Plasma neurofilament light chain in children with relapsing MS receiving teriflunomide or placebo: A post hoc analysis of the randomized TERIKIDS trial.

BACKGROUND: The phase 3 TERIKIDS study demonstrated efficacy and manageable safety for teriflunomide versus placebo in children with relapsing multiple sclerosis (RMS). OBJECTIVE: Evaluate plasma neurofilament light chain (pNfL) concentrations in TERIKIDS. METHODS: Patients received placebo or teriflunomide (14 mg adult equivalent) for up to 96 weeks in the double-blind (DB) period. In the open-label extension (OLE), all patients received teriflunomide until up to 192 weeks after randomization. pNfL was measured using single-molecule array assay (Simoa® NF-light™). RESULTS: Baseline mean age was 14.5 years; 69.4% were female. Baseline geometric least square mean pNfL levels were similar for teriflunomide (n = 78) and placebo (n = 33) patients (19.83 vs 18.30 pg/mL). Over the combined DB and OLE periods, pNfL values were lower for teriflunomide versus placebo (analysis of variance p < 0.01; Week 192: 10.61 vs 17.32 pg/mL). Observed between-group pNfL differences were attenuated upon adjustment for gadolinium (Gd)-enhancing or new/enlarged T2 lesion counts at DB Week 24. Higher baseline pNfL levels were associated with shorter time since first MS symptom onset, higher baseline Gd-enhancing lesion counts and T2 lesion volume, and increased hazard of high magnetic resonance imaging activity or clinical relapse during the DB period. CONCLUSION: Teriflunomide treatment was associated with significantly reduced pNfL levels in children with RMS. CLINICALTRIALS.GOV IDENTIFIER: NCT02201108.

In vitro evaluation of the activity of teriflunomide against SARS-CoV-2 and the human coronaviruses 229E and OC43.

Previous data have suggested an antiviral effect of teriflunomide, including against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the agent underlying the ongoing COVID-19 pandemic. We undertook an in vitro investigation to evaluate the inhibitory activity of teriflunomide against SARS-CoV-2 in a cell-based assay. Teriflunomide was added to Vero (kidney epithelial) cells that had been infected with SARS-CoV-2. A nucleocapsid immunofluorescence assay was performed to examine viral inhibition with teriflunomide and any potential cytotoxic effect. The 50% effective concentration (EC50) for teriflunomide against SARS-CoV-2 was 15.22 µM. No cytotoxicity was evident for teriflunomide in the Vero cells (i.e., the 50% cytotoxic concentration [CC50] was greater than the highest test concentration of 100 µM). The data were supported by additional experiments using other coronaviruses and human cell lines. In the SARS-CoV-2-infected Vero cells, the prodrug leflunomide had an EC50 of 16.49 µM and a CC50 of 54.80 µM. Our finding of teriflunomide-mediated inhibition of SARS-CoV-2 infection at double-digit micromolar potency adds to a growing body of evidence for a broad-ranging antiviral effect of teriflunomide.

Persistence, Adherence, and Switching to Higher-Cost Therapy in Patients with Multiple Sclerosis Initiating Oral Disease-Modifying Therapies: A Retrospective Real-World Study.

INTRODUCTION: Therapeutic efficacy of disease-modifying therapies (DMTs) for multiple sclerosis (MS) is often hindered by poor persistence and adherence, impacted by patient-perceived efficacy concerns, adverse effects, inconvenience, and forgetfulness. This study measured persistence, adherence, and time to switching to higher-cost therapy among patients with MS initiating teriflunomide, dimethyl fumarate, fingolimod, or diroximel fumarate treatment. METHODS: This retrospective study used Symphony Health US claims data from patients with MS newly initiated on one of four oral DMTs between January and June 2020. Persistence was defined as the duration a patient continued their medication. Adherence was measured using medication possession ratio (MPR); patients with MPR ≥ 80% were considered adherent. Switching was measured by comparing proportions of patients switching and mean time to switch to one of three higher-cost therapies (ocrelizumab, natalizumab, or cladribine). Kaplan-Meier curves assessed persistence. Chi-square tests determined proportions of patients on therapy after 12 months. RESULTS: A total of 6934 patients newly initiated on oral DMTs met study inclusion criteria (teriflunomide, n = 1968; dimethyl fumarate, n = 3409; diroximel fumarate, n = 616; fingolimod, n = 941). Patients newly initiated on teriflunomide and fingolimod had significantly higher persistence rates after 12 months (60% and 66%, respectively vs 44% dimethyl fumarate and 49% diroximel fumarate; p < 0.0001), and the highest proportion of adherent patients at 6 months (71% and 76%, vs 60% dimethyl fumarate and 58% diroximel fumarate) and 12 months (55% and 59%, vs 40% dimethyl fumarate and 44% diroximel fumarate). Mean time to switching to higher-cost therapies ranged from 247 days (diroximel fumarate to natalizumab) to 342 days (teriflunomide to ocrelizumab), with the highest rate of switching in patients on dimethyl fumarate (7%). CONCLUSION: Patients newly initiated on teriflunomide and fingolimod had better real-world persistence and adherence at 6 and 12 months, and longer time to switch to higher-cost therapies, than patients on dimethyl fumarate or diroximel fumarate.

