Hemodynamics of the Frontopolar and Dorsolateral Pre-Frontal Cortex in People with Multiple Sclerosis During Walking, Cognitive Subtraction, and Cognitive-Motor Dual-Task.

INTRODUCTION: Higher cortical activity has been observed in people with multiple sclerosis (pwMS) during walking and dual-tasking. However, further studies in overground walking and considering pre-frontal cortex (PFC) sub-areas are necessary. OBJECTIVES: To investigate PFC activity during a cognitive-motor dual-task (DT) and its single component tasks, in combination with behavioral outcomes in pwMS. METHODS: Fifteen pwMS (EDSS 3.5 [2-5.5], 42 ± 11 years) and 16 healthy controls (HC, 45.2 ± 13.2 years) performed 3 conditions: single motor-walking (SWT), single cognitive - subtracting sevens (SCT), and a DT. Meters walked and the number of correct answers were obtained from which, respectively, the motor (mDTC) and cognitive (cDTC) DT costs were calculated. A functional Near-Infrared Spectroscopy covering the frontopolar and dorsolateral PFC (DLPFC) areas was used to concentration of relative oxyhemoglobin (ΔHbO2) and deoxyhemoglobin (ΔHHb) in the PFC. A repeated 2-way ANOVA (group × conditions) was used to compare ΔHbO2/ΔHHb and behavioral outcomes. RESULTS: PwMS walked shorter distances (P < .002) and answered fewer correct numbers (P < .03) than HC in all conditions, while cDTC and mDTC were similar between groups. PwMS presented higher ΔHbO2 in the frontopolar area than HC in the SWT (P < .001). HC increased ΔHbO2 in frontopolar during the SCT (P < .029) and DT (P < .037) compared with the SWT. CONCLUSION: Higher frontopolar activity in pwMS compared to HC in the SWT suggests reduced gait automaticity. Furthermore, it seems that only HC increased neural activity in the frontopolar in the SCT and DT, which might suggest a limit of cognitive resources to respond to DT in pwMS.

Interlimb coordination and spatiotemporal variability during walking and running in children with developmental coordination disorder and typically developing children.

BACKGROUND: A different interlimb coordination and higher variability in movement patterns is evident in children with Developmental Coordination Disorder (DCD). The impact of DCD on interlimb coordination during walking and running is unknown. AIM: To assess interlimb coordination and spatiotemporal variability during overground walking and running in children with and without DCD. METHODS: Children with DCD and typically developing children (TDC), from 8 to 12 years participated. Children were equipped with portable sensors. Participants walked and ran for 3 min in an oval-path at their comfortable pace. Interlimb coordination, expressed by the phase coordination index (PCI), and spatiotemporal variability (coefficient of variance (CoV)) were collected. RESULTS: Twenty-one children with DCD and 23 TDC participated. During walking, PCI showed similar values in both groups, but a higher spatiotemporal variability was observed in children with DCD. During running, PCI was higher (reduced coordination) in children with DCD than TDC and a higher spatiotemporal variability was shown. CONCLUSIONS AND IMPLICATIONS: Only during running, interlimb coordination of children with DCD was lower than TDC. During both walking and running tasks, spatiotemporal variability was higher in DCD. Current results implicate that difficulties in children with DCD is more prominent when motor coordination is more challenged. WHAT THIS PAPER ADDS: This paper adds to the literature on coordination and gait pattern in children with Developmental Coordination Disorder (DCD) through a cross-sectional analysis of interlimb coordination and variability of spatiotemporal measures of overground walking and running. Overground walking and running were performed in a large oval-path allowing the assessment of coordination and gait patterns in an ecological valid set-up. Our results indicate that during a more demanding task, namely running, children with DCD display a less coordinated running pattern, expressed by a significantly higher phase coordination index, than typically developing peers. During walking, the interlimb coordination was similar between both groups. The current result is in accordance with the hybrid model of DCD that states that motor coordination difficulties in DCD are dpendent on the interaction of the task, individual and environment. This highlights the importance of implementing running assessments in children with DCD and the need for task-oriented running training in clinical practice The study also supports previous findings that children with DCD show a higher variability in their gait pattern of both walking and running, expressed by higher coefficient of variance of spatiotemporal measures, than typically developing peers. Further understanding in the normal development of interlimb coordination during walking and running from childhood into adulthood will enhance interpretations of the phase coordination index in children with and without DCD.

