Transient and Immediate Motor Effects of Exercise in Progressive Multiple Sclerosis (TIME)

Endurance training is a cornerstone of rehabilitation in Multiple Sclerosis (MS) due to its beneficial effects on multiple MS-related symptoms, such as health-related quality of life, aerobic capacity (VO2peak), functional mobility, gait, depressive symptoms, and fatigue. Persons with progressive phenotypes of MS, namely primary progressive MS (PPMS) and secondary progressive (SPMS), represent a minor proportion of the total MS population, thus having been underrepresented in previous studies. The generalizability of existing evidence may be compromised by differences in symptom expression between MS phenotypes, with a dominance of motor symptoms (i.e., paraspasticity and/or paraparesis) in PPMS and SPMS. Adding up to this, clinical experiences of neurologists and sports scientists reveal that the effects of endurance exercise are characterized by a distinct time course, firstly inducing a minor and transient deterioration of motor symptoms that is followed by motor symptom alleviation beyond baseline level. This phenomenon was mainly related to the performance of High-Intensity Interval training (HIIT), but not to moderate-intensity continuous training (MCT). Therefore, this pilot study aims to systematically investigate the time course of acute motor effects on spasticity, functional mobility, gait, and dexterity in persons with PPMS and SPMS following two different endurance training protocols, that are HIIT and MCT.

Blinding of the principal investigator and research assistant towards group allocation is ensured by a unique subject identification code given to each participant.

MCT represents the standard treatment at Valens rehabilitation clinic. Participants will complete one heart-rate-controlled MCT bout within their 3-week inpatient stay.

Exercise intensity will be regulated and heart rate controlled based on the age-predicted heart rate (HRmax), as calculated by the formula 220 minus age in years. Participants will perform six high-intensity intervals (95% HRmax) at high pedalling rates of 80-100 rounds per minute (rpm) for 60-90 seconds each. Intervals are interspersed by active breaks of unloaded pedalling (20 watts, 60-80rpm) aimed to return to 60% HRmax (approximately 1.5-2 min). The duration of the HIIT bout is approximately 21 minutes.

Exercise intensity will be regulated and heart rate controlled based on the age-predicted heart rate (HRmax), as calculated by the formula 220 minus age in years. Participants will continuously train at 60% HRmax and pedal at 60-80 rounds per minute. The duration of the MCT bout is 26 minutes.

Functional mobility is assessed by the Timed-Up-and-Go Test (TUG). For the TUG, participants are asked to get up from a chair, walk a 3 metres distance, perform a 180° turn, return to the chair, and sit down again as fast as possible. Assessment takes place on a single day, before (T0), 5 minutes after (T1), 60 minutes after (T2), 180 minutes after (T3), 300 minutes (T4) after HIIT/MCT cycling bout.

Change from baseline to directly after, 1-hour after, 3-hours after, and 5-hours after the exercise bout

Spasticity of the hip flexors, knee flexors, foot dorsiflexors and respective extensors will be evaluated using the Modified Ashworth Scale (MAS). The participant is placed on a bench in supine position. The outcome assessor performs a passive stretch on the respective muscle group and scores the muscle tone as normal or increased on a 6-category ordinal scale (0, 1, 1+, 2, 3, 4). Assessment takes place on a single day, before (T0), 5 minutes after (T1), 60 minutes after (T2), 180 minutes after (T3), 300 minutes (T4) after HIIT/MCT cycling bout.

Change from baseline to directly after, 1-hour after, 3-hours after, and 5-hours after the exercise bout

Participants rate the extent of perceived spasticity on a Numeric Rating Scale for Spasticity (NRS-S), ranging from 0 ("no spasticity") to 10 ("worst possible spasticity"). Assessment takes place on a single day, before (T0), 5 minutes after (T1), 60 minutes after (T2), 180 minutes after (T3), 300 minutes (T4) after HIIT/MCT cycling bout.

Change from baseline to directly after, 1-hour after, 3-hours after, and 5-hours after the exercise bout

Spatiotemporal features of the gait pattern analysis are captured by the instrumented treadmill C-Mill for a duration of two minutes. Assessment takes place on a single day, before (T0), 5 minutes after (T1), 60 minutes after (T2), 180 minutes after (T3), 300 minutes (T4) after HIIT/MCT cycling bout.

Change from baseline to directly after, 1-hour after, 3-hours after and 5-hours after the exercise bout

Dexterity is assessed by the Virtual Peg Insertion Test (VPIT). The VPIT is a virtual instrumented 3D object manipulation (pick-and-place) task. In seated position, participants are asked to transport virtual pegs into virtual holes as fast as possible. Participants perform four trials with their dominant hand. Spatiotemporal movement trajectories are recorded. Assessment takes place on a single day, before (T0), 5 minutes after (T1), 60 minutes after (T2), 180 minutes after (T3), 300 minutes (T4) after HIIT/MCT cycling bout.

Change from baseline to directly after, 1-hour after, 3-hours after, and 5-hours after the exercise bout

Inclusion Criteria: adult age (≥ 18 years) definite MS diagnosis according the 2017 revised McDonald criteria PPMS/SPMS phenotype according to the 2013 revised Lublin criteria Expanded Disability Status Scale (EDSS) score ≤ 6.0 Informed Consent as documented by signature of participants and PI Exclusion Criteria: severe lower extremity spasticity or severe concomitant disease states (i.e., orthopaedic, cardiovascular, metabolic, psychiatric (e.g., substance abuse), other neurological, other serious medical conditions) impairing the ability to participate inability to follow study procedures (e.g., due to language barriers) suspected non-compliance previous enrolment into the current study enrolment of the investigator, his/her family members, employees, and other dependent persons

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