Real-world outcomes for a complete nationwide cohort of more than 3200 teriflunomide-treated multiple sclerosis patients in The Danish Multiple Sclerosis Registry.

OBJECTIVE: Teriflunomide is a once-daily, oral disease-modifying therapy (DMT) for relapsing forms of multiple sclerosis (MS). We studied clinical outcomes in a real-world setting involving a population-based large cohort of unselected patients enrolled in The Danish Multiple Sclerosis Registry (DMSR) who started teriflunomide treatment between 2013-2019. METHODS: This was a complete nationwide population-based cohort study with prospectively enrolled unselected cases. Demographic and disease-specific patient parameters related to treatment history, efficacy outcomes, and discontinuation and switching rates among other clinical variables were assessed at baseline and during follow-up visits. RESULTS: A total of 3239 patients (65.4% female) started treatment with teriflunomide during the study period, 56% of whom were treatment-naïve. Compared to previously treated patients, treatment-naïve patients were older on average at disease onset, had a shorter disease duration, a lower Expanded Disability Status Scale score at teriflunomide treatment start and more frequently experienced a relapse in the 12 months prior to teriflunomide initiation. In the 3001 patients initiating teriflunomide treatment at least 12 months before the cut-off date, 72.7% were still on treatment one year after treatment start. Discontinuations in the first year were due mainly to adverse events (15.6%). Over the full follow-up period, 47.5% of patients discontinued teriflunomide treatment. Sixty-three percent of the patients treated with teriflunomide for 5 years were relapse-free, while significantly more treatment-naïve versus previously treated patients experienced a relapse during the follow-up (p<0.0001). Furthermore, 85% of the patients with available data were free of disability worsening at the end of follow-up. CONCLUSIONS: Solid efficacy and treatment persistence data consistent with other real-world studies were obtained over the treatment period. Treatment outcomes in this real-world scenario of the population-based cohort support previous findings that teriflunomide is an effective and generally well-tolerated DMT for relapsing MS patients with mild to moderate disease activity.

Directed connectivity between primary and premotor areas underlying ankle force control in young and older adults.

The control of ankle muscle force is an integral component of walking and postural control. Aging impairs the ability to produce force steadily and accurately, which can compromise functional capacity and quality of life. Here, we hypothesized that reduced force control in older adults would be associated with altered cortico-cortical communication within a network comprising the primary motor area (M1), the premotor cortex (PMC), parietal, and prefrontal regions. We examined electroencephalographic (EEG) responses from fifteen younger (20-26 â€‹yr) and fifteen older (65-73 â€‹yr) participants during a unilateral dorsiflexion force-tracing task. Dynamic Causal Modelling (DCM) and Parametric Empirical Bayes (PEB) were used to investigate how directed connectivity between contralateral M1, PMC, parietal, and prefrontal regions was related to age group and precision in force production. DCM and PEB analyses revealed that the strength of connections between PMC and M1 were related to ankle force precision and differed by age group. For young adults, bidirectional PMC-M1 coupling was negatively related to task performance: stronger backward M1-PMC and forward PMC-M1 coupling was associated with worse force precision. The older group exhibited deviations from this pattern. For the PMC to M1 coupling, there were no age-group differences in coupling strength; however, within the older group, stronger coupling was associated with better performance. For the M1 to PMC coupling, older adults followed the same pattern as young adults - with stronger coupling accompanied by worse performance - but coupling strength was lower than in the young group. Our results suggest that bidirectional M1-PMC communication is related to precision in ankle force production and that this relationship changes with aging. We argue that the observed differences reflect compensatory reorganization that counteracts age-related sensorimotor declines and contributes to maintaining performance.

Transcranial Alternating Current Stimulation of the Primary Motor Cortex after Skill Acquisition Improves Motor Memory Retention in Humans: A Double-Blinded Sham-Controlled Study.