High-intensity interval training is feasible, credible and clinically effective in the early subacute stroke stage in the low-income country of Benin.

High-intensity interval training (HIIT) has been shown to benefit stroke patients when implemented three months post-stroke. This study examined HIIT's feasibility and clinical effectiveness in the early post-stroke stage in Benin. This was a prospective interventional study comprising an HIIT programme executed on a recumbent bike, three times/week, 20-30 min/session for 6 weeks, added to a conventional physiotherapy. The primary outcomes were feasibility, credibility and expectancy assessed with credibility and expectancy questionnaire. A maximal exercise test, 6-min walking test (6MWT), 10-m walking test (10mWT), Berg balance scale (BBS) and five repetitions sit-to-stand test (5 R-STS) were performed before and after the training programme. Ten outpatients, with a median age [P25-P75]: 63.5[56.7-71.2] years; time since stroke: 15.0[9.7-21.0] days, started and completed all training sessions without serious adverse events. High scores were observed on the Credibility subscale at admission (27.0[25.7-27.0]), which remained so after intervention (26.5[25.7-27.0]). Expectancy subscale scores were high at admission (25.5[24.0-27.0]) and post-training (25.5[24.5-27.0]). Peak workload (p < 0.001), BBS (p < 0.001), 6MWT (p < 0.001), 10mWT (p < 0.001) and 5 R-STS (p = 0.004) were all improved. HIIT is feasible and safe in the early subacute post-stroke stage and is perceived by patients as highly credible, meeting their expectations of recovery.

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.

Effects of power training in older patients with multiple sclerosis on neurodegeneration, neuromuscular function, and physical function. A study protocol for the "power training in older multiple sclerosis patients (PoTOMS) randomized control trial.

Introduction: Approximately one-third of all persons with multiple sclerosis (pwMS) are older, i.e., having an age ≥60 years. Whilst ageing and MS separately elicit deteriorating effects on brain morphology, neuromuscular function, and physical function, the combination of ageing and MS may pose a particular challenge. To counteract such detrimental changes, power training (i.e., a type of resistance exercise focusing on moderate-to-high loading at maximal intended movement velocity) presents itself as a viable and highly effective solution. Power training is known to positively impact physical function, neuromuscular function, as well as brain morphology. Existing evidence is promising but limited to young and middle-aged pwMS, with the effects of power training remaining to be elucidated in older pwMS. Methods: The presented 'Power Training in Older MS patients (PoTOMS)' trial is a national, multi-center, parallel-group, randomized controlled trial. The trial compares 24 weeks of usual care(n = 30) to 24 weeks of usual care and power training (n = 30). The primary outcome is whole brain atrophy rate. The secondary outcomes include changes in brain micro and macro structures, neuromuscular function, physical function, cognitive function, bone health, and patient-reported outcomes. Ethics and dissemination: The presented study is approved by The Regional Ethics Committee (reference number 1-10-72-222-20) and registered at the Danish Data Protection Agency (reference number 2016-051-000001). All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences independent of the results. The www.clinicaltrials.gov identifier is NCT04762342.

Prevalence and Associated Clinical Characteristics of Walking-Related Motor, Cognitive, and Fatigability in Progressive Multiple Sclerosis: Baseline Results From the CogEx Study.

