Evidence for reticulospinal plasticity underlying motor recovery in Brown-Séquard-plus Syndrome: a case report.

Brown-Séquard Syndrome (BSS) is a rare neurological condition caused by a unilateral spinal cord injury (SCI). Upon initial ipsilesional hemiplegia, patients with BSS typically show substantial functional recovery over time. Preclinical studies on experimental BSS demonstrated that spontaneous neuroplasticity in descending motor systems is a key mechanism promoting functional recovery. The reticulospinal (RS) system is one of the main descending motor systems showing a remarkably high ability for neuroplastic adaptations after incomplete SCI. In humans, little is known about the contribution of RS plasticity to functional restoration after SCI. Here, we investigated RS motor drive to different muscles in a subject with Brown-Séquard-plus Syndrome (BSPS) five months post-injury using the StartReact paradigm. RS drive was compared between ipsi- and contralesional muscles, and associated with measures of functional recovery. Additionally, corticospinal (CS) drive was investigated using transcranial magnetic stimulation (TMS) in a subset of muscles. The biceps brachii showed a substantial enhancement of RS drive on the ipsi- vs. contralesional side, whereas no signs of CS plasticity were found ipsilesionally. This finding implies that motor recovery of ipsilesional elbow flexion is primarily driven by the RS system. Results were inversed for the ipsilesional tibialis anterior, where RS drive was not augmented, but motor-evoked potentials recovered over six months post-injury, suggesting that CS plasticity contributed to improvements in ankle dorsiflexion. Our findings indicate that the role of RS and CS plasticity in motor recovery differs between muscles, with CS plasticity being essential for the restoration of distal extremity motor function, and RS plasticity being important for the functional recovery of proximal flexor muscles after SCI in humans.

Reliability of patient-specific gait profiles with inertial measurement units during the 2-min walk test in incomplete spinal cord injury.

Most established clinical walking tests assess specific aspects of movement function (velocity, endurance, etc.) but are generally unable to determine specific biomechanical or neurological deficits that limit an individual's ability to walk. Recently, inertial measurement units (IMU) have been used to collect objective kinematic data for gait analysis and could be a valuable extension for clinical assessments (e.g., functional walking measures). This study assesses the reliability of an IMU-based overground gait analysis during the 2-min walk test (2mWT) in individuals with spinal cord injury (SCI). Furthermore, the study elaborates on the capability of IMUs to distinguish between different gait characteristics in individuals with SCI. Twenty-six individuals (aged 22-79) with acute or chronic SCI (AIS: C and D) completed the 2mWT with IMUs attached above each ankle on 2 test days, separated by 1 to 7 days. The IMU-based gait analysis showed good to excellent test-retest reliability (ICC: 0.77-0.99) for all gait parameters. Gait profiles remained stable between two measurements. Sensor-based gait profiling was able to reveal patient-specific gait impairments even in individuals with the same walking performance in the 2mWT. IMUs are a valuable add-on to clinical gait assessments and deliver reliable information on detailed gait pathologies in individuals with SCI.Trial registration: NCT04555759.

Neural coordination of bilateral hand movements: evidence for an involvement of brainstem motor centres.

Bilateral hand movements are assumed to be coordinated by a neural coupling mechanism. Neural coupling is experimentally reflected in complex electromyographic (EMG) responses in the forearm muscles of both sides to unilateral electrical arm nerve stimulation (ES). The aim of this study was to examine a potential involvement of the reticulospinal system in neural coupling by the application of loud acoustic stimuli (LAS) known to activate neurons of this system. LAS, ES and combined LAS/ES were applied to healthy subjects during visually guided bilateral hand flexion-extension movements. Muscle responses to the different stimuli were evaluated by electrophysiological recordings. Unilateral electrical ulnar nerve stimulation resulted in neural coupling responses in the forearm extensors (FE) of both sides. Interestingly, LAS evoked bilateral EMG responses that were similar in their configuration to those induced by ES. The presence of startles was associated with a shift of the onset and enhanced amplitude of LAS-induced coupling-like responses. Upon combined LAS/ES application, ES facilitated ipsilateral startles and coupling-like responses. Modulation of coupling-like responses by startles, the similarity of the responses to ES and LAS, and their interaction following combined stimulation suggests that both responses are mediated by the reticulospinal system. Our findings provide novel indirect evidence that the reticulospinal system is involved in the neural coupling of hand movements. This becomes clinically relevant in subjects with a damaged corticospinal system where a dominant reticulospinal system leads to involuntary limb coupling, referred to as associated movements. KEY POINTS: Automatic coordination of hand movements is assumed to be mediated by a neural coupling mechanism reflected by bilateral reflex responses in forearm muscles to unilateral electrical arm nerve stimulation (ES). Loud acoustic stimuli (LAS) were applied to assess a potential involvement of the reticulospinal system in the neural coupling mechanism. LAS evoked a bilateral reflex response in the forearm extensors that was similar to the neural coupling response to ES, and which could be separated from the acoustic startle response. Combined application of LAS and ES resulted in a facilitation of startle and coupling-like responses ipsilateral to ES, thus indicating an interaction of afferences from both stimuli. These novel findings provide indirect evidence that the reticulospinal system is a key motor structure for the coupling of bilateral hand movements.

Prognosis of walking function in multiple sclerosis supported by gait pattern analysis.

BACKGROUND: Walking impairment is a common and highly disabling symptom in people with MS (PwMS). Ambulatory deterioration is poorly characterized in PwMS and reliable prognosis that may guide clinical decisions is elusive. This study aimed to objectively track the progression of clinical walking performance and kinematic gait patterns in PwMS over 4 years, thereby revealing potential prognostic markers for deterioration of ambulatory function. METHODS: Twenty-two PwMS (48.8 ± 9.9 years, 14 females; expanded disability status scale [EDSS]: 4.5 ± 0.9 points) with gait impairments were recruited at the University Hospital Zurich, Switzerland. Gait function was monitored over a period of 4 years using a set of standardized clinical walking tests (timed 25-foot walk [T25FW], 6 min walk test [6MWT], 12-item MS walking scale [MSWS-12]) and comprehensive 3D kinematic gait analysis. Walking decline was assessed in the full patient cohort and in patient sub-groups that were built according to MS type (relapsing-remitting [RRMS], progressive [PMS]) and subjects' pathological gait signature (cluster groups 1-3). RESULTS: In the total cohort (n = 22), we found a significant worsening in the 6MWT (BL vs. 4y: -41.1 m; P = 0.0053), while the performance in the T25FW, MSWS-12 and the EDSS remained unchanged over 4 years. Subjects with PMS (n = 12) showed a significant worsening in the EDSS (BL vs. 4y: +0.6 points; P = 0.0053), which was not observed in participants with RRMS (n = 10). Whereas deterioration of clinical walking function was not different between subjects with RRMS and PMS, we identified differences in clinical walking deterioration between PwMS with varying gait pattern pathologies: Subjects with spastic-paretic gait impairments (cluster 1; n = 9) demonstrated a marked worsening in the T25FW (BL vs. 4y: +2 s; P = 0.0020) and 6MWT (BL vs. 4y: -92.9 m; P < 0.0001) which was not seen in PwMS with an ataxia-like (cluster 2; n = 8) or unstable walking pattern (cluster 3; n = 5). Deterioration of clinical walking performance in cluster 1 was accompanied by a specific worsening of gait deficits that were characteristic of this cluster at baseline, a phenomenon not found in the other sub-groups. Accordingly, aggravation of cluster 1-specific gait impairments over 4 years predicted deterioration of the 6MWT in the total cohort (n = 22) with an accuracy of 90.9% (sensitivity: 90.9%; specificity: 90.9%; Nagelkerkes coefficient of determination R2: 0.721), unveiling key determinants of MS-related walking decline. CONCLUSIONS: Our findings highlight the potential of quantitative, functional outcomes for objective tracking of disease progression in PwMS. Gait pattern analysis can provide valuable information on the underlying pathomechanisms of gait deterioration and may represent a complementary prognostic tool for walking function in PwMS. CLINICAL TRIAL: clinicaltrials.gov, NCT01576354.

Deep brain stimulation for locomotion in incomplete human spinal cord injury (DBS-SCI): protocol of a prospective one-armed multi-centre study.

INTRODUCTION: Spinal cord injury (SCI) is a devastating condition with immediate impact on the individual's health and quality of life. Major functional recovery reaches a plateau 3-4 months after injury despite intensive rehabilitative training. To enhance training efficacy and improve long-term outcomes, the combination of rehabilitation with electrical modulation of the spinal cord and brain has recently aroused scientific interest with encouraging results. The mesencephalic locomotor region (MLR), an evolutionarily conserved brainstem locomotor command and control centre, is considered a promising target for deep brain stimulation (DBS) in patients with SCI. Experiments showed that MLR-DBS can induce locomotion in rats with spinal white matter destructions of >85%. METHODS AND ANALYSIS: In this prospective one-armed multi-centre study, we investigate the safety, feasibility, and therapeutic efficacy of MLR-DBS to enable and enhance locomotor training in severely affected, subchronic and chronic American Spinal Injury Association Impairment Scale C patients in order to improve functional recovery. Patients undergo an intensive training programme with MLR-DBS while being regularly followed up until 6 months post-implantation. The acquired data of each timepoint are compared with baseline while the primary endpoint is performance in the 6-minute walking test. The clinical trial protocol was written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials checklist. ETHICS AND DISSEMINATION: This first in-man study investigates the therapeutic potential of MLR-DBS in SCI patients. One patient has already been implanted with electrodes and underwent MLR stimulation during locomotion. Based on the preliminary results which promise safety and feasibility, recruitment of further patients is currently ongoing. Ethical approval has been obtained from the Ethical Committee of the Canton of Zurich (case number BASEC 2016-01104) and Swissmedic (10000316). Results will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT03053791.

Fall-related functional impairments in patients with neurological gait disorder.

Falls are common in patients with neurological disorders and are a primary cause of injuries. Nonetheless, fall-associated gait characteristics are poorly understood in these patients. Objective, quantitative gait analysis is an important tool to identify the principal fall-related motor characteristics and to advance fall prevention in patients with neurological disorders. Fall incidence was assessed in 60 subjects with different neurological disorders. Patients underwent a comprehensive set of functional assessments including instrumented gait analysis, computerized postural assessments and clinical walking tests. Determinants of falls were assessed by binary logistic regression analysis and receiver operator characteristics (ROC). The best single determinant of fallers was a step length reduction at slow walking speed reaching an accuracy of 67.2% (ROC AUC: 0.669; p = 0.027). The combination of 4 spatio-temporal gait parameters including step length and parameters of variability and asymmetry were able to classify fallers and non-fallers with an accuracy of 81.0% (ROC AUC: 0.882; p < 0.001). These findings suggest significant differences in specific spatio-temporal gait parameters between fallers and non-fallers among neurological patients. Fall-related impairments were mainly identified for spatio-temporal gait characteristics, suggesting that instrumented, objective gait analysis is an important tool to estimate patients' fall risk. Our results highlight pivotal fall-related walking deficits that might be targeted by future rehabilitative interventions that aim at attenuating falls.

Characterizing cognitive-motor impairments in patients with myotonic dystrophy type 1.

Myotonic Dystrophy Type 1 (DM1) is the most frequent hereditary, adult-onset muscular dystrophy. Nevertheless, DM1-associated cognitive-motor impairments have not been fully characterized so far. This study aimed at profiling cognitive and locomotor dysfunctions in these patients. In addition, cognitive-motor interactions were assessed using a dual-task paradigm. Comprehensive cognitive-motor impairment profiles were generated for 19 patients with DM1 and 19 healthy subjects by thorough clinical, biomechanical and neuropsychological examinations. Detailed gait analysis was performed using a 3D motion capture system, whereas cognitive function was assessed using a standardized neuropsychological test battery. Patients with DM1 showed impaired functional mobility, gait velocity and endurance. DM1-related gait pathology was mainly characterized by enhanced dynamic instability, gait variability, and restricted ankle dorsiflexion. Patients' cognitive impairments particularly concerned attentional functions. Dual-task conditions induced gait deviations that slightly differed between patients and controls. DM1-associated cognitive impairments correlated with reduced functional mobility and impaired ankle dorsiflexion. Patients with DM1 revealed significant impairments of walking function, balance and cognitive performance. Differential cognitive-motor interference and significant interactions between cognitive and motor dysfunctions point towards a prominent role of cognition in gait performance of patients with DM1.

Targeted Walking in Incomplete Spinal Cord Injury: Role of Corticospinal Control.

Locomotor recovery after incomplete spinal cord injury (iSCI) is influenced by spinal and supraspinal networks. Conventional clinical gait analysis fails to differentiate between these components. There is evidence that corticospinal control is enhanced during targeted walking, where each foot must be continuously placed on visual targets in randomized order. This study investigates the potential of targeted walking in the functional assessment of corticospinal integrity. Twenty-one controls and 16 individuals with chronic iSCI performed normal and targeted walking on a treadmill while electromyograms (EMGs) and kinematics were recorded. Precision (% of accurate foot placements) in targeted walking was significantly lower in individuals with iSCI (82.9 ± 14.7%, controls: 94.9 ± 4.0%). Although the overall kinematic pattern was comparable between walking conditions, controls showed significantly higher semitendinosus (ST) activity before heel-strike during targeted walking. This was accompanied by a shift of relative EMG intensity from 90-120 Hz to lower frequencies of 20-60 Hz, previously associated with corticospinal control of muscle activity. Targeted walking in individuals with iSCI evoked smaller EMG changes, suggesting that the switch to more corticospinal control is impaired. Accordingly, mildly impaired iSCI individuals revealed higher adaptations to the targeted walking task than more-impaired individuals. Recording of EMGs during targeted walking holds potential as a research tool to reveal further insights into the neuromuscular control of locomotion. It also complements findings of pre-clinical studies and is a promising novel surrogate marker of integrity of corticospinal control in individuals with iSCI and other neurological impairments. Future studies should investigate its potential for diagnosis or tracking recovery during rehabilitation.

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.

Familiarization with treadmill walking: How much is enough?

Treadmill-based gait analysis is widely used to investigate walking pathologies and quantify treatment effects on locomotion. Differential sensorimotor conditions during overground vs. treadmill walking necessitate initial familiarization to treadmill walking. Currently, there is no standardized treadmill acclimatization protocol and insufficient familiarization potentially confounds analyses. We monitored initial adaptations to treadmill walking in 40 healthy adults. Twenty-six walking parameters were assessed over 10 minutes with marker-based kinematic analysis and acclimatization profiles were generated. While 16 walking parameters demonstrated initial acclimatization followed by plateau performance, ten parameters remained stable. Distal lower limb control including ankle range of motion, toe trajectory and foot clearance underwent substantial adaptations. Moreover, intralimb coordination and gait variability also demonstrated acclimatization, while measures of symmetry and interlimb coordination did not. All parameters exhibiting a plateau after acclimatization did so within 6-7 minutes (425 strides). Older participants and those naïve to treadmill walking showed adaptations with higher amplitudes but over similar timescales. Our results suggest a minimum of 6 minutes treadmill acclimatization is required to reach a stable performance, and that this should suffice for both older and naïve healthy adults. The presented data aids in optimizing treadmill-based gait analysis and contributes to improving locomotor assessments 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.

Arm swing asymmetry in overground walking.

Treadmill experiments suggest that left-dominant arm swing is common in healthy walking adults and is modulated by cognitive dual-tasking. Little is known about arm swing asymmetry in overground walking. We report directional (dASI) and non-directional arm swing symmetry indices (ndASI) from 334 adults (mean age 68.6 ± 5.9 y) walking overground at comfortable (NW) and fast (FW) speeds and while completing a serial subtraction task (DT). dASI and ndASI were calculated from sagittal shoulder range of motion data generated by inertial measurement units affixed to the wrist. Most (91%) participants were right-handed. Group mean arm swing amplitude was significantly larger on the left in all walking conditions. During NW, ndASI was 39.5 ± 21.8, with a dASI of 21.9 ± 39.5. Distribution of dASI was bimodal with an approximately 2:1 ratio of left:right-dominant arm swing. There were no differences in ndASI between conditions but dASI was smaller during DT compared to FW (15.2 vs 24.6; p = 0.009). Handedness was unrelated to ndASI, dASI or the change in ASI metrics under DT. Left-dominant arm swing is the norm in healthy human walking irrespective of walking condition or handedness. As disease markers, ndASI and dASI may have different and complementary roles.

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.

Positive effects of fampridine on cognition, fatigue and depression in patients with multiple sclerosis over 2 years.

OBJECTIVE: To assess the effects of PR-fampridine on cognitive functioning, fatigue and depression in patients with multiple sclerosis (PwMS). METHODS: Thirty-two PwMS were included in this trial. Cognitive performance was assessed in an open-label and randomized double-blind, placebo-controlled study design using a comprehensive neuropsychological test battery as well as questionnaires examining depression and fatigue. RESULTS: We found significant improvements in cognitive measures assessing alertness (tonic alertness, p = 0.0244 and phasic alertness, p = 0.0428), psychomotor speed (p = 0.0140) as well as verbal fluency (p = 0.0002) during open-label treatment with PR-fampridine. These effects of performance were paralleled by patients' perception of reduced fatigue (physical, p = 0.0131; cognitive, p = 0.0225; total, p = 0.0126). Fampridine-induced improvements in phasic alertness (p = 0.0010) and measures of fatigue (physical, p = 0.0014; cognitive, p = 0.0003; total, p = 0.0005) were confirmed during randomized, double-blind, placebo-controlled assessment in the second year. In addition, we found positive effects of PR-fampridine on depressive symptoms (p = 0.0049). We demonstrated persisting beneficial effects of PR-fampridine on fatigue in PwMS over a period of more than 2 years. Drug responsiveness regarding cognitive performance and fatigue was not limited to walking responders. CONCLUSIONS: Our data demonstrate significant positive effects of treatment with PR-fampridine over 2 years on different cognitive domains as well as fatigue and depression in a cohort of PwMS. These findings imply that PR-fampridine should be considered as symptomatic treatment improving aspects of cognition, fatigue and depression in PwMS.

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.