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Background: Multiple sclerosis (MS) is a leading cause of neurological disability among young and middle-aged adults worldwide, and disability is measured using a variety of approaches, including patient reported outcome measures (PROMs) such as the Patient Determined Disease Steps (PDDS) scale. There is limited evidence for the validity of inferences from the middle-range of scores on the PDDS (i.e., 3 "gait disability" - 6 "bilateral support"), but that range of scores seemingly represents moderate disability characterized by varying levels of walking dysfunction., Purpose: The current study examined whether the middle-range of scores from the PDDS reflect varying levels of walking dysfunction among people with MS., Method: Participants (N = 374) completed the Patient Determined Disease Steps (PDDS) scale, Multiple Sclerosis Walking Scale-12 (MSWS-12), timed 25-foot walk (T25FW), six-minute walk (6 MW), Modified Fatigue Impact Scale (MFIS), and Multiple Sclerosis Impact Scale-29 (MSIS-29), and underwent a neurological exam for generating an Expanded Disability Status Scale (EDSS) score as part of screening and baseline data collection for a clinical trial of exercise training in MS. We undertook a series of linear trend analyses that examined differences in the outcomes of EDSS, T25FW, 6 MW, MSWS-12, MFIS subscales, and MSIS-29 subscales across the 4 levels of PDDS scores (i.e., 3-6)., Results: There were statistically significant and strong linear trends for EDSS (F 1,370 = 306.1, p < .0001, η 2  = 0.48), T25FW (F 1,370 = 161.0, p < .0001, η 2  = 0.32), 6 MW (F 1,370 = 178.9, p < .0001, η 2  = 0.34), and MSWS-12 (F 1,370 = 97.0, p < .0001, η 2  = 0.24). There was a strong correlation between PDDS and EDSS scores (r s = 0.695, 95% CI = 0.643, 0.748). Both PDDS and EDSS scores had strong correlations with walking outcomes, yet weaker correlations with measures of fatigue and QOL., Conclusion: The PDDS could serve as a simple, inexpensive, and rapidly administered PROM for remote screening and early detection of walking dysfunction for initial eligibility into clinical trials and practice for managing mobility-specific disability in MS., Registration: The study was registered on ClinicalTrials.gov on March 19, 2018 (NCT03468868)., (© 2024. The Author(s).)

Depression and anxiety are the most frequent neuropsychiatric symptoms of multiple sclerosis (MS), an autoimmune-mediated demyelinating neurodegenerative disease. Their prevalence is 25-65% and 20-54%, respectively, often associated with chronic fatigue and cognitive impairment, but usually not correlated with motor and other deficits, suggesting different pathophysiological mechanisms. Both disorders often arise before MS diagnosis, lead to faster disability and impair the quality of life. Risk factors are (young) age, genetic and family history burden. While no specific neuropathological data for depression (and anxiety) in MS are available, modern neuroimaging studies showed bilateral fronto-temporal, subcortical and limbic atrophies, microstructural white matter lesions and disruption of frontoparietal, limbic and neuroendocrine networks. The pathogenesis of both depression and anxiety in MS is related to shared mechanisms including oxidative stress, mitochondrial dysfunction, neuroinflammation and neuroendocrine mechanisms inducing complex functional and structural brain lesions, but they are also influenced by social and other factors. Unfortunately, MS patients with anxiety, major depression or suicidal thoughts are often underassessed and undertreated. Current treatment, in addition to antidepressant therapy include transcranial magnetic stimulation, cognitive, relaxation, dietary and other healthcare measures that must be individualized. The present state-of- the-art review is based on systematic analysis of PubMed, Google Scholar and Cochrane Library until May 2024, with focus on the prevalence, clinical manifestation, neuroimaging data, immune mechanisms and treatment options. Depression and anxiety in MS, like in many other neuroimmune disorders, are related, among others, to multi-regional patterns of cerebral disturbances and complex pathogenic mechanisms that deserve further elucidation as a basis for early diagnosis and adequate management to improve the quality of life in this disabling disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Physical inactivity and comorbidities (e.g., hypertension) result in poor prognoses among persons with chronic, disabling conditions including multiple sclerosis, Parkinson disease, and stroke. Theory can guide the design of behavior change interventions that can be delivered remotely for broad scale implementation. We hypothesize that theory-based behavior change interventions can increase physical activity and reduce comorbidities and associated consequences among persons with chronic, disabling conditions., (Copyright © 2022 by the American College of Sports Medicine.)

Exercise is becoming more integrated into the management of multiple sclerosis (MS) and is promoted to manage impairments and symptoms. Whereas extensive research outlines factors impacting participation, less is known regarding how medicalized exercise promotion might impact views of exercise and self. We conducted a secondary data analysis to understand how medicalized exercise-promotion paradigms impact the meaning and roles of exercise among those with MS. Twenty-two interviews were selected for reanalysis with an interpretative phenomenological analysis methodology and a critical disability studies lens. Three themes were identified: Constant Vigilance (worry about exercise), Productivity and Social Engagement (exercise to feel productive, engage socially, and enhance self-worth), and Exercise as Medicine/Self-Care (exercise to manage MS, relax, improve mental well-being, prevent/reverse disability, and stay healthy). This research underscores that exercise occupies many contradictory roles reflecting a medicalized exercise-promotion paradigm for those with MS, and this should inform exercise promotion practices.

Pandemic restrictions have led to changes in therapy plans and disrupted rehabilitation services for people with multiple sclerosis. CogEx is an international, multicentre MS dual-intervention (cognitive rehabilitation, aerobic exercise) randomized, controlled rehabilitation trial confined to people with progressive disease. The primary outcome is cognition (processing speed).There are 11 treatment sites in six countries with participants required to make 27 site visits over 12 weeks. Collectively, the large, in-person demands of the trial, and the varying international policies for the containment of COVID-19, might disproportionately impact the administration of CogEx. During the first lockdown, all centres closed on average for 82.9 (SD = 24.3) days. One site was required to lockdown on two further occasions. One site remained closed for 16 months. Ten staff (19.2%) were required to quarantine and eight staff (15.4%) tested positive for COVID. 10 of 264 (3.8%) participants acquired COVID-19. All survived. The mean duration of enrollment delay has been [236.7 (SD = 214.5) days]. Restarting participants whose interventions were interrupted by the pandemic meant recalculating the intervention prescriptions for these individuals. While the impact of the pandemic on CogEx has been considerable, all study sites are again open. Participants and staff have shown considerable flexibility and resilience in keeping a complex, international endeavour running. The future in general remains uncertain in the midst of a pandemic, but there is cautious optimism the study will be completed with sufficient sample size to robustly evaluate our hypothesis and provide meaningful results to the MS community on the impact of these interventions on people with progressive MS.Trial registration: The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468. Registration was performed before recruitment was initiated., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Ambulatory disability and cognitive impairment are common and co-occuring manifestations of multiple sclerosis (MS). Neurofunctional training is a specific intervention performed in realistic environments that may have beneficial effects on ambulatory disability in persons with MS who have cognitive impairment. This pilot sudy investigated the feasibility and efficacy of an eight-week home-based neurofunctional training (HBNFT) program vs. home-based resistance training (HBRT) on ambulatory performance in MS patients with cognitive impairment., Methods: Thirty males/females with MS (age 18-50 years, Expanded Disability Status Scale (EDSS) score ≤ 6, and processing speed score ≤ 41.5 as a marker of cognitive impairment) were randomly assigned into HBNFT and HBRT groups. After one week (three sessions) of center-based, supervised training for learning the programs and maximizing safety, the participants completed eight weeks (three sessions per week) of the home-based training programs. The programs were supported through videos, brochures and Digital Video Discs (DVDs) provided during clinic visits (weeks 1 and 5). Ambulatory performance (tandem stance test; tandem walk test; timed up-and-go (TUG); six-minute walk test (6MWT), 10- meter walking test (10MWT); timed 25 foot walk test (T25FWT); five times sit to stand test (5TSTS); six spot step test (SSST); and hand grip) was measured before and after the exercise programs. Feasibility and acceptability of exercise programs was assessed after the eight-week period., Results: HBNFT significantly improved tandem walk test (P = 0.018), SSST (P = 0.026), and 6MWT (P = 0.037) compared with HBRT. No significant changes or differences were observed in other outcomes (P ≥ 0.05). HBNFT was well tolerated and resulted in no adverse events, whereas there were reports of pain, muscle cramps, and extreme fatigue among HBRT participant., Conclusion: The current pilot study provided initial support for HBNFT as a safe and feasible approach for improving some aspects of ambulation in persons with MS who have cognitive impairment. Such a pilot study provides initial proof-of-concept data for the design and implementation of an appropriately-powered randomized controlled trial (RCT) of neuro-functional training vs. traditional resistance exercise in a larger sample of persons with MS who present with co-occurring impairments in mobility and cognition., (Copyright © 2021. Published by Elsevier B.V.)