BACKGROUND: People with progressive multiple sclerosis (PMS) present motor (eg, walking) and cognitive impairments, and report fatigue. Fatigue encompasses fatigability which is objectively measured by the capacity to sustain a motor or cognitive task. OBJECTIVE: To investigate the prevalence of walking and cognitive fatigability (CF) and the associated clinical characteristics in a large sample of PMS patients. METHODS: PMS patients (25-65 years old) were included from 11 sites (Europe and North America), having cognitive impairment (1.28 standard deviation below normative data for the symbol digit modality test [SDMT]). Walking fatigability (WF) was assessed using the distance walk index (DWI) and CF using the SDMT (scores from the last 30 seconds compared to the first 30 seconds). Additional measures were: cognitive assessment-Brief International Cognitive Assessment for multiple sclerosis (MS), cardiorespiratory fitness, 6-minute walk, physical activity, depressive symptoms, perceived fatigue-Modified Fatigue Impact Scale (MFIS), MS impact-MSIS-29, and walking ability. RESULTS: Of 298 participants, 153 (51%) presented WF (DWI = -28.9 ± 22.1%) and 196 (66%) presented CF (-29.7 ± 15%). Clinical characteristics (EDSS, disease duration, and use of assistive device) were worse in patients with versus without WF. They also presented worse scores on MSIS-29 physical, MFIS total and physical and reduced physical capacity. CF patients scored better in the MSIS-29 physical and MFIS psychosocial, compared to non-CF group. Magnitude of CF and WF were not related. CONCLUSIONS: Half of the cognitively-impaired PMS population presented WF which was associated with higher disability, physical functions, and fatigue. There was a high prevalence of CF but without strong associations with clinical, cognitive, and physical functions. TRIAL REGISTRATION NUMBER: The "CogEx-study," www.clinicaltrial.gov identifier number: NCT03679468.

Relevance and use of health policy, health systems and health services research for strengthening rehabilitation in real-life settings: methodological considerations.

Research on health policy, systems, and services (HPSSR) has seen significant growth in recent decades and received increasing attention in the field of rehabilitation. This growth is driven by the imperative to effectively address real-life challenges in complex healthcare settings. A recent resolution on 'Strengthening rehabilitation in health systems' adopted by the World Health Assembly emphasizes the need to support societal health goals related to rehabilitation, particularly to promote high-quality rehabilitation research, including HPSSR. This conceptual paper, discussed with the participants in the 5th Cochrane Rehabilitation Methodological Meeting held in Milan on September 2023, outlines study designs at diverse levels at which HPSSR studies can be conducted: the macro, meso, and micro levels. It categorizes research questions into four types: those framed from the perspective of policies, healthcare delivery organizations or systems, defined patient or provider populations, and important data sources or research methods. Illustrative examples of appropriate methodologies are provided for each type of research question, demonstrating the potential of HPSSR in shaping policies, improving healthcare delivery, and addressing patient and provider perspectives. The paper concludes by discussing the applicability, usefulness, and implementation of HPSSR findings, and the importance of knowledge translation strategies, drawing insights from implementation science. The goal is to facilitate the integration of research findings into everyday clinical practice to bridge the gap between research and practice in rehabilitation.

Between-Day Reliability of the Gait Characteristics and Their Changes During the 6-Minute Walking Test in People With Multiple Sclerosis.

BACKGROUND: Gait characteristics and their changes during the 6-minute walking test (6MWT) in people with multiple sclerosis (pwMS) have been described in the literature, which one may refer to as walking fatigability in the body function level of the International Classification of Functioning, Disability, and Health. However, whether these metrics are reliable is unknown. OBJECTIVE: To investigate the between-day reliability of the gait characteristics and their changes in pwMS and healthy controls (HCs). METHODS: Forty-nine pwMS (EDSS 4.82 ± 1.22 and 54.7 ± 9.36 years) and 23 HCs (50.6 ± 6.1 years) performed the 6MWT, as fast as possible but safely while wearing Inertial Measurement Units. Gait characteristics were measured in the pace, rhythm, variability, asymmetry, kinematics, coordination, and postural control domains and were obtained in intervals of 1 minute during the 6MWT. In addition, gait characteristics change in the last minute compared with the first minute were calculated for all gait variables using a fatigability index (ie, distance walking index). The intraclass correlation coefficient (ICC), Bland-Altman Plots, and Standard error of measurement were applied to investigate reliability. RESULTS: Reliability of gait characteristics, minute-by-minute, and for their changes (ie, using the fatigability index) ranged from poor to excellent (pwMS: ICC 0.46-0.96; HC: ICC 0.09-0.97 and pwMS: ICC 0-0.72; HC: ICC 0-0.77, respectively). CONCLUSION: Besides coordination, at least 1 variable of each gait domain showed an ICC of moderate or good reliability for gait characteristics changes in both pwMS and HC. These metrics can be incorporated into future clinical trials and research on walking fatigability.Clinical Trial Registration: NCT05412043.

