The benefits of exercise training in multiple sclerosis

The benefits of exercise training in multiple sclerosis Robert W. Motl and Lara A. Pilutti Abstract Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelination and neurodegeneration within the CNS. This damage of CNS structures leads to deficits of body functions, which, in turn, affect patient activities, such as walking, and participation. The pathogenesis and resulting consequences of MS have been described as concepts within the International Classification of Functioning, Disability and Health (ICF) model an international standard to describe and measure health and disability. Evidence suggests that exercise training in people with MS has the potential to target and improve many of the components outlined in the ICF model. Although the body of research examining the effects of exercise training on depression, cognition and participatory outcomes is not sufficiently developed, some preliminary evidence is promising. Exercise training is proposed to affect inflammation, neurodegeneration, and CNS structures, but current evidence is limited. In this Review, we discuss evidence from clinical trials that suggests beneficial effects of exercise training on muscle strength, aerobic capacity and walking performance, and on fatigue, gait, balance and quality of life. Issues with current studies and areas of future research are highlighted. Motl, R. W. & Pilutti, L. A. Nat. Rev. Neurol. advance online publication 24 July 2012; doi:10.1038/nrneurol.2012.136 REVIEWS Introduction Multiple sclerosis (MS) is an immune-mediated disease of the CNS that occurs in genetically susceptible people, although susceptibility may be jointly influenced by environ mental factors. 1 MS has a prevalence of 1 per 1,000 adults in the USA, and occurs most frequently in young and middle-aged women of European descent. 2,3 The pathogenesis and associated consequences of MS have been described using the International Classification of Functioning, Disability and Health (ICF) model. 4 This model provides a standard language and framework that can be adopted by clinicians and researchers for understanding health and health-related states. 4 According to the ICF framework, disability in MS is described in terms of body structure, body function, patient activity and participation (Figure 1). 5 The pathogenesis of MS involves inflammatory demyelination of axons within the CNS, with neurodegenerative processes resulting in loss of axons and neurons the CNS body structures. Modifications of body functions in MS include changes in mental functions, often manifesting as fatigue or depression, which occur as a result of axonal demyelination in brain locations that are involved in processing these emotions. 1 Over time, repeated episodes of disease activity and associated axonal and neuronal damage typically manifest in the further loss of mental functions (cognitive impairment) and loss of other body functions, such as cardiovascular function (observed as aerobic Competing interests The authors declare no competing interests. intolerance), neuromusculoskeletal and movement function (often manifesting as muscle weakness and/ or impaired gait), and sensory function (manifesting as imbalance). 1 These changes in body functions lead to altered patient activity impairment of walking performance is a hallmark presentation of MS 6 which can affect participation outcomes such as quality of life (QOL), activities of daily living (ADLs), and levels of recreation, leisure and work. 7 Physical inacti vity, or adoption of a sedentary lifestyle, is common in patients with MS, 8 and can initiate a cycle of deconditioning and worsening of symptoms. 9 By contrast, physical activity behaviour, particularly exercise training, may have benefi cial effects on the various processes of MS outlin ed in the ICF model (Figure 1). 10 In this Review, we present and discuss data from clinical trials (that is, prospective research with human patients to examine the effectiveness of an intervention) that investigated the benefits of exercise training on pathogenesis, CNS structures, body functions, activities and participation in people with MS (Tables 1 and 2). Cross-sectional, prospective and animal research is discussed in areas in which clinical trial data are sparse. Although other literature reviews and meta-analyses on exercise training in patients with MS exist, 11 19 none has comprehensively examined the effects of exercise training on outcomes described in the ICF model. Here, we identify points on the ICF framework for MS in which exercise training may have beneficial effects (Figure 1), and suggest possible mechanistic pathways for the po sitive consequences of exercise training. Department of Kinesiology and Community Health, University of Illinois, Urbana-Champaign, 233 Freer Hall, Urbana, IL 61801, USA (R. W. Motl, L. A. Pilutti). Correspondence to: R. W. Motl robmotl@illinois.edu NATURE REVIEWS NEUROLOGY ADVANCE ONLINE PUBLICATION 1

Key points Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease that results in the progressive accumulation of mental and physical symptoms The International Classification of Functioning, Disability and Health (ICF) model for MS describes pathogenesis and downstream consequences on CNS structures, body functions, patient activities and participation Exercise training has beneficial effects on muscular strength, aerobic capacity and ambulatory performance, and may improve fatigue, gait, balance and quality of life in patients with MS Effects of exercise training on MS pathogenesis, CNS structures, depression, cognition, and participation outcomes have not been adequately investigated or consistently supported Exercise training has meaningful consequences in people with MS, and continued investigation will further elucidate the range of benefits of exercise on the various constructs of the ICF model Exercise: definition and prescription Throughout this article, the term exercise training is used to describe planned, structured and repetitive physical activity undertaken over a prolonged period to maintain or improve physical fitness and functional capacity. 