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Background: Fatigue is common in people with multiple sclerosis (MS). Understanding the relationship between fatigue, physical and neurobehavioural factors is important to inform future research and practice. Few studies explore this explicitly in people with progressive MS (pwPMS)., Objective: To explore relationships between self-reported fatigue, physical and neurobehavioural measures in a large, international progressive MS sample of cognitively impaired people recruited to the CogEx trial., Methods: Baseline assessments of fatigue (Modified Fatigue Impact Scale; MFIS), aerobic capacity (VO 2peak ), time in moderate-vigorous physical activity (MVPA; accelerometery over seven-days), walking performance (6-minute walk test; 6MWT), self-reported walking difficulty (MS Walking Scale; MSWS-12), anxiety and depression (Hospital Anxiety and Depression Scale; HADS and Beck Depression Inventory-II; BDI-II), and disease impact (MS Impact Scale-29, MSIS-29) were assessed. Participants were categorised as fatigued (MFIS Total >=38) or non-fatigued (MFIS Total ≤38)., Statistical Analysis: Differences in individuals categorised as fatigued or non-fatigued were assessed (t-tests, chi square). Pearson's correlation and partial correlations (adjusted for EDSS score, country, sex, and depressive symptoms) determined associations with MFIS Total, MFIS Physical , MFIS Cognitive and MFIS Psychosocial, and the other measures. Multivariable logistic regression evaluated the independent association of fatigue (categorised MFIS Total ) with physical and neurobehavioural measures., Results: The sample comprised 308 pwPMS (62 % female, 27 % primary progressive, 73 % secondary progressive), mean age 52.5 ± 7.2 yrs, median EDSS score 6.0 (4.5-6.5), mean MFIS Total 44.1 ± 17.1, with 67.2 % categorised as fatigued. Fatigued participants walked shorter distances (6MWT, p = 0.043), had worse MSWS-12 scores (p < 0.001), and lower average % in MVPA (p = 0.026). The magnitude of associations was mostly weak between MFIS Total and physical measures (r = 0.13 to 0.18), apart from the MSWS-12 where it was strong (r = 0.51). The magnitude of correlations were strong between the MFIS Total and neurobehavioural measures of anxiety (r = 0.56), depression (r = 0.59), and measures of disease impact (MSIS-physical r = 0.67; MSIS-mental r = 0.71). This pattern was broadly similar for the MSIF subscales. The multivariable model indicated a five-point increase in MSWS-12 was associated with a 14 % increase in the odds of being fatigued (OR [95 %CI]: 1.14 [1.07-1.22], p < 0.0001) CONCLUSION: Management of fatigue should consider both physical and neurobehavioural factors, in cognitively impaired persons with progressive MS., Competing Interests: Declaration of competing interest Luke Connolly has no disclosures to report. Sarah Chatfield has no disclosures to report. Jenny Freeman has been awarded research grants from the NIHR, UK. Amber Salter receives research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the US Department of Defense and is a member of the editorial board for Neurology. She serves as a consultant for Gryphon Bio, LLC. She is a member of the Data and Safety Monitoring Board for Premature Infants Receiving Milking or Delayed Cord Clamping (PREMOD2), Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), and Ocrelizumab for Preventing Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease (CELLO). Maria Pia Amato received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Roche, Pharmaceutical Industries and Fondazione Italiana Sclerosi Multipla. Giampaolo Brichetto has been awarded and receives research support from Roche, Fondazione Italiana Sclerosi Multipla, ARSEP, H2020 EU Call. Jeremy Chataway has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS society, a local principal investigator for commercial trials funded by: Actelion, Novartis and Roche; and has taken part in advisory boards/consultancy for Azadyne, Janssen, Merck, NervGen, Novartis and Roche. Nancy Chiaravalloti is on an Advisory Board for Akili Interactive and is a member of the Editorial Boards of Multiple Sclerosis Journal and Frontiers in NeuroTrauma. Gary Cutter is a member of Data and Safety Monitoring Boards for Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals,Hisun Pharmaceuticals, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Ophazyme, Sanofi Aventis, Reata Pharmaceuticals, Teva pharmaceuticals, VielaBio Inc, Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee). He is on Consulting or Advisory Boards for BioDelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Klein-Buendel Incorporated, Med- immune, Medday, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, TG Therapeutics. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. John DeLuca is an Associate Editor of the Archives of Physical Medicine and Rehabilitation, and Neuropsychology Review; received compensation for consulting services and/ or speaking activities from Biogen Idec, Celgene, MedRhythms, and Novartis; and receives research support from Biogen Idec, National Multiple Sclerosis Society, Consortium of Multiple Sclerosis Centers, and National Institutes of Health. Ulrik Dalgas has received research support, travel grants, and/or teaching honorary from Biogen Idec, Merck-Serono, Novartis, Bayer Schering, and Sanofi Aventis as well as honoraria from serving on scientific advisory boards of Biogen Idec and Genzyme. Rachel Farrell has received honoraria and served on advisory panels for Merck, TEVA, Novartis, Gen- zyme, GW pharma (Jazz pharmaceuticals), Allergan, Merz, Ipsen and Biogen. She is supported in part by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK. Peter Feys is editorial board member of NNR and MSJ, provides consultancy to NeuroCompass and was board of advisory board meetings for BIOGEN. Massimo Filippi is Editor-in-Chief of the Journal of Neurology and Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology, received compensation for consulting services and/or speaking activities from Alexion, Almirall, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceu tical Industries, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Matilde Inglese is Co-Editor for Controversies for Multiple Sclerosis Journal; received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme; and received research support from NIH, NMSS, the MS Society of Canada, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, H2020 EU Call. Cecilia Meza has no disclosures to report. Nancy Moore has no disclosures to report. Robert Motl has no disclosures to report. Maria Assunta Rocca received speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva, and receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Brian Sandroff has no disclosures to report. Anthony Feinstein is on Advisory Boards for Akili Interactive and Roche, and reports grants from the MS Society of Canada, book royalties from Johns Hopkins University Press, Cambridge University Press, Amadeus Press and Glitterati Editions, and speaker's honoraria from Novartis, Biogen, Roche and Sanofi Genzyme. Massimo Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Associate Editor of Radiology, and Associate Editor of Neurological Sciences; received compensation for consulting services and/or speaking activities from Alexion, Almirall, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Sleep, physical activity (PA) and sedentary behavior (SED) have bidirectional associations with mental health in children. The relationships among sleep, PA, SED, with depressive and fatigue symptoms have not been investigated in Pediatric Onset Multiple Sclerosis (POMS) but are needed to inform sleep and PA behavior change interventions., Objectives: (1) To describe sleep quality including: sleep efficiency, latency, total sleep time, number of awakenings, time in bed, and wake after sleep onset using actigraphy in children and adolescents ages 11 to 18 diagnosed with POMS, and to compare these sleep metrics to those of an age- and sex-matched non-MS group (2) To examine the relationship between time spent in sedentary, light (LIPA), moderate and vigorous PA (MVPA), sleep quality, with depression, fatigue, and quality of life in children and adolescents with POMS and an age and sex matched non-MS group., Methods: A cross-sectional study recruited children and adolescents with POMS ages 11 to 18 years followed at a tertiary pediatric hospital (Toronto, Canada) and an age and sex matched non-MS group from the general population. Participants were consented prior to initiation of study procedures. Participants wore an Actiwatch monitor and GT3X accelerometer and completed standardized questionnaires validated to capture data on sleep disturbances, depression, fatigue, and quality of life. Objective sleep data were collected using an Actiwatch including sleep efficiency, total sleep time, number of awakenings, wake after sleep onset (WASO), and sleep latency. A GT3X accelerometer was used to collect PA data including time spent in SED, light (LPA), and moderate to vigorous (MVPA) PA. Correlational analyses and tests of difference were used to compare the groups., Results: 25 POMS (21F; 16.6 years ±1.1 yrs., median Expanded Disability Status Scale (EDSS) =1.5, IQR=1) and 25 Non-MS (22 F; 16±1.3 yrs.) took part. POMS had higher BMI (T= -5.1, P<0.001) compared to Non-MS. No differences in sleep efficiency (MS mean = 87%, vs. 88%) sleep time (MS Mean = 7.3 hrs. vs. 7.4 hrs.,), WASO (MS mean=37 mins. vs. 36 mins), latency (MS mean=15 mins vs. 11 mins), SED (MS mean =763 mins. vs. 730 mins) or PA (MS, mean LPA = 68 mins. vs 60 mins; MS mean MVPA = 12.7 mins. vs. 12.4 mins). Within POMS, higher sleep efficiency was associated