Background: The timed 25-foot walk (T25FW) is a key clinical outcome measure in multiple sclerosis patient management and clinical research., Objectives: To evaluate T25FW performance and factors associated with its change in the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) Placebo Database ( n  = 2465)., Methods: We created confirmed disability progression (CDP) variables for T25FW and Expanded Disability Status Scale (EDSS) outcomes. We used intraclass correlation coefficients (ICCs) and Bland Altman plots to evaluate reliability. We evaluated T25FW changes and predictive validity using a mixed-effects model, survival analysis, and nested case-control analysis., Results: The mean baseline score for the T25FW in this study population was 9.2 seconds, median = 6.1 (standard deviation = 11.0, interquartile range (IQR) = 4.8, 9.0). The T25FW measure demonstrated excellent test-retest reliability (ICC = 0.98). Walk times increased with age, disability, disease type, and disease duration; relapses were not associated with an increase. Patients with T25FW progression had a faster time to EDSS-CDP compared to those without (hazards ratio (HR): 2.6; confidence interval (CI): 2.2, 3.1). Changes in the T25FW were more likely to precede changes in EDSS., Conclusion: This research confirms the association of the T25FW with disability and provides some evidence of predictive validity. Our findings support the continued use of the T25FW in clinical practice and clinical trials.

The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old therapeutic approaches that provide only symptomatic relief. To address this unmet need, an in-person symposium was held in Toronto, Canada, in November 2022 for international researchers and experts in MS and PD to discuss strategies for advancing DMT development. In this Roadmap article, we highlight discussions from the symposium, which focused on therapeutic targets and preclinical models, disease spectra and subclassifications, and clinical trial design and outcome measures. From these discussions, we propose areas for novel or deeper exploration in PD using lessons learned from therapeutic development in MS. In addition, we identify challenges common to the PD and MS fields that need to be addressed to further advance the discovery and development of effective DMTs., Competing Interests: Competing interests: L.V.K. has received research support from Canadian Institutes of Health Research (CIHR), Cure Parkinson’s, Krembil Foundation, Michael J. Fox Foundation for Parkinson’s Research (MJFF), Natural Sciences and Engineering Research Council of Canada, and Parkinson Canada; consultancy fees from Cure Ventures, Ipsen, Knight Therapeutics, Right Brain Bio, and UCB; and honoraria from Canadian Movement Disorders Society, Critical Path for Parkinson’s, International Parkinson and Movement Disorder Society, and IOS Press. A.B.-O. has received personal fees for advisory board participation and/or consulting from Abata, Accure, Atara Biotherapeutics, Biogen, Bristol Myers Squibb (BMS)/Celgene/Receptos, GlaxoSmithKline, Gossamer, Horizon Therapeutics, Immunic, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, Sangamo, Sanofi-Genzyme, and Viracta; and institutional grant support from Biogen Idec, Roche/Genentech, Merck/EMD Serono, and Novartis. R.B. has received research support from Biogen, Eli Lilly, and Roche Genentech, and consulting fees from EMD Serono, Novartis, TG Therapeutics, and Horizon, Jansen. S.F. has received consultancy or speaker fees from Abbvie, Bial, Ipsen, and Lundbeck. U.J.K. holds stock options as a Scientific Advisory Board member for Amprion and has received consultancy fees as a Scientific Advisory Board member for NurrOn and as a member of the data monitoring committee for UCB. E.C.K. has received research funding from Abbvie, Biogen, and Genentech and consulting fees from Banner Life Sciences, EMO Serano, Galen/Atlantica, Greenwich Biosciences, INmune Bio, Myrobalan Therapeutics, OM 1, and TG Therapeutics. M.K. has received travel support and honoraria for advisory boards from Biogen, Roche, Novartis, and EMD Serono. S.K. has received institutional grant support from Biogen, Roche, and Sanofi-Genzyme. A.E.L. has acted as an adviser for AbbVie, Alector, Amylyx, Aprinoia, Biogen, BioAdvance, BlueRock, Biovie, BMS, Denali, Janssen, Jazz, Lilly, Novartis, Paladin, Pharma 2B, PsychoGenetics, Retrophin, Roche, Sun Pharma, and UCB; has received honoraria from Sun Pharma, AbbVie, and Sunovion; has received grants from Brain Canada, CIHR, Edmond J Safra Philanthropic Foundation, MJFF, Ontario Brain Institute, Parkinson Foundation, Parkinson Canada, and W. Garfield Weston Foundation; has acted as an expert witness in litigation related to paraquat and Parkinson disease; and has received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. M.J.M. has received travel support and honoraria for advisory boards from Ipsen, Merz, and Abbvie. D.O. has received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, Bristol Myers Squibb, and Novartis and consulting fees from Biogen Idec, Bristol Myers Squibb, Genentech/Roche, Novartis, Pipeline Therapeutics, and Merck. R.S. has received grants from MS Society of Canada and J.P. Bickell Foundation; consulting fees from Novartis; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Biogen Idec, Sanofi-Genzyme, EMD Serono, and Roche; has served on advisory boards for Novartis; and has received support to attend a scientific meeting from EMD Serono. J.O. has received personal compensation for consulting from Biogen Idec, BMS, Eli Lilly, EMD Serono, Novartis, Roche, and Sanofi-Genzyme, and institutional grant support from Biogen Idec and Roche. A.A., N.A., D.G.D.L., E.A.F., K.K.L., Z.G.-O., J.L.G., M.R.L., P.A.M., T.A.M., V.E.M., M.W.C.R., M.G.S. and A.J.S. declare no competing interests., (© 2024. Springer Nature Limited.)

Objective: Multiple Sclerosis (MS) is a neurological condition which widely affects people 50-60 years of age. While clinical presentations of MS are highly heterogeneous, mobility limitations are one of the most frequent symptoms. This study examines a machine learning (ML) framework for identifying MS through spatiotemporal and kinetic gait features., Methods: In this study, gait data during self-paced walking on an instrumented treadmill from 20 persons with MS and 20 age, weight, height, and gender-matched healthy older adults (HOA) were obtained. We explored two strategies to normalize data and minimize dependence on subject demographics; size-normalization (standard body size-based normalization) and regress-normalization (regression-based normalization using scaling factors derived by regressing gait features on multiple subject demographics); and proposed an ML based methodology to classify individual strides of older persons with MS (PwMS) from healthy controls. We generalized both across different walking tasks and subjects., Results: We observed that regress-normalization improved the accuracy of identifying pathological gait using ML when compared to size-normalization. When generalizing from comfortable walking to walking while talking, gradient boosting machine achieved the optimal subject classification accuracy and AUC of 94.3 and 1.0, respectively and for subject generalization, a multilayer perceptron resulted in the best accuracy and AUC of 80% and 0.86, respectively, both with regression-normalized data., Conclusion: The integration of gait data and ML may provide a viable patient-centric approach to aid clinicians in monitoring MS., Significance: The results of this study have future implications for the way regression normalized gait features may be clinically used to design ML-based disease prediction strategies and monitor disease progression in PwMS.

Background: Major depression disorder (MDD) and severe depression symptoms are highly prevalent in multiple sclerosis (MS). Depression can worsen symptoms of MS and is associated with significantly reduced quality of life and increased risk of suicide. Currently, there is no gold-standard, single treatment available for depression in MS. Pharmacotherapy, cognitive behavior therapy (CBT), and exercise training individually are moderately, yet incompletely, efficacious for managing depression in the general population and MS., Purpose: This review provides an overview of evidence from meta-analyses and systematic reviews for current treatments of depression in persons with MS. This review further develops the rationale for using a combinatory treatment approach in persons with MS., Methods: We performed a narrative review of meta-analyses and systematic reviews regarding the current state of evidence for the three most common treatments of depression in persons with MS (i.e., antidepressant medication, cognitive-behavior therapy, and exercise training). We provide a concise assessment of the overall effect of these treatments on depression in the general population and then persons with MS. We further note short-comings of research on these treatments for depression., Conclusion: There is no single, gold-standard treatment for depression in MS, and we proposed that combinatory treatments should be considered for the management of depression in MS. However, there is a paucity of evidence for the use of combinatory therapy on depression and its outcomes in persons with MS, and this supports direct examination of the feasibility and efficacy of such combinatory approaches for MDD in MS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Individuals with pre-existing chronic illness have shown increased anxiety and depression due to COVID-19. Here, we examine the impact of the COVID-19 pandemic on emotional symptomatology and quality of life in individuals with Progressive Multiple Sclerosis (PMS)., Methods: Data were obtained during a randomized clinical trial on rehabilitation taking place at 11 centers in North America and Europe. Participants included 131 individuals with PMS. Study procedures were interrupted in accordance with governmental restrictions as COVID-19 spread. During study closure, a COVID Impact Survey was administered via telephone or email to all participants, along with measures of depressive symptoms, anxiety symptoms, quality of life, and MS symptomatology that were previously administered pre-pandemic., Results: 4% of respondents reported COVID-19 infection. No significant changes were noted in anxiety, quality of life, or the impact of MS symptomatology on daily life from baseline to lockdown. While total HADS-depression scores increased significantly at follow-up, this did not translate into more participants scoring above the HADS threshold for clinically significant depression. No significant relationships were noted between disease duration, processing speed ability or EDSS, and changes in symptoms of depression or anxiety. Most participants reported the impact of the virus on their psychological well-being, with a little impact on financial well-being. The perceived impact of the pandemic on physical and psychological well-being was correlated with the impact of MS symptomatology on daily life, as well as changes in depression., Conclusions: Overall, little change was noted in symptoms of depression or anxiety or overall quality of life.

