Cardiorespiratory fitness (V̇O2peak) across the adult lifespan in persons with multiple sclerosis and matched healthy controls.

OBJECTIVES: Cardiorespiratory fitness (measured as peak oxygen uptake; V̇O2peak) is a well-established health predictor in the general population and in persons with multiple sclerosis (pwMS). We aimed to investigate differences in V̇O2peak between age groups and the prevalence of V̇O2peak impairments across the adult lifespan in pwMS compared to age- and sex-matched healthy controls (HC). DESIGN: Cross-sectional study. METHODS: Data from 469 pwMS (EDSS range 1.0-7.0), who carried out graded cardiopulmonary exercise testing during their rehabilitation stay at the Valens clinic from 07/2010 to 10/2022, were retrospectively analyzed. Data from 21,063 HC were extracted from previously published studies containing normative reference values. RESULTS: With advanced age (i.e., across age groups), a continuous deterioration of V̇O2peak was observed in both pwMS and HC. Within all age groups, V̇O2peak was reduced in pwMS compared to HC with deficits ranging from 29 % to 40 % for females (p < .05), and from 30 % to 41 % for males (p < .05). However, no age ∗ group interaction was observed in neither males (p = .626) nor females (p = .557). With V̇O2peak impairments defined as values below the 5th percentile of HC, a high prevalence was observed in pwMS, with values ranging from 48 % to 100 % across age groups. CONCLUSIONS: The present data provide evidence for a parallel deterioration of V̇O2peak in pwMS and matched controls with advancing age, coinciding with a high prevalence of impairments in V̇O2peak already present in young adulthood in pwMS. Understanding the extent of impairments as well as the age trajectories of cardiorespiratory fitness in pwMS is crucial for designing optimal rehabilitative and preventive interventions.

The MoxFo initiative - outcomes: Outcome measures in studies of exercise training in multiple sclerosis; scoping review of reviews and classification according to the ICF framework.

BACKGROUND: The number of published studies of exercise training in multiple sclerosis (MS) has grown exponentially with increasing numbers of outcomes capturing exercise effects. This has complicated the selection of relevant indicators and interpretation of intervention effects. OBJECTIVES: The Outcomes subgroup of the MoXFo initiative aimed to (1) identify outcome measures and biomarkers in studies of exercise training in MS; (2) systematically map retrieved outcomes to International Classification of Functioning, Disability and Health (ICF) categories; (3) identify gaps where relevant ICF categories have been omitted. METHODS: Electronic databases and registers were searched from 2010 to July 2020 to identify systematic reviews or meta-analyses of controlled trials of exercise training on any outcome in MS. Retrieved outcomes/biomarkers were mapped to the corresponding ICF category. RESULTS: Eighty-one review articles reporting 235 different outcomes were included. The outcomes corresponded to 15 chapters and 45 categories within the ICF. Outcomes mapped primarily to body function (30 categories) and activities and participation (9 categories) components. Few outcomes mapped to body structures (2 categories) or environmental factors (1 category). CONCLUSION: This sets the stage to develop a resource for researchers/clinicians that will aid in the selection of appropriate outcomes/biomarkers when examining exercise effects in MS.

An Exploratory Study on the Utility of Patient-Generated Health Data as a Tool for Health Care Professionals in Multiple Sclerosis Care.

BACKGROUND: Patient-generated health data (PGHD) are data collected through technologies such as mobile devices and health apps. The integration of PGHD into health care workflows can support the care of chronic conditions such as multiple sclerosis (MS). Patients are often willing to share data with health care professionals (HCPs) in their care team; however, the benefits of PGHD can be limited if HCPs do not find it useful, leading patients to discontinue data tracking and sharing eventually. Therefore, understanding the usefulness of mobile health (mHealth) solutions, which provide PGHD and serve as enablers of the HCPs' involvement in participatory care, could motivate them to continue using these technologies. OBJECTIVE: The objective of this study is to explore the perceived utility of different types of PGHD from mHealth solutions which could serve as tools for HCPs to support participatory care in MS. METHOD: A mixed-methods approach was used, combining qualitative research and participatory design. This study includes three sequential phases: data collection, assessment of PGHD utility, and design of data visualizations. In the first phase, 16 HCPs were interviewed. The second and third phases were carried out through participatory workshops, where PGHD types were conceptualized in terms of utility. RESULTS: The study found that HCPs are optimistic about PGHD in MS care. The most useful types of PGHD for HCPs in MS care are patients' habits, lifestyles, and fatigue-inducing activities. Although these subjective data seem more useful for HCPs, it is more challenging to visualize them in a useful and actionable way. CONCLUSION: HCPs are optimistic about mHealth and PGHD as tools to further understand their patients' needs and support care in MS. HCPs from different disciplines have different perceptions of what types of PGHD are useful; however, subjective types of PGHD seem potentially more useful for MS care.