Is High-Intensity Interval Training More Effective Than Moderate Continuous Training in Rehabilitation of Multiple Sclerosis: A Comprehensive Systematic Review and Meta-analysis.

OBJECTIVES: The present study aimed to conduct meta-analysis to determine whether the high intensity interval training (HIIT) protocol is more beneficial in improving outcome measures compared to moderate continuous training (MCT) in people with multiple sclerosis (PwMS). It also aimed to systematically review the exercise protocols differences. DATA SOURCES: A search strategy, locating HIIT in PwMS, was executed in six databases, PubMed, EMBASE, Web of Science, Central Cochrane, Pedro, and Ovid MEDLine. STUDY SELECTION: Randomized control trials of HIIT utilizing cycle ergometer or recumbent stepper as exercise modalities were included in analysis. Intervention arms should include at least two intervention arms, including HIIT in one arm, and MCT in the other group. DATA EXTRACTION: Data extracted from each study includes the following items: basic details of the study (such as author, date of publication, location, and study design), participant characteristics (sample size, mean age, sex, mean disease duration, and extended disability status scale), specifications of the HITT protocol (exercise modality, session duration, number of intervals/session, interval intensity, recovery intensity, recovery interval, and adverse effect), as well as primary outcomes at baseline and post-intervention (cardiorespiratory fitness, fatigue, body composition, cognitive functions, and blood biomarkers). DATA SYNTHESIS: 22 studies included in the systematic review, 11 were included in random effects model pooled analysis. There was a significant effect in favor of HIIT for VO2max of cardiorespiratory functions compared to MCT (ES=0.45 95%, CI [0.14, 0.76], P=.004), and for memory domain of cognitive functions (ES=0.34 95% CI [0.05, 0.63], P=.02). Statistical significance was not achieved for the other variables. CONCLUSION: HIIT and MCT yield similar results in terms of fatigue, body composition, cognitive functions, and blood biomarkers. However, VO2max of cardiorespiratory functions and memory domain of cognitive functions were in favor of HIIT protocol.

Control intervention design for preclinical and clinical trials: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

Control comparator selection is a critical trial design issue. Preclinical and clinical investigators who are doing trials of stroke recovery and rehabilitation interventions must carefully consider the appropriateness and relevance of their chosen control comparator as the benefit of an experimental intervention is established relative to a comparator. Establishing a strong rationale for a selected comparator improves the integrity of the trial and validity of its findings. This Stroke Recovery and Rehabilitation Roundtable (SRRR) taskforce used a graph theory voting system to rank the importance and ease of addressing challenges during control comparator design. "Identifying appropriate type of control" was ranked easy to address and very important, "variability in usual care" was ranked hard to address and of low importance, and "understanding the content of the control and how it differs from the experimental intervention" was ranked very important but not easy to address. The CONtrol DeSIGN (CONSIGN) decision support tool was developed to address the identified challenges and enhance comparator selection, description, and reporting. CONSIGN is a web-based tool inclusive of seven steps that guide the user through control comparator design. The tool was refined through multiple rounds of pilot testing that included more than 130 people working in neurorehabilitation research. Four hypothetical exemplar trials, which span preclinical, mood, aphasia, and motor recovery, demonstrate how the tool can be applied in practice. Six consensus recommendations are defined that span research domains, professional disciplines, and international borders.

Control intervention design for preclinical and clinical trials: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