20 This definition includes aerobic exercise training such as cycling or walking, progressive resistance exercise or weight training, and nontraditional exercise training (such as yoga), some of which have been examined in patients with MS (Box 1). Leg cycling exercise is often adopted for safety and avoidance of trips, slips and falls that can occur because of drop foot during treadmill walking. Progressive resistance exercise of the lower extremities is undertaken to improve muscle weakness or side-to-side strength asymmetry, which can affect walking in patients with MS. Body-weight-supported treadmill training is typically prescribed for gait rehabilitation in severely affected people with MS. The choice of a mode for exercise training is often driven by personal preferences, accessibility, and capacity of patients, but no mode of training has been universally agreed upon in patients with MS. Two sets of authors have presented recommendations for the structuring of exercise training programmes in patients with MS. 21,22 The first group recommended 20 30 min of aerobic exercise, 3 days per week at 65% maximal oxygen consumption (VO 2peak ), with 5-min periods of both warm-up and cool-down. 21 The authors of the paper point out that duration of exercise might require a gradual progression up to 20 30 min, and intermittent exercise may be necessary during an initial adaptation period for those with severe fatigue. The authors recommended a separate strength training exercise (three sets of 10 12 repetitions through the full range of motion [ROM], with moderate fatigue occurring in the third set) for all major muscle groups. Such recommendations are ideal for patients with MS who demonstrate adequate functional capabilities, conditioning and motivation, but must be modified for people with motor deficits; for example, to involve only passive ROM in patients with severe paresis. 21 No prescription for combined aerobic and resistance training was made. The second group made recommendations for aerobic and strength exercise, as well as combined training, in MS. 22 With regard to aerobic exercise, the recommended modes were cycle ergometry, arm leg ergometry, aquatic exercise, and treadmill walking, at a frequency and intensity of 2 3 days per week at 50 70% VO 2peak or 60 80% of maximal heart rate (HR max ) for a duration of 10 40 min, depending on disability level. With regard to strength training, the recommended mode was with machines that target large muscle groups, particularly those in the lower extremities. Four to eight exercises at a frequency of 2 3 days per week at an intensity range of 8 15 repetition maximum (RM) 15 RM during the initial training phase and 8 10 RM after several months were suggested. The number of sets recommended was initially between one and three, increasing towards three or four sets over time. When combining aerobic and strength training, equal portions should be performed 2 days per week on alternate days with 24 48 h for recovery, using the aforementioned training programme guidelines. The above prescriptions were not based on a systematic literature review among people with MS, as was done in the case of spinal cord injury another chronic, disabling condition. 23 We recommend that researchers adopt the Appraisal of Guidelines, Research and Evaluation II guideline development protocol 24 26 for rigorously develop ing exercise training guidelines among people with MS. Until then, the existing general recommendations 21,22 serve as a reasonable starting point for prescriptive purposes among patients, clinicians, researchers and fitness professionals. Importantly, standardiza tion of the typical exercise prescription is limited, and this is likely to be a contributing factor in the variability of o utcomes between the studies that are reviewed below. Effects on MS pathogenesis Inflammatory factors Inflammation and neurodegeneration are key processes that lead to the damage of CNS structures in MS. Dysregulation of the inflammatory balance in favour of a proinflammatory state is characteristic of MS, 27 and may represent a potential target for modulation via exer cise training. 28 Two randomized controlled trials (RCTs) and two pre post single-group clinical trials have provided mixed conclusions regarding the effects of exercise training on peripheral proinflammatory and anti-inflammatory markers in people with MS. 29 32 In one RCT, involving 20 people with relapsing remitting MS (Expanded Disability Status Scale [EDSS] scores 0.0 4.0), a supervised, 8-week training programme that combined aerobic and resistance exercise (20 min per exercise mode on 3 days per week) was investigated. 29 Statistically significant decreases in systemic levels of the proinflammatory cytokines IFN-γ and IL-17, but not of the anti-inflammatory cytokine IL-4, were observed following exercise compared with a non-exercise control. 29 Conversely, another trial reported no change in levels of the proinflammatory cytokine IL-6 after an 8-week aerobic exercise intervention (30 min of leg cycling at 60% VO 2peak, 2 days per week) in 15 people with MS (mean EDSS score 2.0) compared with 13 non- exercising patients with MS (mean EDSS score 2.5). 30 Overall, some evidence suggests that exercise training may alter 2 ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol

Physical activity behaviour Exercise training Lifestyle behaviour ICF model of MS MS pathogenesis Inflammation Neurodegeneration Body structures (CNS) Axonal damage or loss Neuronal loss Body functions Mental: fatigue, depression, cognition Cardiovascular: aerobic power Neuromusculoskeletal: gait, muscle strength Sensory: balance Activities Walking performance Participation Quality of life Activities of daily living Recreation, leisure and work Figure 1 Interactions between exercise and the ICF model of MS pathogenesis. The ICF model outlines the consequences of MS pathogenesis, including effects on structure and function of the body, and on patient activities and participation. Exercise could have beneficial effects at each of these stages, from influences on cellular processes, such as reduction of inflammation, to improved patient participation in the community. Abbreviations: ICF, International Classification of Functioning, Disability and Health; MS, multiple sclerosis. peripheral inflammatory markers, but this research area is not sufficiently developed. Neurotrophic factors Neurotrophic factors are involved in neuroprotection, neuroplasticity, and maintenance of neuronal health. Consequently, these factors might mediate the effects of exercise training on CNS structures and body functions that have been observed in research on animals and aged humans. 