Effects of inpatient energy management education and high-intensity interval training on health-related quality of life in persons with multiple sclerosis: A randomized controlled superiority trial with six-month follow-up.

BACKGROUND: Fatigue is one of the most frequent symptoms in persons with multiple sclerosis (pwMS) and impacts health-related quality of life (HRQoL). A multidisciplinary rehabilitation approach is recommended for the treatment of fatigue in pwMS. However, high-quality evidence exists only for unimodal interventions, such as physical therapies/exercise or energy/fatigue management programmes. The primary objective of the current study was to test the hypothesis that a combination of inpatient energy management education (IEME) and high-intensity interval training (HIIT) is superior to a combination of progressive muscle relaxation (PMR) and moderate continuous training (MCT) for improving HRQoL at 6-month follow-up in fatigued pwMS. METHODS: A randomized (1:1) controlled superiority trial with fatigued pwMS >18 years of age, with Expanded Disability Status Scale (EDSS) score ≤6.5, recruited at the Valens clinic, Switzerland. Participants in the experimental group performed IEME twice and HIIT 3 times per week and those in the usual care group performed PMR twice and MCT 3 times per week, during a 3-week inpatient rehabilitation stay. Primary outcome was HRQoL (Physical and Mental Component Scales of the Medical Outcome Study 36-item Short Form Health Survey (SF-36)), assessed at entry to the clinic (T0), after 3 weeks' rehabilitation (T1) and 4 (T2) and 6 (T3) months after T0. Secondary outcomes included SF-36 subscales, fatigue (Fatigue Scale for Motor and Cognitive Functions (FSMC)), mood (Hospital Anxiety and Depression Scale (HADS)), self-efficacy for performing energy conservation strategies (Self-Efficacy for Performing Energy Conservation Strategies Assessment (SEPECSA)), self-perceived competence in activities of daily living (Occupational Self Assessment (OSA)) and cardiorespiratory fitness (peak oxygen consumption (VÈ®2peak)). Data were analysed using a mixed model for repeated measures approach. RESULTS: A total of 106 pwMS (age (years): 49.75 (9.87), 66% female, EDSS: 4.64 (1.32)) were recruited. There were no significant group × time interaction effects in the primary and secondary outcomes. There were significant between-group differences in the pairwise comparisons of the group × time interaction in favour of the IEME + HIIT group at: (i) T1 in cardiorespiratory fitness (p = 0.011) and SEPECSA (p = 0.032); (ii) T2 in SF-36 mental health subscale (p = 0.022), HADS anxiety subscale (p = 0.014) and SEPECSA (p = 0.040); (iii) T3 in SF-36 physical functioning subscale (p = 0.012) and SEPECSA (p = 0.003). CONCLUSION: IEME + HIIT was not superior to PMR + MCT regarding the effects on HRQoL (SF-36 Physical and Mental Component Scales) at 6-month follow-up in pwMS. However, there were significant between-group differences in favour of IEME + HIIT in physical functioning and mental health (SF-36 subscales), anxiety (HADS), cardiorespiratory fitness (VÈ®2peak) and self-efficacy (SEPECSA) at different measurement time-points that need to be considered in clinical practice.

Physical activity is related to disease severity and fatigue, but not to relapse rate in persons with relapsing remitting multiple sclerosis - a self-reported questionnaire based study.

Introduction: Based on theoretical models, physical activity has been introduced as a promoting method to mitigate the disease severity, fatigue and relapse rate in multiple sclerosis. The primary objective of the study was to investigate the relation between self-reported physical activity level and disease severity, fatigue and relapse rate in persons with relapsing remitting multiple sclerosis (RRMS). Methods: A survey was offered to persons with RRMS from March 2019 to August 2021 (n = 253). Physical activity level, fatigue and disease severity were determined using the Godin Leisure-Time Questionnaire (GLTEQ), the Patient Determined Disease Steps (PDDS) scale and the Fatigue Scale for Motor and Cognitive Functions (FSMC). Additionally, participants' relapse rate was recorded. Results: Bivariate correlations revealed an inverse relation between physical activity level and PDDS (ρ = -0.279; p < 0.001) as well as between physical activity and FSMC (r = -0.213, p < 0.001), but not between physical activity and relapse rate (r = 0.033, p > 0.05). Multiple linear regression analyses explained 12.6% and 5.2% of the variance of PDDS and FSMC. Conclusion: Our findings confirm a relation between self-reported physical activity, disease severity and fatigue in persons with RRMS. However, self-reported physical activity level does not seem to affect the annualised relapse rate.