Background: Within the pediatric MS population, physical activity (PA) has been associated with positive health outcomes such as lower lesion and relapse rates (Grover et. al., 2015). Recently, associations between variables from a social-cognitive theory (SCT) and levels of PA in youth with multiple sclerosis have been reported (Sikes & Motl, 2020), suggesting a SCT-based intervention may be efficacious in changing PA. We developed and delivered a 12-week SCT-based intervention and sought to gain an understanding of youth's perspectives on PA over time., Methods: We performed a qualitative analysis on 34 coaching call transcripts from 13 participants as part of a theory-based intervention promoting PA in youth with MS (NCT03137602). Coaching calls were semi-structured and each participant was scheduled to have three coaching calls spaced monthly for three months. We used an inductive content analysis approach to analyze the data (Elo and Kyngas, 2008)., Results: General themes from the calls aligned with the SCT constructs. Youth consistently discussed facilitators for changing PA over time, including a positive attitude, goal setting and social connectedness. There was increasing conversation around PA barriers over time including the environment and a lack of time., Conclusion: Youth perceptions on PA can be either positive or negative and can change over time. There is an underlying emergence and importance of social connectedness within PA behaviours. Increases in coaching call content related to goal setting suggest a positive effect of coaching and SCT in these areas. Future studies will focus on interactions between SCT constructs, particularly social connectedness and increased physical activity., (Published by Elsevier B.V.)

Background: Impaired cognition and ambulation are common in multiple sclerosis (MS). Dalfampridine is the first Food and Drug Administration (FDA)-approved medication to treat impaired ambulation in MS. Dalfampridine may benefit patients with cognitive impairment, given its effects on saltatory conduction and the association between cognitive and motor function., Objective: To examine the effects of dalfampridine on cognition in MS. To determine if the anticipated improved cognition is grounded in dalfampridine's effects on ambulation., Methods: Adults with MS were randomized to dalfampridine ( n  = 45) or placebo ( n  = 16) for 12 weeks. Cognition and motor function were assessed at baseline and end-point., Results: T25FW and 6-minute walk (6MW) performance improved at end-point in the treatment group but not in the placebo group ( p  < 0.05). Our primary outcome, performance on the Symbol Digit Modalities Test, did not improve. About 30% ( n  = 12) of the dalfampridine group demonstrated ⩾20% improved ambulation and were categorized "responders." Among "responders", Symbol Digit Modalities test performance did not improve. However, performance on the Paced Auditory Serial Addition Test improved among "responders" ( p  < 0.05)., Conclusion: Dalfampridine benefits timed ambulation but not cognition. Some improvement among ambulation "responders" is consistent with prior reports of cognition-motor coupling in MS ( ClinicalTrials.gov #: NCT02006160).

Context: Excessive weight is a health problem that can exacerbate multiple sclerosis (MS) symptoms and its associated comorbidities such as depression and fatigue. In addition, weight may be a moderator of exercise effects on depression and fatigue symptoms., Objective: This study aimed to investigate the effects of exercise training on fatigue and depression in normal and overweight individuals with MS., Methods: Sixty-six persons with MS were randomly assigned into an exercise or control condition based on body weight status (overweight vs. normal weight). The exercise conditions involved 8-weeks of interval exercise at 60%-75% Watt peak , while the control condition did not involve any exercise. Fatigue, depression, aerobic capacity, time up and go (TUG) and body mass index were measured before and following the 8-week period., Results: There were no significant relationship's revealed for weight status interactions for any of the variables examined. There were significant condition main effects for fatigue, depression, aerobic capacity and TUG, and significant improvements were noted for the exercise conditions, but not in the non-exercising control group., Conclusion: The results from this study confirm that exercise is an effective therapeutic intervention for improving fatigue, depression and functional parameters, independent of initial weight status, in persons with MS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is an autoimmune-mediated disease of the central nervous system characterized by inflammation, demyelination and chronic progressive neurodegeneration. Among its broad and unpredictable range of clinical symptoms, cognitive impairment (CI) is a common and disabling feature greatly affecting the patients' quality of life. Its prevalence is 20% up to 88% with a wide variety depending on the phenotype of MS, with highest frequency and severity in primary progressive MS. Involving different cognitive domains, CI is often associated with depression and other neuropsychiatric symptoms, but usually not correlated with motor and other deficits, suggesting different pathophysiological mechanisms. While no specific neuropathological data for CI in MS are available, modern research has provided evidence that it arises from the disease-specific brain alterations. Multimodal neuroimaging, besides structural changes of cortical and deep subcortical gray and white matter, exhibited dysfunction of fronto-parietal, thalamo-hippocampal, default mode and cognition-related networks, disruption of inter-network connections and involvement of the γ-aminobutyric acid (GABA) system. This provided a conceptual framework to explain how aberrant pathophysiological processes, including oxidative stress, mitochondrial dysfunction, autoimmune reactions and disruption of essential signaling pathways predict/cause specific disorders of cognition. CI in MS is related to multi-regional patterns of cerebral disturbances, although its complex pathogenic mechanisms await further elucidation. This article, based on systematic analysis of PubMed, Google Scholar and Cochrane Library, reviews current epidemiological, clinical, neuroimaging and pathogenetic evidence that could aid early identification of CI in MS and inform about new therapeutic targets and strategies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background and Purpose: Individuals with multiple sclerosis (MS) want health advice regarding participation in their choice of exercise. To address this need, a flexible exercise participation programme (FEPP) was developed, underpinned by the MS aerobic exercise guidelines and supported by a physiotherapist using behaviour change techniques. The aim of this study was to investigate the feasibility of the FEPP for individuals with minimal disability from MS., Methods: A feasibility study utilising a single group pre/post-intervention design was conducted. The 12-week FEPP was completed by 10 individuals with MS (EDSS 0-3.5). Exercise progression in duration, intensity or frequency of exercise (in line with MS exercise guidelines) was guided by a self-perceived weekly energy level score, and weekly telephone coaching sessions using behavioural change techniques. Trial feasibility was assessed via measures of process (recruitment and retention), resources/management (communication time; data entry) and scientific feasibility (safety; compliance). Secondary FEPP feasibility outcomes included the Goal Attainment Scale (GAS) T-score, exercise participation (weekly exercise diary), high-level mobility (HiMAT), vitality (Subjective Vitality Scale), biomarkers for inflammation (cytokines levels [IL2, IL4, IL6, IL10, TNF and IFNγ]), and acceptability (participant survey)., Results: Process: In total, 11 (85%) of 13 eligible participants enroled at baseline with 10 (91%) completing the study. Resources/management: Coaching sessions included a baseline interview-mean 39 min (SD: 6.6) and telephone coaching-mean 10 min (SD: 3.8) per week. Outcome measure data collection time-mean 44 min (SD: 2.1). Scientific feasibility: Two participants experienced a fall during their exercise participation. Self-reported compliance was high (99%). GAS T-scores increased significantly, indicating achievement of exercise participation goals. Secondary outcomes showed trends towards improvement., Discussion: The FEPP was feasible, safe and highly acceptable for use with individuals with MS and warrants a larger trial to explore effectiveness., (© 2022 The Authors. Physiotherapy Research International published by John Wiley & Sons Ltd.)