33 Two studies have examined exercise training effects on brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and insulin-like growth factor (IGF-1) in people with MS. 30,34 One 8-week RCT of aerobic exercise (30 min of leg cycling at 60% VO 2peak, 2 days per week) reported no change in resting levels of serum BDNF and NGF in 15 people with MS (mean EDSS score 2.0) compared with 13 non- exercising patents with MS (mean EDSS score 2.5). 30 Another 8-week pre post single-group clinical trial of aerobic exercise (30 min of leg cycle ergometry at 60% VO 2peak, 3 days per week) reported no change in resting BDNF or IGF-1 levels in 11 people with relapsing remitting MS (EDSS scores 0.0 5.5). 34 Collectively, the currently available evidence does not support an effect of exercise training on neurotrophic factors in people with MS, although this conclusion is based on two clinical trials that assayed systemic samples. Additional research using samples from cerebrospinal fluid is warranted. Effects on CNS structures MS is a disease that involves damage of white and grey matter tissue, and such damage is eventually associated with the loss of body functions. No research has yet examined the effects of exercise training on brain structure in people with MS. However, data are available from cross-sectional studies on the effects of aerobic fitness on brain grey matter volume and white matter tract integrity, 35 as well as on the influence of physical activity on resting-state functional connectivity of the hippocampus and cortex 36 in people with MS. For example, one study in a sample of 21 people with MS (EDSS scores 0 6) found high aerobic capacity or VO 2peak to correlate positively with grey matter volume in the right postcentral gyrus and midline cortical structures (namely, the medial frontal gyrus, anterior cingulate cortex and precuneus), and to be associated with high fractional anisotropy in the left thalamic radiation and right anterior corona radiata, and with low lesion load. 35 Such cross-sectional evidence is supported by data showing the positive effects of exercise training on reducing striatal synaptic and dendritic abnormalities in the experimental auto immune encephalomyelitis animal model of MS. 37 A wealth of data in the gerontology literature regarding aerobic fitness and exercise training effects on preservation of brain structure 38 40 indicates that such adaptations account for improvements in cognition. 41 43 Collectively, there is promising, yet nascent, research supporting the consideration of exercise training effects on CNS structures in MS, and this evidence parallels the large, well-developed body of literature showing the bene ficial effects of exercise on brain structure and function in older adults. Effects on body functions Mental functions Changes in mental functions in patients with MS (often manifesting as fatigue, depression and impaired cognition) largely depend on the extent and location of damage within the CNS. For example, many patients with MS have impairments in cognitive processing speed; 44 such impairment is associated with whole-brain atrophy 45 and topo graphically specific atrophy within the frontal and tem poral cortices. 46,47 Cognitive impairment negatively affects activities, such as ability to work or drive, and participation outcomes, such as QOL, in patients with MS. 48 The prevalence and downstream consequences of fatigue and depression parallel those seen with impaired cognition. Fatigue Over 20 clinical trials have examined the effect of exercise training on fatigue in people with MS, 30,49 71 with NATURE REVIEWS NEUROLOGY ADVANCE ONLINE PUBLICATION 3

Table 1 Evidence for the effects of exercise training on pathogenesis, body structure and body function in MS ICF outcome n Participant characteristics* Design and intervention Results Multiple sclerosis pathogenesis Inflammation 32 11 Age: 40.0 years (10.0 years) EDSS range: 0.0 5.5 Course: RR Duration: not reported Neurodegeneration 30 28 Age: 39.0 years (9.0 years) exercise, 40.0 years (11.0 years) control EDSS: 2.0 (1.4) exercise, 2.5 (0.8) control Course: RR, SP, PP Duration: 11.4 years (1.6 years) for all Body structures Axonal and neuronal loss 35 21 Age: 44.2 years (1.9 years) EDSS: 2.2 (range 0 6) Course: RR Duration: 7.3 years (0.1 years) Body functions Fatigue 50 24 Age: 40.5 years (12.7 years) EDSS: not reported (ambulatory without aid) Course: RR, SP Duration: 5.4 years (4.4 years) Depression 58 47 Age: 41.1 years (2.0 years) EDSS: 3.8 (0.3) Duration: 9.3 years (1.6 years) Cognition 74 95 Age: 43.8 years (6.3 years) EDSS: median (IQR) 2.0 (1.5 3.5) exercise, 2.5, (2.0 3.5) control Duration: 6.0 years (6.5 years) exercise, 5.5 years (6.4 years) control Aerobic capacity 65 19 Age: 41.0 years (8.0 years) EDSS: 3.5 (median) Duration: 8.0 years (5.0 years) Muscular strength 75 38 Age: 47.7 years (10.4 years) EDSS: 3.7 (0.9) Course: RR Duration: 6.6 years (5.9 years) Gait 99 8 Age: 46.0 years (11.5 years) EDSS range: 2.5 5.5 Course: RR Duration: not reported Balance 62 10 Age: 50.0 years (11.9 years) EDSS: 5.0 (range 3.0 6.5) Duration: 16.0 years (11.5 years) Design: pre post trial Mode: leg ergometry Mode: leg ergometry Supervised: not reported Design: cross-sectional Mode: not applicable Supervised: not applicable Mode: variety of activities (treadmill, cycling, StairMaster, arm-strengthening, volleyball, outdoor walking) (2 /week), no (1 /week) Mode: leg and arm ergometry Mode: week 1 3 inpatient rehabilitation (5 /week RT Thera-Bands, 5 /week AT), week 4 26 at-home exercise (4 /week RT, 1 /week AT) (weeks 1 3), no (weeks 4 26) with crossover Mode: leg ergometry Mode: progressive lower-extremity RT (five exercises) Design: pre post trial Mode: progressive lower-extremity RT (five exercises) Design: pre post trial Mode: group core stability, stretching class IFN-γ, tumour necrosis factor-α IL-6 (trend) Brain-derived neurotrophic factor, nerve growth factor CR associated with structural brain integrity and lesion load Fatigue (Modified Fatigue Impact Scale) Depression (Profile of Mood States) at week 5 and 10 Depression at week 15 Paced Auditory Serial Addition Task Maximal oxygen consumption Peak