Consolidation leading to retention of motor memory following motor practice involves activity-dependent plastic processes in the corticospinal system. To investigate whether beta-band transcranial alternating current stimulation (tACS) applied immediately following skill acquisition can enhance ongoing consolidation processes and thereby motor skill retention 20 adults participated in a randomized, double-blinded, sham-controlled study. Participants received tACS at peak beta-band corticomuscular coherence (CMC) frequency or sham tACS for 10 min following practice of a visuomotor ankle dorsiflexion task. Performance was measured as the average percentage time on target. Electroencephalograhy (EMG) was measured at Cz and EMG from the right tibialis anterior muscle. CMC and intramuscular coherence (IMC) were estimated during 2-min tonic dorsiflexion. Motor skill retention was tested 1 and 7 days after motor practice. From the end of motor practice to the retention tests, motor performance improved more in the tACS group compared with the sham tACS group after 1 (P = 0.05) and 7 days (P < 0.001). At both retention tests, beta-band IMC increased in the tACS group compared with post-tACS. Beta-band CMC increased in the tACS group at retention day 1 compared with post-tACS. Changes in CMC but not IMC were correlated with performance 1 and 7 days following practice. This study shows that tACS applied at beta-band CMC frequency improves consolidation following visuomotor practice and increases beta-band CMC and IMC. We propose that oscillatory beta activity in the corticospinal system may facilitate consolidation of the motor skill.

Acute high-intensity football games can improve children's inhibitory control and neurophysiological measures of attention.

Recent studies suggest that a single bout of exercise can lead to transient performance improvements in specific cognitive domains in children. However, more knowledge is needed to determine the key exercise characteristics for obtaining these effects and how they translate into real-world settings. In the present study, we investigate how small-sided football games of either high- or moderate-intensity affect measures of inhibitory control in a school setting. Eighty-one children (mean age 11.8, 48 boys) were randomly allocated to three groups performing 20-minute of high-intensity small-sided real football games (SRF), moderate-intensity small-sided walking football games (SWF) or resting (RF). Behavioral measures of inhibitory control and neurophysiological measures of attention (P300 latency and amplitude) were obtained during a flanker task performed at baseline and 20 minutes following the intervention. Retention of declarative memory was assessed in a visual memory task 7 days after the intervention. Measures of inhibitory control improved more in children performing SRF compared to SWF 19 ms, 95% CI [7, 31 ms] (P = 0.041). This was paralleled by larger increases in P300 amplitudes at Fz in children performing SRF compared both to RF in congruent (3.54 µV, 95% CI [0.85, 6.23 µV], P = 0.039) and incongruent trials (5.56 µV, 95% CI [2.87, 8.25 µV], P < 0.001) and compared to SWF in incongruent trials (4.10 µV, 95% CI [1.41, 6.68 µV], P = 0.010). No effects were found in measures of declarative memory. Together this indicates that acute high-intensity small-sided football games can transiently improve measures of inhibitory control and neurophysiological correlates of attention. Intense small-sided football games are easily implementable and can be employed by practitioners, for example, during breaks throughout the school day.

Corticospinal control of normal and visually guided gait in healthy older and younger adults.

We investigated age-related differences in corticospinal control of muscle activity during normal and visually guided (VG) walking. Young (n = 15, 22.1 ± 1.7 years) and older (n = 15, 68.3 ± 2.7 years) participants performed normal walking and VG walking requiring precise foot placement based on visual cues. Coherence analysis was used to quantify coupling between electroencephalography and electromyography from the anterior tibial muscle (corticomuscular) and between the 2 ends of the anterior tibial muscle (intramuscular) at 15-50 Hz during the swing phase of walking as markers of corticospinal activity. Our results indicated that corticomuscular and intramuscular coherence was lower in older compared to young participants during both tasks. In addition, coherence was generally greater during VG than during normal walking across age groups, although during late swing, older participants drove several of the observed task-related coherence increases. Performance on the VG task was lower in older compared to young participants and was correlated with task-related corticomuscular coherence modulations within the older group. These results suggest age-related differences in the corticospinal control of walking, with possible implications for precision control of foot placement based on visual information.

The development of functional and directed corticomuscular connectivity during tonic ankle muscle contraction across childhood and adolescence.