with more SED (SR= 0.4, p = 0.05), while higher sleep efficiency was associated with less SED in Non-MS (SR = -0.7, p< 0.0). In children with POMS, less sleep time, shorter sleep onset latency and more WASO was associated with more SED (SR range = -0.45 to -0.58, P< 0.01). Higher sleep efficiency was associated with less fatigue. Less WASO was associated with lower depression, lower fatigue (SR = 0.67, p<0.01) and better quality of life (SR= -0.6, p<0.01). Greater LPA was associated with lower sleep onset latency (-0.45, p<0.05)., Conclusions: Children with POMS did not differ in Actiwatch monitored sleep quality metrics. However, within the POMS group sleep quality was associated with better fatigue, depression and QOL. Further, total sleep time, WASO and latency associated with time spent SED and LPA, which independently associate with mental health outcome. Longitudinal work should determine the temporal associations between WASO, sleep latency, sleep time, PA, and mental health outcomes and whether reallocation of specific sleep or PA behaviors (time to sleep, total sleep time, sedentary to MVPA) result in improved depression fatigue, or quality of life in children and adolescents with POMS., Competing Interests: Declaration of Competing Interest Samantha Stephens has no declarations of interest. Robert Motl has no declarations of interest. Marcia Finlayson, has no declarations of interest; Dr. Indra Narang has no declarations of interest; Shelly Weiss has no declaration of interest; Dr. Ann Yeh has received research funding from NMSS, CMSC, CIHR, NIH, OIRM, SCN, CBMH Chase an Idea, SickKids Foundation, Rare Diseases Foundation, MS Scientific Foundation, McLaughlin center, Leong Center, Peterson Foundation. Investigator initiated research funding from Biogen. Scientific advisory: Hoffman-LaRoche.  Speaker honoraria: Biogen, Saudi Epilepsy Society, NYU, MS-ATL; ACRS, PRIME, CNPS., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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: 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.)

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: Physiological factors such as muscle weakness and balance could explain declines in walking distance by multiple sclerosis (MS) patients. The purpose of this study was to characterize levels and examine associations among decline in walking distance, balance and muscular strength in women with mild MS., Methods: Participants included 28 women with mild relapsing-remitting MS and 21 women without MS. We executed the 6-min walk test (6MWT) to verify declines in walking distance. Isokinetic knee flexion (KF) and extension (KE) muscle strength was measured using a dynamometer. Balance was quantified using a force platform, with eyes open and closed, on a rigid and foam surface., Results: The MS patients presented declines in walking, lower KF muscle strength, and worse balance than controls. KF strength and balance correlated with walking in the MS group. The KF strength explained differences between groups in walking. The KF strength and balance presented as predictors of walking slowing down in the 6MWT, in mild MS., Conclusion: Women with mild MS have strength impairment of knee flexor muscles and balance control impairment that may explain walking related motor fatigability during prolonged walking., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: There has been remarkable growth in research examining physical activity behavior (any bodily movement produced by skeletal muscle contraction that results in energy expenditure) among people living with multiple sclerosis (MS) over the past decade. The current meta-analysis quantified physical activity participation levels in persons with MS compared with non-diseased and other clinical populations., Methods: We searched PUBMED, PsycINFO and Web of Science using the keywords physical activity, exercise, and physical fitness in conjunction with MS. We conducted a quantitative synthesis of the difference in physical activity participation levels among persons with MS compared with non-diseased populations and other clinical populations and then examined moderators that might explain variation in the overall effect size (ES)., Results: 21 studies were included involving 5303 persons with MS and yielded a mean ES of -0.57 (95% CI=-0.76, 60.37). The weighted mean ES was heterogeneous (Q=443.811, df=31, p<0.001). The magnitude of the mean ES increased when comparing the MS population with non-diseased populations, but decreased when comparing MS with clinical populations., Conclusion: The cumulative evidence reinforces that persons with MS are less physically active than non-diseased, but not clinical populations, and this observation supports the need for new efforts on promoting physical activity across the MS community., (Copyright © 2017 Elsevier B.V. All rights reserved.)