Complexity and pitfalls in maximal exercise testing for persons with multiple sclerosis.

BACKGROUND AND PURPOSE: Valid measurements of cardiorespiratory fitness in persons with multiple sclerosis (pwMS) are essential during inpatient rehabilitation for a precise evaluation of the current health status, for defining appropriate exercise intensities, and for evaluation of exercise intervention studies. We aim (i) to examine the proportion of pwMS who attain the American College of Sports Medicine (ACSM) criteria for maximal effort during graded cardiopulmonary exercise testing (CPET) and (ii) to provide insight into participant characteristics that limit maximal exercise performance. METHODS: This cross-sectional study comprises a retrospective examination of ACSM criteria for maximal effort during graded CPET of n = 380 inpatient pwMS (mean age = 48 ± 11 years, 66% female). Chi-squared or Fisher's exact tests were conducted to compare differences in the distribution of criteria achieved. Participants' characteristics were examined as potential predictors using binary logistic regression. RESULTS: Only 60% of the overall sample attained a respiratory exchange ratio ≥ 1.10. With regard to the definition applied, only 24% or 40% of the participants achieved an oxygen consumption plateau, and 17% or 50% attained the heart rate criterion. Forty-six percent met at least two of three criteria. Disability status, gender, disease course, and body mass index were associated with the attainment of maximal effort. CONCLUSIONS: Our findings suggest that a relevant proportion of inpatient pwMS do not attain common criteria utilized to verify maximal oxygen consumption. Identified predictors for criteria attainment can be used to create models to predict cardiorespiratory fitness and to optimize CPET protocols in restrictive groups of pwMS.

Cycling in primary progressive multiple sclerosis (CYPRO): study protocol for a randomized controlled superiority trial evaluating the effects of high-intensity interval training in persons with primary progressive multiple sclerosis.

BACKGROUND: Primary progressive multiple sclerosis (PPMS) is the least prevalent multiple sclerosis (MS) phenotype. For persons with PPMS (pwPPMS), pharmacological treatment options are limited. As a complementary non-pharmacological treatment, endurance training improves the health-related quality of life (HRQoL), numerous MS symptoms, and MS-related performance impediments. High-intensity interval training (HIIT) has been shown to induce superior effects compared to moderate-intensity continuous training (MCT). As current evidence is based on MS samples with mixed phenotypes, generalizability to pwPPMS remains unclear. METHODS: CYPRO is a parallel-group, single-center, and single-blind randomized controlled superiority trial evaluating the effects of HIIT compared to MCT in pwPPMS. Sixty-one pwPPMS are randomized (1:1) to perform volume-matched HIIT or MCT sessions on bicycle ergometers two to three times per week in addition to standard rehabilitative care during their three-week inpatient stay at Valens rehabilitation clinic, Switzerland. Standard rehabilitative care comprises endurance and strength training, physiotherapy, and occupational therapy. HIIT sessions include six 90-second intervals at 95% peak heart rate (HRpeak), interspersed by 90-second active breaks with unloaded pedaling, aimed to reach 60%HRpeak. MCT represents the standard treatment at Valens rehabilitation clinic and is performed as continuous cycling at 60%HRpeak for the duration of 26 minutes. The primary outcome is cardiorespiratory fitness, assessed as peak oxygen consumption (V̇O2peak) during cardiopulmonary exercise testing (CPET). Secondary outcomes include peak power output during CPET, walking capacity, cognitive performance, HRQoL, fatigue, anxiety and depressive symptoms, and blood-derived biomarkers (e.g., serum neurofilament light chain, glial fibrillary acidic protein, kynurenine pathway metabolites) related to MS pathophysiology. All outcomes are assessed at baseline and discharge after three weeks. Venous blood sampling is additionally performed immediately and two hours after the first HIIT or MCT session. DISCUSSION: CYPRO will expand current knowledge on symptom management and rehabilitation in MS to the subpopulation of pwPPMS, and will contribute to the exploration of potential disease-modifying effects of endurance training in MS. The superiority design of CYPRO will allow deriving explicit recommendations on endurance training design in pwPPMS that can be readily translated into clinical practice. TRIAL REGISTRATION: CYPRO has been prospectively registered at ClinicalTrials.gov on 8 February 2022 (NCT05229861).

