Effects of multidisciplinary inpatient rehabilitation on everyday life physical activity and gait in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis is a progressive neurological disease that affects the central nervous system, resulting in various symptoms. Among these, impaired mobility and fatigue stand out as the most prevalent. The progressive worsening of symptoms adversely alters quality of life, social interactions and participation in activities of daily living. The main objective of this study is to bring new insights into the impact of a multidisciplinary inpatient rehabilitation on supervised walking tests, physical activity (PA) behavior and everyday gait patterns. METHODS: A total of 52 patients, diagnosed with multiple sclerosis, were evaluated before and after 3 weeks of inpatient rehabilitation. Each measurement period consisted of clinical assessments and 7 days home monitoring using foot-mounted sensors. In addition, we considered two subgroups based on the Expanded Disability Status Scale (EDSS) scores: 'mild' (EDSS < 5) and 'severe' (EDSS ≥ 5) disability levels. RESULTS: Significant improvements in fatigue, quality of life and perceived mobility were reported. In addition, walking capacity, as assessed by the 10-m walking test, two-minute walk test and timed-up-and-go test, improved significantly after rehabilitation. Regarding the home assessment, mildly disabled patients significantly increased their locomotion per day and complexity of daily PA pattern after rehabilitation, while severely disabled patients did not significantly change. There were distinct and significant differences in gait metrics (i.e., gait speed, stride length, cadence) between mildly and severely disabled patients, but the statistical models did not show a significant overall rehabilitation effect on these gait metrics. CONCLUSION: Inpatient rehabilitation showed beneficial effects on self-reported mobility, self-rated health questionnaires, and walking capacity in both mildly and severely disabled patients. However, these improvements do not necessarily translate to home performance in severely disabled patients, or only marginally in mildly disabled patients. Motivational and behavioral factors should also be considered and incorporated into treatment strategies.

Exploring the Major Barriers to Physical Activity in Persons With Multiple Sclerosis: Observational Longitudinal Study.

BACKGROUND: Physical activity (PA) represents a low-cost and readily available means of mitigating multiple sclerosis (MS) symptoms and alleviating the disease course. Nevertheless, persons with MS engage in lower levels of PA than the general population. OBJECTIVE: This study aims to enhance the understanding of the barriers to PA engagement in persons with MS and to evaluate the applicability of the Barriers to Health Promoting Activities for Disabled Persons (BHADP) scale for assessing barriers to PA in persons with MS, by comparing the BHADP score with self-reported outcomes of fatigue, depression, self-efficacy, and health-related quality of life, as well as sensor-measured PA. METHODS: Study participants (n=45; median age 46, IQR 40-51 years; median Expanded Disability Status Scale score 4.5, IQR 3.5-6) were recruited among persons with MS attending inpatient neurorehabilitation. They wore a Fitbit Inspire HR (Fitbit Inc) throughout their stay at the rehabilitation clinic (phase 1; 2-4 wk) and for the 4 following weeks at home (phase 2; 4 wk). Sensor-based step counts and cumulative minutes in moderate to vigorous PA were computed for the last 7 days at the clinic and at home. On the basis of PA during the last 7 end-of-study days, we grouped the study participants as active (≥10,000 steps/d) and less active (<10,000 steps/d) to explore PA barriers compared with PA level. PA barriers were repeatedly assessed through the BHADP scale. We described the relevance of the 18 barriers of the BHADP scale assessed at the end of the study and quantified their correlations with the Spearman correlation test. We evaluated the associations of the BHADP score with end-of-study reported outcomes of fatigue, depression, self-efficacy, and health-related quality of life with multivariable regression models. We performed separate regression analyses to examine the association of the BHADP score with different sensor-measured outcomes of PA. RESULTS: The less active group reported higher scores for the BHADP items Feeling what I do doesn't help, No one to help me, and Lack of support from family/friends. The BHADP items Not interested in PA and Impairment were positively correlated. The BHADP score was positively associated with measures of fatigue and depression and negatively associated with self-efficacy and health-related quality of life. The BHADP score showed an inverse relationship with the level of PA measured but not when dichotomized according to the recommended PA level thresholds. CONCLUSIONS: The BHADP scale is a valid and well-adapted tool for persons with MS because it reflects common MS symptoms such as fatigue and depression, as well as self-efficacy and health-related quality of life. Moreover, decreases in PA levels are often related to increases in specific barriers in the lives of persons with MS and should hence be addressed jointly in health care management.

Implementation of Remote Activity Sensing to Support a Rehabilitation Aftercare Program: Observational Mixed Methods Study With Patients and Health Care Professionals.

BACKGROUND: Physical activity is central to maintaining the quality of life for patients with complex chronic conditions and is thus at the core of neurorehabilitation. However, maintaining activity improvements in daily life is challenging. The novel Stay With It program aims to promote physical activity after neurorehabilitation by cultivating self-monitoring skills and habits. OBJECTIVE: We examined the implementation of the Stay With It program at the Valens Rehabilitation Centre in Switzerland using the normalization process theory framework, focusing on 3 research aims. We aimed to examine the challenges and facilitators of program implementation from the perspectives of patients and health care professionals. We aimed to evaluate the potential of activity sensors to support program implementation and patient acceptance. Finally, we aimed to evaluate patients' engagement in physical activity after rehabilitation, patients' self-reported achievement of home activity goals, and factors influencing physical activity. METHODS: Patients were enrolled if they had a disease that was either chronic or at risk for chronicity and participated in the Stay With It program. Patients were assessed at baseline, the end of rehabilitation, and a 3-month follow-up. The health care professionals designated to deliver the program were surveyed before and after program implementation. We used a mixed methods approach combining standardized questionnaires, activity-sensing data (patients only), and free-text questions. RESULTS: This study included 23 patients and 13 health care professionals. The diverse needs of patients and organizational hurdles were major challenges to program implementation. Patients' intrinsic motivation and health care professionals' commitment to refining the program emerged as key facilitators. Both groups recognized the value of activity sensors in supporting program implementation and sustainability. Although patients appreciated the sensor's ability to monitor, motivate, and quantify activity, health care professionals saw the sensor as a motivational tool but expressed concerns about technical difficulties and potential inaccuracies. Physical activity levels after patients returned home varied considerably, both within and between individuals. The self-reported achievement of activity goals at home also varied, in part because of vague definitions. Common barriers to maintaining activity at home were declining health and fatigue often resulting from heat and pain. At the 3-month follow-up, 35% (8/23) of the patients withdrew from the study, with most citing deteriorating physical health as the reason and that monitoring and discussing their low activity would negatively affect their mental health. CONCLUSIONS: Integrating aftercare programs like Stay With It into routine care is vital for maintaining physical activity postrehabilitation. Although activity trackers show promise in promoting motivation through monitoring, they may lead to frustration during health declines. Their acceptability may also be influenced by an individual's health status, habits, and technical skills. Our study highlights the importance of considering health care professionals' perspectives when integrating new interventions into routine 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.

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.

Feasibility and scalability of a fitness tracker study: Results from a longitudinal analysis of persons with multiple sclerosis.

Background: Consumer-grade fitness trackers offer exciting opportunities to study persons with chronic diseases in greater detail and in their daily-life environment. However, attempts to bring fitness tracker measurement campaigns from tightly controlled clinical environments to home settings are often challenged by deteriorating study compliance or by organizational and resource limitations. Objectives: By revisiting the study design and patient-reported experiences of a partly remote study with fitness trackers (BarKA-MS study), we aimed to qualitatively explore the relationship between overall study compliance and scalability. On that account, we aimed to derive lessons learned on strengths, weaknesses, and technical challenges for the conduct of future studies. Methods: The two-phased BarKA-MS study employed Fitbit Inspire HR and electronic surveys to monitor physical activity in 45 people with multiple sclerosis in a rehabilitation setting and in their natural surroundings at home for up to 8 weeks. We examined and quantified the recruitment and compliance in terms of questionnaire completion and device wear time. Furthermore, we qualitatively evaluated experiences with devices according to participants' survey-collected reports. Finally, we reviewed the BarKA-MS study conduct characteristics for its scalability according to the Intervention Scalability Assessment Tool checklist. Results: Weekly electronic surveys completion reached 96%. On average, the Fitbit data revealed 99% and 97% valid wear days at the rehabilitation clinic and in the home setting, respectively. Positive experiences with the device were predominant: only 17% of the feedbacks had a negative connotation, mostly pertaining to perceived measurement inaccuracies. Twenty-five major topics and study characteristics relating to compliance were identified. They broadly fell into the three categories: "effectiveness of support measures", "recruitment and compliance barriers", and "technical challenges". The scalability assessment revealed that the highly individualized support measures, which contributed greatly to the high study compliance, may face substantial scalability challenges due to the strong human involvement and limited potential for standardization. Conclusion: The personal interactions and highly individualized participant support positively influenced study compliance and retention. But the major human involvement in these support actions will pose scalability challenges due to resource limitations. Study conductors should anticipate this potential compliance-scalability trade-off already in the design phase.

Non-equivalent, but still valid: Establishing the construct validity of a consumer fitness tracker in persons with multiple sclerosis.

Tools for monitoring daily physical activity (PA) are desired by persons with multiple sclerosis (MS). However, current research-grade options are not suitable for longitudinal, independent use due to their cost and user experience. Our objective was to assess the validity of step counts and PA intensity metrics derived from the Fitbit Inspire HR, a consumer-grade PA tracker, in 45 persons with MS (Median age: 46, IQR: 40-51) undergoing inpatient rehabilitation. The population had moderate mobility impairment (Median EDSS 4.0, Range 2.0-6.5). We assessed the validity of Fitbit-derived PA metrics (Step count, total time in PA, time in moderate to vigorous PA (MVPA)) during scripted tasks and free-living activity at three levels of data aggregation (minute, daily, and average PA). Criterion validity was assessed though agreement with manual counts and multiple methods for deriving PA metrics via the Actigraph GT3X. Convergent and known-groups validity were assessed via relationships with reference standards and related clinical measures. Fitbit-derived step count and time in PA, but not time in MVPA, exhibited excellent agreement with reference measures during scripted tasks. During free-living activity, step count and time in PA correlated moderately to strongly with reference measures, but agreement varied across metrics, data aggregation levels, and disease severity strata. Time in MVPA weakly agreed with reference measures. However, Fitbit-derived metrics were often as different from reference measures as reference measures were from each other. Fitbit-derived metrics consistently exhibited similar or stronger evidence of construct validity than reference standards. Fitbit-derived PA metrics are not equivalent to existing reference standards. However, they exhibit evidence of construct validity. Consumer-grade fitness trackers such as the Fitbit Inspire HR may therefore be suitable as a PA tracking tool for persons with mild or moderate MS.

Methodological heterogeneity biases physical activity metrics derived from the Actigraph GT3X in multiple sclerosis: A rapid review and comparative study.

Background: Physical activity (PA) is reduced in persons with multiple sclerosis (MS), though it is known to aid in symptom and fatigue management. Methods for measuring PA are diverse and the impact of this heterogeneity on study outcomes is unclear. We aimed to clarify this impact by comparing common methods for deriving PA metrics in MS populations. Methods: First, a rapid review of existing literature identified methods for calculating PA in studies which used the Actigraph GT3X in populations with MS. We then compared methods in a prospective study on 42 persons with MS [EDSS 4.5 (3.5-6)] during a voluntary course of inpatient neurorehabilitation. Mixed-effects linear regression identified methodological factors which influenced PA measurements. Non-parametric hypothesis tests, correlations, and agreement statistics assessed overall and pairwise differences between methods. Results: In the rapid review, searches identified 421 unique records. Sixty-nine records representing 51 eligible studies exhibited substantial heterogeneity in methodology and reporting practices. In a subsequent comparative study, multiple methods for deriving six PA metrics (step count, activity counts, total time in PA, sedentary time, time in light PA, time in moderate to vigorous PA), were identified and directly compared. All metrics were sensitive to methodological factors such as the selected preprocessing filter, data source (vertical vs. vector magnitude counts), and cutpoint. Additionally, sedentary time was sensitive to wear time definitions. Pairwise correlation and agreement between methods varied from weak (minimum correlation: 0.15, minimum agreement: 0.03) to perfect (maximum correlation: 1.00, maximum agreement: 1.00). Methodological factors biased both point estimates of PA and correlations between PA and clinical assessments. Conclusions: Methodological heterogeneity of existing literature is high, and this heterogeneity may confound studies which use the Actigraph GT3X. Step counts were highly sensitive to the filter used to process raw accelerometer data. Sedentary time was particularly sensitive to methodology, and we recommend using total time in PA instead. Several, though not all, methods for deriving light PA and moderate to vigorous PA yielded nearly identical results. PA metrics based on vertical axis counts tended to outperform those based on vector magnitude counts. Additional research is needed to establish the relative validity of existing methods.

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.

Goal-directed upper limb movement patterns and hand grip forces in multiple sclerosis.

Background: Upper limb disability in persons with Multiple Sclerosis (pwMS) leads to increased dependence on caregivers. To better understand upper limb disability, observer-based or time-based clinical assessments have been applied. However, these only poorly capture the behavioural aspects underlying goal-directed task performance. Objective: We aimed to document alterations in goal-directed upper limb movement patterns and hand grip forces in a cohort of pwMS (n = 123) with mild to moderate upper limb impairments. Methods: We relied on the Virtual Peg Insertion Test (VPIT), a technology-aided assessment with a goal-directed pick-and-place task providing a set of validated digital health metrics. Results: All metrics indicated significant differences to an able-bodied reference sample (p < 0.001), with smoothness, speed, and grip force control during object manipulation being most affected in pwMS. Such abnormalities negatively influenced the time to complete the goal-directed task (p < 0.001, R2 = 0.77), thereby showing their functional relevance. Lastly, abnormalities in movement patterns and grip force control were consistently found even in pwMS with clinically normal gross dexterity and grip strength. Conclusion: This work provides a systematic documentation on goal-directed upper limb movement patterns and hand grip forces in pwMS, ultimately paving the way for an early detection of MS sign using digital health metrics.

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.

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.

Toward a Remote Assessment of Walking Bout and Speed: Application in Patients With Multiple Sclerosis.

Gait speed as a powerful biomarker of mobility is mostly assessed in controlled environments, e.g. in the clinic. With wearable inertial sensors, gait speed can be estimated in an objective manner. However, most of the previous works have validated the gait speed estimation algorithms in clinical settings which can be different than the home assessments in which the patients demonstrate their actual performance. Moreover, to provide comfort for the users, devising an algorithm based on a single sensor setup is essential. To this end, the goal of this study was to develop and validate a new gait speed estimation method based on a machine learning approach to predict gait speed in both clinical and home assessments by a sensor on the lower back. Moreover, two methods were introduced to detect walking bouts during daily activities at home. We have validated the algorithms in 35 patients with multiple sclerosis as it often presents with mobility difficulties. Therefore, the robustness of the algorithm can be shown in an impaired or slow gait. Against silver standard multi-sensor references, we achieved a bias close to zero and a precision of 0.15 m/s for gait speed estimation. Furthermore, the proposed machine learning-based locomotion detection method had a median of 96.8% specificity, 93.0% sensitivity, 96.4% accuracy, and 78.6% F1-score in detecting walking bouts at home. The high performance of the proposed algorithm showed the feasibility of the unsupervised mobility assessment introduced in this study.

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.

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.