Background: Impairments in speech and social cognition have been reported in people with multiple sclerosis (pwMS), although their relationships with neuropsychological outcomes and their clinical utility in MS are unclear., Objectives: To evaluate word finding, prosody and social cognition in pwMS relative to healthy controls (HC)., Methods: We recruited people with relapsing MS (RMS, n = 21), progressive MS (PMS, n = 24) and HC (n = 25) from an outpatient MS clinic. Participants completed a battery of word-finding, social cognitive, neuropsychological and clinical assessments and performed a speech task for prosodic analysis., Results: Of 45 pwMS, mean (SD) age was 49.4 (9.4) years, and median (range) Expanded Disability Severity Scale score was 3.5 (1.0-6.5). Compared with HC, pwMS were older and had slower information processing speed (measured with the Symbol Digit Modalities Test, SDMT) and higher depression scores. Most speech and social cognitive measures were associated with information processing speed but not with depression. Unlike speech, social cognition consistently correlated with intelligence and memory. Visual naming test mean response time (VNT-MRT) demonstrated worse outcomes in MS versus HC (p = .034, Nagelkerke's R 2  = 65.0%), and in PMS versus RMS (p = .009, Nagelkerke's R 2  = 50.2%). Rapid automatised object naming demonstrated worse outcomes in MS versus HC (p = .014, Nagelkerke's R 2  = 49.1%). These word-finding measures showed larger effect sizes than that of the SDMT (MS vs. HC, p = .010, Nagelkerke's R 2  = 40.6%; PMS vs. RMS, p = .023, Nagelkerke's R 2  = 43.5%). Prosody and social cognition did not differ between MS and HC., Conclusions: Word finding, prosody and social cognition in MS are associated with information processing speed and largely independent of mood. Impairment in visual object meaning perception is potentially a unique MS disease-related deficit that could be further explored and cautiously considered as an adjunct disability metric for MS., (© 2022 The British Psychological Society.)

Objectives: This study adopted a qualitative research design with directed content analysis and examined the interpretations of physical activity, exercise, and sedentary behaviour by persons with multiple sclerosis., Methods: Fifty three persons with multiple sclerosis who were enrolled in an exercise trial took part in semi-structured interviews regarding personal interpretations of physical activity, exercise, and sedentary behaviours., Results: Forty three percent of participants indicated a consistent understanding of physical activity, 42% of participants indicated a consistent understanding of exercise, and 83% of participants indicated a consistent understanding of sedentary behaviour with the standard definitions. There was evidence of definitional ambiguity (i.e., 57, 58, and 11% of the sample for physical activity, exercise, and sedentary behaviour, respectively); 6% of the sample inconsistently defined sedentary behaviour with standard definitions. Some participants described physical activity in a manner that more closely aligned with exercise and confused sedentary behaviour with exercise or sleeping/napping., Conclusions: Results highlight the need to provide and utilise consistent definitions for accurate understanding, proper evaluation and communication of physical activity, exercise, and sedentary behaviours among persons with multiple sclerosis., Practice Implications: The application of consistent definitions may minimise ambiguity, alleviate the equivocality of findings in the literature, and translate into improved communication about these behaviours in multiple sclerosis. Implications for Rehabilitation The symptoms of multiple sclerosis can be managed through participation in physical activity and exercise. Persons with multiple sclerosis are not engaging in sufficient levels of physical activity and exercise for health benefits. Rehabilitation professionals should use established definitions of physical activity, exercise, and sedentary behaviours when communicating about these behaviours among persons with multiple sclerosis.

Background: Exercise training is a promising approach for managing multiple sclerosis (MS), but existing research has not focused on black individuals with MS. This is important as black individuals with MS may experience a more aggressive disease course, increased comorbidities, and have a poorer prognosis with disease modifying therapies., Materials and Methods: Thirty-two black adults with mild-to-moderate MS related disability participated in a patient-informed, three-month, home-based, racially tailored, exercise program. The exercise program, Project GEMS, was modified for black persons with MS through patient feedback. The feasibility of the modified exercise program was measured through the four domains of process (e.g., recruitment and retention), resources (e.g., communication and monetary costs), management (e.g., of data management and safety reporting), and scientific outcomes (e.g., safety, burden, adherence, experience, and treatment effect)., Results: This exercise program was feasible, safe, and well received based on data analysis and formative evaluation. Twenty-four participants completed post-assessment (75%; two dropped out, six did not return follow-up assessments). The exercise program cost a total of $3726.57 (personnel costs = $2128.74 USD, $20.87 USD per/h; exercise program costs = $1597.83 USD, mean cost per person = $46.93). Participants were adherent with 70% of the 48 exercise sessions via self-reported exercise logs. There was a significant and large increase (t = -5.1, p < .001, d = -1.0) in exercise behavior as measured by the Godin Leisure-Time Exercise Questionnaire., Conclusion: The results support the feasibility, acceptability, safety, and efficacy of this intervention for increasing exercise behavior among black adults with mild-to-moderate MS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Multiple sclerosis (MS) is a disease of the central nervous system that causes ataxia and deficits in balance. Exercise-based therapies have been identified as integral to the recovery of motor function in MS, but few studies have investigated non-traditional movement interventions. We examined a targeted ballet program (TBP) designed to mitigate ataxia and improve balance in females with mild-to-moderate relapsing-remitting MS., Methods and Findings: Twelve females with mild-to-moderate disability due to MS were assessed for study eligibility for the study. Ten participants met the inclusion criteria. Two were lost to unrelated health complications. Eight participants completed the TBP. The TBP met twice a week for 60 minutes for 16 weeks. Assessments included (a) the International Cooperative Ataxia Rating Scale (ICARS), (b) the Mini-Balance Evaluations Systems Test (Mini-BESTest), (c) smoothness of movement during a five-meter walk, and (d) balance in a step to stand task before and after the TBP. There were no TBP-related adverse events. Single-tailed paired samples t-tests and Wilcoxon tests were conducted. Improvements were observed in ICARS (p = 7.11E-05), Mini-BESTest (p = 0.001), smoothness of movement in the left (p = 0.027) and right (p = 0.028) sides of the body, and balance in a step-to-stand task in the back (p = 0.025) direction. Results yielded 42% and 58% improvements in the mean Mini-BESTest and ICARS scores, respectively., Conclusions: This study adds to current research by providing support for a TBP intervention targeting ataxia and balance in MS. The TBP was well tolerated, improved balance, and mitigated ataxia. Clinical improvements were larger than those of previous studies on physical rehabilitation in MS with similar outcome measures., Trial Registration: ISRCTN ISRCTN67916624., Competing Interests: The authors have declared that no competing interests exist.

