Study participants
Participants are recruited through advertisements and information circulated throughout the University of Regina, community organizations (e.g., MS Canada), healthcare facilities (e.g., local tertiary rehabilitation centre), and the Office of the Saskatchewan MS Clinical Research Chair. The Office of the Saskatchewan MS Clinical Research Chair (ML) oversees a database of PwMS in the province who have consented to be contacted about participating in future MS-related research.
In the enrolment stage, a study team member screens participants for eligibility and provides them with a written informed consent form. Prospective participants have at least 24 hours to review the informed consent form and discuss it with a study team member. The written informed consent form is signed by the participant and returned to the study team in advance or at the outset of the first study assessment session. Consent is re-established verbally at the outset of all subsequent assessment sessions. To be eligible for participation in this study, individuals must be: older than 18 years of age, diagnosed with MS by a neurologist, have an expanded Patient-Determined Disease Steps Score (PDDS) between 3 and 6 (i.e., experiences gait impairment but is ambulatory with or without aid), and considered not sufficiently active to achieve substantial health benefits (i.e., Godin-Shephard Leisure-Time Exercise Questionnaire score < 24) (44). Individuals will be excluded if they: are unable to provide consent, have experienced a relapse in the past three months (self-reported, neurologist-confirmed), or are deemed to have a high-risk for exercise-related harm by a Canadian Society for Exercise Physiology accredited Clinical Exercise Physiologist (CSEP-CEP). Participants are informed that they can withdraw their participation and data from the trial at any time. Additional information collected from participants upon joining the study include age, sex, gender (self-reported), MS type, disease duration, medications, 29-Item Multiple Sclerosis Impact Scale score (45), clinical magnetic resonance imaging results (if available), other health conditions, and contraindications to TMS.
Study Arm Allocation
All consenting participants who have completed a baseline assessment are stratified into either a mild (PDDS of 3–4) or moderate (PDDS of 5–6) impairment category. Participants from each strata are then randomly allocated to one of the three study arms: task-oriented exercise, generalized resistance and aerobic exercise, or stretching control. Allocation is completed by an administrative assistant not involved in data collection or analyses. Randomization lists were computer-generated in small blocks to help achieve balance across groups. The randomization list was created prior to participant recruitment by a research team member not involved in data collection or analyses.
Blinding
Given the nature of the intervention, only the outcome assessors involved in the data collection and data analysts are blinded to the study groups and unblinding will not occur. Nevertheless, study participants are told that activities are individualized and not informed of the different study arms. Interventions are also scheduled to avoid contact between participants of different study arms and participants are asked to not describe their activities to those outside of their exercise group. Although it is not possible to blind program instructors to the intervention that they deliver, instructors are not made aware of the study aim and hypothesis.
Interventions
The study includes three interventions: ‘task-oriented’ exercise (experimental), ‘generalized resistance and aerobic’ exercise (comparison), and ‘stretching’ exercise (control). All interventions involve 60-minute in-person sessions delivered three times per week for 12 weeks in groups of two to four participants. The volume and duration of exercise training aligns with other MS-focused literature reporting changes in motor function following various exercise interventions (21, 22, 46). Likewise, the group training approach is supported by work suggesting that PwMS enjoy social support during exercise (47).
Interventions are completed under the supervision of a qualified exercise professional (i.e., kinesiologist and/or CSEP-CEP) with a 4-year undergraduate degree in kinesiology (or equivalent post-secondary degree) and a minimum of six months prior experience working with people with neurological conditions. The supervising exercise professionals are trained to deliver the interventions according to the study design and are provided with participants’ baseline assessment results prior to the first intervention session to support preparation. Training of the exercise professionals was completed with a standardized programme and delivered by the same instructor. As the exercise professionals must make practical decisions on how to adapt approaches to the individual needs of each participant, the first one to three sessions of each intervention are considered part of the intake process whereby the exercise professional(s) become familiar with the participants and identify suitable activities that meet the intervention criteria. A study team member attends an intervention session in the sixth week of delivery to monitor and evaluate aspects of intervention fidelity.
All interventions involve the whole body but differ in focus and content (Table 1). The task-oriented exercise intervention focuses on walking with elements of tailored functional strengthening, balance, agility, and repetitive, skill-based task (i.e., walking) practice similar to the ‘Fitness and Mobility Exercise’ (i.e., FAME) program, an established, evidence-based exercise program for people with stroke (48, 49). A key element of this intervention is that it is entirely comprised of weight-bearing activities that train coordinated, functional lower-extremity movements rather than isolating muscle groups. As all activities are completed in standing, all upper-extremity movements will simultaneously train postural control. The duration and frequency of sessions ensures that high volumes of repetitions can be achieved, and rest provided, features of training that are considered crucial for induction of experience-dependent neuroplasticity (50, 51).