People living with multiple sclerosis (MS for short) can find it difficult to maintain treatment plans. This can impact how well disease-modifying therapies (DMTs) work. This means treatments may not be as effective at controlling symptoms or stopping new symptoms (relapse). In this study, we looked at health records of 6934 previously diagnosed people living with MS in the USA. These people started DMTs for the first time between January and June 2020. Researchers studied how long people continued their treatment (known as persistence) and how often people took their treatment as recommended (adherence). We also studied how many people switched to a more expensive treatment (ocrelizumab, natalizumab, or cladribine). We measured persistence based on how many days people continued their treatment. We measured adherence through the number of people who took their treatment at least 80% of the time. After 1 year, more people who took teriflunomide and fingolimod continued treatment than people on dimethyl fumarate or diroximel fumarate. These people were also more likely to follow their treatment plan. People taking dimethyl fumarate were most likely to switch to a more expensive treatment. On average, people who changed to a more expensive treatment did so after around 8 months. In this study, we found that people with MS who started teriflunomide or fingolimod for the first time were more likely to continue treatment and take treatment as recommended than those on dimethyl fumarate or diroximel fumarate. They also took longer to switch to a more expensive treatment.

Vaccine Response in Patients With Multiple Sclerosis Receiving Teriflunomide.

Many patients with multiple sclerosis (MS) receive disease-modifying therapies (DMTs), such as teriflunomide, to reduce disease activity and slow progression. DMTs mediate their efficacy by modulating or suppressing the immune system, which might affect a patient's response to vaccination. As vaccines against the SARS-CoV-2 virus become available, questions have arisen around their efficacy and safety for patients with MS who are receiving DMTs. Data are beginning to emerge regarding the potential influence of certain DMTs on a patient's response to coronavirus disease 2019 (COVID-19) vaccines and are supported by evidence from vaccination studies of other pathogens. This review summarizes the available data on the response to vaccines in patients with MS who are receiving DMTs, with a focus on teriflunomide. It also provides an overview of the leading COVID-19 vaccines and current guidance around COVID-19 vaccination for patients with MS. Though few vaccination studies have been done for this patient population, teriflunomide appears to have minimal influence on the response to seasonal influenza vaccine. The evidence for other DMTs (e.g., fingolimod, glatiramer acetate) is less consistent: some studies suggest no effect of DMTs on vaccine response, whereas others show reduced vaccine efficacy. No unexpected safety signals have emerged in any vaccine study. Current guidance for patients with MS is to continue DMTs during COVID-19 vaccination, though adjusted timing of dosing for some DMTs may improve the vaccine response.

Transcutaneous spinal direct current stimulation increases corticospinal transmission and enhances voluntary motor output in humans.

Optimization of motor performance is of importance in daily life, in relation to recovery following injury as well as for elite sports performance. The present study investigated whether transcutaneous spinal direct current stimulation (tsDCS) may enhance voluntary ballistic activation of ankle muscles and descending activation of spinal motor neurons in able-bodied adults. Forty-one adults (21 men; 24.0 ± 3.2 years) participated in the study. The effect of tsDCS on ballistic motor performance and plantar flexor muscle activation was assessed in a double-blinded sham-controlled cross-over experiment. In separate experiments, the underlying changes in excitability of corticospinal and spinal pathways were probed by evaluating soleus (SOL) motor evoked potentials (MEPs) following single-pulse transcranial magnetic stimulation (TMS) over the primary motor cortex, SOL H-reflexes elicited by tibial nerve stimulation and TMS-conditioning of SOL H-reflexes. Measures were obtained before and after cathodal tsDCS over the thoracic spine (T11-T12) for 10 min at 2.5 mA. We found that cathodal tsDCS transiently facilitated peak acceleration in the ballistic motor task compared to sham tsDCS. Following tsDCS, SOL MEPs were increased without changes in H-reflex amplitudes. The short-latency facilitation of the H-reflex by subthreshold TMS, which is assumed to be mediated by the fast conducting monosynaptic corticomotoneuronal pathway, was also enhanced by tsDCS. We argue that tsDCS briefly facilitates voluntary motor output by increasing descending drive from corticospinal neurones to spinal plantar flexor motor neurons. tsDCS can thus transiently promote within-session CNS function and voluntary motor output and holds potential as a technique in the rehabilitation of motor function following central nervous lesions.