Blood-brain barrier (BBB) and neurotrophic factors seemingly have an important role in multiple sclerosis pathology. Physical activity may influence blood-brain barrier function and levels of neurotrophic factors, and such effects might be moderated by body weight status. This study investigated the effect of exercise training on markers of blood-brain barrier permeability and neurotrophic factors as a function of weight status in multiple sclerosis patients. Sixty three persons with relapsing remitting multiple sclerosis who were normal weight (n: 33) or overweight (n: 33) were randomly assigned into groups of exercise (normal weight training, n: 18; overweight training group, n: 18) or no exercise (normal weight control, n: 15; overweight control group, n: 15). The intervention consisted of 8 weeks (3 days per week) of cycling undertaken at 60-70% peak power. Resting blood concentrations of s100 calcium-binding protein B (s100b) and neuron-specific enolase as BBB permeability markers, neurotrophic factors and cytokines (Interleukin-10 and tumor necrosis factor alpha) were evaluated before and after the intervention. There were significant weight, training, and interaction effects on brain-derived neurotrophic factor and platelet-derived growth factor; however, ciliary neurotrophic factor and nerve growth factor did not demonstrate any effect. Brain-derived neurotrophic factor and platelet-derived growth factor were significantly increased from pre-post in normal weight exercise. Significant weight, training, and interaction effects were found for s100b. In detail, s100b was significantly increased from pre-post in normal weight exercise. In contrast, neuron-specific enolase and cytokines did not demonstrate any effect. Generally, Exercise training may alter markers of BBB permeability and neurotrophic factor status in normal weight persons with multiple sclerosis; however, overweight participants may be more resistant to these effects of exercise., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Fatigue is a common symptom of multiple sclerosis (MS) and can adversely affect all aspect of quality of life. The etiology of fatigue remains unclear, and its treatments are suboptimal. Characterizing the phenotypes of fatigued persons with MS may help advance research on fatigue's etiology and identify ways to personalize fatigue interventions to improve quality of life. The purpose of this study was to identify fatigue phenotypes; examine phenotype stability overtime; and characterize phenotypes by health and function, social and environmental determinants, psychosocial factors, and engagement in healthy behaviors., Methods: We conducted a longitudinal study over a 3-month period with 289 fatigued participants with MS. To identify fatigue phenotypes and determine transition probabilities, we used latent profile and transition analyses with valid self-report measures of mental and physical fatigue severity, the mental and physical impact of fatigue, depression, anxiety, and sleep quality. We used ANOVAs and effect sizes to characterize differences among phenotypes., Results: The best fitting model included six subgroups of participants: Mild Phenotype, Mild-to-Moderate Phenotype, Moderate-to-Severe Phenotype, Severe Phenotype, Fatigue-dominant Phenotype, and Mental Health-dominant Phenotype. The transition analysis indicated that phenotypic membership was highly stable. Variables with a large eta squared effect size included environmental barriers, self-efficacy, and fatigue catastrophizing., Conclusion: These results indicate that the magnitude of fatigue experienced may be more important to consider than the type of fatigue when characterizing fatigue phenotypes. Future research should explore whether tailoring interventions to environmental barriers, self-efficacy, and fatigue catastrophizing reduce the likelihood of transitioning to a more severe phenotype., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: This article provided an updated quantitative synthesis of physical activity levels in persons with multiple sclerosis compared with controls and other clinical populations., Design: A systematic search through PubMed, Scopus, and PsycINFO was conducted for articles published between August 2016 and July 2022. Articles that included a group comparison of at least one measurement of physical activity between adults with multiple sclerosis and controls or other clinical populations were included in the meta-analysis., Results: Twenty-four studies met the inclusion criteria and yielded a total of 119 comparisons. There was a moderate difference in physical activity levels between persons with multiple sclerosis and controls (effect size = -0.56, P < 0.01), but no significant difference between persons with multiple sclerosis and other clinical populations (effect size = 0.01, P = 0.90). The pooled effect sizes comparing multiple sclerosis with controls ( Q104 = 457.9, P < 0.01) as well as with clinical populations ( Q13 = 108.4, P < 0.01) were heterogeneous. Moderating variables included sex, disability status, measurement method, outcome, intensity, and application of a multiple sclerosis-specific cut-point., Conclusions: Physical activity levels remain significantly lower in persons with multiple sclerosis compared with controls, but the magnitude of difference has become smaller over the past decade. There is a need for continued development of effective physical activity programs that can reach the greater community with multiple sclerosis., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate the bivariate correlations between objective physical activity (PA), self-efficacy, and a range of multiple sclerosis (MS) symptom measures. Also, to determine whether any MS symptom measures moderate the relationship between self-efficacy and PA., Method: Baseline analysis from a randomized control trial exercise plus a behavior change intervention was used. Fifty-nine physically inactive people with a definite diagnosis of MS were included. Participants were asked to record 7-day objective PA with the SenseWear Armband. Additionally, measures of self-efficacy (Exercise Self-Efficacy Scale), walking endurance (6-min walk test), impact of walking (12-Item MS Walking Scale [MSWS-12]), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]) and fatigue (Modified Fatigue Impact Scale) were assessed before intervention. Pearson's correlations and moderation analysis were conducted., Results: Self-efficacy was positively associated with PA (r = .30, p < .05). HADS-Depression (r = -.25, p < .05) and MSWS-12 (r = -.31, p < .01) demonstrated statistically significant negative correlations with self-efficacy but not with PA. Moderation analysis illustrated a significant interaction between anxiety and self-efficacy (r = .39, p < .03) with an R2 value of .15. The interaction was significant at lower values of anxiety, suggesting that the relationship between self-efficacy and PA is stronger when levels of anxiety are lower., Conclusion: This article confirms the potential role of MS symptoms, in particular anxiety, in explaining PA behavior in an inactive sample of persons with multiple sclerosis (pwMS). Further exploration is warranted, and future PA interventions should acknowledge the potential interplay of psychosocial constructs such as self-efficacy and anxiety in changing PA behavior among pwMS. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Objective: To synthesize current knowledge of the modifiable psychosocial constructs associated with physical activity (PA) participation in people with multiple sclerosis., Data Sources: A search was conducted through October 2015 in 8 electronic databases: CINAHL, PubMed, SPORTDiscus, Web of Knowledge, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and PsycINFO., Study Selection: Cohort and intervention studies were included if they (1) included an objective or subjective measure of PA; (2) measured at least 1 modifiable psychosocial construct; and (3) reported bivariate correlations (or these could be extracted) between the PA and psychosocial construct measures. A total of 13,867 articles were screened for inclusion, and 26 were included in the final analysis., Data Extraction: Meta-analyses of correlations were conducted using the Hedges-Olkin method. Where a meta-analysis was not possible, results were reported descriptively., Data Synthesis: Meta-analyses indicated a pooled correlation coefficient between (1) objective PA and self-efficacy (n=7) of r=.30 (P<.0001), indicating a moderate, positive association; (2) subjective PA and self-efficacy (n=7) of r=.34 (P<.0001), indicating a moderate, positive association; (3) subjective PA and goal-setting (n=5) of r=.44 (P<.0001), indicating a moderate-to-large positive association; and 4) subjective PA and outcome expectancies (n=4) (physical: r=.13, P=.11; social: r=.19, P<.0001; self-evaluative: r=.27, P<.0001), indicating small-moderate positive associations. Other constructs such as measures of health beliefs, enjoyment, social support, and perceived benefits and barriers were reported to be significantly correlated with PA in individual studies, but the number of studies was not sufficient for a meta-analysis., Conclusions: Future PA interventions should continue to focus on the psychosocial constructs of self-efficacy and goal-setting. However, there is a need to explore the associations between other constructs outside those reported in this review., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Multiple sclerosis (MS) is a neurological disease that has different clinical presentations and illness trajectories. The aim of this study was to explore factors that are important for quality of life (QoL) of people with MS (pwMS), and to understand how they may differ across three subtypes., Methods: Both convenience and purposive sampling were employed. Semi-structured interviews were conducted with people with relapsing-remitting MS (n = 16), secondary progressive MS (n = 14), and primary progressive MS (n = 13). All interviews were audio recorded and then transcribed verbatim for thematic analysis involving both inductive and deductive processes. A separate analysis for each subtype was made during the inductive process before examining for similarities and differences across the three subtypes in the deductive process., Findings: Four factors were identified to have an important influence on QoL of pwMS: restricted and disrupted enjoyment, disturbed future, challenged sense of self, and well-being of significant others. The themes reflect how pwMS commonly perceived enjoyment as a purpose of life, while also illustrating how their QoL may be questioned because of new perspectives going forward with MS, challenges to their sense of self, and increased concerns for their significant others as a result of MS. Subtype differences were attributed to different illness trajectories: relapsing or progressive., Conclusions: There are subtype differences in the negative impact of MS on QoL. Clinicians are encouraged to understand the challenges of different illness trajectories, in particular the traumatic nature of relapses and steady worsening of symptoms among those with progressive subtypes of MS., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Purpose: The symptom of fatigue impairs function in people with multiple sclerosis (MS). Choosing appropriate measures to assess fatigue is challenging. The purpose of this article is to report the findings of a systematic review of patient-reported fatigue measures for people with MS., Methods: PubMed, CINAHL, and Embase databases were searched through January 2020 using terms related to fatigue and MS. Studies were included if the sample size was 30 or more or smaller samples if adequately powered, and if information about measurement characteristics (ie, test-retest reliability, content validity, responsiveness, interpretability, or generalizability) of the measure(s) could be extracted. Study quality was appraised with the 2-point COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. Data about measurement characteristics, psychometrics, and clinical utility were extracted and results were synthesized., Results: Twenty-four articles met inclusion criteria with information about 17 patient-reported fatigue measures. No studies had critical methodologic flaws. Measurement characteristic data were not available for all measures. Clinical utility varied in time to complete and fatigue domains assessed., Discussion and Conclusions: Five measures had data pertaining to all properties of interest. Of these, only the Modified Fatigue Impact Scale (MFIS) and Fatigue Severity Scale (FSS) had excellent reliability, responsiveness data, no notable ceiling/floor effects, and high clinical utility. We recommend the MFIS for comprehensive measurement and the FSS for screening of subjective fatigue in people with MS.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A443 )., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Academy of Neurologic Physical Therapy, APTA.)

Background and Purpose: Individuals with multiple sclerosis (MS) frequently report low physical activity and psychosocial support due to concerns with transportation, time, finances, access to services, and lack of caregiver support. These barriers can be addressed by online group interventions; however, utility of such programs in individuals with MS has not been examined yet. The purpose of this retrospective study was, therefore, to ( a ) investigate the feasibility, safety, and outcomes of a virtual group exercise program in individuals with MS, and ( b ) explore the participant perceptions after the program., Methods: Retrospective data from the medical records of 17 individuals with MS (mean [SD] age = 53.5 [12.3] years, body mass index = 28.2 [7.2]) who completed the virtual 13-week group exercise program, pre- and posttraining functional status questionnaires, and the end-of-program feedback were extracted. The exercise program included aerobic, resistance, balance, and flexibility training components recommended for people with MS. Feasibility, safety, outcomes, and participant perceptions were determined by adherence to the prescribed daily exercise dosage, number of adverse events, within-group differences in self-reported functional status, and thematic analysis of the participant feedback, respectively., Results: Participants were adherent (79%), reported minimal adverse effects, and demonstrated significant changes ( P < 0.05) in functional status posttraining. Several themes on the perceived barriers, facilitators, and suggestions for improvement were identified., Discussion and Conclusions: A virtual 13-week group exercise program can be feasible, safe, effective, and well received by individuals with MS. Future research should investigate the dose-response effectiveness of telehealth and compare various telehealth models of exercise training using large randomized controlled trials.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A434 , which demonstrates an overview of the study)., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Academy of Neurologic Physical Therapy, APTA.)