Control comparator selection is a critical trial design issue. Preclinical and clinical investigators who are doing trials of stroke recovery and rehabilitation interventions must carefully consider the appropriateness and relevance of their chosen control comparator as the benefit of an experimental intervention is established relative to a comparator. Establishing a strong rationale for a selected comparator improves the integrity of the trial and validity of its findings. This Stroke Recovery and Rehabilitation Roundtable (SRRR) taskforce used a graph theory voting system to rank the importance and ease of addressing challenges during control comparator design. "Identifying appropriate type of control" was ranked easy to address and very important, "variability in usual care" was ranked hard to address and of low importance, and "understanding the content of the control and how it differs from the experimental intervention" was ranked very important but not easy to address. The CONtrol DeSIGN (CONSIGN) decision support tool was developed to address the identified challenges and enhance comparator selection, description, and reporting. CONSIGN is a web-based tool inclusive of seven steps that guide the user through control comparator design. The tool was refined through multiple rounds of pilot testing that included more than 130 people working in neurorehabilitation research. Four hypothetical exemplar trials, which span preclinical, mood, aphasia, and motor recovery, demonstrate how the tool can be applied in practice. Six consensus recommendations are defined that span research domains, professional disciplines, and international borders.

The influence of bias in randomized controlled trials on rehabilitation intervention effect estimates: what we have learned from meta-epidemiological studies.

This study aimed to synthesize evidence from studies that addressed the influence of bias domains in randomized controlled trials on rehabilitation intervention effect estimates and discuss how these findings can maximize the trustworthiness of an RCT in rehabilitation. We screened studies about the influence of bias on rehabilitation intervention effect estimates published until June 2023. The characteristics and results of the included studies were categorized based on methodological characteristics and summarized narratively. We included seven studies with data on 227,806 RCT participants. Our findings showed that rehabilitation intervention effect estimates are likely exaggerated in trials with inadequate/unclear sequence generation and allocation concealment when using continuous outcomes. The influence of blinding was inconsistent and different from the rest of medical science, as meta-epidemiological studies showed overestimation, underestimation, or neutral associations for different types of blinding on rehabilitation treatment effect estimates. Still, it showed a more consistent pattern when looking at patient-reported outcomes. The impact of attrition bias and intention to treat has been analyzed only in two studies with inconsistent results. The risk of reporting bias seems to be associated with overestimation of treatment effects. Bias domains can influence rehabilitation treatment effects in different directions. The evidence is mixed and inconclusive due to the poor methodological quality of RCTs and the limited number and quality of studies looking at the influence of bias and treatment effects in rehabilitation. Further studies about the influence of bias in RCTs on rehabilitation intervention effect estimates are needed.

Auditory attention measured by EEG in neurological populations: systematic review of literature and meta-analysis.

Sensorimotor synchronization strategies have been frequently used for gait rehabilitation in different neurological populations. Despite these positive effects on gait, attentional processes required to dynamically attend to the auditory stimuli needs elaboration. Here, we investigate auditory attention in neurological populations compared to healthy controls quantified by EEG recordings. Literature was systematically searched in databases PubMed and Web of Science. Inclusion criteria were investigation of auditory attention quantified by EEG recordings in neurological populations in cross-sectional studies. In total, 35 studies were included, including participants with Parkinson's disease (PD), stroke, Traumatic Brain Injury (TBI), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS). A meta-analysis was performed on P3 amplitude and latency separately to look at the differences between neurological populations and healthy controls in terms of P3 amplitude and latency. Overall, neurological populations showed impairments in auditory processing in terms of magnitude and delay compared to healthy controls. Consideration of individual auditory processes and thereafter selecting and/or designing the auditory structure during sensorimotor synchronization paradigms in neurological physical rehabilitation is recommended.

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.

Physiotherapy practices in acute and sub-acute stroke in a low resource country: A prospective observational study in Benin.

BACKGROUND AND OBJECTIVE: Physiotherapy is highly recommended for early recovery from stroke. This study aimed to document physiotherapy practices for people with acute and early sub-acute stroke in Benin. METHODS: In this prospective observational study, physiotherapists working with acute stroke people documented the content of their treatment from six hospitals in Benin during the first session, at 2-week, and 1-month post-stroke with a standardized physiotherapy documentation form. We used the motricity index (MI) and trunk control test (TCT) to assess impairments, and the 10-meter walk test (10mWT), functional independence measure (FIM), walking, stair climbing, and dressing upper body subscales were used for activity limitations. RESULTS: Fifteen physiotherapists (60 % male, mean±SD age=31.3±5.8 years) recorded treatment sessions for 77 stroke participants (53.2 % male, mean±SD age=57.7±12.5 years). Physiotherapists focused on conventional physiotherapy approaches, including musculoskeletal (67 % of pre-functional activity time) and neuromuscular (53 % of sitting activity time) interventions. A significant difference was found between the therapy time delivered for people with mild, moderate, and severe stroke (p < 0.001). The MI (p= 0.033) and TCT (p= 0.002) measures showed significant improvement at 2-week and 1-month (p< 0.001) post-stroke, while 10mWT, FIM walking, stair climbing, and dressing upper body items significantly increased at 1-month (p< 0.001) but not at 2-week post-stroke. CONCLUSION: Physiotherapists working with acute stroke patients in Benin mainly use conventional neuromuscular and musculoskeletal interventions. In contrast, aerobic exercises were rarely employed regardless of stroke severity. Furthermore, our findings showed that the volume of physiotherapy sessions varied by stroke severity.

Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis (CogEx): a randomised, blinded, sham-controlled trial.

BACKGROUND: Cognitive dysfunction in people with relapsing-remitting multiple sclerosis can improve with cognitive rehabilitation or exercise. Similar effects have not been clearly shown in people with progressive multiple sclerosis. We aimed to investigate the individual and synergistic effects of cognitive rehabilitation and exercise in patients with progressive multiple sclerosis. METHODS: CogEx was a randomised, sham-controlled trial completed in 11 hospital clinics, universities, and rehabilitation centres in Belgium, Canada, Denmark, Italy, UK, and USA. Patients with progressive multiple sclerosis were eligible for inclusion if they were aged 25-65 years and had an Expanded Disability Status Scale (EDSS) score of less than 7. All had impaired processing speed defined as a performance of 1·282 SD or greater below normative data on the Symbol Digit modalities Tests (SDMT). Participants were randomly assigned (1:1:1:1), using an interactive web-response system accessed online from each centre, to cognitive rehabilitation plus exercise, cognitive rehabilitation plus sham exercise, exercise plus sham cognitive rehabilitation, or sham exercise plus sham cognitive rehabilitation. The study statistician created the randomisation sequence that was stratified by centre. Participants, outcome assessors, and investigators were blinded to group allocation. The study statistician was masked to treatment during analysis only. Interventions were conducted two times per week for 12 weeks: cognitive rehabilitation used an individualised, computer-based, incremental approach to improve processing speed; sham cognitive rehabilitation consisted of internet training provided individually; the exercise intervention involved individualised aerobic training using a recumbent arm-leg stepper; and the sham exercise involved stretching and balance tasks without inducing cardiovascular strain. The primary outcome measure was processing speed measured by SDMT at 12 weeks; least squares mean differences were compared between groups using linear mixed model in all participants who had a 12-week assessment. The trial is registered with ClinicalTrials.gov, NCT03679468, and is completed. FINDINGS: Between Dec 14, 2018, and April 2, 2022, 311 people with progressive multiple sclerosis were enrolled and 284 (91%) completed the 12-week assessment (117/311 [38%] male and 194/311 [62%] female). The least squares mean group differences in SDMT at 12 weeks did not differ between groups (p=0·85). Compared with the sham cognitive rehabilitation and sham exercise group (n=67), differences were -1·30 (95% CI -3·75 to 1·16) for the cognitive rehabilitation plus exercise group (n=70); -2·78 (-5·23 to -0·33) for the sham cognitive rehabilitation plus exercise group (n=71); and -0·71 (-3·11 to 1·70) for the cognitive rehabilitation plus sham exercise group (n=76). 11 adverse events possibly related to the interventions occurred, six in the exercise plus sham cognitive rehabilitation group (pain, dizziness, and falls), two in the cognitive rehabilitation plus sham exercise group (headache and pain), two in the cognitive rehabilitation and exercise group (increased fatigue and pain), and one in the dual sham group (fall). INTERPRETATION: Combined cognitive rehabilitation plus exercise does not seem to improve processing speed in people with progressive multiple sclerosis. However, our sham interventions were not inactive. Studies comparing interventions with a non-intervention group are needed to investigate whether clinically meaningful improvements in processing speed might be attainable in people with progressive multiple sclerosis. FUNDING: MS Canada.

