Cognitive rehabilitation effects on grey matter volume and Go-NoGo activity in progressive multiple sclerosis: results from the CogEx trial.

BACKGROUND: Research on cognitive rehabilitation (CR) and aerobic exercise (EX) to improve cognition in progressive multiple sclerosis (PMS) remains limited. CogEx trial investigated the effectiveness of CR and EX in PMS: here, we present MRI substudy volumetric and task-related functional MRI (fMRI) findings. METHODS: Participants were randomised to: 'CR plus EX', 'CR plus sham EX (EX-S)', 'EX plus sham CR (CR-S)' and 'CR-S plus EX-S' and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task). RESULTS: 104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25-62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in 'CR plus EX-S' (p=0.02). Groups performing CR (ie, 'CR plus EX' and 'CR plus EX-S') exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. 'CR plus EX-S' patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula. CONCLUSIONS: In PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements. TRIAL REGISTRATION NUMBER: NCT03679468.

Randomized Controlled Trial of the Behavioral Intervention for Physical Activity in Multiple Sclerosis Project: Response Heterogeneity and Predictors of Change.

BACKGROUND: We reported that a social cognitive theory-based (SCT), Internet-delivered behavioral intervention increased device-measured minutes/day of moderate-to-vigorous physical activity (MVPA) over a 6-month period among persons with multiple sclerosis (MS). This paper examined the pattern and predictors of heterogeneity in change for MVPA. Based on previous research, we hypothesized that mild MS disability, fewer MS symptoms, lower baseline MVPA, and positive SCT characteristics (e.g., high exercise self-efficacy) would be associated with greater change in MVPA. METHOD: Persons with MS (N = 318) were randomized into behavioral intervention (n = 159) or attention/social contact control (n = 159) conditions that were administered via Internet websites and supported with behavioral coaching. Demographic, clinical, symptom, behavioral, and SCT data were from before the 6-month period of delivering the conditions, and MVPA data were from before and after the 6-month period. We examined heterogeneity based on waterfall plots, box plots, and the Levene statistic. We identified predictors of MVPA change using bivariate correlation and multiple, linear regression analyses per condition. RESULTS: The Levene statistic indicated statistically significant heterogeneity of variances for MVPA change between conditions (p = .003), and the waterfall plots and box plots indicated greater heterogeneity in MVPA change for the behavioral intervention. MVPA change score was correlated with baseline MVPA (r = - .33 and r = - .34, p = .0004 and p = .0001) in both conditions and walking impairment (r = - .188, p = .047) and race (r = .233, p = .014) in the behavioral intervention condition. The regression analysis indicated that baseline MVPA (Standardized B = - .449, p = .000002), self-reported walking impairment (Standardized B = - .310, p = .0008), and race (Standardized B = .215, p = .012) explained 25.6% of variance in MVPA change for the behavioral intervention condition. CONCLUSION: We provide evidence for walking impairment, baseline MVPA, and race as predictors of the heterogeneity in the pattern of MVPA change with a behavioral intervention.

Attrition, adherence, and compliance to exercise training interventions in persons with traumatic brain injury: a systematic review of training studies.

BACKGROUND: Exercise training (ET) is a promising rehabilitation approach for long-term negative consequences of traumatic brain injury (TBI). However, little is known regarding overall rates of attrition, adherence, and compliance to ET in TBI. OBJECTIVE: The purpose of this systematic review was to estimate average attrition, adherence, and compliance rates in ET studies in persons with TBI. METHODS: Databases were searched from inception to April 15, 2024. Two authors independently extracted data related to attrition, adherence, compliance, and possible moderators identified a priori. RESULTS: The average rate of attrition from 45 studies was 14.4%, although the majority of studies had small sample sizes (i.e. n < 42). Based on hierarchical linear regression, the most influential predictors of attrition were sample size and study design. A minority of studies reported adherence (44.4%) or compliance (22.2%) but those that did reported good average adherence (85.1%) and compliance (77.7%). These studies support the ability of persons with TBI to complete an ET intervention as prescribed. CONCLUSIONS: Researchers can use this information to ensure adequate power to detect a true effect of ET in persons with TBI. Researchers conducting ET studies in persons with TBI should clearly and thoroughly report data on attrition, adherence, and compliance.