Background and Purpose: Fatigue following neurological conditions negatively impacts daily activities, reducing overall quality of life. Transcranial direct current stimulation (tDCS) for fatigue management is still underexplored. This scoping review explores its use in managing fatigue among various neurological conditions., Methods: A thorough literature search was carried out using PubMed, Scopus, CINAHL, Web of Science, Embase, ProQuest, and the Cochrane Library. Google Scholar and clinicaltrials.gov were manually searched for gray literature and ongoing trials, respectively. Regardless of the study design, all studies utilizing tDCS for the management of fatigue in various neurological conditions were considered. Two reviewers independently screened all the studies, following which the data were retrieved., Results: Studies employing tDCS for fatigue management across neurological conditions is as follows: Multiple sclerosis (MS) (n = 28, 66%), stroke (n = 5, 12%), Parkinson's disease (PD) (n = 4, 10%), post-polio syndrome (PPS) (n = 2, 5%), traumatic brain injury (TBI) (n = 2, 5%), and amyotrophic lateral sclerosis (n = 1, 2%). All the studies used anodal stimulation, with the common stimulation site being the left dorsolateral prefrontal cortex for MS, stroke, and PD. A stimulation intensity of 1.0-4.0 mA with a duration ranging from 15 to 30 min in 1 to 24 sessions were commonly reported. The Fatigue Severity Scale (n = 21) and Modified Fatigue Impact Scale (n = 17) were frequently implemented outcome measures. Regardless of the study design, 36/42 (85.7%) studies reported an improvement in fatigue scores in the tDCS group. The common adverse events noted were tingling (n = 8, 35%), headache (n = 6, 26%), and itching (n = 6, 26%)., Discussion: Application of tDCS for fatigue was explored in individuals with stroke, PD, PPS, and TBI after MS. Even though a wide range of treatment parameters and outcome measures were adopted to assess and target fatigue, tDCS proves to have a promising role in alleviating this symptom., (© 2023 The Authors. Physiotherapy Research International published by John Wiley & Sons Ltd.)

Background: Because multiple sclerosis (MS) is an autoimmune disease and many individuals with MS take disease-modifying drugs that suppress immune response, serious concerns have been expressed about the potential effect of COVID-19 on those with this chronic condition., Objectives: The purpose of this research was to utilize the most recent 5 years of data from an ongoing longitudinal study of health promotion and quality of life (QoL) among people with long-standing MS to investigate changes across time in functional limitations, health promotion, and health-related QoL., Methods: Participants are mailed an annual survey to complete about their health promotion, depressive symptoms, health status, social support, MS-related functional limitations, and QoL. Differences across time were analyzed with repeated measures of analysis of variances and planned contrasts., Results: In 2021, the 141 participants had a mean age of 69 years and had been diagnosed with MS for 34 years, on average. Most had attended college, were married/partnered women, and reported adequate economic resources. Thirty-seven percent reported they were in poor to fair health. Physical activity and health responsibility scores decreased significantly during 2020-2021 compared with 2017-2019. Significant changes in depressive symptoms, social support, and functional limitation scores followed a different pattern, with the largest changes occurring between 2018 and 2019. QoL and other health promotion scores did not change significantly across time., Discussion: The relatively small changes in health indicators revealed here suggest that older people with long-standing MS may have generally been able to maintain their health promotion, functional abilities, and QoL from before to during the COVID-19 pandemic. However, nurses and other providers should support them to resume their physical activity and regular provider contact as COVID-19 restrictions are eased. The patterns observed here demonstrate the importance of examining changes across an extended period, rather than simply looking at 1 year before and 1 year after a major event, such as COVID-19. These findings can help nurses understand how to help their patients with chronic health conditions maximize their health as they move forward., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose: The flexible exercise participation program (FEPP) is a novel intervention developed to enable individuals with multiple sclerosis (MS) participate and progress in an exercise or sport of their choice. The FEPP is underpinned by guidelines on aerobic exercise for individuals with MS and is supported by a physiotherapist using behaviour change techniques. As part of a FEPP feasibility trial, the aim of this nested study was to explore the experience of participation in the FEPP from the perspective of individuals with MS. The objectives were to (i) determine the acceptability of the FEPP and (ii) identify recommendations for improvement., Methods: A mixed methods study using a sequential explanatory design was conducted. Part I consisted of a quantitative participant survey. Survey data were analysed descriptively using SPSS and informed the protocol for part II - qualitative interviews. Interview data were analysed thematically using NVivo. Part III consisted of integration of quantitative and qualitative data to allow greater explanation of survey responses. Individuals with MS who had participated in the FEPP feasibility trial were invited to take part in the study., Results: The FEPP was highly acceptability to the 10 participants. Five themes emerged to describe the experience of participating in the FEPP: (i) exploring exercise boundaries, (ii) measuring energy, (iii) acknowledging accountability, (iv) adjusting to exercising in a pandemic and (v) sustaining participation. Recommendations for improving the FEPP included changes to energy level monitoring and incorporation of peer support mechanisms., Discussion: Participants found the FEPP highly acceptable and valued the flexibility to choose their own activity and the health professional support. Based on participant recommendations, future versions of the FEPP will include daily rather than weekly monitoring of exercise and peer support to further enable individuals with MS to find the right balance with exercise and sport., (© 2021 John Wiley & Sons Ltd.)

Background and Purpose: Valid measurements of cardiorespiratory fitness in persons with multiple sclerosis (pwMS) are essential during inpatient rehabilitation for a precise evaluation of the current health status, for defining appropriate exercise intensities, and for evaluation of exercise intervention studies. We aim (i) to examine the proportion of pwMS who attain the American College of Sports Medicine (ACSM) criteria for maximal effort during graded cardiopulmonary exercise testing (CPET) and (ii) to provide insight into participant characteristics that limit maximal exercise performance., Methods: This cross-sectional study comprises a retrospective examination of ACSM criteria for maximal effort during graded CPET of n = 380 inpatient pwMS (mean age = 48 ± 11 years, 66% female). Chi-squared or Fisher's exact tests were conducted to compare differences in the distribution of criteria achieved. Participants' characteristics were examined as potential predictors using binary logistic regression., Results: Only 60% of the overall sample attained a respiratory exchange ratio ≥ 1.10. With regard to the definition applied, only 24% or 40% of the participants achieved an oxygen consumption plateau, and 17% or 50% attained the heart rate criterion. Forty-six percent met at least two of three criteria. Disability status, gender, disease course, and body mass index were associated with the attainment of maximal effort., Conclusions: Our findings suggest that a relevant proportion of inpatient pwMS do not attain common criteria utilized to verify maximal oxygen consumption. Identified predictors for criteria attainment can be used to create models to predict cardiorespiratory fitness and to optimize CPET protocols in restrictive groups of pwMS., (© 2023 European Academy of Neurology.)

Background and Purpose: Physical activity may represent a disease-modifying therapy in persons with multiple sclerosis (pwMS). To date, there is limited research regarding mechanisms based on brain imaging for understanding the beneficial effects of physical activity in pwMS. This study examined the relationship between physical activity levels and thalamic and hippocampal volumes and brain metabolism in pwMS., Methods: The sample of 52 pwMS (37.3 ± 9.6 years of age; 35 females, 17 males) underwent a combination of volumetric magnetic resonance imaging and magnetic resonance spectroscopy. Current and lifetime physical activity were assessed using actigraphy and the adapted version of the Historical Activity Questionnaire, respectively., Results: Positive associations were observed between both actigraphy and self-reported levels of moderate-to-vigorous physical activity (MVPA) and thalamic and hippocampal volumes. Regarding brain metabolism, actigraphy and self-reported levels of MVPA were positively associated with higher hippocampal and thalamic levels of N-acetylaspartate/creatine ratio (NAA/Cr: marker of neural integrity and cell energy state)., Conclusions: This study provides novel evidence for a positive association between physical activity and thalamic and hippocampal volume and metabolism in pwMS. These findings support the hypothesis that physical activity, particularly MVPA, may serve as a disease-modifying treatment by improving brain health in pwMS., (© 2021 American Society of Neuroimaging.)

