2026

Study information

• Verified date: November 2023
• Source: University of Aarhus
• Contact: Lars Hvid, PhD
• Phone: 93508717
• Email: lhvid[@]ph.au.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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 In an ongoing exploratory study (unpublished), the investigators have observed that functional CNS and PNS outcomes deteriorate with disability progression from healthy to mildly to moderately disabled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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 54
• Est. completion date: May 31, 2026
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

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.

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
University of Aarhus	Aarhus University Hospital, University of Copenhagen

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Voluntary activation I	Assessed by Interpolated Twitch Technique (ITT) (dorsal flexion). Unit (intended): %	Change from Baseline to 10 weeks
Secondary	Voluntary activation II	EMG amplitude during MVC (plantar flexion and dorsal flexion). Unit (intended): µV	Change from Baseline to 10 weeks
Secondary	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
Secondary	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
Secondary	Ultrasound	Measure of muscle thickness of the tibialis anterior. Unit (intended): mm	Change from Baseline to 10 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	MEP amplitude (resting)	Peak-to-peak of averaged MEP (20 stimulations of 120% rMT). Unit (intended): mV	Change from Baseline to 10 weeks
Secondary	MEP amplitude (active)	Peak-to-peak of averaged MEP (20 stimulations of 120% rMT). Unit (intended): mV	Change from Baseline to 10 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Timed 25 feet walk test (T25FWT)	Objective test that measures walking speed. Unit (intended): seconds.	Change from Baseline to 10 weeks
Secondary	6-minute walk test (6MWT)	Objective test that measures walking endurance. Unit (intended): meters.	Change from Baseline to 10 weeks
Secondary	Six spot step test (SSST)	Objective test that measures walking coordination and balance. Unit (intended): seconds.	Change from Baseline to 10 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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