The combined deleterious effects of multiple sclerosis and ageing on neuromuscular function.

BACKGROUND: The prevalence of older (>60 years) people with multiple sclerosis (pwMS) is increasing. This introduces numerous challenges, as both MS and ageing independently contribute to the deterioration of neuromuscular function. AIM: The aim was to compare the neuromuscular function in pwMS and healthy controls (HC) across three age groups: young, middle-aged, and old. METHODS: Using a cross-sectional study design, the maximal muscle strength (Fmax) and rate of force development (RFD) of the knee extensors (KE) and plantar flexors (PF) were assessed using an isokinetic dynamometer. In addition, voluntary activation (VA) and resting twitch (RT) were measured using the interpolated twitch technique. RESULTS: The Fmax, RFD, and VA of the KE were reduced in pwMS compared to HC across age groups. In pwMS, reductions were observed in PF Fmax, RFD, and RT, predominantly in the middle-aged and old age groups. Reductions increased with age in KE for both groups (except for VA) but in PF only for pwMS. The "trajectory" differed between pwMS and HC, as pwMS showed reductions from young to middle age, while HC showed reductions from middle to old age in KE. CONCLUSION: The combined negative effects of MS and ageing on neuromuscular function were especially present in the PF but also substantial in the KE. RFD showed large deficits for pwMS compared to HC across age groups. The findings can partly be explained by a reduction in VA and RT, but further investigations of neural regulation are needed to explain large RFD deficits.

The MoXFo initiative - study design: Considerations related to study design and methodology in exercise research for people with multiple sclerosis.

BACKGROUND: Exercise as a subset of physical activity is a cornerstone in the management of multiple sclerosis (MS) based on its pleiotropic effects, but continued progression of the field requires better future designs and methodologies. OBJECTIVES: This paper outlines the work of the 'Study design and methodology' group of the MoXFo (moving exercise research forward) initiative, and addresses critical aspects and future directions when defining the research question of interest, and subsequently, designing the study and exercise intervention in MS patients. METHODS: The work is based on the formation of an international expert panel formed within the MoXFo initiative. We provide a structured and concise synthesis of exercise-specific MS research challenges and considerations when designing randomized controlled trials (RCTs). RESULTS: Challenges and considerations are presented using the Patient population, Intervention, Comparator, Outcomes, Timing, Setting (PICOTS) framework, thereby forming a new and specific MS exercise PICOTS framework. CONCLUSION: We propose that researchers should carefully consider and align all elements of this MS exercise PICOTS framework when developing future research questions and study designs, ultimately improving the quality of new exercise studies in people with MS.

Neuromuscular rate of force development discriminates fallers in ambulatory persons with multiple sclerosis - an exploratory study.

BACKGROUND: Falls as well as fall-related injuries (e.g., bone fractures) are common in persons with multiple sclerosis (pwMS). Whilst some studies have identified lower extremity maximal muscle strength (Fmax) as one among several risk factors, no previous studies have investigated the association between rate of force development (RFD; ability to generate a rapid rise in muscle force) and falls in pwMS. Not only is RFD substantially compromised (and more so than Fmax) in pwMS, studies involving other neurodegenerative populations have shown that RFD - to a greater extent than Fmax - is crucial for counteracting unexpected perturbations and avoiding falling. OBJECTIVE: To explore whether knee extensor RFD (and Fmax) can discriminate fallers from non-fallers in pwMS. METHODS: Knee extensor neuromuscular function (comprising RFD50ms and RFD200ms (force developed in the interval 0-50 ms and 0-200 ms, respectively) as well as Fmax) of the weaker leg was assessed by isokinetic dynamometry. Falls were determined by 1-year patient recall, with pwMS subsequently being classified as non-fallers (0 falls), fallers (1-2 falls), or recurrent fallers (≥3 falls). RESULTS: A total of n=53 pwMS were enrolled in the study, with n=24 classified as non-fallers (63% females, 48 years, EDSS 2.2), n=16 as fallers (88% females, 57 years, EDSS 3.3), and n=13 as recurrent fallers (46% females, 60 years, EDSS 4.2). Compared with non-fallers, neuromuscular function was reduced in both fallers (RFD50 -4.42 [-7.47;-1.37] Nm.s-1.kg-1, -48%; RFD200 -1.45 [-2.98;0.07] Nm.s-1.kg-1, -24%; Fmax -0.42 [-0.81;-0.03] Nm.kg-1, -21%) and recurrent fallers (RFD50 -5.69 [-8.94;-2.43] Nm.s-1.kg-1, -62%; RFD200 -2.26 [-3.89;-0.63] Nm.s-1.kg-1, -38%; Fmax -0.38 [-0.80;0.03] Nm.kg-1, -19%). Across all participants, associations were observed between RFD50ms and falls (rs = -0.46 [-0.67;-0.24], between RFD200ms and falls (rs = -0.34 [-0.59;-0.09]), and between Fmax and falls (rs = -0.24 [-0.48;0.01]). CONCLUSION: In this exploratory study, knee extensor neuromuscular function was able to discriminate fallers from non-fallers in pwMS, with RFD being superior to Fmax. Routine assessment of lower extremity neuromuscular function (RFD50ms in particular) may be a helpful tool in identifying pwMS at future risk of falling.