Table 1
Overview of interventions and example exercises.
| Task-oriented | Resistance + Aerobic | Stretching control |
Format | • Station-based circuit • Whole body movements • Standing • Free/cuff weights | • Machine circuit • Isolated movements • Seated, supported • Pneumatic resistance | • Group instruction • Isolated movements • Seated, supported |
Exercises | • Sit-to-stands • Step ups • Toe lift weight shifts • Wall push-up • Marching arm raises | • Knee flexion/extension • Full leg extension • Hip abduction/adduction • Chest press/seated row • Shoulder press/pulldown | • Quad/hamstring stretch • Triceps surae stretch • Hip flex/ext stretch • Pec/deltoid stretch • Shoulder rolls |
| • Overground walking (30 min) | • Recumbent cycling (30 min) | • Relaxation activities (30 min) |
Prescription | • Up to 5 minutes of continuous repetitions • Progressive loading and movement complexity • RPE 5–6/10 | • 1–3 sets, 8–15 reps • Progressive loading • RPE 5–6/10 | • 1–3 sets, 20 s stretches, 8–15 reps for range of motion • Movements unloaded • RPE 1–2/10 |
Notes: These are examples activities and prescriptions, rather than the full interventions. RPE, rating of perceived exertion. |
The generalized resistance and aerobic exercise intervention uses machine-based resistance training and recumbent cycling. In contrast to task-oriented exercise above, all activities are performed in seated, non-weight-bearing positions. The intervention is designed to target major muscle groups and meet general fitness-based recommendations for resistance and aerobic exercise for PwMS (15, 19, 52, 53). The stretching exercise intervention involves stretching and relaxation activities in supported, non-weight-bearing positions with no external loading. This intervention serves as a control for confounding variables such as physical conditioning gained via transportation to intervention and study sessions, social interaction, secondary lifestyle changes (e.g., diet, sleep), and potential placebo effects from regular interaction with an exercise professional.
In the task-oriented exercise and generalized resistance and aerobic exercise interventions, heart rates are recorded with a chest-strap heart rate monitor and step count determined using a FitBit Inspire placed on the ankle (54, 55). For all interventions, the activities led by the exercise professional and the participants rating of perceived effort (0–10 scale) are recorded to ensure alignment with the study design. The study team documents any circumstances leading to discontinuation or modification of interventions (e.g., injury, worsening disease symptoms); however, participants are retained in the trial whenever possible to prevent missing data. If a participant misses an intervention session, a study team member contacts the participant as a ‘check-in’ via phone, text, or email depending on participant preference.
Outcome measures
All outcomes are assessed at baseline, after completion of the 12-week intervention, and at a six-week retention time point (Table 2). At each time point, outcome measures are collected across three separate assessment sessions within a seven-day period. A study team member schedules the sessions and contacts participants 24 hours prior to the first of the three sessions as a reminder. The assessment sessions include: 1) All clinical assessments conducted in a 90-minute session, 2) TMS and fitness-based measures obtained in a two-hour session, and 3) Blood samples collected in a 30-minute session.
Table 2. Schedule of study enrolment, intervention and assessments.
|
Study period
|
|
Enrollment
|
Allocation
|
Baseline Ax
|
Intervention
|
Post Ax
|
Retention Ax
|
Time point
|
|
Week 0
|
Week 0
|
Weeks 1-12
|
Week 13
|
Week 18
|
Enrolment:
Eligibility screen
Informed consent
Study group allocation
|
|
|
|
|
|
|
×
|
|
|
|
|
|
×
|
|
|
|
|
|
|
×
|
|
|
|
|
Intervention:
|
|
|
|
|
|
|
Task-oriented exercise
|
|
|
|
×
|
|
|
Generalized exercise
|
|
|
|
×
|
|
|
Stretching control
|
|
|
|
×
|
|
|
Assessments:
|
|
|
|
|
|
|
Baseline variables (See Table 2)
|
|
×
|
|
|
|
|
Primary outcome:
|
|
|
|
|
|
|
T25-FWT
|
|
|
×
|
|
×
|
×
|
Secondary outcome:
|
|
|
|
|
|
|
TA aMT
|
|
|
×
|
|
×
|
×
|
Tertiary outcomes:
|
|
|
|
|
|
|
Additional clinical measures
|
|
|
×
|
|
×
|
×
|
Additional TMS measures
|
|
|
×
|
|
×
|
×
|
Blood marker measures
|
|
|
×
|
|
×
|
×
|
Fitness measures
|
|
|
×
|
|
×
|
×
|
Exit surveys
|
|
|
|
|
×
|
×
|
Notes: T25-FWT, Timed 25-Foot Walk Test; TA aMT, tibialis anterior muscle active motor threshold; TMS, transcranial magnetic stimulation; Ax, assessment
Clinical measures
Walking speed will be measured as time to complete (0-180 s) the Timed 25-Foot Walk Test (T25-FWT). Change in T25-FWT time from the baseline to post-intervention time point is the primary outcome of the study. The T25-FWT provides an assessment of mobility and lower-extremity function through a measurement of fast walking speed (56, 57) and is the most commonly used measure of walking function in PwMS (57) with evidence of strong validity, reliability, responsiveness, and clinical benchmarks in MS (56, 58–60). Further clinical assessments are conducted to ensure a comprehensive clinical evaluation, including the Mini Balance Evaluation Systems Test (comprehensive balance) (61), the Modified Ashworth Scale (spasticity) (62), the 9-hole Peg Test (dexterity) (63), the Symbol Digits Modalities Test (cognitive processing speed) (64), a weekly self-report of falls, and the expanded PDDS score. Clinical assessments described above are completed by a blinded licensed Physical Therapist.