power output Maximum isometric strength knee flexors and extensors % GC in stance and swing phases % GC in double support phase Step and stride length Balance (Berg Balance Scale) *EDSS and disease duration reported as mean (SD) unless other wise noted. increase; decrease; no statistically significant change. Thera-Bands (The Hygenic Corporation, Akron, OH). Abbreviations: AT, aerobic training; CP, chronic progressive; CR, cardiorespiratory fitness; EDSS; Expanded Disability Status Scale; GC, gait cycle; IQR, interquartile range; PP, primary progressive; RP, relapsing progressive; RR, relapsing remitting; SP, secondary progressive; RCT, randomized controlled trial; RT, resistance training. both positive and null outcomes reported. Some studies described improvements in fatigue following aerobic exercise, 50 52 resistance exercise, 53,71 a combination of both, 54 or yoga, 51 whereas other studies reported no beneficial changes in fatigue after exercise training. 30,55 58 One pilot RCT, involving 24 independently ambulatory people with early MS, compared the effects of aerobic exercise training (40 min of leg ergometry or treadmill walking at light-to-moderate intensity, 2 days per week under supervision, and self-selected, home-based exercise, 1 day per week) on Modified Fatigue Impact Scale scores versus a control condition (monthly visit with physiotherapist). 50 Aerobic exercise led to a reduction in fatigue that was maintained for 12 weeks after the intervention, whereas no changes were observed in the control group. This finding contrasts with results from another RCT in which no difference in Fatigue Severity Scale score was reported between aerobic exercise (30 min of cycle ergometry at aerobic threshold four times per week for 3 4 weeks) and control (normal physical therapy) in 26 people with MS (EDSS scores 1.0 6.5). 56 4 ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol

Table 2 Evidence for the effects of exercise training on activities and participation outcomes in MS ICF outcome n Participant characteristics* Design and intervention Activities Ambulatory performance 67 16 Age range: 30 65 years EDSS: not reported Duration: not reported Participation Quality of life 111 22 Age: 47.2 years (4.8 years) EDSS range: 0 5 Duration: 7.0 years (5.6 years) Activities of daily living 93 29 Age: 49.7 years (11.0 years) RAGT, 51.0 years (15.5 years) CWT EDSS: median 6.5 Course: RR, SP, PP Duration: 15.0 years (8.0 years) RAGT, 15.0 years (9.0 years) CWT Recreation, leisure and work 58 26 Age: 45.2 years (8.7 years) EDSS range: 2.5 6.5 Course: RR, CP, RP Duration: 11.2 years (8.5 years) Mode: treadmill walking Mode: water-based aerobic activity Mode: RAGT Mode: leg ergometry Results 10-metre timed walk performance Health-related quality of life (MS Quality of Life 54) Activities of daily living (Extended Barthel Index) Sport-related activity Work- and leisure time-related activity (Baecke Activity Questionnaire) *EDSS and disease duration reported as mean (SD) unless otherwise noted. Increase; no statistically significant change. Abbreviations: CP, chronic progressive; CWT, conventional walking training; EDSS, Expanded Disability Status Scale; ICF, International Classification of Functioning, Disability and Health; MS; multiple sclerosis; PP, primary progressive; RAGT, robot-assisted gait training; RP, relapsing progressive; RR, relapsing remitting; SP, secondary progressive; RCT, randomized controlled trial. These studies show that exercise training does not worsen and might actually improve symptomatic fatigue in people with MS, although, notably, the trials were not designed to test the possibility of fatigue worsening with exercise training. According to one meta- analysis, exercise training results in a 0.19-SD improvement in fatigue, but with substantial hetero geneity between studies, 72 as was also noted in another literature review. 11 The fact that the researchers in many of the examined studies did not focus on people with elevated fatigue may be one explanation for this heterogeneity. 11,73 Depression Beyond fatigue, examinations have been performed to determine the effects of exercise training on symptoms of depression in people with MS. Two studies provided evidence supporting beneficial effects on depression, 53,59 whereas six studies reported either no sustained improvement or no change in depressive symptoms following exercise training. 30,51,55,58,66,74 One RCT compared the effect of supervised progressive resistance training (lower-extremity progressive resistance exercise on 2 days per week for 12 weeks) versus control (delayed exercise) on depressive mood in 38 people with MS (relapsing remitting clinical course, EDSS scores 3.0 5.5). 53 Notably, depression was a secondary outcome of the primary trial, which focused on strength and function. 75 A statistically significant improvement in depressive mood was observed in the exercise group, but not in the control group, after the 12-week intervention period. Of note, the control group did not demonstrate an improvement in depressive mood during the delayed exercise administration, suggesting inconsistency in the pattern of change in depressive mood with exercise training in MS. Box 1 Exercise training modalities in MS patients Exercise training in people with multiple sclerosis (MS) has included aerobic, resistance, combined aerobic and resistance, alternative, and adapted training modalities. The most commonly used mode of aerobic training in people with MS has been leg cycle ergometry, either alone or in combination with arm ergometry, and treadmill walking has also been used. 58 Resistance training protocols have included traditional weight machines, free weights, Thera-Bands (The Hygenic Corporation, Akron, OH), and weighted-vest and body-weight exercises. 75 Combined aerobic and resistance training protocols have included various combinations of the above-described aerobic and resistance training modalities. 29 Alternative exercise training protocols have included yoga, balance and core stability training, aquatic exercise, and sport climbing. 62 For individuals with advanced MS and mobility limitations, adapted exercise modalities have been used, such as body-weight-supported treadmill walking with or without robotic assistance. 60 Abbreviation: MS, multiple sclerosis. Another RCT examined the effect of supervised aerobic exercise training (a 15-week programme of 30 min of arm and leg ergometry at 60% VO 2peak, 3 days per week) versus a control condition (delayed exercise) on depressive mood in people with MS (mean EDSS scores of 3.8 and 2.9 for exercise and control groups, respectively). Exercise training resulted in transient improvements of depressive mood during the first 5 and 10 weeks of the intervention, but such effects were not maintained immediately after the 15-week intervention. 58 The inclusion of MS patients without depressive symptoms in RCTs of exercise training may be one explanation for such inconsistencies, 66 particularly given that exercise NATURE REVIEWS NEUROLOGY ADVANCE ONLINE PUBLICATION 5