In adults, oscillatory activity in the sensorimotor cortex is coherent with contralateral muscle activity at beta frequencies (15-35 Hz) during tonic contraction. This functional coupling reflects the involvement of the sensorimotor cortex, the corticospinal pathway, and likely also ascending sensory feedback in the task at hand. However, little is known about the developmental trajectory of task-related corticomuscular connectivity relating to the voluntary control of the ankle muscles. To address this, we recorded electroencephalography (EEG) from the vertex (Cz) and electromyography (EMG) from ankle muscles (proximal and distal anterior tibial, TA; soleus, SOL; gastrocnemius medialis, GM) in 33 participants aged 7-23 yr during tonic dorsi- and plantar flexion requiring precise maintenance of a submaximal torque level. Coherence was calculated for Cz-TA, Cz-SOL, TA-TA, and SOL-GM signal pairs. We found strong, positive associations between age and beta band coherence for Cz-TA, Cz-SOL, and TA-TA, suggesting that oscillatory corticomuscular connectivity is strengthened during childhood development and adolescence. Directionality analysis indicated that the primary interaction underlying this age-related increase was in the descending direction. In addition, performance during dorsi- and plantar flexion tasks was positively associated with age, indicating more precise control of the ankle joint in older participants. Performance was also positively associated with beta band coherence, suggesting that participants with greater coherence also exhibited greater precision. We propose that these results indicate an age-related increase in oscillatory corticospinal input to the ankle muscle motoneuron pools during childhood development and adolescence, with possible implications for maturation of precision force control. Within the theoretical framework of predictive coding, we suggest that our results may reflect an age-related increase in reliance on feedforward control as the developing nervous system becomes better at predicting the sensory consequences of movement. These findings may contribute to the development of novel intervention strategies targeting improved sensorimotor control in children and adolescents with central motor disorders.

Using Corticomuscular and Intermuscular Coherence to Assess Cortical Contribution to Ankle Plantar Flexor Activity During Gait.

The present study used coherence and directionality analyses to explore whether the motor cortex contributes to plantar flexor muscle activity during the stance phase and push-off phase during gait. Subjects walked on a treadmill, while EEG over the leg motorcortex area and EMG from the medial gastrocnemius and soleus muscles was recorded. Corticomuscular and intermuscular coherence were calculated from pair-wise recordings. Significant EEG-EMG and EMG-EMG coherence in the beta and gamma frequency bands was found throughout the stance phase with the largest coherence towards push-off. Analysis of directionality revealed that EEG activity preceded EMG activity throughout the stance phase until the time of push-off. These findings suggest that the motor cortex contributes to ankle plantar flexor muscle activity and forward propulsion during gait.

Impaired Ability to Suppress Excitability of Antagonist Motoneurons at Onset of Dorsiflexion in Adults with Cerebral Palsy.

We recently showed that impaired gait function in adults with cerebral palsy (CP) is associated with reduced rate of force development in ankle dorsiflexors. Here, we explore potential mechanisms. We investigated the suppression of antagonist excitability, calculated as the amount of soleus H-reflex depression at the onset of ankle dorsiflexion compared to rest, in 24 adults with CP (34.3 years, range 18-57; GMFCS 1.95, range 1-3) and 15 healthy, age-matched controls. Furthermore, the central common drive to dorsiflexor motoneurons during a static contraction in the two groups was examined by coherence analyses. The H-reflex was significantly reduced by 37% at the onset of dorsiflexion compared to rest in healthy adults (P < 0.001) but unchanged in adults with CP (P = 0.91). Also, the adults with CP had significantly less coherence. These findings suggest that the ability to suppress antagonist motoneuronal excitability at movement onset is impaired and that the central common drive during static contractions is reduced in adults with CP.

Oscillatory Corticospinal Activity during Static Contraction of Ankle Muscles Is Reduced in Healthy Old versus Young Adults.

Aging is accompanied by impaired motor function, but age-related changes in neural networks responsible for generating movement are not well understood. We aimed to investigate the functional oscillatory coupling between activity in the sensorimotor cortex and ankle muscles during static contraction. Fifteen young (20-26 yr) and fifteen older (65-73 yr) subjects were instructed to match a target force by performing static ankle dorsi- or plantar flexion, while electroencephalographic (EEG) activity was recorded from the cortex and electromyographic (EMG) activity was recorded from dorsi- (proximal and distal anterior tibia) and plantar (soleus and medial gastrocnemius) flexor muscles. EEG-EMG and EMG-EMG beta band (15-35 Hz) coherence was analyzed as an index of corticospinal activity. Our results demonstrated that beta cortico-, intra-, and intermuscular coherence was reduced in old versus young subjects during static contractions. Old subjects demonstrated significantly greater error than young subjects while matching target forces, but force precision was not related to beta coherence. We interpret this as an age-related decrease in effective oscillatory corticospinal activity during steady-state motor output. Additionally, our data indicate a potential effect of alpha coherence and tremor on performance. These results may be instrumental in developing new interventions to strengthen sensorimotor control in elderly subjects.

Increased central common drive to ankle plantar flexor and dorsiflexor muscles during visually guided gait.

When we walk in a challenging environment, we use visual information to modify our gait and place our feet carefully on the ground. Here, we explored how central common drive to ankle muscles changes in relation to visually guided foot placement. Sixteen healthy adults aged 23 ± 5 years participated in the study. Electromyography (EMG) from the Soleus (Sol), medial Gastrocnemius (MG), and the distal and proximal ends of the Tibialis anterior (TA) muscles and electroencephalography (EEG) from Cz were recorded while subjects walked on a motorized treadmill. A visually guided walking task, where subjects received visual feedback of their foot placement on a screen in real-time and were required to place their feet within narrow preset target areas, was compared to normal walking. There was a significant increase in the central common drive estimated by TA-TA and Sol-MG EMG-EMG coherence in beta and gamma frequencies during the visually guided walking compared to normal walking. EEG-TA EMG coherence also increased, but the group average did not reach statistical significance. The results indicate that the corticospinal tract is involved in modifying gait when visually guided placement of the foot is required. These findings are important for our basic understanding of the central control of human bipedal gait and for the design of rehabilitation interventions for gait function following central motor lesions.

Characterization of corticospinal activation of finger motor neurons during precision and power grip in humans.

Direct and indirect corticospinal pathways to finger muscles may play a different role in control of the upper extremity. We used transcranial magnetic stimulation (TMS) and coherence analysis to characterize the corticospinal drive to the first dorsal interosseous (FDI) and abductor pollicis brevis (APB) when active during a precision and power grip task. In experiment 1, single motor units were recorded during precision grip and power grip in 20 adults (25.2 ± 7.1 years). Post-stimulus time histograms (PSTH) were obtained following TMS. In experiment 2, coherence and cross-correlation analysis of the FDI and APB surface EMG were used to investigate the temporal organization of corticospinal drive during precision grip and power grip in 15 adults (27.4 ± 8.1 years). We found no significant differences in PSTH peak onset (26.6 ± 1.9 vs. 26.7 ± 2.0 ms, p = 0.75), maximal peak (27.4 ± 1.9 vs. 27.4 ± 1.9 ms, p = 1.0) or peak duration (2.3 ± 1.1 vs. 2.3 ± 1.0 ms, p = 0.75) for the 11 recovered motor units during precision grip and power grip. Also, no significant difference in coherence or the width of the synchronization peaks during precision grip (7.2 ± 3.7 ms) and power grip (7.9 ± 3.1 ms) could be observed (p = 0.59). The short duration of peaks elicited in the PSTH of single motor units following TMS and central synchronization peaks of voluntarily activated motor units during precision and power grip suggests that the direct corticospinal pathway (the corticomotoneuronal system) is equally involved in the control of both tasks. The data do not support that indirect pathways would make a larger contribution to power grip.

Improved cognitive performance in preadolescent Danish children after the school-based physical activity programme "FIFA 11 for Health" for Europe - A cluster-randomised controlled trial.

OBJECTIVE: Recent studies have shown promising effects of physical activity on cognitive function, but there is a need to investigate this link in real-life settings such as schools. Hence, the objective of the present pilot study was to investigate whether the school-based physical activity programme "FIFA 11 for Health" for Europe could improve cognitive performance in preadolescent Danish children. METHODS: The pilot study used an 11-week cluster-randomised intervention study design. School classes were randomly assigned to either a control group (CG) (n = 93 children, age = 11.8, s = 0.2 years), which performed the obligatory daily school-based physical activity (5 × 45 minutes per week); or an intervention group (IG) (n = 838 children, age = 11.9, s = 0.4 years), which substituted 2 × 45 minutes per week of the daily school physical activity with the "FIFA 11 for Health" for Europe programme. The programme combines small-sided football games, drills and health education. Cognitive performance was evaluated at baseline and follow-up. RESULTS: The IG improved their cognitive performance compared to the CG for psychomotor function (56, sx- = 22 ms, p < .001), attention (39, sx- = 17 ms, p = .012) and working memory (79, sx- = 35 ms, p = .020). CONCLUSION: This pilot study provides evidence that the school-based physical activity programme "FIFA 11 for Health" for Europe can improve cognitive performance in preadolescent Danish schoolchildren. Future studies should attempt to disentangle the effects of "FIFA 11 for Health" for Europe on cognitive performance by investigating the characteristics of the programme's physical activity.

Development and aging of human spinal cord circuitries.

The neural motor circuitries in the spinal cord receive information from our senses and the rest of the nervous system and translate it into purposeful movements, which allow us to interact with the rest of the world. In this review, we discuss how these circuitries are established during early development and the extent to which they are shaped according to the demands of the body that they control and the environment with which the body has to interact. We also discuss how aging processes and physiological changes in our body are reflected in adaptations of activity in the spinal cord motor circuitries. The complex, multifaceted connectivity of the spinal cord motor circuitries allows them to generate vastly different movements and to adapt their activity to meet new challenges imposed by bodily changes or a changing environment. There are thus plenty of possibilities for adaptive changes in the spinal motor circuitries both early and late in life.

Motor Skills and Exercise Capacity Are Associated with Objective Measures of Cognitive Functions and Academic Performance in Preadolescent Children.

OBJECTIVE: To investigate associations between motor skills, exercise capacity and cognitive functions, and evaluate how they correlate to academic performance in mathematics and reading comprehension using standardised, objective tests. METHODS: This cross-sectional study included 423 Danish children (age: 9.29±0.35 years, 209 girls). Fine and gross motor skills were evaluated in a visuomotor accuracy-tracking task, and a whole-body coordination task, respectively. Exercise capacity was estimated from the Yo-Yo intermittent recovery level 1 children's test (YYIR1C). Selected tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were used to assess different domains of cognitive functions, including sustained attention, spatial working memory, episodic and semantic memory, and processing speed. Linear mixed-effects models were used to investigate associations between these measures and the relationship with standard tests of academic performance in mathematics and reading comprehension. RESULTS: Both fine and gross motor skills were associated with better performance in all five tested cognitive domains (all P<0.001), whereas exercise capacity was only associated with better sustained attention (P<0.046) and spatial working memory (P<0.038). Fine and gross motor skills (all P<0.001), exercise capacity and cognitive functions such as working memory, episodic memory, sustained attention and processing speed were all associated with better performance in mathematics and reading comprehension. CONCLUSIONS: The data demonstrate that fine and gross motor skills are positively correlated with several aspects of cognitive functions and with academic performance in both mathematics and reading comprehension. Moreover, exercise capacity was associated with academic performance and performance in some cognitive domains. Future interventions should investigate associations between changes in motor skills, exercise capacity, cognitive functions, and academic performance to elucidate the causality of these associations.

Acute Exercise and Motor Memory Consolidation: The Role of Exercise Timing.

High intensity aerobic exercise amplifies offline gains in procedural memory acquired during motor practice. This effect seems to be evident when exercise is placed immediately after acquisition, during the first stages of memory consolidation, but the importance of temporal proximity of the exercise bout used to stimulate improvements in procedural memory is unknown. The effects of three different temporal placements of high intensity exercise were investigated following visuomotor skill acquisition on the retention of motor memory in 48 young (24.0 ± 2.5 yrs), healthy male subjects randomly assigned to one of four groups either performing a high intensity (90% Maximal Power Output) exercise bout at 20 min (EX90), 1 h (EX90+1), 2 h (EX90+2) after acquisition or rested (CON). Retention tests were performed at 1 d (R1) and 7 d (R7). At R1 changes in performance scores after acquisition were greater for EX90 than CON (p < 0.001) and EX90+2 (p = 0.001). At R7 changes in performance scores for EX90, EX90+1, and EX90+2 were higher than CON (p < 0.001, p = 0.008, and p = 0.008, resp.). Changes for EX90 at R7 were greater than EX90+2 (p = 0.049). Exercise-induced improvements in procedural memory diminish as the temporal proximity of exercise from acquisition is increased. Timing of exercise following motor practice is important for motor memory consolidation.