Numerous disorders are characterised by fatigue as a highly disabling symptom. Fatigue plays a particularly important clinical role in multiple sclerosis (MS) where it exerts a profound impact on quality of life. Recent concepts of fatigue grounded in computational theories of brain-body interactions emphasise the role of interoception and metacognition in the pathogenesis of fatigue. So far, however, for MS, empirical data on interoception and metacognition are scarce. This study examined interoception and (exteroceptive) metacognition in a sample of 71 persons with a diagnosis of MS. Interoception was assessed by prespecified subscales of a standard questionnaire (Multidimensional Assessment of Interoceptive Awareness [MAIA]), while metacognition was investigated with computational models of choice and confidence data from a visual discrimination paradigm. Additionally, autonomic function was examined by several physiological measurements. Several hypotheses were tested based on a preregistered analysis plan. In brief, we found the predicted association of interoceptive awareness with fatigue (but not with exteroceptive metacognition) and an association of autonomic function with exteroceptive metacognition (but not with fatigue). Furthermore, machine learning (elastic net regression) showed that individual fatigue scores could be predicted out-of-sample from our measurements, with questionnaire-based measures of interoceptive awareness and sleep quality as key predictors. Our results support theoretical concepts of interoception as an important factor for fatigue and demonstrate the general feasibility of predicting individual levels of fatigue from simple questionnaire-based measures of interoception and sleep., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Pediatric-onset multiple sclerosis (POMS), is the manifestation of multiple sclerosis in individuals before 18 years of age. About a third of children with POMS show some form of lower cognitive performance. The purpose of this study is to examine using quantitative meta-analyses the effect size of altered performance between children with and without POMS on overall intelligence quotient (IQ), information processing speed, and language functions. We searched the literature for studies that reported scores on cognitive tests administered to children with and without POMS. Studies were systematically reviewed using PRISMA guidelines. We analyzed data from 14 studies that examined 1283 children with and without POMS when cognitive categories consisted of five or more studies. Effect sizes, publication bias and potential confounds were considered. Significant cognitive differences are revealed for all categories with the strongest effect observed for overall IQ. A moderate effect is observed for information processing speed, and small effects for verbal fluency and verbal memory. Cognitive abilities present differently in children with POMS and a better understanding of this manifestation will inform intervention and remediation tools that can improve clinical and educational practice for the benefit of children with POMS., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The present review focuses on exercise as a treatment for depression in multiple sclerosis. While exercise has emerged as a potentially useful treatment in the general psychiatry-depression literature, the findings from a small number of multiple sclerosis-related treatment trials are equivocal. Methodological limitations, including the absence of depression as a primary endpoint, characterize all the studies completed to date. Given that limitations in study design can be rectified, it is time to put exercise to the test once more. Depressed multiple sclerosis patients and those involved in their care are looking for guidance here because the prevailing zeitgeist promotes the benefits of exercise to mood. But first, some clarity is needed.

In persons with multiple sclerosis (PwMS), synchronizing walking to auditory stimuli such as to music and metronomes have been shown to be feasible, and positive clinical effects have been reported on step frequency and perception of fatigue. Yet, the dynamic interaction during the process of synchronization, such as the coupling of the steps to the beat intervals in music and metronomes, and at different tempi remain unknown. Understanding these interactions are clinically relevant, as it reflects the pattern of step intervals over time, known as gait dynamics. 28 PwMS and 29 healthy controls were instructed to walk to music and metronomes at 6 tempi (0-10% in increments of 2%). Detrended fluctuation analysis was applied to calculate the fractal statistical properties of the gait time-series to quantify gait dynamics by the outcome measure alpha. The results showed no group differences, but significantly higher alpha when walking to music compared to metronomes, and when walking to both stimuli at tempi + 8, + 10% compared to lower tempi. These observations suggest that the precision and adaptation gain differ during the coupling of the steps to beats in music compared to metronomes (continuous compared to discrete auditory structures) and at different tempi (different inter-beat-intervals).

Gait impairments in persons with multiple sclerosis (pwMS) leading to decreased ambulation and reduced walking endurance remain poorly understood. Our objective was to assess gait asymmetry (GA) and bilateral coordination of gait (BCG), among pwMS during the six-minute walk test (6MWT), and determine their association with disease severity. We recruited 92 pwMS (age: 46.6 ± 7.9; 83% females) with a range of clinical disability, who completed the 6MWT wearing gait analysis system. GA was assessed by comparing left and right swing times, and BCG was assessed by the phase coordination index (PCI). Several functional and subjective gait assessments were performed. Results show that gait is more asymmetric and less coordinated as the disease progresses (p < 0.0001). Participants with mild MS showed significantly better BCG as reflected by lower PCI values in comparison to the other two MS severity groups (severe: p = 0.001, moderate: p = 0.02). GA and PCI also deteriorated significantly each minute during the 6MWT (p < 0.0001). GA and PCI (i.e., BCG) show weaker associations with clinical MS status than associations observed between functional and subjective gait assessments and MS status. Similar to other neurological cohorts, GA and PCI may be important parameters to assess and target in interventions among pwMS.

Restless legs syndrome (RLS) is a sleep disorder that may exacerbate many of the symptoms and consequences of multiple sclerosis (MS), and may have further implications for health-related quality of life (HRQOL). The present study examined the relationships among RLS, symptoms and HRQOL in people with MS. Participants with MS (n = 275) completed the Cambridge-Hopkins Restless Legs Syndrome Questionnaire, the International Restless Legs Syndrome Study Group Scale, the Multiple Sclerosis Impact Scale, the Pittsburgh Sleep Quality Index, the Fatigue Severity Scale, the Hospital Anxiety and Depression Scale and the Patient Determined Disease Steps. There were 74 (26.9%) persons with MS who had RLS (MS + RLS). The MS + RLS group reported worse physical and psychological HRQOL (p = 0.020 and p = 0.017, respectively) and greater perceived fatigue (p = 0.006) and anxiety symptoms (p = 0.042) than the MS-only group. Within the MS + RLS group, RLS severity was associated with physical (r = 0.43) and psychological (r = 0.46) HRQOL, sleep quality (r = 0.38), perceived fatigue (r = 0.28), depression (r = 0.38) and anxiety (r = 0.28). The relationships between RLS severity and the domains of HRQOL were attenuated when accounting for fatigue, depression and/or anxiety. Worse RLS severity was associated with reduced HRQOL, which was accounted for by fatigue, depression and anxiety., (© 2019 European Sleep Research Society.)

Cognitive impairment is a common and devastating manifestation of multiple sclerosis (MS). Although disease-modifying therapies have been efficacious for reducing relapse rates in MS, such treatments are ineffective for treating cognitive dysfunction. Alternative treatment approaches for mitigating cognitive problems are greatly needed in this population. To date, cognitive rehabilitation and exercise training have been identified as possible candidates for treating MS-related cognitive impairment; however, cognitive dysfunction is still often considered to be poorly managed in patients with MS. This Review provides a comprehensive overview of recent developments in the treatment and management of cognitive impairment in people with MS. We describe the theoretical rationales, current states of the science, field-wide challenges and recent advances in cognitive rehabilitation and exercise training for treating MS-related cognitive impairment. We also discuss future directions for research into the treatment of cognitive impairment in MS that should set the stage for the inclusion of cognitive rehabilitation and exercise training into clinical practice within the next decade.

Regeneration of myelin, following injury, can occur within the central nervous system to reinstate proper axonal conductance and provide trophic support. Failure to do so renders the axons vulnerable, leading to eventual degeneration, and neuronal loss. Thus, it is essential to understand the mechanisms by which remyelination or failure to remyelinate occur, particularly in the context of demyelinating and neurodegenerative disorders. In multiple sclerosis, oligodendrocyte progenitor cells (OPCs) migrate to lesion sites to repair myelin. However, during disease progression, the ability of OPCs to participate in remyelination diminishes coincident with worsening of the symptoms. Remyelination is affected by a broad range of cues from intrinsic programming of OPCs and extrinsic local factors to the immune system and other systemic elements including diet and exercise. Here we review the literature on these diverse inhibitory factors and the challenges they pose to remyelination. Results spanning several disciplines from fundamental preclinical studies to knowledge gained in the clinic will be discussed., (© 2019 Wiley Periodicals, Inc.)

Multiple sclerosis (MS) is a central nervous system (CNS) disorder characterized by inflammation, demyelination, and neurodegeneration. Emerging research suggests that exercise has therapeutic benefits for MS patients but the clinical data have focused primarily on non-CNS outcomes. In this review, we discuss evidence in preclinical MS models that exercise influences oligodendrocyte proliferation and repopulation, remyelination, neuroinflammation, neuroprotection, axonal regeneration, and astrogliosis. Evidence for the therapeutic effects of exercise in MS is further supplemented by data from other CNS diseases, including Alzheimer's disease, Parkinson's disease, and spinal cord injury. These results motivate studies into the benefits that exercise confers within the CNS in MS., (© 2019 Wiley Periodicals, Inc.)

