Impaired speed-dependent modulation of the gait pattern in multiple sclerosis.

BACKGROUND: Walking dysfunction is common in people with multiple sclerosis (MS). Besides walking speed or endurance, one crucial feature of ambulatory function is the ability to adjust the gait pattern according to walking speed which relies on the integrity of spinal motor centres, their reciprocal connections to supraspinal networks and peripheral sensory input. OBJECTIVE: To investigate the capacity of people with MS to modify their gait pattern in response to changes in walking speed. METHODS: 3D gait analysis during free treadmill walking was performed in 35 people with MS and 20 healthy controls. Twelve kinematic parameters ranging from basic spatiotemporal measures to complex indicators of intralimb coordination were assessed at different absolute and relative walking speeds. RESULTS: Cadence, double-limb support time, trunk movements and especially measures of intralimb coordination demonstrated significantly less speed-dependent modifications in MS than in controls. These limitations were more prominent in subjects with stronger MS-related impairment (worse outcome in clinical walking tests, higher Expanded Disability Status Scale). CONCLUSION: The incapacity to modify specific elements of the walking pattern according to walking speed contributes to gait dysfunction in people with MS limiting activities of daily living. Gait modulation may serve as sensitive marker of walking function in MS. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01576354; first posted April 12, 2012.

Repeated assessment of key clinical walking measures can induce confounding practice effects.

Accurate functional outcome measures are critical for both clinical trials and routine patient assessments. Many functional outcomes improve with test repetition, a phenomenon that can confound the findings of longitudinal assessments. In this viewpoint, we tackle the poorly considered issue of practice effects in prevailing clinical walking tests based on current literature, while also presenting the original data from our own work, in which we investigated practice effects in the timed 25-foot walk (T25FW), timed-up and go (TUG), and 2-minute walk test (2MWT). In these tests, performed on 3 consecutive days in 10 patients with multiple sclerosis and 40 healthy controls, we observed significant practice effects in several established walking outcomes, including a 9.0% improvement in patients' TUG performance (p = 0.0146). Pre-training in these walking tests prior to baseline measurement may mitigate practice effects, thereby improving the accuracy and value of their repeated use in research and clinical settings.

Probing Corticospinal Control During Different Locomotor Tasks Using Detailed Time-Frequency Analysis of Electromyograms.

Locomotion relies on the fine-tuned coordination of different muscles which are controlled by particular neural circuits. Depending on the attendant conditions, walking patterns must be modified to optimally meet the demands of the task. Assessing neuromuscular control during dynamic conditions is methodologically highly challenging and prone to artifacts. Here we aim at assessing corticospinal involvement during different locomotor tasks using non-invasive surface electromyography. Activity in tibialis anterior (TA) and gastrocnemius medialis (GM) muscles was monitored by electromyograms (EMGs) in 27 healthy volunteers (11 female) during regular walking, walking while engaged in simultaneous cognitive dual tasks, walking with partial visual restriction, and skilled, targeted locomotion. Whereas EMG intensity of the TA and GM was considerably altered while walking with partial visual restriction and during targeted locomotion, dual-task walking induced only minor changes in total EMG intensity compared to regular walking. Targeted walking resulted in enhanced EMG intensity of GM in the frequency range associated with Piper rhythm synchronies. Likewise, targeted walking induced enhanced EMG intensity of TA at the Piper rhythm frequency around heelstrike, but not during the swing phase. Our findings indicate task- and phase-dependent modulations of neuromuscular control in distal leg muscles during various locomotor conditions in healthy subjects. Enhanced EMG intensity in the Piper rhythm frequency during targeted walking points toward enforced corticospinal drive during challenging locomotor tasks. These findings indicate that comprehensive time-frequency EMG analysis is able to gauge cortical involvement during different movement programs in a non-invasive manner and might be used as complementary diagnostic tool to assess baseline integrity of the corticospinal tract and to monitor changes in corticospinal drive as induced by neurorehabilitation interventions or during disease progression.

Profiling walking dysfunction in multiple sclerosis: characterisation, classification and progression over time.

Gait dysfunction is a common and relevant symptom in multiple sclerosis (MS). This study aimed to profile gait pathology in gait-impaired patients with MS using comprehensive 3D gait analysis and clinical walking tests. Thirty-seven patients with MS walked on the treadmill at their individual, sustainable speed while 20 healthy control subjects walked at all the different patient's paces, allowing for comparisons independent of walking velocity. Kinematic analysis revealed pronounced restrictions in knee and ankle joint excursion, increased gait variability and asymmetry along with impaired dynamic stability in patients. The most discriminative single gait parameter, differentiating patients from controls with an accuracy of 83.3% (χ2 test; p = 0.0001), was reduced knee range of motion. Based on hierarchical cluster and principal component analysis, three principal pathological gait patterns were identified: a spastic-paretic, an ataxia-like, and an unstable gait. Follow-up assessments after 1 year indicated deterioration of walking function, particularly in patients with spastic-paretic gait patterns. Our findings suggest that impaired knee/ankle control is common in patients with MS. Personalised gait profiles and clustering algorithms may be promising tools for stratifying patients and to inform patient-tailored exercise programs. Responsive, objective outcome measures are important for monitoring disease progression and treatment effects in MS trials.

Minimum toe clearance: probing the neural control of locomotion.

Minimum toe clearance (MTC) occurs during a highly dynamic phase of the gait cycle and is associated with the highest risk of unintentional contact with obstacles or the ground. Age, cognitive function, attention and visual feedback affect foot clearance but how these factors interact to influence MTC control is not fully understood. We measured MTC in 121 healthy individuals aged 20-80 under four treadmill walking conditions; normal walking, lower visual field restriction and two Stroop colour/word naming tasks of two difficulty levels. Competition for cognitive and attentional resources from the Stroop task resulted in significantly lower mean MTC in older adults, with the difficult Stroop task associated with a higher frequency of extremely low MTC values and subsequently an increased modelled probability of tripping in this group. While older adults responded to visual restriction by markedly skewing MTC distributions towards higher values, this condition was also associated with frequent, extremely low MTC values. We reveal task-specific, age-dependent patterns of MTC control in healthy adults. Age-related differences are most pronounced during heavy, distracting cognitive load. Analysis of critically-low MTC values during dual-task walking may have utility in the evaluation of locomotor control and fall risk in older adults and patients with motor control deficits.

Increasing cognitive load attenuates right arm swing in healthy human walking.

Human arm swing looks and feels highly automated, yet it is increasingly apparent that higher centres, including the cortex, are involved in many aspects of locomotor control. The addition of a cognitive task increases arm swing asymmetry during walking, but the characteristics and mechanism of this asymmetry are unclear. We hypothesized that this effect is lateralized and a Stroop word-colour naming task-primarily involving left hemisphere structures-would reduce right arm swing only. We recorded gait in 83 healthy subjects aged 18-80 walking normally on a treadmill and while performing a congruent and incongruent Stroop task. The primary measure of arm swing asymmetry-an index based on both three-dimensional wrist trajectories in which positive values indicate proportionally smaller movements on the right-increased significantly under dual-task conditions in those aged 40-59 and further still in the over-60s, driven by reduced right arm flexion. Right arm swing attenuation appears to be the norm in humans performing a locomotor-cognitive dual-task, confirming a prominent role of the brain in locomotor behaviour. Women under 60 are surprisingly resistant to this effect, revealing unexpected gender differences atop the hierarchical chain of locomotor control.

Monitoring long-term efficacy of fampridine in gait-impaired patients with multiple sclerosis.

OBJECTIVE: To expand upon the limited knowledge of the long-term effects of prolonged-release (PR) fampridine in patients with multiple sclerosis (PwMS) regarding safety, walking improvements, and changes in drug responsiveness. METHODS: Fifty-three PwMS who completed the FAMPKIN core study were included in this extension trial. Drug efficacy was assessed in an open-label and randomized double-blind, placebo-controlled study design with regular baseline assessments over a period of 2 years using the Timed 25-Foot Walk (T25FW), 6-Minute Walk Test (6MWT), and 12-item MS Walking Scale (MSWS-12) as outcome measures. RESULTS: The data showed good tolerability and persisting efficacy of PR fampridine during long-term treatment in PwMS. Significant improvements in walking speed, endurance, and self-perceived ambulatory function were observed during open-label (T25FW: +11.5%; 6MWT: 10.7%; MSWS-12: 6.1 points) and double-blind controlled treatment with PR fampridine (T25FW: +13.1%; 6MWT: 11.9%; MSWS-12: 7.4 points). Several patients showed changes in drug responsiveness over time, resulting in an increased proportion of patients exceeding 10% or 20% improvements in walking measures after long-term treatment. CONCLUSIONS: Efficacy and tolerability data confirmed PR fampridine as a valuable long-term treatment for improving ambulatory function in gait-impaired PwMS. Similar results in open-label and double-blind phases reveal that the walking tests used are objective and reliable. The considerable proportion of patients in whom responsiveness to PR fampridine changed over time emphasizes the importance of regular reassessment of drug efficacy in clinical practice to optimize treatment. Such reassessments seem to be particularly important in patients with poor initial drug responses, as this group demonstrated enhanced responsiveness after long-term treatment. CLINICALTRIALSGOV IDENTIFIER: NCT01576354. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that PR fampridine significantly improved gait compared to placebo in a 2-week study in PwMS who had been using PR fampridine for 2 years.

Prolonged-release fampridine in multiple sclerosis: Improved ambulation effected by changes in walking pattern.

BACKGROUND: Prolonged-release fampridine (PR-fampridine, 4-aminopyridine) increases walking speed in the timed 25-foot walk test (T25FW) in some patients (timed-walk responders) with multiple sclerosis (MS). OBJECTIVE: To explore the effects of PR-fampridine on different aspects of walking function and to identify associated gait modifications in subjects with MS. METHODS: In this prospective, randomized, placebo-controlled, double-blind, phase II study (FAMPKIN; clinicaltrials.gov, NCT01576354), subjects received a 6-week course of oral placebo or PR-fampridine treatment (10 mg, twice daily) before crossing over. Using 3D-motion-analysis, kinematic and kinetic parameters were assessed during treadmill walking (primary endpoint). Clinical outcome measures included T25FW, 6-minute walk test (6MWT), and balance scales. Physical activity in everyday life was measured with an accelerometer device. RESULTS: Data from 55 patients were suitable for analysis. Seventeen subjects were timed-walk responders under PR-fampridine. For the total study population and for responders, a significant increase in walking speed (T25FW) and distance (6MWT) was observed. Gait pattern changes were found at the single-subject level and correlated with improvements in the T25FW and 6MWT. Physical activity was increased in responders. CONCLUSION: PR-fampridine improves walking speed, endurance, and everyday physical activity in a subset of subjects with MS and leads to individual modifications of the gait pattern.