TMS measures
Measures are obtained to characterize corticospinal excitability and cortical inhibition for the tibialis anterior (TA) and first dorsal interosseous (FDI) muscles of the self-reported stronger limb. Change in corticospinal excitability for TA, reflected by the active motor threshold (aMT) expressed as a percentage of maximum stimulator output (%MSO) across baseline to completion of interventions, is the secondary outcome. Additional TMS measures collected for TA and FDI muscles include: resting motor threshold (rMT), motor evoked potential amplitude and latency at 120% rMT, ascending slope of the MEP stimulus-response curve (FDI only), MEP amplitude and latency at 125% aMT for TA and 155% aMT for FDI, and cortical silent period (CSP) duration.
TMS and EMG Procedures
TMS measures are collected by blinded research assistants trained by the Principal Investigator (CSM). During TMS assessments, all muscle responses are recorded using surface electromyography (EMG). The areas of electrode placement are rubbed with abrasive gel to remove dead skin and cleaned with 70% isopropyl alcohol. Bipolar gel Ag-AgCl electrodes (22 mm2) are placed over the target muscle belly with a grounding electrode on a nearby bony prominence (i.e., medial malleolus, styloid process). All EMG signals are pre-amplified (×1000) and band-pass filtered at 10 − 1,000 Hz using PowerLab amplification and EMG Systems (AD Instruments, Colorado, USA). Data for all evoked potentials are sampled at 2,000 Hz and recorded from 100 ms before to 400 ms after stimulus delivery.
TMS is applied using a Magstim 2002 stimulator (Magstim, Whitland, UK) connected to a 110-mm, concave, double-cone coil or a 70 mm figure-of-eight coil (D70 Alpha Coil) for study of the TA or FDI muscles, respectively. Coils are positioned with anterior-to-posterior current flow. Sites near the estimated motor representations are explored to determine the stimulation site at which the largest amplitude MEPs are elicited at the lowest stimulation intensity (i.e., the hotspot). With Brainsight neuronavigation software (Rogue Resolutions, Montreal, CA), the optimal stimulation site is recorded and used to maintain coil position and orientation for all TMS delivery. During TMS delivery, interstimulus intervals are maintained at approximately 4–6 s throughout all measurement protocols. rMT and aMT are determined by finding the lowest stimulation intensity (%MSO) that evokes MEPs of at least 50 µV and 200 µV, respectively, in five out of ten consecutive trials (65). For TMS in the active muscle condition, participants maintain a low-level background muscle contraction (~ 10% of maximum voluntary muscle activity). The participant’s maximal voluntary muscle activity for the target muscle (TA or FDI) is first determined by recording EMG, rectified and low-pass filtered at 3 Hz during maximal voluntary isometric contraction. The peak EMG obtained from two efforts with two minutes rest between attempts is recorded as the participants maximal voluntary EMG. For subsequent TMS measures collected in the active muscle state, participants use visual feedback to maintain target muscle activity within a band on the computer monitor marking 8–12% maximal EMG. Short rest periods of 15–30 s are provided every 5–10 stimuli. For subsequent TMS measures, the number and intensity of stimuli delivered for study of the TA muscle are purposefully limited based on pilot participant feedback regarding tolerability and comfort of receiving TMS via the double-cone coil.