Effects of oily fish intake on cognitive and socioemotional function in healthy 8-9-year-old children: the FiSK Junior randomized trial.

BACKGROUND: Long-chain n-3 PUFAs (n-3 LCPUFAs) accrete in the brain during childhood and affect brain development. Randomized trials in children show inconsistent effects of n-3 LCPUFAs on cognitive and socioemotional function, and few have investigated effects of fish per se. OBJECTIVES: We aimed to investigate the effects of oily fish consumption on overall and domain-specific cognitive and socioemotional scores and explore sex differences. METHODS: Healthy 8-9-y-old children (n = 199) were randomly allocated to receive ∼300 g/wk oily fish or poultry (control) for 12 ± 2 wk. At baseline and endpoint, we assessed attention, processing speed, executive functions, memory, emotions, and behavior with a large battery of tests and questionnaires and analyzed erythrocyte fatty acid composition. RESULTS: One hundred and ninety-seven (99%) children completed the trial. Children in the fish group consumed 375 (25th-75th percentile: 325-426) g/wk oily fish resulting in 2.3 (95% CI: 1.9, 2.6) fatty acid percentage points higher erythrocyte n-3 LCPUFA than in the poultry group. The overall cognitive performance score tended to improve by 0.17 (95% CI: -0.01, 0.35) points in children who received fish compared with poultry, supported by n-3 LCPUFA dose dependency. This was driven mainly by fewer errors [-1.9 (95% CI: -3.4, -0.3)] in an attention task and improved cognitive flexibility measured as faster reaction time [-51 ms (95% CI: -94, -7 ms)] in a complex relative to a simple task ("mixing cost"). The fish intervention furthermore reduced parent-rated Strength and Difficulties Questionnaire total difficulties by -0.89 (95% CI: -1.60, -0.18) points mainly due to a -0.63 (95% CI: -1.11, -0.16) points reduction in internalizing problems that was reflected in tendency to a decrease in the overall socioemotional problems score of -0.13 (95% CI: -0.26, 0.01) points. The overall effects were similar in boys and girls. CONCLUSIONS: Oily fish dose-dependently improved cognitive function, especially attention and cognitive flexibility, and reduced socioemotional problems. The results support the importance of n-3 LCPUFAs for optimal brain function and fish intake recommendations in children.The trial was registered at www.clinicaltrials.gov as NCT02809508.

Dynamics of postural control during bilateral stance - Effect of support area, visual input and age.

The present study investigated the effect of support area, visual input and aging of the dynamics of postural control during bilateral stance. Fifteen young (22.1 ±â€¯1.7 years) and fifteen older (68.3 ±â€¯2.7 years) individuals completed four different 90 s bilateral stance trials: 1) shoulder wide feet distance with eyes open, 2) shoulder wide feet distance with eyes closed, 3) narrow feet distance with eyes open, and 4) narrow feet distance with eyes closed on a force plate form. The anterior (AP) and mediolateral (ML) center of pressure (COP) trajectories were calculated from the middle 60 s of the ground reaction forces and moments. Sample entropy (SaEn), correlation dimension (CoD), the largest Lyapunov exponent (LyE) and entropic half-life (ENT½) were calculated for the COP in both directions. In young individuals, a narrower support area resulted in a restricted movement solution space with lower SaEn, lower LyE and longer ENT½ in the executed motor control strategy, whereas it increased the CoD in the older individuals. During the eyes closed trials, SaEn, CoD and LyE increased and decreased ENT½ for both groups in the AP direction and increased SaEn and LyE in the ML direction for the older individuals alone. This indicates that aging is associated with direction- and task-dependent changes in the dynamics of the executed COP movements during postural stance tasks.

Exploring correlations between neuropsychological measures and domain-specific consistency in associations with n-3 LCPUFA status in 8-9 year-old boys and girls.

Long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFA) have in some studies been associated with cognitive and socioemotional outcomes in children, but results are inconsistent possibly due to the use of different tests and potential gender-specific effects. The objective of this cross-sectional study was to explore overall patterns in neuropsychological scores as well as correlations between scores within specific domains, and to examine potential gender differences and consistency in associations with n-3 LCPUFA status. In 199 Danish 8-9 year-old children, we performed a large battery of tests and questionnaires on attention, processing speed, executive functions, memory, and socioemotional traits, and measured erythrocyte fatty acid composition. Principal component analyses (PCA) showed that most of the variation in both cognitive performance and socioemotional traits was explained by overall performance, followed by speed-accuracy trade off and externalizing vs. internalizing problems, respectively. Boys had higher speed, lower attention and higher externalizing problem scores than girls. Measures of performance within both processing speed and attention domains correlated moderately, whereas no correlations were found for measures of executive functions apart from some weak correlations for impulsivity. Parent-rated scores for both externalizing and internalizing problems correlated strongly, whereas correlations with child-rated scores were weak. Scores within specific domains did not consistently associate with n-3 LCPUFA, except for processing speed measures which all pointed to faster processing with increased n-3 LCPUFA status. Gender differences in the associations were observed for attention and impulsivity. Child- but not parent-rated internalizing and social problems tended to associate directly with n-3 LCPUFA, supported by increased internalizing problems measured by the PCA component. In conclusion, measures of speed and attention seem to represent these domains in general, whereas single measures of more complex cognitive functions should be interpreted with caution. One approach could be to use multiple tests and create multivariate scores to guide interpretations. Furthermore, the results indicate a need to consider both parent- and child-rated socioemotional scores and gender differences in neuropsychological functions e.g. in investigations of n-3 LCPUFA effects.

