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NCT Number: NCT06374108

Resistance Training and Corticospinal Excitability in 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.

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Key information

Conditions

Multiple Sclerosis Autoimmune Diseases Autoimmune Diseases of the Nervous System Demyelinating Autoimmune Diseases, CNS Demyelinating Diseases Immune System Diseases Nervous System Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Department of Public Health, Aarhus, Central Jutland, Denmark

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About this study

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 In an ongoing exploratory study (unpublished), the investigators have observed that functional CNS and PNS outcomes deteriorate with disability progression from healthy to mildly to moderately disabled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

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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).

Treatment and study plan

Progressive resistance training

Behavioral

The RT exercise regime will focus on lower extremity exercises (60-90% of 1 repetition maximum) as well as incorporating functional exercises.

Primary outcomes

  1. MEP/Mmax ratio

    Time frame: Change from Baseline to 10 weeks

    Cortical excitability measured as amplitude percentage ratio between MEP (resting) and Mmax (Cmap of TA). Unit (intended): %

Secondary outcomes

  1. Muscle strength

    Time frame: Change from Baseline to 10 weeks

    Maximal voluntary contraction (MVC) is the maximal force-generating capacity (plantar flexion and dorsal flexion). Unit (intended): N

  2. Voluntary activation I

    Time frame: Change from Baseline to 10 weeks

    Assessed by Interpolated Twitch Technique (ITT) (dorsal flexion). Unit (intended): %

  3. Voluntary activation II

    Time frame: Change from Baseline to 10 weeks

    EMG amplitude during MVC (plantar flexion and dorsal flexion). Unit (intended): μV

  4. Force Steadiness

    Time frame: Change from Baseline to 10 weeks

    A quantitative measure of the ability to control muscle tonus (dorsal flexion). Unit (intended): root-mean-square (RMS) error (Coefficient of Variation (CV))

  5. Rate of Force Developement

    Time frame: Change from Baseline to 10 weeks

    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

  6. Ultrasound

    Time frame: Change from Baseline to 10 weeks

    Measure of muscle thickness of the tibialis anterior. Unit (intended): mm

  7. Resting Motor Threshold (rMT)

    Time frame: Change from Baseline to 10 weeks

    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)

  8. Active Motor Threshold (aMT)

    Time frame: Change from Baseline to 10 weeks

    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)

  9. MEP latency (resting)

    Time frame: Change from Baseline to 10 weeks

    The transmission time from stimulating the cortex to the start of the evoked potential in the EMG of the target muscle. Unit (intended): ms

  10. MEP latency (active)

    Time frame: Change from Baseline to 10 weeks

    The transmission time from stimulating the cortex to the start of the evoked potential in the EMG of the target muscle. Unit (intended): ms

  11. MEP amplitude (resting)

    Time frame: Change from Baseline to 10 weeks

    Peak-to-peak of averaged MEP (20 stimulations of 120% rMT). Unit (intended): mV

  12. MEP amplitude (active)

    Time frame: Change from Baseline to 10 weeks

    Peak-to-peak of averaged MEP (20 stimulations of 120% rMT). Unit (intended): mV

  13. Short-interval intracortical Inhibition (SICI)

    Time frame: Change from Baseline to 10 weeks

    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) (%).

  14. Intracortical facilitation (ICF)

    Time frame: Change from Baseline to 10 weeks

    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) (%).

  15. Cortical Silent Period (CSP)

    Time frame: Change from Baseline to 10 weeks

    The temporary interruption of electromyographic signal from a muscle following a motor-evoked potential (MEP) triggered by transcranial magnetic stimulation (TMS). Unit (intended): ms

  16. Central Motor Conduction Time (CMCT)

    Time frame: Change from Baseline to 10 weeks

    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

  17. EEG-EMG coherence (0-1)

    Time frame: Change from Baseline to 10 weeks

    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.

  18. Timed 25 feet walk test (T25FWT)

    Time frame: Change from Baseline to 10 weeks

    Objective test that measures walking speed. Unit (intended): seconds.

  19. 6-minute walk test (6MWT)

    Time frame: Change from Baseline to 10 weeks

    Objective test that measures walking endurance. Unit (intended): meters.

  20. Six spot step test (SSST)

    Time frame: Change from Baseline to 10 weeks

    Objective test that measures walking coordination and balance. Unit (intended): seconds.

  21. 5 sit-to-stand (5STS)

    Time frame: Change from Baseline to 10 weeks

    Objective test that measures functional lower limb muscle strength and power. Unit (intended): seconds.

  22. 9-step stair ascend (9SSA)

    Time frame: Change from Baseline to 10 weeks

    Objective test that measures functional lower limb muscle strength and power. Unit (intended): seconds.

  23. Patient determined disease steps (PDDS)

    Time frame: Change from Baseline to 10 weeks

    A patient-reported measure of disability. Unit (intended): score (0-8; 0 is normal).

  24. Multiple Sclerosis Walking Scale (MSWS)

    Time frame: Change from Baseline to 10 weeks

    Questionnaire that measures quality of life. Unit (intended): score (0-100; 0 is better).

  25. Modified fatigue impact scale (MFIS)

    Time frame: Change from Baseline to 10 weeks

    Questionnaire that measures the impact fatigue has on daily life. Unit (intended): score (0-84; 0 is better)

  26. MS impact scale (MSIS)

    Time frame: Change from Baseline to 10 weeks

    Questionnaire that measures the impact MS has on daily life. Unit (intended): score (29-145; 29 is better)

  27. Falls-efficacy scale - international (FES-1)

    Time frame: Change from Baseline to 10 weeks

    Questionnaire that measures concerns about falling. Unit (intended): score (16-64; 16 is better)

  28. The Physical Activity Enjoyment Scale (PACES)

    Time frame: Change from Baseline to 10 weeks

    Questionnaire that measures enjoyment for physical activity. Unit (intended): score (8-56; Higher score reflect greater level of enjoyment)

  29. Brief pain inventory (BPI)

    Time frame: Change from Baseline to 10 weeks

    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.

  30. Baecke physical activity

    Time frame: Change from Baseline to 10 weeks

    Questionnaire (patient-reported outcome) assessing patient-reported participation in physical activities. Unit (intended): Score range is continuous (0-xx). Higher is better.

  31. Accelerometry

    Time frame: Change from Baseline to 10 weeks

    Method used to measures and analyze movement and acceleration in three dimensions of a person (physical activity). Unit (intended): g (m/s^2)

Study contacts

Contact information is provided by the study sponsor or research team.

Lars Hvid, PhD

CONTACT

[email protected]

93508717

Sponsors and collaborators

Lead sponsor

University of Aarhus

Other

Collaborators

  • Aarhus University Hospital
  • University of Copenhagen

Registry information

Official study title

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

Acronym: NEXIMS

Important dates

Study start
2024
Primary completion
2025
Study completion
2026
First posted
Apr 18, 2024
Registry last updated
Dec 11, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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