Corticospinal excitability for TA is further explored at rest by delivering ten single-pulse stimuli at an intensity of 120%rMT and calculating the average peak-to-peak MEP amplitude. For FDI, a stimulus-response curve is constructed by delivering ten single-pulse stimuli in a random order at stimulus intensities ranging from 90–150%rMT in 10% increments (70 stimuli total). The stimulus intensity by MEP amplitude relationship will be plotted, fit with a sigmoidal curve, and the slope of the ascending portion of the curve calculated (66). Average latency of MEP responses elicited during these protocols will also be determined.
Cortical inhibition is evaluated by measurement of the CSP. While participants maintain 10% of their maximal muscle activity (see above) in the target muscle, ten TMS pulses are delivered at 125%aMT for TA and twenty pulses at 155%aMT for FDI. The duration of the transient reduction in muscle activity following the MEP in the target muscle will be quantified as the CSP (43). Average peak-to-peak amplitude and latency of MEPs elicited in these protocols will also be calculated.
Fitness measures
Lower-extremity strength and endurance is determined by number of repetitions completed in the 30-second Sit-to-Stand Test in a standardized chair (67). The sit-to-stand movement is performed without use of the arms for those who are able, while others use their arms to assist the movements across all assessments. Upper-extremity strength is measured by peak isometric grip force for each hand (68). Participants complete two trials with each hand interspersed with two minutes of rest. A maximal exercise test is conducted on a recumbent cross trainer (NuStep T5XR, Plymouth, UK) to assess peak oxygen uptake (V̇O2). After determining resting heart rate and blood pressure, participants complete a two-minute warm-up at a self-selected step rate and power output and then begin the test with a workload of 15 W. The workload is increased every minute by 5 W for those with PDDS scores of 5–6 and by 10 W for those with PDDS scores of 3–4. During exercise testing, the following measurements are monitored: expired O2 and CO2 concentrations and air flow via a metabolic cart (TrueOne 2400; ParvoMedics, Sandy, UT), heart rate via a chest-strap heart rate monitor (Polar Electro; Oy, Kempele, Finland), and Borg's 6–20 scale rating of perceived exertion (RPE). The test is stopped and peak V̇O2 recorded when at least one of the following criteria are met: a plateau in V̇O2 and heart rate with further increase in workload, a respiratory exchange ratio > 1.1, a RPE > 17, an inability to maintain the target workload, and volitional exhaustion. The recumbent stepper was chosen for the exercise test to mitigate any differences that might arise due to specificity of training. Fitness measures are collected by blinded research assistants trained by the Principal Investigator, with graded maximal exercise tests conducted under the supervision of a CSEP-CEP.
Blood marker measures
Systemic blood markers to be measured are serum TNF-α (35), BDNF (34), and NF-L (37, 38). Blood samples are collected by a licensed phlebotomist at an off-campus location by venipuncture from the antecubital fossa to a vacutainer tube with no additive. The samples are allowed to clot and then centrifuged at 2,000 g for 30 minutes at 4°C. Serum is aliquoted, transported to campus on ice, and stored at -80°C within two hours of collection. Concentrations of all analytes will be measured using assays with appropriate sensitivity and reliability. Given low concentrations of NF-L, ultrasensitive assays will be considered for analysis in addition to more standard enzyme-linked immunosorbent assays. Assays will be run by a study team member in a preliminary analysis once a third of the projected sample has completed the study. Additional samples will be run in a single, batched analysis following completion of all data collection. Further blood markers linked to MS disease progression and exercise (e.g., interleukin-6) may be added to the analysis protocol if sample volume permits.
Study feasibility and experience
We record adherence to interventions and assessments, missing data, and adverse events. At the end of the intervention period and at study completion, participants complete exit surveys that query acceptability of interventions and assessments. The exit surveys also include questions related to any physical activity performed outside of intervention sessions and between intervention completion and retention testing. We also intend to develop a complementary qualitative study of participant and exercise professional experiences and perceptions of delivery of task-oriented exercise programming to PwMS with specific consideration of initial impairment level (i.e., PDDS of 3–4 and PDDS of 5–6).
Adverse Events
Any adverse events will be self-reported by the participants and/or reported by exercise professionals and study personnel. Adverse events will be reported to the Institutional Research Ethics Board as required and assessed by the study team for seriousness, expectedness and causality following the guidelines of the National Health and Medical Research Council position statement for monitoring and reporting of safety for clinical trials (69).