The serum kynurenine pathway metabolic profile is associated with overweight and obesity in multiple sclerosis.

BACKGROUND: Overweight and obesity increase multiple sclerosis (MS) susceptibility, disease severity, and disability progression. Kynurenine pathway (KP) dysregulation is present in overweight and obesity, and in MS. Since the effect of overweight and obesity on KP dysregulation in persons with MS (pwMS) remains to be established, this study primarily aims to explore the effect of overweight and obesity on the serum KP metabolic profile in pwMS. METHODS: This cross-sectional study represents a secondary analysis of a randomized clinical trial at Valens rehabilitation clinic, Switzerland. Registration was performed on 22 April 2020 at clinicaltrials.gov (NCT04356248, https://clinicaltrials.gov/ct2/show/NCT04356248). The first participant was enrolled on 13 July 2020. Based on body mass index (BMI), 106 MS inpatients (Expanded Disability Status Scale (EDSS) score ≤ 6.5) were dichotomised to a lean group (LG, BMI < 25 kg/m2), and an overweight/obese group (OG, BMI ≥ 25 kg/m2). Targeted metabolomics (LC-MS/MS) was performed to determine serum concentrations of tryptophan (TRP), KP downstream metabolites, and neopterin (Neopt). Correlations between BMI, kynurenine-to-TRP ratio (KTR), and serum concentrations of TRP, KP downstream metabolites, and Neopt were calculated. ANCOVA was used to determine differences in KTR, and serum concentrations of TRP, KP downstream metabolites and Neopt between OG and LG, and across MS phenotypes. RESULTS: Higher BMI correlated with higher KTR (r = 0.425, p <0.001) and serum concentrations of most KP downstream metabolites, but not with EDSS score. Higher KTR (r = 0.470, p < .001) and serum concentrations of most KP downstream metabolites correlated with a higher serum concentration of Neopt. The OG (n = 44, 59% female, 51.68 (9.98) years, EDSS: 4.71 (1.37)) revealed higher KTR (0.026 (0.007) vs. 0.022 (0.006), p=.001) and serum concentrations of most KP downstream metabolites than the LG (n = 62, 71% female, 48.37 (9.63) years, EDSS: 4.60 (1.29)). KP metabolic profiles did not differ between MS phenotypes. CONCLUSION: Overweight and obesity are associated with a systemic elevation of KP metabolic flux and an accumulation of most KP downstream metabolites in pwMS. Further research is needed to clarify if KP involvement serves as a mechanism linking overweight and obesity with symptom expression, disease severity, and disability progression in pwMS.

The Effect on Muscle Activity of Reaching Beyond Arm's Length on a Mobile Seat: A Pilot Study for Trunk Control Training for People After Stroke.

Objective: This pilot study compared muscle activity during lateral reaching tasks between mobile and stable sitting using a novel therapy chair in people after stroke and healthy controls. Design: Observational pilot study. Setting: This study was conducted in a rehabilitation center for people after stroke and at the university's movement laboratory for healthy participants. Participants: A total of eleven people after stroke and fifteen healthy people (N=26) took part. Interventions: Lateral reaching exercises to the ipsilateral and contralateral sides were performed on a mobile and a stable seat. Main Outcome Measure: Muscular activity of the multifidus, erector spinae and external oblique was measured bilaterally. A within-subject linear mixed model was applied to analyze the effects of seat condition, task, muscle side, and group. Results: A seat condition effect was found for the multifidus and external oblique that was dependent on the muscle side and task. During ipsilateral reaching, the activity of the multifidi decreased for people after stroke on the mobile seat, while increasing for healthy participants. The erector spinae showed no condition effect. Decreased activity of the external oblique was found for both groups on the mobile seat. Conclusions: Mobile sitting influences muscular activity. However, these preliminary results should be further investigated in order to generate recommendations for rehabilitation.

Three weeks of rehabilitation improves walking capacity but not daily physical activity in patients with multiple sclerosis with moderate to severe walking disability.