Impaired gait function in adults with cerebral palsy is associated with reduced rapid force generation and increased passive stiffness.

OBJECTIVE: It is still not clarified whether spasticity contributes to impairments of gait function. Here we compared biomechanical measures of muscle weakness and stiffness of ankle muscles to impairments of gait function in adults with cerebral palsy (CP). METHODS: Twenty-four adults with CP (mean age 34.3, range 18-57 years) and fifteen healthy age-matched controls were biomechanically measured for passive and reflex-mediated stiffness of the ankle plantarflexors at rest, maximal voluntary plantarflexion and dorsiflexion effort (MVCpf,df) and rate of force development (RFDpf,df). Kinematic analysis of the ankle joint during treadmill walking was obtained by 3-D motion analysis. RESULTS: Passive stiffness was significantly increased in adults with CP compared to controls. Passive stiffness and RFDdf were correlated to reduced toe lift. RFDpf provided the best correlation to push-off velocity, range of movement in the ankle joint and gait speed. Reflex-mediated stiffness was not correlated to any parameters of impaired gait. CONCLUSIONS: Impaired gait function in adults with CP is associated with reduced RFD and increased passive stiffness of ankle muscles. SIGNIFICANCE: These findings suggest that reduced rapid force generation and increased passive stiffness of ankle muscles rather than increased reflex-mediated stiffness (spasticity) likely contributes to impaired gait function in adults with CP.

The effects of cardiovascular exercise on human memory: a review with meta-analysis.

We reviewed the evidence for the use of cardiovascular exercise to improve memory and explored potential mechanisms. Data from 29 and 21 studies including acute and long-term cardiovascular interventions were retrieved. Meta-analyses revealed that acute exercise had moderate (SMD=0.26; 95% CI=0.03, 0.49; p=0.03; N=22) whereas long-term had small (SMD=0.15; 95% CI=0.02, 0.27; p=0.02; N=37) effects on short-term memory. In contrast, acute exercise showed moderate to large (SMD=0.52; 95% CI=0.28, 0.75; p<0.0001; N=20) whereas long-term exercise had insignificant effects (SMD=0.07; 95% CI=-0.13, 0.26; p=0.51; N=22) on long-term memory. We argue that acute and long-term cardiovascular exercise represent two distinct but complementary strategies to improve memory. Acute exercise improves memory in a time-dependent fashion by priming the molecular processes involved in the encoding and consolidation of newly acquired information. Long-term exercise, in contrast, has negligible effects on memory but provides the necessary stimuli to optimize the responses of the molecular machinery responsible for memory processing. Strategically combined, acute and long-term interventions could maximize the benefits of cardiovascular exercise on memory.

Premotor cortex modulates somatosensory cortex during voluntary movements without proprioceptive feedback.

Movement perception relies on sensory feedback, but the involvement of efference copies remains unclear. We investigated movements without proprioceptive feedback using ischemic nerve block during fMRI in healthy humans, and found preserved activation of the primary somatosensory cortex. This activation was associated with increased interaction with premotor cortex during voluntary movements, which demonstrates that perception of movements relies in part on predictions of sensory consequences of voluntary movements that are mediated by the premotor cortex.

Watching your foot move--an fMRI study of visuomotor interactions during foot movement.

The objective of this study was to investigate brain areas involved in distinguishing sensory events caused by self-generated movements from similar sensory events caused by externally generated movements using functional magnetic resonance imaging. Subjects performed 4 types of movements: 1) self-generated voluntary movement with visual feedback, 2) externally generated movement with visual feedback, 3) self-generated voluntary movement without visual feedback, and 4) externally generated movement without visual feedback, this design. This factorial design makes it possible to study which brain areas are activated during self-generated ankle movements guided by visual feedback as compared with externally generated movements under similar visual and proprioceptive conditions. We found a distinct network, comprising the posterior parietal cortex and lateral cerebellar hemispheres, which showed increased activation during visually guided self-generated ankle movements. Furthermore, we found differential activation in the cerebellum depending on the different main effects, that is, whether movements were self- or externally generated regardless of visual feedback, presence or absence of visual feedback, and activation related to proprioceptive input.