Exercise Therapy in Early Multiple Sclerosis Improves Physical Function But Not Cognition: Secondary Analyses From a Randomized Controlled Trial.

BACKGROUND: Exercise positively affects multiple sclerosis (MS) symptoms, physiological systems, and potentially cognition. However, an uninvestigated "window of opportunity" exists for exercise therapy early in the disease. OBJECTIVE: This study presents secondary analyses from the Early Multiple Sclerosis Exercise Study, and aims to investigate the efficacy of exercise on physical function, cognition, and patient-reported measures of disease and fatigue impact early in the disease course of MS. METHODS: This randomized controlled trial (n = 84, time since diagnosis <2 years) included 48 weeks of aerobic exercise or an active control condition (health education) and between-group changes are based on repeated measurement mixed regression models. Physical function tests included measures of aerobic fitness, walking (6-minute walk, Timed 25-foot walk, Six-spot step test), and upper-limb dexterity. Tests of processing speed and memory evaluated cognition. The questionnaires Multiple Sclerosis Impact Scale and Modified Fatigue Impact Scale assessed perception of disease and fatigue impact. RESULTS: Following early exercise aerobic fitness showed superior between-group physiological adaptations (4.0 [1.7; 6.3] ml O2/min/kg; large effect size [ES = 0.90]). No other outcomes showed significant between-group differences, yet all measures of walking and upper-limb function showed small-to-medium effect sizes in favor of exercise (ES = 0.19-0.58). Overall disability status as well as cognition were unaffected by exercise, whereas perception of disease and fatigue impact were reduced in both groups. CONCLUSION: In early MS, 48 weeks of supervised aerobic exercise seem to positively modify physical function, but not cognitive function. Perception of disease and fatigue impact may be modifiable by exercise in early MS. TRIAL REGISTRATION: Clinicaltrials.gov (identifier: NCT03322761).

Identification of disability status in persons with multiple sclerosis by lower limb neuromuscular function - Emphasis on rate of force development.

BACKGROUND: Neurodegeneration is an inevitable consequence of multiple sclerosis (MS) leading to impaired neuromuscular function, especially of the lower extremities. Whilst maximal muscle strength (or force; Fmax) is the most examined feature of neuromuscular function, the ability to rapidly increase muscle force (= rate of force development; RFD) appear to be preferentially sensitive towards neurodegeneration and potentially also of great importance for physical function. The purpose of the present study was to comprehensively examine and compare different outcome measures of neuromuscular function (with specific emphasis given to RFD) across disability status in persons with MS (pwMS), and in comparison, to age- and sex-matched healthy controls (HC). METHODS: A total of n=34 HC and n=99 pwMS were enrolled in the study, with the latter being divided into Expanded Disability Status Scale (EDSS) subgroups: MSmild (EDSS 0-2.5, n=51), MSmoderate (EDSS 3.0-4.5, n=33), and MSsevere (EDSS 5-6.5, n=15). Knee extensor neuromuscular function was assessed by Fmax and RFD (RFD50ms and RFD200ms, respectively; calculated in the interval 0-50 ms and 0-200 ms relative to the onset of contraction) with simultaneous electromyography (maximal EMG (EMGFmax) and rate of EMG rise (rEMG50ms and rEMG200ms, respectively)). Voluntary muscle activation derived from the interpolated twitch technique was also determined during additional Fmax trials. Lastly, physical function was assessed by the 5 x sit-to-stand test (5STS), the timed 25-foot walk test (T25FWT), and the 2-min walking test (2MWT). RESULTS: Substantial differences (∼deficits) (p<0.05) were observed for all pwMS subgroups compared to HC across all neuromuscular function outcome measures; RFD50ms (MSmild -22%, MSmoderate -36%, MSsevere -66%), RFD200ms (-12%, -21%, -51%), and Fmax (-11%, -14%, -33%). Somewhat comparable differences (∼deficits) (p<0.05) were observed for voluntary muscle activation (rEMG50ms, rEMG200ms, EMGFmax, and activation) and for physical function (5STS, T25FWT, and 2MT). Deficits in neuromuscular function were strongly associated with EDSS (p<0.05) (RFD50ms: slope steepness -13% per 1 point increase in EDSS, r2=0.79; RFD200ms: slope steepness -10%, r2=0.84; Fmax: slope steepness -6%, r2=0.82). Fmax and RFD were associated with physical function outcome measures (p<0.05) to a comparable extent (r2-values ranging from 0.21 to 0.35). CONCLUSION: Lower extremity neuromuscular function is impaired in pwMS compared to HC with differences (∼deficits) becoming greater with increasing disability status. RFD was preferentially sensitive in capturing differences (∼deficits) across disability status and by showing strong associations with EDSS. Altogether, knee extensor RFD could serve as a simple objective marker of disability status or even progression in pwMS, that may be helpful to both researchers and clinicians.

