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| Name | Class |
|---|---|
| Aarhus University Hospital | OTHER |
| University of Copenhagen | OTHER |
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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.
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 In an ongoing exploratory study (unpublished), the investigators have observed that functional CNS and PNS outcomes deteriorate with disability progression from healthy to mildly to moderately disabled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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| High dose resistance training | Active Comparator | 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). |
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| Low dose resistance training | Active Comparator | 10 weeks intervention with 1 weekly supervised resistance training session (low dose resistance training; 10 sessions in total). |
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| Waitlist control. | No Intervention | 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 . |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Lars Hvid, PhD | Contact | 93508717 | lhvid@ph.au.dk |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Public Health | Recruiting | Aarhus | Central Jutland | 8000 | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41991058 | Derived | Andersen TM, Riis H, Tankisi H, Mamoei S, Langeskov-Christensen M, Dalgas U, Lundbye-Jensen J, Hvid LG. Effects of supervised progressive resistance training on corticospinal excitability in persons with multiple sclerosis: A randomized controlled trial protocol for the NEXIMS study. Contemp Clin Trials. 2026 Jun;165:108317. doi: 10.1016/j.cct.2026.108317. Epub 2026 Apr 15. |
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| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
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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 |
| 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 |
| 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 |
| Department of Nutrition, Exercise and Sports, University of Copenhagen | Recruiting | Copenhagen | Copenhagen N | 2200 | Denmark |
|
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |