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Background A moderate to high level of physical activity, including regular exercise, represents an established behavioral and rehabilitative approach for persons with multiple sclerosis (pwMS). Although being increasingly proposed to limit disease activity and progression, high-quality evidence is lacking. Objective The objective of the study is to provide valuable information for MS clinicians and researchers by systematically evaluating the current state of evidence (i) whether exercise interventions affect established clinical measures of disease activity and progression in pwMS (i.e., EDSS, relapse rate, lesion load, brain volume, MSFC) and (ii) how the physical activity and fitness level interact with these measures. Methods Literature search was conducted in MEDLINE, EMBASE, CINAHL, and SPORTDiscus. Evaluation of evidence quality was done based on standards published by The American Academy of Neurology. Results It is likely that exercise improves the MSFC score, whereas the EDSS score, lesion load, and brain volume are likely to remain unchanged over the intervention period. It is possible that exercise decreases the relapse rate. Results from cross-sectional studies indicate beneficial effects of a high physical activity or fitness level on clinical measures which, however, is not corroborated by high evidence quality. Conclusions A (supportive) disease-modifying effect of exercise in pwMS cannot be concluded. The rather low evidence quality of existing RCTs underlines the need to conduct more well-designed studies assessing different measures of disease activity or progression as primary end points. A major limitation is the short intervention duration of existing studies which limits meaningful exercise-induced effects on most disability measures. Findings from cross-sectional studies are difficult to contextualize regarding clinical importance due to their solely associative character and low evidence quality. PROSPERO registration number CRD42020188774.

Nicotinamide adenine dinucleotide (NAD+) is an evolutionarily highly conserved coenzyme with multi-faceted cell functions, including energy metabolism, molecular signaling processes, epigenetic regulation, and DNA repair. Since the discovery that lower NAD+ levels are a shared characteristic of various diseases and aging per se, several NAD+-boosting strategies have emerged. Other than pharmacological and nutritional approaches, exercise is thought to restore NAD+ homeostasis through metabolic adaption to chronically recurring states of increased energy demand. In this review we discuss the impact of acute exercise and exercise training on tissue-specific NAD+ metabolism of rodents and humans to highlight the potential value as NAD+-boosting strategy. By interconnecting results from different investigations, we aim to draw attention to tissue-specific alterations in NAD+ metabolism and the associated implications for whole-body NAD+ homeostasis. Acute exercise led to profound alterations of intracellular NAD+ metabolism in various investigations, with the magnitude and direction of changes being strongly dependent on the applied exercise modality, cell type, and investigated animal model or human population. Exercise training elevated NAD+ levels and NAD+ metabolism enzymes in various tissues. Based on these results, we discuss molecular mechanisms that might connect acute exercise-induced disruptions of NAD+/NADH homeostasis to chronic exercise adaptions in NAD+ metabolism. Taking this hypothesis-driven approach, we hope to inspire future research on the molecular mechanisms of exercise as NAD+-modifying lifestyle intervention, thereby elucidating the potential therapeutic value in NAD+-related pathologies.

The integrative immune markers neutrophil-lymphocyte-ratio (NLR), platelet-lymphocyte-ratio (PLR) and systemic immune inflammation index (SII) are established markers in clinical patient care. Adoption of these markers in elite athletics might prove beneficial for monitoring training and health. Blood samples of 195 healthy national Olympic squad athletes were collected before a graded bicycle-ergometric exercise test until complete exhaustion. Measurements included white blood cells, lymphocytes and platelets, allowing for the calculation of the integrative immune markers. Correlations between athlete characteristics (sex, age, sporting discipline, training experience, training volume) and integrative immune marker-values were assessed. In a subgroup analysis a second blood sample was collected from 25 athletes at 1 minute after exercise test to assess its effect on the immune marker levels.An inverse correlation between peak power output and SII-level (Pearson correlation coefficient=−.270, p

Nicotinamide adenine dinucleotide (NAD

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. Supplementary Information The online version contains supplementary material available at 10.1007/s40120-021-00274-z.

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.

Both, objective and self-perceived cognitive deficits, are frequently observed in patients with cancer before, during, and after medical treatment [1,2]. This phenomenon, also known as cancer-relat...

Over the last decades the cellular immune inflammation markers neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII = NLR × platelets) have emerged in clinical context as markers of disease-related inflammation and are now widely appreciated due to their integrative character. Transferring these clinically established inflammation markers into exercise physiology seems highly beneficial, especially due to the low temporal, financial and infrastructural resources needed for assessment and calculation. Therefore, the aim of this review is to summarize evidence on the value of the integrative inflammation markers NLR, PLR and SII for depiction of exercise-induced inflammation and highlight potential applications in exercise settings. Despite sparse evidence, multiple investigations revealed responsiveness of the markers to acute and chronic exercise, thereby opening promising avenues in the field of exercise physiology. In performance settings, they might help to infer information for exercise programming by reflecting exercise strain and recovery status or periods of overtraining and increased infection risk. In health settings, application involves the depiction of anti-inflammatory effects of chronic exercise in patients exhibiting chronic inflammation. Further research should, therefore, focus on establishing reference values for these integrative markers in athletes at rest, assess the kinetics and reliability in response to different exercise modalities and implement the markers into clinical exercise trials to depict anti-inflammatory effects of chronic exercise in different patient collectives.

Purpose Physical activity promises to reduce disease-related symptoms and therapy-related side effects in patients suffering from aggressive lymphoma (L) or acute leukemia (AL). For an efficient training program, determination of patients’ physical capacity with a purposive exercise test is crucial. Here, we evaluated the feasibility and suitability of a graded exercise test (GXT) frequently applied in patients suffering from solid tumors by assessing whether patients achieved criteria for maximal exercise testing according to the American College of Sports Medicine (ACSM). Methods The GXT was performed by 51 patients with an aggressive L or AL prior to the start or in the earliest possible phase of high-dose chemotherapy, following a recommended protocol for cancer patients, starting at 20 Watts (W), with an increase of 10 W/min until volitional exhaustion. Subsequently, we investigated whether the following ACSM criteria were fulfilled: (1) failure of heart rate to increase despite increasing workload, (2) post-exercise capillary lactate concentration ≥ 8.0 mmol L−1, (3) rating of perceived exertion at exercise cessation > 17 on the 6–20 Borg Scale. Results Out of 51 patients, two, six, and 35 participants met the first, second, and third criterion, respectively. No relevant relationships between the completion of the criteria and patients’ characteristics (e.g., gender, age) were found. Conclusion Although results of this study suggest a general feasibility of the applied GXT, the ACSM criteria were not met by the majority of the participants. Therefore, this study raises doubts about the suitability of the GXT protocol and the ACSM criteria for this group of patients., Support Care Cancer

Purpose The programmed cell death protein 1 (PD-1) has become a promising target in cancer immunotherapy. PD-1 expression of CD8+ T-cells may be increased via the exploitation of aryl hydrocarbon receptor (AhR) signaling with kynurenine (KYN) as a ligand. Since exercise affects KYN metabolism, we exploratory investigated the influence of acute exercise bouts on AhR and PD-1 levels of CD8+ T-cells. Method In this study, 24 healthy males (age: 24.6 ± 3.9 years; weight 83.9 ± 10.5 kg; height: 182.4 ± 6.2 cm) completed a single bout of endurance (EE) and resistance exercise (RE) in a randomly assigned order on separate days. Blood samples were drawn before (t0), after (t1), and 1 h after (t2) both conditions. T-cell populations, the level of cytoplasmic AhR, and surface PD-1 were assessed by flow cytometry. Results T-cell populations changed over time, indicated by an increase in the absolute numbers of CD3+ lymphocytes after EE (p p = .036) and in PD-1+ CD8+ T-cells after EE (p = .021). Proportions of T-cell populations changed only after EE (t0–t2: p = .029; t1-t2: p = .006). The level of cytoplasmic AhR decreased immediately after exercise in both exercise conditions (EE: p = .009; RE: p = .036). The level of surface PD-1 decreased 1 h after EE (p = .005). Conclusion We analyzed the level of surface PD-1 and cytoplasmic AhR following acute physical exercise for the first time. Especially EE was observed to impact both AhR and PD-1 levels, undermining its role as the AhR-PD-1 axis modulator. These results provide new insights into the impact of exercise on AhR-signaling, which could potentially be relevant for various chronic diseases.

Purpose Due to distinct immuno- and neuro-modulatory properties, growing research interest focuses on exercise-induced alterations of the kynurenine (KYN) pathway in healthy and clinical populations. To date, knowledge about the impact of different acute strength exercise modalities on the KYN pathway is scarce. Therefore, we investigated the acute effects of hypertrophic (HYP) compared to maximal (MAX) strength loadings on the KYN pathway regulation. Methods Blood samples of twelve healthy males (mean age and weight: 23.5 ± 3.2 years; 77.5 ± 7.5 kg) were collected before (T0), immediately after (T1), and 1 h after completion (T2) of HYP (5 sets with 10 repetitions at 80% of 1RM) and MAX (15 sets with 1RM) loadings performed in a randomized cross-over design. Serum concentrations of tryptophan (TRP), KYN, kynurenic acid (KA), and quinolinic acid (QA) were assessed using high-performance liquid chromatography. Results The KA/KYN ratio increased from T0 to T1 (p = 0.01) and decreased from T1 to T2 (p = 0.011) in HYP, while it was maintained within MAX. Compared to MAX, serum concentrations of KA were greater in HYP at T1 (p = 0.014). Moreover, the QA/KA ratio was significantly lower in HYP than in MAX at T1 (p = 0.002). Conclusion Acute HYP loading led to increases in the metabolic flux yielding KA, thereby possibly promoting immunosuppression and neuroprotection. Our findings emphasize the potential of acute HYP exercise as short-term modulator of KYN pathway downstream to KA in healthy males and need to be proven in other samples., Eur J Appl Physiol;120

Physical performance could be negatively affected by sleep deficiency and fatigue. The present study assesses the role of sleep quality, fatigue and motivation on cardiovascular performance (VO

Alterations in immunological homeostasis induced by acute exercise have been frequently reported. In view of the growing amount of repetitive exercise stimuli in competitive sports, quick recovery plays a superior role. Therefore, we examined whether aqua cycling affects cellular immunological recovery. After performing 300 countermovement jumps with maximal effort male sport students (n = 20; 24.4 ± 2.2 years) were randomized into either an aqua cycling (AC) or a passive recovery (P) group. AC pedaled in chest-deep water without resistance, while P lay in a supine position. Each recovery protocols lasted 30 min. Blood samples were taken at Baseline, Post-exercise, Post-recovery and 1 h (h), 2 h, 4 h, 24 h, 48 h and 72 h after recovery. Outcomes comprised white blood cell (WBC) counts, lymphocyte (LYM) counts and LYM subsets (CD4/CD8 ratio). Additionally, cellular inflammation markers (neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and systemic immune-inflammation index (SII)) were calculated. In both groups, WBC, NLR and SII were significantly increased compared to Baseline up to and including 4 h after recovery. Significant interaction effects were found for WBC (Post-recovery, 2 h and 4 h), NLR (Post-recovery), SII (Post-recovery) and CD4/CD8 ratio (2 h) with values of AC being higher than of P. Interestingly, AC provoked a stronger but not prolonged immunological disturbance than P. NLR and SII may present simple, more integrative markers to screen exercise-induced alterations in immune homeostasis/recovery in athletes and clinical populations. More research is warranted to elucidate the clinical and practical relevance of these findings.

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).

Purpose The programmed cell death protein 1 (PD-1) has become a promising target in cancer immunotherapy. PD-1 expression of CD8+ T-cells may be increased via the exploitation of aryl hydrocarbon receptor (AhR) signaling with kynurenine (KYN) as a ligand. Since exercise affects KYN metabolism, we exploratory investigated the influence of acute exercise bouts on AhR and PD-1 levels of CD8+ T-cells. Method In this study, 24 healthy males (age: 24.6 ± 3.9 years; weight 83.9 ± 10.5 kg; height: 182.4 ± 6.2 cm) completed a single bout of endurance (EE) and resistance exercise (RE) in a randomly assigned order on separate days. Blood samples were drawn before (t0), after (t1), and 1 h after (t2) both conditions. T-cell populations, the level of cytoplasmic AhR, and surface PD-1 were assessed by flow cytometry. Results T-cell populations changed over time, indicated by an increase in the absolute numbers of CD3+ lymphocytes after EE (p

The essential amino acid tryptophan (TRP) is primarily degraded through the kynurenine (KYN) pathway, which is dysregulated in several chronic diseases. KYN pathway metabolites have immune- and neuro-modulatory properties and are involved in th de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Currently, little evidence exists demonstrating that physical exercise may influence this pathway. However, differences between acute and chronic stimuli as well as the influence of exercise modalities remain to be investigated. Here, we provide an overview of existing studies and present results of a randomized cross-over trial on acute effects of a single-bout of resistance and endurance exercise.24 healthy male adults conducted both an acute endurance exercise (EE) and resistance exercise (RE) session. Blood samples were collected before, immediately after and one hour after cessation of each exercise session. Outcomes comprised serum levels of TRP, KYN, kynurenic acid (KA), quinolinic acid (QA) and calculated ratios. Gene expression of the enzymes indoleamine 2,3 dioxygenase (IDO) 1 and kynurenine aminotransferase (KAT) 4 was measured in peripheral blood mononuclear cells (PBMCs). Moreover, serum concentrations of the potential KYN pathway mediators interleukin (IL)-6 and cortisol were determined. Finally, we investigated baseline correlations between immune cell subsets, potential mediators and initial KYN pathway activation outcomes.The KYN/TRP ratio correlated positively with IL-6 and CD56bright NK-cells and negatively with CD56dim NKcells. Expression of IDO1 in PBMCs correlated positively with IL-6, regulatory T-cells and CD56bright NK-cells, whereas negative correlations to cytotoxic T-cells and CD56dim NKcells were revealed. A significant time effect on KYN/TRP ratio was detected for RE. Regarding KA and KA/KYN ratio, an increase after exercise followed by a decrease at the follow- up measurement was revealed in EE. KAT4 expression also increased after exercise in EE. Moreover, elevated QA levels were observed after the EE session.In contrast to chronic exercise interventions, single-bouts of endurance exercise provoke acute alterations on KYN pathway outcomes in humans. Our results indicate that EE induces stronger alterations than RE. Enhanced conversion of KYN to both, KA and QA suggest a peripheral KYN clearance, thereby preventing pathological accumulation within the CNS. Future acute and chronic exercise studies are needed to examine the role of NAD+ synthesis starting with TRP and the interplay between KYN pathway activation and mid- to long-term immunological modulations.

Background: A noticeable proportion of adolescents with depression do not respond to guideline recommended treatment options. This systematic review and meta-analysis investigated the effectiveness of physical activity interventions as an alternative or complementary treatment for adolescents (12-18 years) with depression. The characteristics of the physical activity treatment that were most effective in reducing symptoms in adolescents with depression and the impact of methodological shortcomings in the existing research were also examined. Methods: Medline, PsycINFO, SPORTDiscus, ProQuest, and CENTRAL were searched for eligible records. Effect size estimates were pooled based on the application of a random-effects model. Potential moderation by physical activity characteristics (i.e., intensity, type, context, and time frame) and methodological features (i.e., type of control group and diagnostic tool to identify depression at baseline) was investigated by means of subgroup analyses and meta-regressions. The certainty of evidence was assessed by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The primary outcome was the antidepressant effect of physical activity at postintervention measurement time point. As secondary outcomes, the sustainability of effects after the end of physical activity treatment and the acceptability of physical activity treatments were assessed. Overall, 10 studies were included in the qualitative synthesis and 9 studies involving 431 patients were included in the quantitative synthesis. Results: A moderate, significant antidepressant effect of physical activity was found (Hedges' g = -0.47, 95% CI = -0.71 to -0.24). Heterogeneity was small (T2 = 0.0313, I 2 = 27%, p = 0.18). However, the certainty of evidence was downgraded to low because the included studies contained serious methodological limitations. Moderator analyses revealed that session intensity significantly moderated the antidepressant effect of physical activity. Moreover, noticeably smaller effect sizes were found in studies that used non-physical activity sham treatments as control treatments (e.g., playing board games), compared to studies that used no control group treatments. Only three studies assessed the sustainability of effects after the end of physical activity treatment. The results suggest that the antidepressant effects further increase after the end of physical activity interventions. There was no significant difference in dropout risk between the physical activity and control groups. Conclusions: This review suggests that physical activity is effective in treating depression in adolescents. Physical activity sessions should be at least moderately intense [rate of perceived exertion (RPE) between 11 and 13] to be effective. Furthermore, our results suggest that physical activity treatments are well accepted. However, the low methodological quality in included studies might have led to effect overestimation. Therefore, more studies with higher methodological quality are needed to confirm the recommendation for physical activity treatments in adolescents with depression.

Objectives Exercise-induced cellular mobilization might play a role in treatment and prevention of several diseases. However, little is known about the impact of different exercise modalities on immune cell mobilization and clinical cellular inflammation markers. Therefore, the present study aimed to investigate differences between acute endurance exercise (EE) and resistance exercise (RE) on cellular immune alterations. Methods Twenty-four healthy men conducted an acute EE (cycling at 60% of peak power output) and RE (five exercise machines at 70% of the one-repetition maximum) session lasting 50 minutes in randomized order. Blood samples were collected before, after and one hour after exercise cessation. Outcomes included counts and proportions of leukocytes, neutrophils (NEUT), lymphocytes (LYM), LYM subsets, CD4/CD8 ratio, and the clinical cellular inflammation markers NEUT/LYM ratio (NLR), platelets/LYM ratio (PLR), and systemic immune inflammation index (SII). Results Alterations in all outcomes were revealed except for CD8+ T cells, CD4/CD8 ratio, NLR, and PLR. EE induced a stronger cellular immune response and provoked alterations in more immune cell populations than RE. SII was altered only after EE. Conclusion An acute EE session causes a stronger mobilization of immune cells than RE. Additionally, SII represents an integrative marker to depict immunological alterations.

Purpose Prolonged periods of intense cognitive activity lead to a state of mental exhaustion. While widespread strategies to recover from mental exhaustion (i.e., watching TV) are non-effective, aerobic exercise seems to be a promising approach. This can be explained by the acute and chronic aerobic exercise-induced benefits on the central nervous system. Methods This study investigated the potential of a single bout of moderate aerobic exercise (65–75% of each participants’ individual V˙O2peak) to recover from experimentally induced mental exhaustion. A randomized controlled trial on healthy adults (N = 99) was conducted. They performed 60 min of a cognitively demanding test battery, in order to induce mental exhaustion. Subsequently, they were randomized to one of three treatments: 30 min of moderate aerobic exercise on a cycle ergometer, 30 min of a simple lower body stretching routine (= active control treatment) or watching a popular sitcom (= passive control treatment). Cognitive flexibility performance, mood, tiredness, restlessness, self-perceived cognitive capacity, and motivation were assessed before and after treatment. Results The empirical results showed that moderate aerobic exercise led to a better recovery for cognitive flexibility (mean difference divided by pooled standard deviation, Cohen's d= 0.737), mood (d= 0.405), tiredness (d= 0.480), self-perceived cognitive capacity (d= 0.214), and motivation (d= 0.524) compared to active control treatment. Moderate aerobic exercise was also more effective than passive control treatment (d= 0.102 - 0.286) with the exemption of tiredness (d= 0.015) and restlessness (d = -0.473). Conclusion In conclusion, this study suggests that a single bout of acute aerobic exercise supports regeneration of cognitive flexibility performance and of subjective well-being. This holds true not just compared to artificial active control treatment but also compared to widespread leisure time activity, namely watching TV.