Multimethodological validation of the modified fatigue impact scale in a Danish population of people with Multiple Sclerosis.

OBJECTIVE: To provide a multimethodological validation of MFIS in compliance with the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) guidelines using a Danish population of patients with Multiple Sclerosis (pwMS). METHODS: Factor analytic and multidimensional Rasch analytic methods were applied to investigate the structural validity of MFIS. We employed measurement and bi-factor models to address divergence and convergence. McDonalds ω was used to assess reliability. Cross-cultural and nomological validity was assessed in relation to relevant external populations and constructs, respectively. Responsiveness was evaluated following one month of multi-disciplinary rehabilitation (MDR). RESULTS: Based on data from 424 Danish MS patients, the MFIS showed an acceptable fit to both factor analytic and multidimensional Rasch models. MFIS was found to be dominated by a general factor but with considerable substructure present. Sufficient divergence was found between cognitive and physical subdomains, but not the psychosocial subscale. Mc Donald's ωt of 0.96 indicated good reliability of the scale, however, with low specific reliability of the psychosocial subscale. Homogeneity across Danish and European populations of pwMS supported cross-cultural validity. Explorative factor analysis of the nomological network of MFIS revealed expected convergence with cognitive and physical aspects. MFIS showed good responsiveness as indicated by moderate to large effect sizes following MDR. CONCLUSION: The Danish version of the MFIS showed good reliability, a good structural, cross-cultural, and nomological validity an acceptable fit to a multidimensional Rasch analysis, and a good responsiveness. The psychosocial subscale of the MFIS however should be interpreted with caution.

Investigating the potential disease-modifying and neuroprotective efficacy of exercise therapy early in the disease course of multiple sclerosis: The Early Multiple Sclerosis Exercise Study (EMSES).

BACKGROUND: Potential supplemental disease-modifying and neuroprotective treatment strategies are warranted in multiple sclerosis (MS). Exercise is a promising non-pharmacological approach, and an uninvestigated 'window of opportunity' exists early in the disease course. OBJECTIVE: To investigate the effect of early exercise on relapse rate, global brain atrophy and secondary magnetic resonance imaging (MRI) outcomes. METHODS: This randomized controlled trial (n = 84, disease duration <2 years) included 48 weeks of supervised aerobic exercise or control condition. Population-based control data (Danish MS Registry) was included (n = 850, disease duration <2 years). Relapse rates were obtained from medical records, and patients underwent structural and diffusion-kurtosis MRI at baseline, 24 and 48 weeks. RESULTS: No between-group differences were observed for primary outcomes, relapse rate (incidence-rate-ratio exercise relative to control: (0.49 (0.15; 1.66), p = 0.25) and global brain atrophy rate (-0.04 (-0.48; 0.40)%, p = 0.87), or secondary measures of lesion load. Aerobic fitness increased in favour of the exercise group. Microstructural integrity was higher in four of eight a priori defined motor-related tracts and nuclei in the exercise group compared with the control (thalamus, corticospinal tract, globus pallidus, cingulate gyrus) at 48 weeks. CONCLUSION: Early supervised aerobic exercise did not reduce relapse rate or global brain atrophy, but does positively affect the microstructural integrity of important motor-related tracts and nuclei.

Comparison Between Isometric and Concentric Motor Fatigability in Persons With Multiple Sclerosis and Healthy Controls - exploring central and peripheral contributions of motor fatigability.

BACKGROUND: Motor fatigability (i.e. contraction-induced reduction in muscle strength) from a concentric task associate stronger to walking and perception of fatigue in persons with multiple sclerosis (pwMS), compared with an isometric task. However, the central and peripheral contributions of motor fatigability between these tasks have not been investigated. OBJECTIVE: Compare the central and peripheral contributions of motor fatigability in the knee extensors in a sustained isometric fatigability protocol versus a concentric fatigability protocol and in pwMS versus healthy controls (HCs). METHODS: Participants (n=31 pwMS; n=15 HCs) underwent neuromuscular testing before and immediately after two knee extensor fatigability tasks (sustained isometric and concentric) in an isokinetic dynamometer. Neuromuscular testing of fatigability consisted of maximal voluntary contraction, voluntary activation (central/neural contributor), and resting twitch (peripheral/muscular contributor) determined by the interpolated twitch technique. RESULTS: Sustained isometric and concentric fatigability protocols resulted in motor fatigability for both pwMS and HCs, with no between-protocols differences for either group. Regression analysis showed that motor fatigability variance in pwMS was mainly attributed to central fatigability in the sustained isometric protocol and to both central and peripheral fatigability in the concentric protocol. In HCs, the variance in sustained isometric and concentric fatigability were attributed to both peripheral and central fatigability. CONCLUSION: Central and peripheral contributions of motor fatigability differed between sustained isometric and concentric protocols as well as between pwMS and HCs. These between-protocol differences in pwMS provide a neuromuscular dimension to the reported difference in the strength of associations of concentric and isometric tasks to walking and perception of fatigue in pwMS.

Study protocol: randomised controlled trial evaluating exercise therapy as a supplemental treatment strategy in early multiple sclerosis: the Early Multiple Sclerosis Exercise Study (EMSES).

INTRODUCTION: In the relapsing remitting type of multiple sclerosis (MS) reducing relapses and neurodegeneration is crucial in halting the long-term impact of the disease. Medical disease-modifying treatments have proven effective, especially when introduced early in the disease course. However, patients still experience disease activity and disability progression, and therefore, supplemental early treatment strategies are warranted. Exercise appear to be one of the most promising supplemental treatment strategies, but a somewhat overlooked 'window of opportunity' exist early in the disease course. The objective of this study is to investigate exercise as a supplementary treatment strategy early in the disease course of MS. METHODS AND ANALYSIS: The presented Early Multiple Sclerosis Exercise Study is a 48-week (plus 1-year follow-up) national multicentre single-blinded parallel group randomised controlled trial comparing two groups receiving usual care plus supervised high-intense exercise or plus health education (active control). Additionally, data will be compared with a population-based control group receiving usual care only obtained from the Danish MS Registry. The primary outcomes are annual relapse rate and MRI derived global brain atrophy. The secondary outcomes are disability progression, physical and cognitive function, MS-related symptoms, and exploratory MRI outcomes. All analyses will be performed as intention to treat. ETHICS AND DISSEMINATION: The study is approved by The Central Denmark Region Committees on Health Research Ethics (1-10-72-388-17) and registered at the Danish Data Protection Agency (2016-051-000001 (706)). All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences. TRIAL REGISTRATION NUMBER: NCT03322761.

Physical activity is associated with neuromuscular and physical function in patients with multiple sclerosis independent of disease severity.

PURPOSE: Examine the association between physical activity and neuromuscular and physical function in patients with multiple sclerosis when also considering disease severity. METHODS: 91 patients with multiple sclerosis were enrolled. Assessments included physical activity by 7-day thigh-worn accelerometry, knee extensor neuromuscular function by dynamometry (maximal isometric muscle strength, rate of force development (0-50 ms)), and physical function by 5× sit-to-stand, 2-min walk test, and timed 25 ft walk test. Physical activity tertile comparisons along with simple and multiple regressions (adjusting for age, gender, EDSS, time since diagnosis) were performed. RESULTS: Physical activity tertiles revealed differences (p < 0.05) in maximal muscle strength (1.77 ≈ 1.97 < 2.28 Nm/kg), rate of force development (4.66 < 8.03 ≈ 10.55 Nm/kg/s), 5× sit-to-stand (11.4 ≈ 9.7 > 8.5 s), 2-min walk test (153 < 183 < 207 m), and timed 25 ft walk test (6.3 > 4.4 > 4.3 s). Moreover, physical activity was associated (p < 0.05) with maximal muscle strength and rate of force development (r2 = 0.13-0.15) along with 5× sit-to-stand, 2-min walk test, and timed 25 ft walk test (r2 = 0.18-0.24), also after adjusting for age + gender + EDSS + time since diagnosis (r2 = 0.25-0.37 and 0.24-0.52), with physical activity consistently being a strong predictor. CONCLUSIONS: Higher levels of physical activity are associated with greater neuromuscular and physical function in ambulatory patients with multiple sclerosis independent of disease severity. These findings emphasize the importance of performing regular physical activity at all stages of multiple sclerosis.IMPLICATIONS FOR REHABILITATIONPhysical activity is associated with neuromuscular and physical function, independent of disease severity.Physical activity may be important in improving or preserving neuromuscular and physical function at all stages of ambulatory multiple sclerosis patients, yet longitudinal studies are warranted.Clinicians and rehabilitation professionals should encourage ambulatory patients at all stages of their disease to be as physically active as possible.

Walking Training Enhances Corticospinal Excitability in Progressive Multiple Sclerosis-A Pilot Study.

Background: Inflammatory lesions and neurodegeneration lead to motor, cognitive, and sensory impairments in people with multiple sclerosis (MS). Accumulation of disability is at least partially due to diminished capacity for neuroplasticity within the central nervous system. Aerobic exercise is a potentially important intervention to enhance neuroplasticity since it causes upregulation of neurotrophins and enhances corticospinal excitability, which can be probed using single-pulse transcranial magnetic stimulation (TMS). Whether people with progressive MS who have accumulated substantial disability could benefit from walking rehabilitative training to enhance neuroplasticity is not known. Objective: We aimed to determine whether 10 weeks of task-specific walking training would affect corticospinal excitability over time (pre, post, and 3-month follow-up) among people with progressive MS who required walking aids. Results: Eight people with progressive MS (seven female; 29-74 years old) with an Expanded Disability Status Scale of 6-6.5 underwent harness-supported treadmill walking training in a temperature controlled room at 16°C (10 weeks; three times/week; 40 min at 40-65% heart rate reserve). After training, there was significantly higher corticospinal excitability in both brain hemispheres, reductions in TMS active motor thresholds, and increases in motor-evoked potential amplitudes and slope of the recruitment curve (REC). Decreased intracortical inhibition (shorter cortical silent period) after training was noted in the hemisphere corresponding to the stronger hand only. These effects were not sustained at follow-up. There was a significant relationship between increases in corticospinal excitability (REC, area under the curve) in the hemisphere corresponding to the stronger hand and lessening of both intensity and impact of fatigue on activities of daily living (Fatigue Severity Scale and Modified Fatigue Impact Scale, respectively). Conclusion: Our pilot results support that vigorous treadmill training can potentially improve neuroplastic potential and mitigate symptoms of the disease even among people who have accumulated substantial disability due to MS.

A Head-to-Head Comparison of an Isometric and a Concentric Fatigability Protocol and the Association With Fatigue and Walking in Persons With Multiple Sclerosis.

Background. Fatigue is one of the most frequent symptoms in persons with multiple sclerosis (MS). Distinction is made between subjective perceptions of fatigue and objective measures of fatigability. Fatigability can be measured by different protocols. Yet no studies have compared isometric and concentric contraction protocols of the lower extremities head-to-head. Therefore, the purpose of the present study was to (1) compare 2 such protocols head-to-head and (2) to investigate the association between fatigability evoked by the 2 protocols and measures of fatigue and walking. Methods. A total of 45 patients with MS had their walking capacity measured objectively by the 6-minute walk test (6MWT) and subjectively by the 12-item Multiple Sclerosis Walking Scale (MSWS-12). Fatigue was measured by the Modified Fatigue Impact Scale (MFIS) and fatigability by 2 knee extension protocols: sustained isometric and concentric. Results. The sustained isometric protocol induced a higher degree of fatigability than the concentric protocol (P < .01). Regression analyses revealed that sustained isometric fatigability was not associated with either measures of fatigue or walking (all r2 = 0.00; P = .85-.99), whereas the concentric protocol was significantly associated with fatigue (r2 = 0.20; P < .01), 6MWT (r2 = 0.09; P < .05), and MSWS-12 (r2 = 0.16; P < .01). Furthermore, after adjusting for maximal strength and sex, concentric fatigability remained a strong and significant predictor of fatigue (ß = 0.49) and walking (6MWT: ß = -0.26; MSWS: ß = 0.37). Conclusion. This study provides the first evidence that a lower-extremity concentric fatigability protocol provides superior reflection of both fatigue and walking when compared with a sustained isometric protocol. We suggest that concentric protocols should be the focus of future studies investigating fatigability.

Exercise as Medicine in Multiple Sclerosis-Time for a Paradigm Shift: Preventive, Symptomatic, and Disease-Modifying Aspects and Perspectives.

PURPOSE OF REVIEW: For many years, exercise was controversial in multiple sclerosis (MS) and thought to exacerbate symptoms and fatigue. However, having been found to be safe and effective, exercise has become a cornerstone of MS rehabilitation and may have even more fundamental benefits in MS, with the potential to change clinical practice again. The aim of this review is to summarize the existing knowledge of the effects of exercise as primary, secondary, and tertiary prevention in MS. RECENT FINDINGS: Initial studies established exercise as an effective symptomatic treatment (i.e., tertiary prevention), but recent studies have evaluated the disease-modifying effects (i.e., secondary prevention) of exercise as well as the impact on the risk of developing MS (i.e., primary prevention). Based on recent evidence, a new paradigm shift is proposed, in which exercise at an early stage should be individually prescribed and tailored as "medicine" to persons with MS, alongside conventional medical treatment.

Is there an overlooked "window of opportunity" in MS exercise therapy? Perspectives for early MS rehabilitation.

While early medical treatment has proven effective in MS, early-phase MS rehabilitation has not gained much attention in MS research and clinical practice. Exercise therapy is one of the most promising treatment strategies in MS rehabilitation. Here, we provide a topical review investigating when exercise therapy is initiated in existing MS studies, showing that exercise is initiated at a rather late disease stage, where it predominantly serves as a symptomatic treatment. Recent findings in MS suggest that exercise may have neuroprotective and disease-modifying effects. Such findings along with the findings from medical trials that an early-stage "window of opportunity" exists leads to the proposal that early exercise therapy should be an increased focus in research and clinical practice for persons with MS. A further perspective relates to other rehabilitation interventions that are also initiated at a later disease stage, as these may also take advantage of an early-phase approach.

Balance and walking performance are improved after resistance and aerobic training in persons with chronic stroke.

PURPOSE: To investigate the effect of different types of physical training on balance performance and whether improved balance correlates with improved walking performance. METHODS: Forty eight participants with chronic stroke were randomly assigned to aerobic training on cycle ergometer (AT-group), resistance training of the lower extremities (RT-group), or sham training of upper extremities (ST-group). Participants exercised 3 d/week for 12 weeks. Balance (Berg Balance Scale), peak oxygen uptake rate, isometric knee extensor strength, maximal gait speed, and 6 minute walk test were measured at baseline and after 12 weeks. RESULTS: Training specific effects were observed; the AT-group improved peak oxygen uptake rate by 15.5 (6.0-25.0)%, the RT-group improved non-paretic knee extensor strength by 35.1 (18.3-51.9)% and the ST-group improved non-paretic knee extensor strength by 8.9 (0.7-17.1)%. All groups improved balance (6.0 (95% CI: 3.2-8.8)%), maximal gait speed (10.2 (6.5-14.0)%), and 6 minute walk distance (12.4 (8.8-15.9)%) but balance improvements did not correlate with improvements in muscle strength, peak oxygen uptake rate, or walking. CONCLUSIONS: Physical exercise improves balance and walking performance, but improved balance is not a prerequisite for functional improvements in chronic stroke. Implications for Rehabilitation Aerobic training and progressive resistance training show small significant improvements in balance and walking, indicating a possible clinical relevance of these training modalities. Improvements in balance may not be a prerequisite for improvements in walking distance when assistive devices are allowed during walking tests.