training is effective for managing this symptom in the general (non-ms) population of adults with depression. Cognition Only two RCTs have examined exercise training effects on cognition in people with MS, with null results. One of these RCTs examined the effects of a 26-week intervention that combined supervised (weeks 1 3) and unsupervised (weeks 4 26) resistance exercise training, performed on 3 4 days per week using elastic bands, with aerobic exercise training on 1 day per week, compared with a control intervention (delayed inpatient rehabilitation). 74 The primary outcome change in Multiple Sclerosis Functional Composite (MSFC) scores was measured in the trial cohort of 95 people with MS, with median EDSS scores of 2.0 and 2.5 for exercise and control groups, respectively. 74 An improvement in overall MSFC scores was observed in the intervention group compared with the control group, although cognition, measured using the Paced Auditory Serial Addition Task (PASAT), showed no significant change with exercise training compared with control. The other RCT examined the effects of a 6 month period of aerobic exercise (supervised, very-light-to-moderateintensity cycle ergometry with occasional Swiss ball exercises on 1 day per week, combined with encouragement of regular home exercise), yoga (90 min of supervised Iyengar yoga, 1 day per week, with encouragement of daily home practice), or wait-list control. Primary outcomes involved a battery of cognitive tests, including the Stroop Color Word Task, Cambridge Neuropsychological Test Automated Battery, modified Useful Field of View task, and PASAT, measured in 57 people with MS (EDSS scores 1.5 6.0). 51 Overall, exercise had no effect on any measure of cognition. The nature of the exercise training stimulus itself (that is, low-intensity, infrequent weekly routine, and/ or largely unsupervised delivery) could explain the null results in these two RCTs. The exercise training stimuli were not as rigorous as those used in the gerontology field, 76 wherein consistent evidence for improved cognition after exercise training is found. 42,77 On a positive note, aerobic fitness and physical activity have been associ ated with better cognition in cross-sectional studies of people with MS who have vastly differing levels of disability (mean EDSS score 2.6 and median EDSS score 6.0, respectively). 78,79 This initial cross-sectional evidence combined with the gerontology literature 39,42,80 has prompted interest in the continued investigation of exercise training and cognition in MS. 76 Other body functions MS-related axonal damage and neurodegeneration are likely to contribute to the impairment of other body functions, such as cardiovascular, neuromusculoskeletal, movement and sensory functions. 81,82 Muscle strength and aerobic capacity are reduced in people with MS, 83,84 and imbalance is common and debilitating in these individuals. 7 Spatiotemporal gait parameters are also altered in people with MS. 85,86 Such impairments of body functions contribute to limitations in activities, and restrictions in participation. 7,13 Neuromusculoskeletal function Evidence exists for beneficial effects of exercise training on muscle strength in people with MS. Results from single-group pre post RCTs show that muscle strength improves following resistance training, 49,71,75,87 91 combined aerobic and resistance training, 54 aquatic training, 92 and robot-assisted gait training. 93 One RCT compared the effects of supervised progressive resistance training (lower-extremity progressive resistance exercise on 2 days per week for 12 weeks) versus control (delayed treatment) on maximum isometric strength of the knee extensors and flexors in 38 people with relapsing remitting MS (EDSS scores 3.0 5.5). 75 Compared with baseline strength, a significant improvement in maximum isometric strength of both muscles was observed in the exercise group, but not in the control group, after the 12-week intervention period. Importantly, the changes in strength were maintained during a 12-week period of self-guided exercise after the intervention, and similar improvements in strength were obtained for the control group during the delayed 12-week period of training. One recent review indicated that progressive resistance training exercise increases lower-extremity muscle strength in people with MS, and that the improvements are restricted to the muscle groups targeted during training; 73 notably, this specificity of change in muscles targeted during training is not unique to individuals with MS. Cardiovascular function Support for the beneficial effects of exercise training on aerobic fitness in people with MS has been consistent. RCTs and single-group pre post studies have reported improvements in aerobic fitness, assessed as VO 2peak and peak power output (W peak ), after aerobic exercise training, 30,32,56 58,65,94 96 as well as after combined aerobic, resistance and stretching exercise. 29 For example, one RCT with crossover compared the effects of aerobic exercise training (30 min of leg cycling at 60% W peak, 3 days per week over 8 weeks) and neurological rehabilitation (comparable frequency and duration of respiratory postural and respiratory motor synergies and stretching) on maximal exercise tolerance in 19 people with MS who had mild-to-moderate dis ability (median EDSS score 3.5). 65 Statistically significant increases in VO 2peak and W peak were observed in those who followed the aerobic exercise training programme, but not in those who received neuro logical rehabilitation. A quasi- experimental study compared the effects of aerobic exercise training (30 min of combined arm and leg ergometry at 55 60% VO 2peak, 3 days per week over a 6-month period) versus control (no treatment) on VO 2peak in 23 people with MS. 96 Changes in aerobic fitness were compared between people classified as ambulatory (n = 11, EDSS scores 1.0 4.5) and semiambulatory (n = 8, EDSS scores 5.0 6.5). 96 Ambulatory and semi-ambulatory people who engaged in aerobic 6 ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol

exercise showed 19% and 7% improvements in VO 2peak, respectively, but those in the control group showed a 12% decline in this parameter. Collectively, the evidence supports the beneficial effects of aerobic exercise training on aerobic fitness in people with MS, but the effects might be greater in those who are ambulatory and perhaps have a capacity for undertaking larger volumes of training. If correct, this would highlight the importance of identifying training modalities other than traditional arm and/or leg cycle ergometry (such as the NuStep [NuStep Inc., Ann Arbor, MI] recumbent arm and leg cross-trainer) for increasing aerobic fitness in those who have ambulatory problems. Movement and sensory functions Research examining exercise training effects on balance and gait parameters in MS is limited. The four singlegroup pre post studies that have been performed indicate that combined aerobic, resistance and stretching exercise, 29 aquatic training, 68,97 and group stability exercise 62 improve balance outcomes. One of these pilot studies, involving 10 people with MS (EDSS scores 3.0 6.5), reported that 10 weeks of stretching and core stability training for 1 h per week improved balance, as assessed using the Berg Balance Scale. 62 Only one small pilot RCT and three single-group pre post trials have examined the effects of exercise training on gait parameters in MS, 95,98 100 with three of these studies indicating beneficial effects of training. 98 100 In one study, involving eight people with MS (EDSS scores 2.5 5.5), 8 weeks of twice-weekly lower-extremity, progressive resistance training improved the percentage of the gait cycle spent in double-support, stance and swing phases, as well as step and stride length. 99 Overall, exercise training has been shown to improve balance and gait parameters, but the evidence is based on a limited number of largely nonrandomized controlled trials. Effects on activities The progressive accumulation of deficits in body functions limits the capacity of people with MS to perform activities, particularly those that require the patient to walk. The progressive loss of ambulation is a hallmark feature of MS, affecting upwards of 80% of patients, and results in compromised participation, including loss of social en gagement, unemployment, and compromised QOL. 7 Over 25 clinical trials have examined the effect of exercise training on ambulatory outcomes in people with MS. 49,55,59,60,62 68,71,75,88 91,93,97,98,100 105 Walking speed (measured using the Timed 25-Foot Walk [T25FW] test and 10-metre walk test) and endurance (measured over 2-min and 6-min walks) are the most commonly assessed outcomes of ambulation in these studies. Walking speed is shown to improve following combined or isolated aerobic or resistance training, 59,67,75,89,91,100 as well as after calisthenic, stability or aquatic training. 68,97,104,105 One RCT with crossover compared the effects of aerobic exercise training (30 min of treadmill training at 55 85% HR max, 3 days per week over an 8-week period) and control (delayed treatment) on 10-metre walk performance in 16 people with MS who could walk 10 m in <60 s using an aid if necessary. 67 A statistically significant reduction in baseline 10-metre walk time was seen in those who took part in aerobic exercise training, but not in controls. Improvements in walking endurance are primarily seen following aerobic training, 55,65,66,101,102 but resistance training 66,75 or combined aerobic and resistance training exercise 91 have also shown benefits on this outcome. A randomized comparator trial examined the change on 2 min walk distance after supervised continuous (20 min at 45% W peak ), intermittent (20 min of cycles consisting of 30 s at 90% W peak followed by 30 s rest), and combined (10 min each of continuous and intermittent training) exercise performed on 2 days per week over 12 weeks. 101 This study involved 61 adults with MS who could walk with or without assistance. A statistically significant increase in 2-min walk distance was observed after 6 weeks of training in all three aerobic exercise conditions, but additional changes were not observed over the remainder of the 12-week intervention. Interestingly, walking speed and endurance have both been shown to improve following robot-assisted treadmill training in people with MS who have gait impairment, 93,103 which may reflect an effect of the task-specific nature of this training modality. Such improvements were observed after 15 sessions of bodyweight- supported treadmill training with the Lokomat (Hocoma AG, Volketswil) robot assisted treadmill in 14 people with MS with a median EDSS score of 6.5 (range 6.0 7.5), 93 and after six training sessions of body-weightsupported treadmill training with or without Lokomat in 13 people with MS with a mean EDSS score of 4.9. 103 Collectively, the evidence supports beneficial effects of exercise training on walking speed and endurance in people with MS, as quantified in a meta-analysis, 106 and such improvements may be associated with changes in body functions. 13 One caveat is that many studies have not focused on people who have walking impairment, as defined by EDSS or T25FW thresholds, thereby limiting our understanding of exercise training effects on am bulation in this population with severe disability. Effects on participation The consequences of MS ultimately include compromised QOL and ADLs, and reduced participation in recreation, sport, leisure and work activity. Indeed, QOL is greatly compromised in people with MS compared with both the general population and people living with other chronic diseases and conditions. 107 110 The pervasive downstream influence of MS supports the critical need to identify factors that might mitigate or improve participation outcomes in this population. Quality of life Over 20 clinical trials have examined the effects of exercise training on QOL in people with MS. 30,50 53,55,56, 58 62,65,66,71,74,89,94,101,105,111 Some RCTs have indicated that aerobic and resistance exercise training were effective for improving QOL, 30,53,111 although this improvement NATURE REVIEWS NEUROLOGY ADVANCE ONLINE PUBLICATION 7