Statistical Analysis and Sample Size Calculation
Baseline data collection will include both demographic and MS-related information (Table 3). The primary statistical analysis will compare T25-FWT performance at the post-intervention time point between the three study arms using ANCOVA (analysis of covariance) with a between-groups factor (task-oriented, generalized resistance and aerobic exercise, stretching control) and adjusting for baseline T25-FWT performance (28). Planned pairwise comparisons will directly test differences between each study arm. Comparison of the secondary outcome and all other outcome measures at the post-intervention time point across study arms will follow the primary analysis methods (i.e., ANCOVA adjusting for relevant baseline measure). Exploratory analysis of change in outcome measures across all time points and between study arms will use a linear mixed effects model with Time point, Study arm, and Baseline T25-FWT performance as fixed factors. Participant will be a random factor. The models will account for dependencies/correlations resulting from repeated measurements. Final exploratory analyses will re-run all statistical tests with data disaggregated by sex (70–72). For all statistical tests, the alpha will be 0.05. Point and 95% confidence interval estimates for study arm differences will be determined. Participants will be analyzed in the study arm to which they were randomized (i.e., intention-to-treat principle). Multiple imputation will be used to minimize biased estimates from missing data with the analysis based on a missing at random assumption (73). We will conduct an interim analysis when 50% of the sample has completed study procedures. This interim analysis will allow dissemination (i.e., conference presentations) of preliminary findings. There is no stopping rule for the trial because no serious adverse events from the intervention are anticipated.
Table 3
Baseline data collection variables.
Variables |
Age (years) |
Sex |
Gender (optional) |
Height |
Weight |
BMI |
Type of MS |
Year of MS onset (e.g., first symptom) |
Year of MS diagnosis (by a neurologist) |
Most recent relapse (month/year) |
Patient Determined Disease Step |
Walking aid or assistive devices |
More affected side (upper and lower body) |
Medications (incl. disease-modifying therapy) |
29-Item Multiple Sclerosis Impact Scale |
Clinical MRI availability |
Other health conditions |
Employment/Work status |
Typical Day |
Fall history past 7 days |
Fall history complete/triggers |
Godin Physical Activity/Leisure Questionnaire |
TMS contraindications |
Notes: BMI, body mass index; MS, multiple sclerosis |
The sample size was calculated based on the primary hypothesis and outcome. Most prior work studying the effects of exercise on walking speed has used interventions that cannot be distinctly classified as task- or non-task-oriented exercise, and has not compared the effects of different types of exercise (21, 22). Thus, our sample size calculation is informed by a study in which combined gait and dual-task training resulted in a greater improvement in walking speed than lower-extremity resistance exercise in PwMS (28). The combined gait and dual-task training (n = 26) yielded an average improvement in walking speed of 21.4%, while the resistance exercise (n = 12) yielded only a 2.5% change (i.e., null) (28). The effect size describing the difference between groups in change in walking speed was large and significant (Cohen’s d = 0.95, 95% CI: 0.2–1.7) (28). As the proposed intervention is longer and of higher volume than the prior work (28), we expect an effect size of similar or greater magnitude. Thus, based on the effect size reported in the prior work (28), we determined that a total of 63 participants (n = 21 per study arm) will be required to detect a clinically important mean difference of 20% in walking speed on the T25-FWT (59, 74) between study arms at the post-intervention time point with a two-sided significance level of 5%, a power of 85%, and equal allocation to the three arms of the trial.
Monitoring and Data Management
This study, including the participant consent form, has received ethical approval from the University of Regina Research Ethics Board (REB file 2021 − 197). Given that this is a low-risk intervention, no data monitoring review committee is required; however, the University of Regina Research Ethics Board has the authority to audit the study at any time to ensure compliance with approved protocols. Meetings of the research team will be held every three to six months to discuss day-to-day management and organisation of the study, including participant recruitment, delivery of the intervention, and participant monitoring.
All data, including the final trial dataset, is de-identified, coded and stored on a University of Regina server that is accessed only by members of the study team from password-protected computers. Physical copies of the data recording sheets are stored in locked filing cabinets at the University of Regina. All data is checked regularly by the study team to ensure protocols and ethical guidelines for data collection and analysis are followed. Study-related documents will be archived at the University of Regina at the end of the study and stored for a minimum of five years according to current ethical guidelines.
Dissemination Plan
Findings describing the primary outcome analysis will be reported in scientific publications, which will include results regardless of the direction or magnitude of the effect. The results will also be presented at national and international conferences that target researchers and healthcare providers. Authorship on scientific publications and conference presentations will be determined as per recommendations from the International Committee of Medical Journal Editors (75). Dissemination of non-academic outputs (e.g., lay summaries and public presentations) will capitalize on partnerships with local exercise and rehabilitation centres and the Saskatchewan Division of the Multiple Sclerosis Society of Canada. Pending results, future creation of MS-specific task-oriented exercise resources could support program implementation. Access to de-identified data will be granted upon reasonable request.