BACKGROUND: Patients with multiple sclerosis have low levels of physical activity. This is of concern because low activity levels are related to cardiovascular disease, poor walking ability, and reduced quality of life. The aim of this study was to evaluate the impact of rehabilitation on daily physical activity and walking capacity in patients with multiple sclerosis who have moderate to severe walking disability. METHODS: This exploratory, observational study of 24 patients with multiple sclerosis examined daily physical activity, walking capacity and fatigue before and after 3 weeks of inpatient rehabilitation. Inpatient rehabilitation included physiotherapy (30-60 min, 5 times/week), strength and endurance training (30-45 min, 3-5 times/week), occupational therapy (30 min, 2-3 times/week), and neuropsychological training (30 min, 2 times/week). There were no specific interventions to target daily levels of physical activity. RESULTS: Daily physical activity did not change after rehabilitation (physical activity: effect size = -0.23, 95% confidence interval (95% CI) 0.02‒0.62). There were significant improvements in walking capacity (Two-Minute Walk Test: effect size = 0.74, 95% CI 0.31‒1.16, +17 m, 20.2%) and mobility (Timed Up and Go Test: effect size = 0.65, 95% CI 0.22‒1.07, ‒2.1 s, 14.9%). Motor and cognitive fatigue (Fatigue Scale for Motor: effect size = 0.56, 95% CI 0.14‒0.99 and Cognitive Functions: effect size = 0.44, 95% CI 0.01‒0.86) improved significantly after rehabilitation. CONCLUSION: Three weeks of rehabilitation improved walking capacity, but not daily physical activity, in patients with multiple sclerosis with moderate to severe walking disability. To increase physical activity, it may be necessary to add specific behavioural interventions to the rehabilitation programme. The intervention plan should include strategies to overcome personal and environmental barriers.

Surface electromyographic activity of trunk muscles during trunk control exercises for people after stroke; effect of a mobile and stable seat for rehabilitation.

The aim of this study was to explore differences in trunk muscle activity on a stable and mobile seat for people after stroke and healthy participants. Trunk control exercises are known to have a beneficial effect on trunk control, balance, and mobility after stroke. The effect of such exercises could be enhanced by the use of a mobile seat to provide further training stimuli. However, little research on the musculoskeletal effects of trunk training on mobile seats has been carried out. On a stable and a mobile seat, thirteen people after stroke and fifteen healthy participants performed two selective trunk control exercises, which were lateral flexion initiated by the pelvis and the thorax. The maximal surface electromyography relative to static sitting of the muscles multifidus, erector spinae, and obliquus externus was recorded bilaterally. The effects of group, seat condition, trunk control exercise, and muscle side were investigated employing within-subject linear-mixed-models. Compared to the stable seat, the maximal muscle activity of people after stroke on the mobile seat was higher during the thorax-initiated exercise and lower during the pelvis-initiated exercise. Healthy participants showed opposite results with higher muscle activity on the mobile seat during the pelvis-initiated exercise. For trunk control training on a mobile seat with high muscle activation people after stroke should perform trunk control exercises initiated by the thorax, for training with lower muscle activity people after stroke should initiate selective trunk movements by the pelvis. The results can support the planning of progressive trunk control rehabilitation programs.

The aerobic capacity - fatigue relationship in persons with Multiple Sclerosis is not reproducible in a pooled analysis of two randomized controlled trials.

BACKGROUND: Fatigue is one of the most frequent symptoms of persons with Multiple Sclerosis (pwMS) but has limited treatment options. Aerobic capacity and endurance training have been discussed as relevant factors to improve fatigue. However, over the last decades, results have been equivocal. This secondary analysis of two pooled parallel group RCTs of three weeks of endurance training (high intensity interval training (HIIT) and moderate continuous training (MCT)) for pwMS aimed to (I) reproduce reported associations between aerobic capacity and fatigue on a cross-sectional and interventional level. The analysis further aimed to (II) investigate intervention effects on fatigue in a severely fatigued subgroup and (III) analyze differences in changes of fatigue between peak oxygen uptake (VO2peak) responders and non-responders. METHODS: Both RCTs were conducted in the same inpatient rehabilitation clinic in Valens, Switzerland. Original primary outcomes were cognitive function (RCT1) and change in proportion of circulating regulatory T-cells (RCT2). PwMS (n = 131) with a relapsing-remitting or secondary progressive MS phenotype and Expanded Disability Status Scale score between 1 - 6.5 were eligible. Over the two studies participants exercised 3 - 5 times per week on cycle ergometers at intensities of 65 - 70% of maximum heart rate (HRmax) for 30 min (MCT groups) or three times per week with five 90 - 180 s intervals at intensities of 85% - 100% of HRmax and 90 s rest intervals (HIIT groups). Main outcome measures for the present secondary analysis were VO2peak measured during a cardiopulmonary exercise test and the Fatigue Scale for Motor and Cognitive Functions (FSMC), both assessed at the start and end of inpatient rehabilitation. RESULTS: Baseline correlations did not reveal a significant association between VO2peak and FSMC. There were no significant improvements in fatigue after the HIIT and MCT in the overall sample or the subsample of severely fatigued pwMS and no significant differences in fatigue changes between VO2peak-responders and non-responders. CONCLUSIONS: Our analysis did not confirm the aerobic capacity - fatigue relationship on a cross-sectional and experimental level, even when analyzing subgroups that should benefit the most according to proposed hypotheses.

Systematic Review of Exercise Studies in Persons with Multiple Sclerosis: Exploring the Quality of Interventions According to the Principles of Exercise Training.

INTRODUCTION: The objective of this systematic review is to explore the application and reporting of (i) the principles of exercise training in exercise trials, (ii) the components of exercise prescription, and (iii) the adherence towards the prescribed programmes in randomised controlled trials (RCTs) in persons with multiple sclerosis (pwMS). METHODS: The MEDLINE, CINAHL, SPORTDiscus, PubMed and Embase electronic databases were searched from 1 January 2000 to 16 October 2020. RCTs comprising at least 3 weeks of aerobic and/or resistance exercise intervention in pwMS that reported at least one physiological outcome and were published in peer-reviewed journals were eligible for inclusion. RESULTS: Out of 52 RCTs included in this review, 58 intervention arms were examined. None applied more than four principles of exercise training. Specificity was addressed by 85%, progression by 33%, overload by 59%, initial values by 26%, reversibility by 0% and diminishing returns by 2% of trials. Fifty-two percent of trials reported all components of exercise prescription, and 3% of trials reported the level of adherence to the prescribed exercise. CONCLUSION: This systematic review reveals that exercise training principles were not respected in the majority of included RCTs. The weak quality of reported exercise interventions limits the interpretation of the studies' results and potentially leads to an underestimation of 'exercise as medicine' in pwMS. Also, the vague descriptions of exercise prescription and adherence impede the reproducibility of results. Future studies must attend to all principles of exercise training and provide transparent information on the prescribed and performed programmes to develop specific and valid exercise recommendations for pwMS. SYSTEMATIC REVIEW REGISTRATION: CRD42020162671, 28/04/2020, PROSPERO.

VO2peak Response Heterogeneity in Persons with Multiple Sclerosis: To HIIT or Not to HIIT?

Exercise is described to provoke enhancements of cardiorespiratory fitness in persons with Multiple Sclerosis (pwMS). However, a high inter-individual variability in training responses has been observed. This analysis investigates response heterogeneity in cardiorespiratory fitness following high intensity interval (HIIT) and moderate continuous training (MCT) and analyzes potential predictors of cardiorespiratory training effects in pwMS. 131 pwMS performed HIIT or MCT 3-5x/ week on a cycle ergometer for three weeks. Individual responses were classified. Finally, a multiple linear regression was conducted to examine potential associations between changes of absolute peak oxygen consumption (absolute ∆V̇O2peak/kg), training modality and participant's characteristics. Results show a time and interaction effect for ∆V̇O2peak/kg. Absolute changes of cardiorespiratory responses were larger and the non-response proportions smaller in HIIT vs. MCT. The model accounting for 8.6% of the variance of ∆V̇O2peak/kg suggests that HIIT, younger age and lower baseline fitness predict a higher absolute ∆V̇O2peak/kg following an exercise intervention. Thus, this work implements a novel approach that investigates potential determinants of cardiorespiratory response heterogeneity within a clinical setting and analyzes a remarkable bigger sample. Further predictors need to be identified to increase the knowledge about response heterogeneity, thereby supporting the development of individualized training recommendations for pwMS.

Do baseline cognitive status, participant specific characteristics and EDSS impact changes of cognitive performance following aerobic exercise intervention in multiple sclerosis?

PURPOSE: Cognitive impairment is a common symptom of multiple sclerosis (MS). Physical exercise represents a promising non-pharmacological therapy option, however, potential predictors for successful cognitive improvements mediated by exercise remain to be elucidated in order to optimize targeted exercise training regimens. One of the most promising exercise training regime in this context is high-intensity interval training (HIIT). Against this backdrop, this study i) analysed the effects of a three-week HIIT compared to moderate continuous exercise on cognitive performance and ii) investigated potential predictors for changes of cognitive performance following a three-week aerobic exercise intervention. METHODS: Datasets of two randomized controlled trials (RCT) were pooled, resulting in a total sample size of n = 130 persons with MS (pwMS) who either performed HIIT or moderate intensity continuous (MCT) exercise 3-5x/ week for three weeks. Cognitive performance was assessed with the Brief International Cognitive Assessment for MS. I) Potential within (time) and interaction (time x group) effects for cognitive performance were investigated with univariate analyses of covariance (ANCOVA). II) Potential predictors for changes of cognitive performance were assessed by multiple linear regression models. RESULTS: ANCOVA revealed significant time effects for all cognitive outcomes and a time x group interaction for verbal learning (p=.045), with HIIT inducing superior effects compared to moderate continuous exercise (MCT). Cognitive status (impaired/intact cognition) (p= .008) and exercise regime (HIIT/moderate continuous) (p=.040) influenced changes of verbal learning. Cognitive status (p=.006) and EDSS (p=.048) affected changes of visuospatial memory in pwMS. The models accounted for 5.4% and 7.7% of the variance. CONCLUSION: Cognitive status, exercise regime and EDSS potentially impact changes of specific cognitive domains following aerobic exercise. Further predictors for changes of cognitive performance following an aerobic exercise intervention need to be investigated as current results accounted only for a limited amount of variance. RCTs that investigate effects of physical exercise on cognitive performance should include only pwMS with impaired baseline cognitive performance. To better understand the impact of exercise on cognitive performance, it is furthermore recommendable to include cognitive assessments in clinical routine.

Exercise Diminishes Plasma Neurofilament Light Chain and Reroutes the Kynurenine Pathway in Multiple Sclerosis.

OBJECTIVE: To examine acute (single-bout) and training effects of high-intensity interval training (HIIT) vs standard exercise therapy (moderate continuous training [MCT]) on plasma neurofilament light chain (pNfL) and kynurenine (KYN) pathway of tryptophan degradation metabolites in persons with multiple sclerosis (pwMS). METHODS: Sixty-nine pwMS (Expanded Disability Status Scale score 3.0-6.0) were randomly assigned to a HIIT or an MCT group. Changes in pNfL and KYN pathway metabolites measured in blood plasma were assessed before, after, and 3 hours after the first training session as well as after the 3-week training intervention. RESULTS: Acute exercise reduced pNfL and increased the KYN pathway flux toward the neuroprotective kynurenic acid (KA). Changes in pNfL correlated positively with changes in KA and negatively with the quinolinic acid-to-KA ratio. HIIT consistently led to greater effects than MCT. Following the 3-week training intervention, the KYN pathway was activated in HIIT compared with MCT. CONCLUSION: Future studies and clinical assessments of pNfL should consider acute exercise as confounding factor for measurement reliability. Moreover, exercise-induced KYN pathway rerouting might mediate neuroprotection, potentially underlying the benefits in rehabilitation for pwMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that acute HIIT diminishes pNfL and increases KA levels, and 3 weeks of HIIT activate the KYN pathway in pwMS. TRIAL REGISTRATION INFORMATION: Clinical trial registration number: NCT03652519.

High-intensity interval training and energy management education, compared with moderate continuous training and progressive muscle relaxation, for improving health-related quality of life in persons with multiple sclerosis: study protocol of a randomized controlled superiority trial with six months' follow-up.

BACKGROUND: Persons with multiple sclerosis (PwMS) often have reduced aerobic capacity and report fatigue as the most disabling symptom impacting their health-related quality of life (HRQoL). A multidisciplinary rehabilitation approach is recommended for successful management of symptoms, although there is little supporting evidence. The aim of this study is to evaluate the effect of a multimodal therapy approach, including endurance training and patient education, during a three-week inpatient rehabilitation stay, on HRQoL in PwMS at six months follow-up. Inpatient energy management education (IEME) + high-intensity interval training (HIIT) will be compared with progressive muscle relaxation (PMR) + moderate continuous training (MCT). METHODS: This study has a two-armed single-blind randomized controlled superiority trial design. One hundred six PwMS-related fatigue (relapsing-remitting or chronic progressive phenotypes; Expanded Disability Status Scale (EDSS) ≤ 6.5) will be recruited at the Valens clinic, Switzerland, and randomized into either an experimental (EG) or a control group (CG). EG: participants will perform IEME twice and HIIT three times per week during the three-week rehabilitation stay. IEME is a group-based intervention, lasting for 6.5 h over three weeks. HIIT contains of five 1.5-min high-intensive exercise bouts on a cycle ergometer at 95-100% of peak heart rate (HRpeak), followed by active breaks of unloaded pedalling for 2 min to achieve 60% of HRpeak. CG: participants will perform PMR twice and MCT three times per week during the three-week rehabilitation stay, representing local usual care. PMR consists of six 1-h relaxation group sessions. MCT consists of 24-min continuous cycling at 65% of HRpeak. The primary outcome is HRQoL (Physical and Mental Component Summaries of the Medical Outcome Study 36-item Short Form Health Survey; SF-36), measured at entry to the clinic (baseline, T0), three weeks after T0 (T1) and at four (T2) and six (T3) months after T0. Secondary outcomes comprise cardiorespiratory fitness, inflammatory markers (measured at T0 and T1), fatigue, mood, self-efficacy, occupational performance, physical activity (measured at T0, T1, T2 and T3) and behaviour changes in energy management (measured at T2 and T3). DISCUSSION: This study will provide detailed information on a multimodal therapy approach to further improve rehabilitation for PwMS. TRIAL REGISTRATION: This trial was prospectively registered at ClinicalTrials.gov ( NCT04356248 ; 22 April 2020).

Dual-Task Treadmill Training for the Prevention of Falls in Parkinson's Disease: Rationale and Study Design.

Various factors, such as fear of falling, postural instability, and altered executive function, contribute to the high risk of falling in Parkinson's disease (PD). Dual-task training is an established method to reduce this risk. Motor-perceptual task combinations typically require a patient to walk while simultaneously engaging in a perceptual task. Motor-executive dual-tasking (DT) combines locomotion with executive function tasks. One augmented reality treadmill training (AR-TT) study revealed promising results of a perceptual dual-task training with a markedly reduced frequency of falls especially in patients with PD. We here propose to compare the effects of two types of concurrent tasks, perceptual and executive, on high-intensity TT). Patients will be trained with TT alone, in combination with an augmented reality perceptual DT (AR-TT) or with an executive DT (Random Number Generation; RNG-TT). The results are expected to inform research on therapeutic strategies for the training of balance in PD.

Exercise training and cognitive performance in persons with multiple sclerosis: A systematic review and multilevel meta-analysis of clinical trials.

BACKGROUND: Cognitive impairment is common, debilitating, and poorly managed in persons with multiple sclerosis (pwMS). Exercise training might have positive effects on cognitive performance in pwMS, yet the overall magnitude, heterogeneity, and potential moderators remain unclear. OBJECTIVE: This three-level meta-analysis aims to identify the effects of exercise training and those of exercise modalities on global and domain-specific cognitive performance in pwMS. METHODS: MEDLINE, PsycInfo, SportDiscus, CENTRAL, and EMBASE were screened for randomized and non-randomized clinical trials from inception to 27 January 2020, yielding 3091 articles. Based on titles and abstracts, 75 articles remained in the selection process. After full-text evaluation, 13 studies were finally selected (PROSPERO pre-registered). RESULTS: The pooled effect of exercise training on the global cognitive performance was null (g = 0.04, 95% confidence interval (CI): -0.11 to 0.18) and no significant differences were displayed among domains. Heterogeneity within studies was null (I(2)2= 0.0%) and between studies was low (I(3)2= 25.1%). None of the moderators (exercise modalities, age, Expanded Disability Status Scale (EDSS), supervision, cognitive domains) reached significance. However, the exercise volume explained most of the overall heterogeneity (slope = 4.651 × 10-5, R(2)2 = 100%, R(3)2 = 52.34%). CONCLUSION: These results do not support the efficacy of exercise training on global or domain-specific cognitive performance in pwMS. Future studies are needed to determine whether higher training dose are beneficial.

High-intensity interval training reduces neutrophil-to-lymphocyte ratio in persons with multiple sclerosis during inpatient rehabilitation.

In persons with multiple sclerosis (PwMS), the neutrophil-to-lymphocyte ratio (NLR) is associated with disability status, symptomatology and disease activity. High-intensity interval training (HIIT) improves many symptoms in PwMS and may positively influence disease progression. Here, we present results from a randomized controlled trial during inpatient rehabilitation on immediate (single bout) and training (3-week intervention) effects of HIIT versus moderate continuous training on NLR and related cellular inflammation markers. Only HIIT reduced the NLR over the 3-week intervention period. These training effects might be due to repetitive inflammatory states with compensatory anti-inflammatory counterbalancing after each HIIT session.