Background The relevance of regular moderate to intense exercise for ameliorating psychomotor symptoms in persons with multiple sclerosis (pwMS) is becoming increasingly evident. Over the last two decades, emerging evidence from clinical studies and animal models indicate immune regulatory mechanisms in both periphery and the central nervous system that may underlie these beneficial effects. The integrity of the blood-brain barrier as the main structural interface between periphery and brain seems to play an important role in MS. Reducing the secretion of proteolytic matrix metalloproteinases (MMP), i.e. MMP-2, as disruptors of blood-brain barrier integrity could have profound implications for MS. Methods In this two-armed randomized controlled trial 64 participants with relapsing-remitting MS (RRMS) (EDSS 0–4.0) will be allocated to either an intervention group or a passive wait list control group. The intervention group will perform 60 min of combined functional resistance and endurance exercises 3x per week over a period of 12 weeks in a community-based and publicly available setting. Changes in serum concentration of MMP-2 will be the primary outcome. Secondary outcomes are numbers of immune cell subsets, soluble (anti-) inflammatory factors, physical capacity, cognitive performance, physical activity behavior, gait performance, and patient-reported outcomes. All outcome measures will be assessed at baseline and after week 12 with an additional blood sampling before, during and immediately after a single training session in week 6. Discussion To our knowledge, this will be the first RCT to investigate both the acute and chronic effects of a community-based intense functional resistance and endurance exercise regimen in persons with RRMS. Combining analysis of biological and cognitive or psychological outcomes may provide a better understanding of the MS-specific symptomology. Trial registration DRKS00017091; 05th of April, 2019; International Clinical Trials Registry Platform.

Background: Acute aerobic exercise leads to positive physiological adaptations within the central nervous system. These findings inspired research on potential cognitive benefits following acute aerobic exercise. The effects of acute aerobic exercise on subsequent cognitive performance, by far, have been the most researched for interference control, a subcomponent of executive function. The results of primary studies on the effects of acute aerobic exercise on subsequent interference control performance are inconsistent. Therefore, we used meta-analytic methods to pool available effect sizes, and to identify covariates that determine the magnitude of exercise-induced interference control benefits. Methods: Medline, PsycINFO, and SPORTDiscus were searched for eligible records. Hedges' g corrected standardized mean difference values (SMDs) were used for analyses. Random-effects weights were used to pool effect sizes. Moderator analyses were conducted using meta-regressions and subgroups analyses. Covariates that were here tested for moderation included parameters of the applied exercise regimen (exercise intensity and exercise duration), characteristics of examined participants (age and fitness), and methodological features of existing research (type of control group, familiarization with test procedure, type of test variable, delay between exercise cessation, and testing). Results: Fifty studies, with data from 2,366 participants, were included in qualitative and quantitative synthesis. A small, significant beneficial effect of acute aerobic exercise on time-dependent measures of interference control was revealed (k = 49, Hedges' g = −0.26, 95%CI: −34 to −0.18). Effect sizes from time-dependent measures of interference control varied widely and heterogeneity reached statistical significance (T2 = 0.0557, I2 = 28.8%). Moderator analyses revealed that higher exercise intensities (vigorous intensity and high-intensity interval training), also participants at younger or older age, and participants who are familiar with the testing procedure prior to the experiment, benefitted most from acute aerobic exercise. However, noticeable heterogeneity remained unexplained within specific subgroups (high-intensity interval training, preadolescent children, and active and supervised control group). Conclusion: Acute aerobic exercise improves subsequent interference control performance. However, the covariates exercise intensity, participants' age, and familiarization with testing procedure determine the magnitude of that effect. Methodological features were not found to influence the magnitude of effects. This dismisses some doubts that exercise induced benefits for interference control performance are scientific artifacts. The fact that large heterogeneity remained unexplained in some subgroups indicates the need for further research on covariates within these subgroups. It should be noted that effect sizes for all analyses were small. © Copyright © 2019 Oberste, Javelle, Sharma, Joisten, Walzik, Bloch and Zimmer.

ObjectiveTo 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).MethodsSixty-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.ResultsAcute 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.ConclusionFuture 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 EvidenceThis 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 InformationClinical trial registration number: NCT03652519.

Emerging evidence highlights the substantial role of the kynurenine pathway in various physiological systems and pathological conditions. Physical exercise has been shown to impact the kynurenine pathway in response to both single (acute) and multiple (chronic) exercise training stimuli. In this perspective article, we briefly outline the current knowledge concerning exercise-induced modulations of the kynurenine pathway and discuss underlying mechanisms. Furthermore, we expose the potential involvement of exercise-induced kynurenine pathway modulations on energy homeostasis (eg, through de novo synthesis of NAD+) and finally suggest how these modulations may contribute to exercise-induced benefits in the prevention and treatment of chronic diseases.