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 In an ongoing exploratory study (unpublished), the investigators have observed that functional CNS and PNS outcomes deteriorate with disability progression from healthy to mildly to moderately disabled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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
54
The RT exercise regime will focus on lower extremity exercises (60-90% of 1 repetition maximum) as well as incorporating functional exercises.
Department of Public Health
Aarhus, Central Jutland, Denmark
RECRUITINGDepartment of Nutrition, Exercise and Sports, University of Copenhagen
Copenhagen, Copenhagen N, Denmark
RECRUITINGMEP/Mmax ratio
Cortical excitability measured as amplitude percentage ratio between MEP (resting) and Mmax (Cmap of TA). Unit (intended): %
Time frame: Change from Baseline to 10 weeks
Muscle strength
Maximal voluntary contraction (MVC) is the maximal force-generating capacity (plantar flexion and dorsal flexion). Unit (intended): N
Time frame: Change from Baseline to 10 weeks
Voluntary activation I
Assessed by Interpolated Twitch Technique (ITT) (dorsal flexion). Unit (intended): %
Time frame: Change from Baseline to 10 weeks
Voluntary activation II
EMG amplitude during MVC (plantar flexion and dorsal flexion). Unit (intended): μV
Time frame: 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))
Time frame: 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
Time frame: Change from Baseline to 10 weeks
Ultrasound
Measure of muscle thickness of the tibialis anterior. Unit (intended): mm
Time frame: Change from Baseline to 10 weeks
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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)
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: Change from Baseline to 10 weeks
MEP amplitude (resting)
Peak-to-peak of averaged MEP (20 stimulations of 120% rMT). Unit (intended): mV
Time frame: Change from Baseline to 10 weeks
MEP amplitude (active)
Peak-to-peak of averaged MEP (20 stimulations of 120% rMT). Unit (intended): mV
Time frame: 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) (%).
Time frame: 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) (%).
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: Change from Baseline to 10 weeks
Timed 25 feet walk test (T25FWT)
Objective test that measures walking speed. Unit (intended): seconds.
Time frame: Change from Baseline to 10 weeks
6-minute walk test (6MWT)
Objective test that measures walking endurance. Unit (intended): meters.
Time frame: Change from Baseline to 10 weeks
Six spot step test (SSST)
Objective test that measures walking coordination and balance. Unit (intended): seconds.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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.
Time frame: 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.
Time frame: 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)
Time frame: Change from Baseline to 10 weeks