Primary results of a phase-III, randomized controlled trial of the Behavioral Intervention for increasing Physical Activity in Multiple Sclerosis project.

BACKGROUND: We undertook a phase-III, randomized controlled trial (RCT) that examined the effectiveness of a behavioral intervention based on social cognitive theory (SCT) and delivered through the Internet using e-learning approaches for immediate and sustained increases in physical activity among persons with multiple sclerosis (MS). METHOD: The study followed a parallel group RCT design. Persons with MS (N = 318) were randomized into either behavioral intervention (n = 159) or attention/social contact control (n = 159) conditions. The conditions were administered over a 6-month period by persons who were uninvolved in screening, recruitment, random assignment, and outcome assessment. There was a 6-month follow-up period without access of conditions. We collected outcome data every 6 months over the 12-month period. The primary outcome was device-measured minutes/day of moderate-to-vigorous physical activity (MVPA). The data analysis involved a modified intent-to-treat approach (i.e. those who received the allocated conditions) using a linear mixed model. RESULTS: There was a significant group by time interaction on the primary outcome of device-measured minutes/day of MVPA (p < 0.005). MVPA was increased immediately after the 6-month period in the behavioral intervention compared with control, and this difference was sustained over the 6-month follow-up. CONCLUSION: This study provides evidence for the effectiveness of a widely scalable approach for increasing MVPA in persons with MS.

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.

Blood pressure and cognition in older adults with multiple sclerosis: preliminary examination.

BACKGROUND: Comorbid conditions, particularly vascular comorbidity, are common in MS and may hasten the CNS damage and disease manifestations. We undertook a preliminary examination of the association between blood pressure (BP) and cognitive function in samples of older adults with MS and healthy controls. METHODS: Older adults with MS (n = 29) and healthy controls (n = 29) completed the Brief International Cognitive Assessment for MS (BICAMS) battery and underwent assessment of BP. The data were analyzed using the Baron and Kenny approach for examining blood pressure as an explanatory variable for group differences in cognition. RESULTS: The MS group, as expected, had significantly lower California Verbal Learning Test-II (CVLT-II) z-scores from the BICAMS and higher diastolic BP (DBP) than healthy controls. DBP had statistically significant correlations with CVLT-II z-scores in the overall sample (r = - .42) and MS subsample (r = - .51), but not healthy controls(r = - .29); the correlation was not attenuated when controlling for age and disability status in the MS subsample (pr = - .48). Group initially explained 6% of the variance in z-scores from the CVLT-II (ß = - 0.24). The inclusion of DBP accounted for an additional 14% of the variance in z-scores from the CVLT-II, and DBP(ß = - 0.39), but not group (ß = - 0.13), was a significant correlate of CVLT-II z-scores; the results were unchanged when controlling for anxiety and depression scores. CONCLUSION: Our results provide preliminary, cross-sectional support for future population-based research examining DBP, hypertension, and verbal memory in older adults with MS.

Neuroimaging Technology in Exercise Neurorehabilitation Research in Persons with MS: A Scoping Review.

There is increasing interest in the application of neuroimaging technology in exercise neurorehabilitation research among persons with multiple sclerosis (MS). The inclusion and focus on neuroimaging outcomes in MS exercise training research is critical for establishing a biological basis for improvements in functioning and elevating exercise within the neurologist's clinical armamentarium alongside disease modifying therapies as an approach for treating the disease and its consequences. Indeed, the inclusion of selective neuroimaging approaches and sensor-based technology among physical activity, mobility, and balance outcomes in such MS research might further allow for detecting specific links between the brain and real-world behavior. This paper provided a scoping review on the application of neuroimaging in exercise training research among persons with MS based on searches conducted in PubMed, Web of Science, and Scopus. We identified 60 studies on neuroimaging-technology-based (primarily MRI, which involved a variety of sequences and approaches) correlates of functions, based on multiple sensor-based measures, which are typically targets for exercise training trials in MS. We further identified 12 randomized controlled trials of exercise training effects on neuroimaging outcomes in MS. Overall, there was a large degree of heterogeneity whereby we could not identify definitive conclusions regarding a consistent neuroimaging biomarker of MS-related dysfunction or singular sensor-based measure, or consistent neural adaptation for exercise training in MS. Nevertheless, the present review provides a first step for better linking correlational and randomized controlled trial research for the development of high-quality exercise training studies on the brain in persons with MS, and this is timely given the substantial interest in exercise as a potential disease-modifying and/or neuroplasticity-inducing behavior in this population.

The relationship between processing speed and verbal and non-verbal new learning and memory in progressive multiple sclerosis.

OBJECTIVE: Processing speed (PS) deficits are the most common cognitive deficits in multiple sclerosis (MS), followed by learning and memory deficits, and are often an early cognitive problem. It has been argued that impaired PS is a primary consequence of MS, which in turn decreases learning. The current analysis examined the association between PS and learning in a large cohort of individuals with progressive MS. METHODS: Baseline data from a randomized clinical trial on rehabilitation taking place at 11 centers across North America and Europe were analyzed. Participants included 275 individuals with clinically definite progressive MS (primary, secondary) consented into the trial. RESULTS: Symbol Digit Modalities Test (SDMT) significantly correlated with California Verbal Learning Test-II (CVLT-II) (r = 0.21, p = 0.0003) and Brief Visuospatial Memory Test-Revised (BVMT-R) (r = 0.516, p < 0.0001). Receiver operating characteristic (ROC) analysis of the SDMT z score to distinguish between impaired and non-impaired CVLT-II performance demonstrated an area under the curve (AUC) of 0.61 (95% confidence interval (CI): 0.55-0.68) and a threshold of -1.62. ROC analysis between SDMT and BVMT-R resulted in an AUC of 0.77 (95% CI: 0.71-0.83) and threshold of -1.75 for the SDMT z score to predict impaired BVMT-R. CONCLUSION: Results indicate little ability beyond chance to predict CVLT-II from SDMT (61%), albeit statistically significant. In contrast, there was a 77% chance that the model could distinguish between impaired and non-impaired BVMT-R. Several potential explanations are discussed.

Cardiorespiratory fitness and free-living physical activity are not associated with cognition in persons with progressive multiple sclerosis: Baseline analyses from the CogEx study.

BACKGROUND: Aerobic exercise training (physical activity for improving cardiorespiratory fitness) represents a promising approach for managing cognitive impairment in multiple sclerosis (MS). However, there is limited evidence that levels of physical activity and fitness are associated with cognition in progressive MS. OBJECTIVE: We examined associations among cardiorespiratory fitness, moderate-to-vigorous physical activity (MVPA), and cognitive performance in a large, international progressive MS sample. METHODS: Two hundred forty European and North American persons with progressive MS underwent cardiorespiratory fitness measurement on a recumbent stepper, wore an ActiGraph GT3X + accelerometer for 7 days for measuring MVPA, and underwent the Brief International Cognitive Assessment in MS. RESULTS: Cardiorespiratory fitness was not significantly correlated with Symbol Digit Modalities Test (SDMT; r = -0.01; r = -0.04), California Verbal Learning Test-II (CVLT-II; r = 0.05; r = 0.05), or Brief Visuospatial Memory Test-Revised (BVMT-R; r = -0.14; r = -0.14) z-scores controlling for age, sex, and education. MVPA and SDMT (r = 0.05), CVLT-II (r = -0.07), and BVMT-R (r = 0.01) z-scores were not significantly correlated. CONCLUSION: Cardiorespiratory fitness and MVPA were not associated with cognition in this large progressive MS sample, yet these outcomes represent critical manipulation checks for documenting the success of the CogEx trial. This highlights the importance of examining other exercise-related mechanisms-of-action for improving cognition in progressive MS.

Do subcortical gray matter volumes and aerobic capacity account for cognitive-motor coupling in multiple sclerosis?

BACKGROUND: There is evidence of cognitive-motor coupling in multiple sclerosis (MS) such that the slowing of cognitive processing speed correlates with the worsening of walking speed and endurance. OBJECTIVE: The current study first established the presence of cognitive-motor coupling and second examined the possibility that volumes of subcortical gray matter (SGM) structures and aerobic capacity might explain the coupling of cognitive and motor functions in persons with MS. METHODS: We included data from 62 persons with clinically definite MS who underwent assessments of cognitive processing speed, walking performance, and aerobic capacity, and completed magnetic resonance imaging (MRI) within 7 days of the aforementioned assessments. RESULTS: The strong correlations between cognitive processing speed and walking performance were attenuated in magnitude and not statistically significant when controlling for aerobic capacity alone and aerobic capacity and SGM volumes together. The associations between cognitive processing speed and walking performance remained statistically significant when controlling for SGM volumes alone. CONCLUSION: Aerobic capacity may be an important target for neurorehabilitation-based approaches for managing co-occurring cognitive and motor dysfunction in MS.

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.

The Neurologist as an Agent of Exercise Rehabilitation in Multiple Sclerosis.

This review hypothesizes that the neurologist represents the linchpin of exercise behavior change within comprehensive multiple sclerosis (MS) care settings. This is based on a series of recent articles that developed actionable practice models for accomplishing such behavior change through the neurologist as the primary agent. This provides tangible, next steps for exercise promotion in MS.

Aerobic reserve capacity in multiple sclerosis-Preliminary evidence.

OBJECTIVES: Aerobic reserve capacity reflects the available energy for performing everyday life tasks, and it has been studied in older adult populations. This preliminary study examined proof of concept and measurement of aerobic reserve capacity in multiple sclerosis (MS). MATERIALS & METHODS: Twenty-one fully ambulatory people with MS performed a maximal, cardiopulmonary exercise test (CPET). We calculated aerobic reserve capacity based on the difference between peak aerobic power (VO2peak ) and first stage oxygen consumption (VO2 ). Participants completed assessments for disability (Expanded Disability Status Scale, EDSS), cognition (Symbol Digit Modalities Test, SDMT), mood (Beck Depression Inventory, BDI), walking endurance (six-minute walk distance, 6MWD), walking speed (Timed Twenty-Foot Walk, T25FW), impact of MS (Multiple Sclerosis Impact Scale, MSIS-29), and anthropometric measurements (height and weight). RESULTS: Aerobic reserve capacity was 9.3 ± 3.7 ml/kg/min. Aerobic reserve capacity was positively associated with VO2peak (ρ = .67, p < .01), time to exhaustion (ρ = .63, p < .01), and SDMT (ρ = .51, p < .05). Aerobic reserve capacity was negatively associated with BMI (ρ = -.62, p < .01) and RHR (ρ = -0.47, p < .05). CONCLUSION: We provide preliminary evidence that aerobic reserve capacity is a feasible outcome derived from maximal CPET (eg, modified Balke protocol) in MS. Aerobic reserve capacity was associated with clinically relevant outcomes and could become an important outcome for rehabilitation in future research.

The preliminary effects of moderate aerobic training on cognitive function in people with TBI and significant memory impairment: a proof-of-concept randomized controlled trial.

This single-blinded RCT investigated cognitive effects of aerobic exercise in persons with TBI-related memory impairment. Five participants . were randomly assigned to 12-weeks of either supervised moderate intensity aerobic cycling or an active control. Outcome measures included neuropsychological assessments and structural neuroimaging (MRI,). The exercise group demonstrated greater improvements on auditory verbal learning (RAVLT; d=1.54) and processing speed (SDMT; d=1.58). The exercise group showed larger increases in volume of the left hippocampus (d=1.49) and right thalamus (d=1.44). These pilot data suggest that 12-weeks of moderate intensity aerobic cycling may improve memory and processing speed in those with TBI-related memory impairments.

Symptom clusters and quality of life in persons with multiple sclerosis across the lifespan.

PURPOSE: To describe symptom clusters based on severity of co-occurring symptoms among adults with multiple sclerosis (MS) by age groups and to further examine symptom clusters as a correlate of quality of life (QOL) by age groups. METHODS: This cross-sectional study enrolled persons with MS between 20 and 79 years of age who completed measures of fatigue, depression, anxiety, sleep quality, and QOL using the 36-Item Short Form Health Survey. Bivariate correlation and partial correlation analyses examined associations among symptoms, QOL, and MS characteristics. K-means cluster analyses determined symptom clusters among the full sample and pre-determined age groups (i.e., 20-39, 40-59, and 60-79). One-way ANOVAs examined differences in QOL among clusters for the overall sample and by age groups. RESULTS: Among the overall sample of 205 participants, symptoms were significantly correlated with QOL and three distinct clusters were identified and differentiated by the magnitude of symptom experience (i.e., mild, moderate, and severe). Results were consistent among young and middle-aged adults; however, among older adults two severe sleep problem clusters were identified that were distinguished by moderate versus severe fatigue, depression, and anxiety. ANOVAs among the overall sample indicated that the three symptom clusters varied significantly for both physical component scores, F(2, 202) = 12.03, p < .001, η2 = .10, and mental component scores, F(2, 202) = 137.92, p < .001, η2 = .58; severe symptom cluster was associated with worse QOL. Patterns in the age subgroup ANOVAs were consistent. CONCLUSIONS: Given the strong association between severity of symptom clusters and QOL, approaches for targeting co-occurring symptoms are critically needed.

Moving exercise research in multiple sclerosis forward (the MoXFo initiative): Developing consensus statements for research.

Exercise as a subset of physical activity is a cornerstone in the management of multiple sclerosis (MS) based on its pleotropic effects. There is an exponential increase in the quantity of research on exercise in MS, yet a number of barriers associated with study content and quality hamper rapid progress in the field. To address these barriers and accelerate discovery, a new international partnership of MS-related experts in exercise has emerged with the goal of advancing the research agenda. As a first step, the expert panel met in May 2018 and identified the most urgent areas for moving the field forward, and discussed the framework for such a process. This led to identification of five themes, namely "Definitions and terminology," "Study methodology," "Reporting and outcomes," "Adherence to exercise," and "Mechanisms of action." Based on the identified themes, five expert groups have been formed, that will further (a) outline the challenges per theme and (b) provide recommendations for moving forward. We aim to involve and collaborate with people with MS/MS organizations (e.g. Multiple Sclerosis International Federation (MSIF) and European Multiple Sclerosis Platform (EMSP)) in all of these five themes. The generation of this thematic framework with multi-expert perspectives can bolster the quality and scope of exercise studies in MS that may ultimately improve the daily lives of people with MS.

Device-Measured Physical Activity and Cognitive Processing Speed Impairment in a Large Sample of Persons with Multiple Sclerosis.

OBJECTIVE: There is accumulating evidence regarding the beneficial effects of physical activity (PA) on cognitive processing speed in persons with multiple sclerosis (MS). However, one overarching limitation of this research is that researchers have not recruited samples who have the actual problem of being studied (i.e., cognitive processing speed impairment). This study examined associations between device-measured PA and cognitive processing speed in a large sample of persons with MS overall and between those with and without cognitive processing speed impairment. METHOD: Three hundred eighty-five persons with MS underwent the oral Symbol Digit Modalities Test (SDMT) and wore an accelerometer for 7 days for PA measurement. We divided the overall sample into subsamples with (n = 140) and without (n = 245) cognitive processing speed impairment based on age, sex, and education-adjusted SDMT Z-scores. RESULTS: After controlling for age and disability status, higher levels of device-measured PA were significantly associated with faster cognitive processing speed overall, and the association was significantly stronger among persons with MS who presented with cognitive processing speed impairment. CONCLUSIONS: This examination provides initial cross-sectional support for informing the development of PA interventions as a possible approach for managing MS-related cognitive processing speed impairment. This highlights the importance of developing purposefully designed trials involving PA interventions for targeting cognitive processing speed as a primary end point among persons with MS with impaired cognitive processing speed.

Study protocol: improving cognition in people with progressive multiple sclerosis: a multi-arm, randomized, blinded, sham-controlled trial of cognitive rehabilitation and aerobic exercise (COGEx).

BACKGROUND: Cognitive dysfunction affects up to 70% of people with progressive MS (PMS). It can exert a deleterious effect on activities of daily living, employment and relationships. Preliminary evidence suggests that performance can improve with cognitive rehabilitation (CR) and aerobic exercise (EX), but existing data are predominantly from people with relapsing-remitting MS without cognitive impairment. There is therefore a need to investigate whether this is also the case in people with progressive forms of the disease who have objectively identified cognitive impairment. It is hypothesized that CR and EX are effective treatments for people with PMS who have cognitive impairment, in particular processing speed (PS) deficits, and that a combination of these two treatments is more effective than each individual treatment given alone. We further hypothesize that improvements in PS will be associated with modifications of functional and/or structural plasticity within specific brain networks/regions involved in PS measured with advanced MRI techniques. METHODS: This study is a multisite, randomized, double-blinded, sham controlled clinical trial of CR and aerobic exercise. Three hundred and sixty subjects from 11 sites will be randomly assigned into one of four groups: CR plus aerobic exercise; CR plus sham exercise; CR sham plus aerobic exercise and CR sham plus sham exercise. Subjects will participate in the assigned treatments for 12 weeks, twice a week. All subjects will have a cognitive and physical assessment at baseline, 12 weeks and 24 weeks. In an embedded sub-study, approximately 30% of subjects will undergo structural and functional MRI to investigate the neural mechanisms underlying the behavioral response. The primary outcome is the Symbol Digit Modalities Test (SDMT) measuring PS. Secondary outcome measures include: indices of verbal and non-verbal memory, depression, walking speed and a dual cognitive-motor task and MRI. DISCUSSION: The study is being undertaken in 6 countries (11 centres) in multiple languages (English, Italian, Danish, Dutch); with testing material validated and standardized in these languages. The rationale for this approach is to obtain a robustly powered sample size and to demonstrate that these two interventions can be given effectively in multiple countries and in different languages. TRIAL REGISTRATION: The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468. Registration was performed before recruitment was initiated.

Quantitative Synthesis of Timed 25-Foot Walk Performance in Multiple Sclerosis.

OBJECTIVE: To provide a meta-analysis of articles that have included the timed 25-foot walk (T25FW) in persons with multiple sclerosis (MS), quantify differences in T25FW scores between those with MS and controls without MS, and quantify differences between categories of disability status and clinical disease courses within MS. DATA SOURCES: The literature search was conducted using 4 databases (Google Scholar, PubMed, Cumulative Index to Nursing and Allied Health, EBSCO Host). We searched reference lists of published articles to identify additional articles. STUDY SELECTION: A systematic literature search identified articles reporting average T25FW performance in seconds between those with MS and controls without MS, between those with MS who had mild and moderate and/or severe disability status, and between relapsing-remitting and progressive clinical courses of MS. DATA EXTRACTION: Information was extracted and categorized based on reported data: comparisons of controls without MS and MS, comparisons of mild and moderate and/or severe MS based on study-defined Expanded Disability Status Scale groups, and comparisons of relapsing-remitting and progressive MS clinical courses. DATA SYNTHESIS: We performed a random effects meta-analysis to quantify differences between groups as estimated by effect sizes (ESs). We expressed the differences in Cohen d as well as the original units of the T25FW (ie, seconds). CONCLUSIONS: There was a large difference in T25FW performance in MS compared with controls without MS (ES=-0.93, mean difference=2.4s, P<.01). Persons with moderate and/or severe disability walked substantially slower compared with mild disability (ES=-1.02, mean difference=5.4s, P<.01), and persons with progressive courses of MS walked substantially slower than relapsing-remitting MS (ES=-1.4, mean difference=13.4s, P<.01).

Progressive resistance exercise training and changes in resting-state functional connectivity of the caudate in persons with multiple sclerosis and severe fatigue: A proof-of-concept study.

Fatigue is one of the most disabling symptoms of multiple sclerosis (MS). While progressive resistance training (PRT) has been shown to reduce fatigue in persons with MS, it is not clear why these reductions occur. One hypothesis is that PRT may induce functional changes to the caudate, a region highly implicated in MS fatigue. The aim of the current study was to study the effects of PRT on overall fatigue impact and resting-state functional connectivity of the caudate in persons with MS reporting severe fatigue. Participants were semi-randomly assigned to either a 16-week home-based PRT (n = 5) or stretching control (n = 5) condition. Both groups demonstrated reductions in overall fatigue impact (main effect of time: F = .84, d = .65). Significant group × time interactions were found, with the PRT group demonstrating post-training increases in functional connectivity between the caudate and left inferior parietal (F = 66.0, p < .001), bilateral frontal (both p < .001), and right insula (F = 21.8, p = .002) regions compared to the stretching group. Furthermore, greater post-training increases in functional connectivity between the caudate and left inferior parietal region were associated with greater decreases in cognitive fatigue (r = -.52) specifically. This study provides initial evidence for the caudate as a potential neural substrate for the beneficial effects of PRT on fatigue in persons with MS.