Table 3 Effects of exercise training on ICF outcomes Outcome Multiple sclerosis pathogenesis Effect of exercise training* Inflammation 1, 2 Neurodegeneration 1, 2 Body structures Axonal and neuronal loss 3 Body functions Fatigue + 1, 2 Depression 1, 2 Cognition 1, 3 Aerobic capacity ++ 1, 2 Muscular strength ++ 1, 2 Gait + 1, 2 Balance + 2 Activities Ambulatory performance ++ 1, 2 Participation Quality of evidence reviewed Quality of life + 1, 2, 3 Activities of daily living 1, 2, 3 Recreation, leisure and work 1 *, no consistent evidence for a beneficial effect; +, limited, but supportive evidence for a beneficial effect; ++, extensive and consistent supportive evidence for a beneficial effect. 1, randomized controlled trial; 2, pre post single-group design or quasi-experimental design; 3, non-experimental, cross-sectional or prospective design. Abbreviation: ICF, International Classification of Functioning, Disability and Health. was not statistically significant in other trials. 59,94 One RCT examined the effects of 45 min of aerobic aquatic exercise (3 days per week for 10 weeks) versus nonexercise control on QOL measured by the MS Quality of Life-54 (MSQOL-54) in 22 people with MS (EDSS scores 5.0) who had not been involved in exercise over the past 6 months. 111 The exercise condition resulted in moderate improvements in nine of 11 MSQOL-54 dimensions compared with the control condition. By comparison, another RCT examined the effects of exercise (60 min of cycle ergometry at 55% VO 2peak and 13 resistance exercises of major muscle groups, 3 days per week for 5 weeks) versus control (patients kept a diary of physical activity) on QOL measured by the SF-36 (Medical Outcomes Trust, Waltham, MA) health survey in 16 people with MS (EDSS scores 4.0). 94 Only one of eight SF-36 dimensions was improved with exercise training compared with control. Importantly, a metaanalysis indicated that the magnitude of improvement in QOL after exercise training approximated 0.25 SDs, and was larger for disease-specific than for generic QOL measures. 94 This summary evidence is important given the apparent inconsistency in the literature, 16 along with small samples that result in low statistical power per study. On the basis of evidence from cross-sectional and prospective examinations in large samples of people with MS who had mild disability, the effects of exercise training on QOL might be mediated through changes in body functions or activities. 112,113 Activities of daily living Four of six clinical trials have supported supervised exercise training, in the form of robot-assisted gait training, conventional walking training, and three intensities of cycle ergometry, as being effective for improving ADLs in people with MS. 93,101,102,105 Notably, no improvements in ADLs were observed following home-based, non- supervised exercise. 74,114 One study involving 29 people with advanced MS (median EDSS score 6.5) compared the effects of 15 sessions over 3 weeks of supervised, robot-assisted gait training versus conventional walking: 93 improvements were reported in ADLs (measured using Extended Barthel Index scores) after both interventions. Cross-sectional and prospective data indicate that physical activity is positively associated with perceived function and tasks of daily living, independent of symptomatology, in 292 MS patients with mild disability. 115,116 Collectively, this research is not sufficiently developed to generate a conclusion, but initial data are promising for beneficial effects of exercise training on ADLs. Two RCTs have examined exercise training effects on participation in recreation, sport, leisure and work activity among people with MS. 56,117 One of these studies, involving 26 people with MS (EDSS scores 1.0 6.5), indicated that compared with a control regimen (normal physical therapy), aerobic exercise training (30 min of cycle ergometry at aerobic threshold, 4 days per week over 3 4 weeks) improved recreation and sport activity, but not work and leisure activity, as measured using the Baecke Activity Questionnaire. 56 The other study indicated that progressive resistance, lower-extremity exercise training had no effect on work and leisure activity in 38 people with MS (EDSS scores 3.0 5.5). 117 Collectively, the research on participation outcomes is not sufficiently developed to generate a firm conclusion on the benefits of exercise for this ICF domain in patients with MS. Limitations and future research The research examining exercise training in MS has notable limitations, which restrict the conclusions that can be drawn from the literature. These limitations include poor reporting on the sample characteristics (such as type and duration of MS, EDSS score, and use of disease- modifying therapies), the occurrence of adverse events (such as relapses, complications and injuries), and compliance with the prescription (adherence rates or fitness adaptations). Other limitations include selection of samples without consideration for elevated levels of a focal construct, such as fatigue or depression, lack of power analyses for justifying the sample size, and control conditions that do not account for social contact or expectations of benefits. Furthermore, the lack of outcome prioritization based on hypotheses seemingly leads to exploratory analyses with elevated type I error rates. 8 ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol

Given these limitations, there are undoubtedly many areas for future research regarding exercise train ing in MS. Research on exercise training for symptom management in MS is warranted; such research might investigate exercise training effects on pain, insomnia or other sleep problems, and spasticity. The continued investigation of exercise training effects on fatigue, depression and cognition is necessary, but should be conducted in cohorts that are screened for elevated symptoms (based on normative data) to avoid possible floor effects. We see considerable potential for research on the effects of exercise training on gait and balance outcomes, consider ing the limited number of clinical trials in this area and the importance of these outcomes. The effects of exercise training on walking performance, particularly among people with onset of walking impairment, have been understudied: the majority of this research has involved patients with EDSS scores <4.0. On a related note, a need exists for research on exercise training modalities and outcomes in people with advanced MS (that is, with EDSS scores 6.5) and progressive clinical courses, given that traditional modes of exercise train ing may not be accessible or beneficial in these indivi duals. Furthermore, exercise training might have considerable rehabilitation potential 18 among those in whom disease-modifying therapies become less effective. 118 Further insight may be gained from the continued investigations of exercise training effects on ADLs and participation in recreation, sport, leisure and work, given the limited number of clinical trials and the importance of such outcomes. Future research should also examine exercise training effects on MS pathogenesis, particularly during relapses, and on CNS structures. In addition, research on lifestyle physical activity referring to the nonspecific accumulation of activity through one s daily routine, such as walking rather than driving and its consequences in people with MS is lacking. An opportunity exists to directly compare the effects of lifestyle physical activity versus exercise training on outcomes of the ICF model (Figure 1); such investigations will be important for patient flexibility and choice with regard to physical activity. Conclusions In this Review, we have provided a summary of exercise training and its consequences, based on the ICF model for people with MS. Extensive and consistent data support the beneficial effects of exercise training on muscular strength, aerobic capacity, and ambulatory performance. Evidence for a beneficial effect of exercise training on fatigue, balance, gait and QOL is supportive, but not overwhelming. No consistent evidence exists to support the beneficial effects of exercise training on inflammation, neurodegeneration, axonal and neuronal loss, depression, cognition, ADLs, and recreation, leisure and work but, notably, there was no apparent evidence of detrimental or negative effects of exercise training. Information on exercise training in those with EDSS scores of 6.0, or in patients during relapse, is limited. Our understanding of exercise training effects in people with MS is further restricted by both the quantity and quality of available research (Table 3). The continued investigation of exercise training in people with MS will provide further evidence and conclusions regarding potential benefits, ranging from effects on cellular processes through to community participation. These studies will be critical to understanding how physical activity may benefit the lives of people with MS. 119 Review criteria Only full-text, English language articles published up until March 2012 were searched for using the terms exercise, physical activity, exercise prescription, exercise therapy, training, fitness, aerobic, strength, resist, ambulatory activity, walk and multiple sclerosis in Ovid MEDLINE, PsychInfo, EMBASE, PEDro, CINAHL, SportDiscus, and the Cochrane Library. The personal literature databases of the authors were additionally searched for relevant publications. Randomized controlled trials were primarily included, along with nonrandomized or single-group pre post trials, on the effects of exercise training on various outcomes in people with multiple sclerosis, supported secondarily by observational research (prospective and cross-sectional designs) and animal studies. 1. Frohman, E. M., Racke, M. K. & Raine, C. S. Multiple sclerosis the plaque and its pathogenesis. N. Engl. J. Med. 354, 942 955 (2006). 2. Mayr, W. T. et al. Incidence and prevalence of multiple sclerosis in Olmsted County, Minnesota, 1985 2000. Neurology 61, 1373 1377 (2003). 3. Page, W. F., Kurtzke, J. F., Murphy, F. M. & Norman, J. E. Jr. Epidemiology of multiple sclerosis in U.S. veterans: V. Ancestry and the risk of multiple sclerosis. Ann. Neurol. 33, 632 639 (1993). 4. International Classification of Functioning, Disability and Health (ICF). World Health Organization [online], http://www.who.int/ classifications/icf/en/ (2001). 5. Coenen, M. et al. The development of ICF Core Sets for multiple sclerosis: results of the International Consensus Conference. J. Neurol. 258, 1477 1488 (2011). 6. Goldman, M. D., Marrie, R. A. & Cohen, J. A. Evaluation of the six-minute walk in multiple sclerosis subjects and healthy controls. Mult. Scler. 14, 383 390 (2008). 7. Larocca, N. G. Impact of walking impairment in multiple sclerosis: perspectives of patients and care partners. Patient 4, 189 201 (2011). 8. Motl, R. W., McAuley, E. & Snook, E. M. Physical activity and multiple sclerosis: a meta-analysis. Mult. Scler. 11, 459 463 (2005). 9. Motl, R. W. Physical activity and irreversible disability in multiple sclerosis. Exerc. Sport Sci. Rev. 38, 186 191 (2010). 10. White, L. J. & Castellano, V. Exercise and brain health implications for multiple sclerosis: Part 1 neuronal growth factors. Sports Med. 38, 91 100 (2008). 11. Andreasen, A., Stenager, E. & Dalgas, U. The effect of exercise therapy on fatigue in multiple sclerosis. Mult. Scler. 17, 1041 1054 (2011). 12. Garrett, M. & Coote, S. Multiple sclerosis and exercise in people with minimal gait impairment a review. Phys. Ther. Rev. 14, 169 180 (2009). 13. Motl, R. W., Goldman, M. D. & Benedict, R. H. Walking impairment in patients with multiple sclerosis: exercise training as a treatment option. Neuropsychiatr. Dis. Treat. 6, 767 774 (2010). 14. Rietberg, M. B., Brooks, D., Uitdehaag, B. M. & Kwakkel, G. Exercise therapy for multiple sclerosis. Cochrane Database of Systematic Reviews Issue 1. Art. No.:CD003980. http://dx. doi.org/10.1002/14651858.cd003980.pub2. 15. Dalgas, U., Stenager, E. & Ingemann-Hansen, T. Multiple sclerosis and physical exercise: recommendations for the application of resistance, endurance- and combined training. Mult. Scler. 14, 35 53 (2008). 16. Asano, M., Dawes, D. J., Arafah, A., Moriello, C. & Mayo, N. E. What does a structured review of the effectiveness of exercise interventions for NATURE REVIEWS NEUROLOGY ADVANCE ONLINE PUBLICATION 9