Assessment and tailored physical rehabilitation approaches in persons with cerebellar impairments targeting mobility and walking according to the International Classification of Functioning: a systematic review of case-reports and case-series.

PURPOSE: Cerebellar impairment (CI) manifests from different etiologies resulting in a heterogenic clinical presentation affecting walking and mobility. Case-reports were reviewed to provide an analytical clinical picture of persons with CI (PwCI) to differentiate cerebellar and non-cerebellar impairments and to identify interventions and assessments used to quantify impact on walking and mobility according to the International Classification of Functioning, Disability and Health (ICF). MATERIALS AND METHODS: Literature was searched in PubMed, Web Of Science and Scopus. Case-reports conducting physical rehabilitation and reporting at least one outcome measure of ataxia, gait pattern, walking or mobility were included. RESULTS: 28 articles with a total of 38 different patients were included. Etiologies were clustered to: spinocerebellar degenerations, traumatic brain injuries, cerebellar tumors, stroke and miscellaneous. The interventions applied were activity-based, including gait and balance training. Participation based activities such as tai chi, climbing and dance-based therapy had positive outcomes on mobility. Outcomes on body function such as ataxia and gait pattern were only reported in 22% of the patients. CONCLUSIONS: A comprehensive test battery to encompass the key features of a PwCI on different levels of the ICF is needed to manage heterogeneity. Measures on body function level should be included in interventions.

This review reports on 38 cerebellar cases from 14 different aetiologies.Distinguishing cerebellar and non-cerebellar symptoms and categorising patients within the three cerebellar syndromes can assist with heterogeneity.Reporting of assessment on the body function level of ICF in terms of ataxia and gait pattern was only present in a minority of reports and thus increased reporting is encouraged.Multimodal and patient-tailored strategies are promising for targeting walking and mobility in persons with cerebellar impairment.

Intermediate outcomes for clinical trials of multiple sclerosis rehabilitation interventions: Conceptual and practical considerations.

BACKGROUND: Rehabilitation is an essential health care service and a critical component of comprehensive multiple sclerosis (MS) care. OBJECTIVE: As part of a 2-day meeting hosted by the International Advisory Committee on Clinical Trials in MS in December 2022, a panel initiated a discussion on the conceptual and practical issues related to selecting intermediate outcomes for clinical trials of MS rehabilitation interventions. RESULTS: The overarching goal of rehabilitation - optimal functioning - was acknowledged as a complex biopsychosocial phenomenon that varies with patient priorities and environmental context. This complexity means that multiple causal pathways and potential intermediate outcomes must be carefully considered during the design of clinical trials in MS rehabilitation that aim to improve functioning. In addition, practical issues must be considered such as psychometric properties of outcome measures, measure type, and characteristics of the target population, including severity of dysfunction. CONCLUSION: This article uses the International Classification of Functioning, Disability and Health as a foundation for determining relevant intermediate outcomes for clinical trials of MS rehabilitation interventions.

Improving the efficiency of clinical trials in multiple sclerosis.

BACKGROUND: Phase 3 clinical trials for disease-modifying therapies in relapsing-remitting multiple sclerosis (RRMS) have utilized a limited number of conventional designs with a high degree of success. However, these designs limit the types of questions that can be addressed, and the time and cost required. Moreover, trials involving people with progressive multiple sclerosis (MS) have been less successful. OBJECTIVE: The objective of this paper is to discuss complex innovative trial designs, intermediate and composite outcomes and to improve the efficiency of trial design in MS and broaden questions that can be addressed, particularly as applied to progressive MS. METHODS: We held an international workshop with experts in clinical trial design. RESULTS: Recommendations include increasing the use of complex innovative designs, developing biomarkers to enrich progressive MS trial populations, prioritize intermediate outcomes for further development that target therapeutic mechanisms of action other than peripherally mediated inflammation, investigate acceptability to people with MS of data linkage for studying long-term outcomes of clinical trials, use Bayesian designs to potentially reduce sample sizes required for pediatric trials, and provide sustained funding for platform trials and registries that can support pragmatic trials. CONCLUSION: Novel trial designs and further development of intermediate outcomes may improve clinical trial efficiency in MS and address novel therapeutic questions.