Impacts of Different Training Modes (Intense Versus Ordinary) on the Immune System and Memory Functions 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. 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.