Impacts of Different Training Modes (Intense Versus Ordinary) on the Immune System and Memory Functions in pwMS
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Study type: Interventional

Summary: 
      Multiple Sclerosis (MS) is a chronic immune-mediated disease of the central nervous system,
      accompanied by varying inflammatory manifestations, demyelinization and axonal loss. With
      chronic progressive or relapsing-remitting disease onsets persons with MS (pwMS)
      progressively develop impaired functional capacity and show reduced physical activity and
      cognitive decline compared to healthy controls. The primary aims of rehabilitation in pwMS
      are therefore to increase levels of activity and participation leading to increase
      independence of the participants. In general exercise ranges from passive physiotherapy-based
      interventions to submaximal endurance training sessions. Current recommendations advise pwMS
      that exercise should be matched with the individual performance capacities. Exercise training
      in pwMS then has the potential to target and improve many components outlined in the
      ICF-model.

      Cytokines and neurotrophic factors have received increased attention in MS research and
      addressed the brain-derived neurotrophic factor (BDNF) as an important mediator of neuronal
      regeneration linking the effects of exercise with MS pathogenesis. Data show positive
      connections between elevated neurotrophin concentrations, induction of neuroplasticity,
      recovery of the motor and cognitive functions and the applied training intensities.
      Similarly, intensive and progressive exercise bouts seem to have greater benefits on
      cardiorespiratory fitness and maximum voluntary strength in elderly and seniors with
      dementia. Therefore, specific exercise prescriptions may be necessary for targeting the
      specific impairments also in pwMS.

      This study aims to evaluate two different training modalities (intensive versus normal) in
      pwMS. It is expected that both modalities will improve cardiorespiratory fitness and
      cognitive functions in pwMS. Based on the findings that higher training intensities
      facilitate greater benefits, it is expected that pwMS will tolerate the intensive training
      intensities and show positive connections to elevated neurotrophin concentrations.

      The results will to help to clearer understand the benefits of each type of exercise conveyed
      for pwMS and will assist in the development of patient-specific exercise prescriptions.
    

Detailed description: 
      This study aims to evaluate two different training modalities (intensive versus normal) in
      pwMS. It is expected that both modalities will improve cardiorespiratory fitness and
      cognitive functions in pwMS. Based on the findings that higher training intensities
      facilitate greater benefits, it is expected that pwMS will tolerate the intensive training
      intensities and show positive connections to elevated neurotrophin concentrations.

      Primary outcomes are the acute (after CPET) and chronic (3-week training intervention)
      changes of neurotrophic factors and cognitive functions. All other measures are secondary
      outcomes (Training values: VO2peak, Workload, Heart rate; Fatigue: FSMC; Anxiety and
      Depression: HADS.

      Participants are eligible if they hold a definite diagnosis of multiple sclerosis (revised
      McDonald criteria), an EDSS score of 1.0 -6.0, they give no written consent, severe
      cardiovascular exacerbations (RR > 240/120, HR above the age predicted maximum of 220-Age)
      are persistent, they hold severe cognitive impairments, they face severe disease progression
      or relapses.

      Main measurements and procedures include:

      Blood sampling: Blood samples (10ml) of the primary outcomes will be taken by vein puncture
      from the antecubital vein in a seated position before the exercise bout and straight after
      reaching VO2peak during cool down, with the participant still seated on the ergometer.

      Before samples are taken the participant will be required to relax for 10 minutes, blood
      sampling will take approximately 5 minutes.

      Cardiopulmonary Exercise Test (CPET): Cardiorespiratory fitness is assessed through a
      progressive CPET performed at baseline on a cycle ergometer at t1 and is repeated the day
      prior to discharge at t2.

      The exercise protocol consists of (a) first 3 minutes at rest (no pedalling) on the cycle
      ergometer; (b) 3 minutes of unloaded pedalling as a warm up; (c) testing phase until the
      participant reaches a symptom limited maximum. Workload is continuously ramp type increased
      by 5-10 Watts every minute to ensure 8-12 minutes of testing; (d) the final 3 minutes are
      unloaded pedalling to cool down. Heart rate (Polar Electro, Kempele, Finland) and blood
      pressure (Riva-Rocci) are monitored for the last 10 seconds every 2 minutes during the test.
      The 10-point BORG scale therapy short-form assesses the rate of perceived exertion (RPE) at
      phases (c) and (d). Blood samples are drawn at rest prior to phase (a) and at the end of CPET
      phase (d) at t1 and t2

      Cognitive assessments: Cognitive assessments will be performed using the German version of
      the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Additionally,
      the German version of the Trail-Making-Pencil-Test versions A/B (TMT-A/B) and Go/noGo (TAP
      version) will be used. Cognitive assessments will be performed at baseline (t1) and repeated
      at t2.

      Fatigue: Fatigue is assessed with the multidimensional FSMC scale before CPET under resting
      conditions. FSMC has defined cut-off scores to classify mildly, moderately and severely
      fatigued patients. Cut-off for fatigue is set for the total score at 43 and for the motoric
      and cognitive sub-scores at 22. The scale has a proven test-retest liability and has been
      translated into multiple languages.

      Depression and Anxiety: Depression and anxiety are assessed with the Hospital Anxiety and
      Depression Scale (HADS). The HADS is a self-assessment questionnaire for adults with physical
      ailments that assess anxiety and depression. The questionnaire consists of 14 items seven for
      anxiety seven for depression with higher scores indicating anxiety or depression.

      Training: Endurance training in both groups consisted of physiologically defined heart rate
      controlled cycling at 50-60 rounds per minutes (rpm) and progressive resistance training. All
      participants will be stratified according to their cardiorespiratory fitness and level of
      cognitive fatigue in to group Intensive Training (IT) and Normal Training (NT). Training
      groups differ in the applied intensities and frequencies.

      The IT will train less frequent but training sessions will be more intensive in its effects.
      Training will be performed daily in six sessions (three morning and three afternoon
      sessions), synchronized and individually matched to a ratio of active versus passive sessions
      of 2:1.

      The NT is the normal training performed out of the daily routine and outlines the usual care
      of the Valens clinic. Training will be performed in maximal eight training sessions and will
      not be synchronized and not individually matched to a ratio of active versus passive
      sessions.
    

Intervention name(s): Intensive Training; Normal Training
Intervention type(s): Behavioral; Behavioral
Intervention description(s): Week 1: Ratio of continuous and interval training of 2:1. Entry point at day one with 20 min of continuous, physiologically defined heart rate controlled cycling at 50-60 rounds per minutes at 75% of HRpeak.
Resistance training is performed with 70% of the subjective-felt 1-round maximum with three sets and 10-12 repetitions and three exercises for the upper and lower extremities.
Week 2 Progression of endurance training: 4x5 minutes with 2 Minutes between each interval performed at 80% of HRmax Progression resistance training: 75% of the subjective-felt 1-round maximum with three sets and 8-10 repetitions and three exercises for the upper and lower extremities.
Week 3 Same as week 2.; The control intervention is the normal rehabilitation program of the Valens clinic.
Other intervention name(s): Endurance and Resistance Training; Endurance and Resistance Training
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Basic Science