People with multiple sclerosis (MS) are likely to benefit from regular exercise, but physical inactivity is more common among people with MS than among the general population. This small randomized study evaluated whether motivational interviewing (MI) affects adherence to and personal experience in an exercise program. Inactive people with MS participating in an eight-week exercise program were randomized to either three brief MI (n = 7) or three health coaching (n = 6) sessions. Session attendance for both conditions was high, and MI fidelity was rigorously and reliably measured using the Motivational Interviewing Treatment Integrity Scales. The feasibility of using this approach was demonstrated with a small sample. Large effects favoring the MI condition were found for physical exertion, affect during exercise, and fatigue, but no effects were found for adherence to the exercise program. Treatment integrity measures of MI were correlated with outcomes in expected directions. Although this study demonstrated the feasibility of this MI approach, the large effect sizes found should be viewed with substantial skepticism and replicated in sufficiently powered studies using objective measures of exercise adherence.

This pretest-posttest, descriptive pilot study examined the feasibility and perceived impact of an 8-week online adaptive yoga program on patients diagnosed with multiple sclerosis. The program incorporated yoga poses, breathing practices, and relaxation techniques. Participants rated their perceived and actual symptom severity, overall quality of life, and perception of program impact, and contributed open-ended narrative comments about the program. All participants reported an overall perceived benefit from study participation and expressed enjoyment in interacting with other patients with multiple sclerosis. The program was found to be safe and rewarding for all participants., Competing Interests: This study was supported by a grant from the International Organization of Multiple Sclerosis Nurses and EMD Serono to Mindy Robert, and in part by the Weber State University Sigma Theta Tau Nu Nu Chapter to Mindy Robert. There are no other financial or funding disclosures or conflicts of interest for the remaining authors., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease of the central nervous system which results in disability over time and reduced quality of life. To increase the sensitivity of the EQ-5D-5L for psychosocial health, four bolt-on items from the AQoL-8D were used to create the nine-item EQ-5D-5L-Psychosocial. We aimed to externally validate the EQ-5D-5L-Psychosocial in a large cohort of people with MS (pwMS) and explore the discriminatory power of the new instrument with EQ-5D-5L/AQoL-8D., Methods: A large representative sample from the Australian MS Longitudinal Study completed the AQoL-8D and EQ-5D-5L (including EQ VAS) and both instruments health state utilities (HSUs) were scored using Australian tariffs. Sociodemographic/clinical data were also collected. External validity of EQ-5D-5L-Psychosocial scoring algorithm was assessed with mean absolute errors (MAE) and Spearman's correlation coefficient. Discriminatory sensitivity was assessed with an examination of ceiling/floor effects, and disability severity classifications., Results: Among 1683 participants (mean age: 58.6 years; 80% female), over half (55%) had moderate or severe disability. MAE (0.063) and the distribution of the prediction error were similar to the original development study. Mean (± standard deviation) HSUs were EQ-5D-5L: 0.58 ± 0.32, EQ-5D-5L-Psychosocial 0.62 ± 0.29, and AQoL-8D: 0.63 ± 0.20. N = 157 (10%) scored perfect health (i.e. HSU = 1.0) on the EQ-5D-5L, but reported a mean HSU of 0.90 on the alternative instruments. The Sleep bolt-on dimension was particularly important for pwMS., Conclusions: The EQ-5D-5L-Psychosocial is more sensitive than the EQ-5D-5L in pwMS whose HSUs approach those reflecting full health. When respondent burden is taken into account, the EQ-5D-5L-Psychosocial is preferential to the AQoL-8D. We suggest a larger confirmatory study comparing all prevalent multi-attribute utility instruments for pwMS., (© 2022. The Author(s).)

Background: The expansion of the availability of advanced imaging methods needs more time, expertise, and resources which is in contrast to the primary goal of the imaging techniques. To overcome most of these difficulties, artificial intelligence (AI) can be used. A number of studies used AI models for multiple sclerosis (MS) diagnosis and reported diverse results. Therefore, we aim to perform a comprehensive systematic review and meta-analysis study on the role of AI in the diagnosis of MS., Methods: We performed a systematic search using four databases including PubMed, Scopus, Web of Science, and IEEE. Studies that applied deep learning or AI to the diagnosis of MS based on any modalities were considered eligible in our study. The accuracy, sensitivity, specificity, precision, and area under curve (AUC) were pooled with a random-effects model and 95% confidence interval (CI)., Results: After the screening, 41 articles with 5989 individuals met the inclusion criteria and were included in our qualitative and quantitative synthesis. Our analysis showed that the overall accuracy among studies was 94% (95%CI: 93%, 96%). The pooled sensitivity and specificity were 92% (95%CI: 90%, 95%) and 93% (95%CI: 90%, 96%), respectively. Furthermore, our analysis showed 92% precision in MS diagnosis for AI studies (95%CI: 88%, 97%). Also, the overall pooled AUC was 93% (95%CI: 89%, 96%)., Conclusion: Overall, AI models can further improve our diagnostic practice in MS patients. Our results indicate that the use of AI can aid the clinicians in accurate diagnosis of MS and improve current diagnostic approaches as most of the parameters including accuracy, sensitivity, specificity, precision, and AUC were considerably high, especially when using MRI data., (© 2022. Fondazione Società Italiana di Neurologia.)

Objectives: Walking impairments are common in individuals with multiple sclerosis. Trunk control is a prerequisite for walking; however, knowledge regarding whether core stability and balance training influence walking is limited. This study aimed to investigate the immediate and long-term effects of a group-based, individualized, comprehensive core stability and balance intervention (GroupCoreDIST) compared with those of standard care on walking., Methods: This assessor-blinded, prospective randomized controlled trial included 80 participants (Expanded Disability Status Scale scores 1-6.5) randomly allocated to GroupCoreDIST, conducted in groups of three for 60 min three times per week for 6 weeks (18 sessions) or standard care (n = 40/40). One participant attended no posttests, leaving 79 subjects for intention-to-treat analysis. The assessments were performed at baseline and at Weeks 7, 18, and 30. Outcomes included the 2-min walk test (2MWT), 10-m walk test-preferred/fast/slow speed (10MWT), Multiple Sclerosis Walking Scale-12 (MSWS-12), Patient Global Impression of Change-walking (PGIC-walking), Rivermead Visual Gait Assessment (RVGA), and ActiGraphsWgt3X-BT activity monitors (ActiGraph). The statistical analyses included repeated-measures mixed models performed in IBM SPSS Version 24., Results: There were no significant between-group differences in the outcome measurements at baseline. The mean differences between groups were significant at all follow-up time points in favour of GroupCoreDIST for the 2MWT, 16.7 m at 7 weeks (95% CI [8.15, 25.25], 15.08 m at 18 weeks (95% CI [6.39, 23.77]) and 16.38 m at 30 weeks (95% CI [7.65, 25.12]; and the PGIC-walking, 0.89 points at 7 weeks (95% CI [1.34, 0.45]), 0.97 points at 18 weeks (95% CI [1.42, 0.52]), and 0.93 points at 30 weeks (95% CI [1.39, 0.48]; all p ≤ .001). The 10MWT-fast speed and the MSWS-12 showed significant between-group differences at 7 and 18 weeks and the RVGA at 7 weeks. No between-group differences were found regarding activity level (ActiGraph) or the 10MWT-preferred or slow speed., Conclusion: Compared with standard care, GroupCoreDIST significantly improved walking immediately after the intervention for up to 24 weeks of follow-up., (© 2019 The Authors Physiotherapy Research International Published by John Wiley & Sons Ltd.)

Objective: More than 80% of people with multiple sclerosis (MS) are affected by spasticity. Spasticity is known to reduce quality of life and contribute to additional symptoms, such as pain and reduced mobility, but the association between spasticity, balance, and mobility has not yet been established. Our aim was to examine whether a relationship exists between spasticity in the lower limbs, balance, and gait, as well as to explore the involvement of different muscle groups., Methods: This study employed a cross-sectional design. Thirty patients with MS were included. The Modified Ashworth Scale (MAS) was used to examine spasticity in the ankle plantar flexors, knee extensors, and hip adductors. Balance was measured using the Mini-Balance Evaluation Systems Test, and gait with the 2-Minute Walk Test. The participants were tested once with no additional follow-up. Spearman's correlation, recursive partitioning, and linear regression analyses were used to explore the association., Results: A significant correlation between gait distance and spasticity in the ankle plantar flexors (ρ = -.69, p < .001) and knee extensors (ρ = -.45, p = .012) was observed. Balance significantly correlated with spasticity in ankle plantar flexors (ρ = -.69, p < .001), knee extensors (ρ = -.52, p = .003), and hip adductors (ρ = -.5, p = .005). The relationship between spasticity in ankle plantar flexors and hip adductors was significant, even from low levels of spasticity, whereas MAS score ≥ 2 was clinically correlated with a decrease in gait and balance function. Adjustments for sex, age, or years since diagnosis had only minor impact on the results., Conclusions: This study indicates that spasticity in the lower limbs is clinically significantly associated with mobility in people with MS., (© 2019 The Authors. Physiotherapy Research International Published by John Wiley & Sons Ltd.)