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

A single bout of high intensity aerobic exercise (~90% VO2peak) was previously demonstrated to amplify off-line gains in skill level during the consolidation phase of procedural memory. High intensity exercise is not always a viable option for many patient groups or in a rehabilitation setting where low to moderate intensities may be more suitable. The aim of this study was to investigate the role of intensity in mediating the effects of acute cardiovascular exercise on motor skill learning. We investigated the effects of different exercise intensities on the retention (performance score) of a visuomotor accuracy tracking task. Thirty six healthy male subjects were randomly assigned to one of three groups that performed either a single bout of aerobic exercise at 20 min post motor skill learning at 45% (EX45), 90% (EX90) maximal power output (Wmax) or rested (CON). Randomization was stratified to ensure that the groups were matched for relative peak oxygen consumption (ml O2/min/kg) and baseline score in the tracking task. Retention tests were carried out at 1 (R1) and 7 days (R7) post motor skill learning. At R1, changes in performance scores were greater for EX90 compared to CON (p<0.001) and EX45 (p = 0.011). The EX45 and EX90 groups demonstrated a greater change in performance score at R7 compared to the CON group (p = 0.003 and p<0.001, respectively). The change in performance score for EX90 at R7 was also greater than EX45 (p = 0.049). We suggest that exercise intensity plays an important role in modulating the effects that a single bout of cardiovascular exercise has on the consolidation phase following motor skill learning. There appears to be a dose-response relationship in favour of higher intensity exercise in order to augment off-line effects and strengthen procedural memory.

Explosive Resistance Training Increases Rate of Force Development in Ankle Dorsiflexors and Gait Function in Adults With Cerebral Palsy.

Kirk, H, Geertsen, SS, Lorentzen, J, Krarup, KB, Bandholm, T, and Nielsen, JB. Explosive resistance training increases rate of force development in ankle dorsiflexors and gait function in adults with cerebral palsy. J Strength Cond Res 30(10): 2749-2760, 2016-Alterations in passive elastic properties of muscles and reduced ability to quickly generate muscle force contribute to impaired gait function in adults with cerebral palsy (CP). In this study, we investigated whether 12 weeks of explosive and progressive heavy-resistance training (PRT) increases rate of force development of ankle dorsiflexors (RFDdf), improves gait function, and affects passive ankle joint stiffness in adults with CP. Thirty-five adults (age: 36.5; range: 18-59 years) with CP were nonrandomly assigned to a PRT or nontraining control (CON) group in this explorative trial. The PRT group trained ankle dorsiflexion, plantarflexion, leg press, hamstring curls, abdominal curls, and back extension 3 days per week for 12 weeks, with 3 sets per exercise and progressing during the training period from 12 to 6 repetition maximums. RFDdf, 3-dimensional gait analysis, functional performance, and ankle joint passive and reflex-mediated muscle stiffness were evaluated before and after. RFDdf increased significantly after PRT compared to CON. PRT also caused a significant increase in toe lift late in swing and a significantly more dorsiflexed ankle joint at ground contact and during stance. The increased toe-lift amplitude was correlated to the increased RFDdf (r = 0.73). No other between-group differences were observed. These findings suggest that explosive PRT may increase RFDdf and facilitate larger range of movement in the ankle joint during gait. Explosive PRT should be tested in clinical practice as part of a long-term training program for adults with CP.

Motor-Enriched Learning Activities Can Improve Mathematical Performance in Preadolescent Children.

Objective: An emerging field of research indicates that physical activity can benefit cognitive functions and academic achievements in children. However, less is known about how academic achievements can benefit from specific types of motor activities (e.g., fine and gross) integrated into learning activities. Thus, the aim of this study was to investigate whether fine or gross motor activity integrated into math lessons (i.e., motor-enrichment) could improve children's mathematical performance. Methods: A 6-week within school cluster-randomized intervention study investigated the effects of motor-enriched mathematical teaching in Danish preadolescent children (n = 165, age = 7.5 ± 0.02 years). Three groups were included: a control group (CON), which received non-motor enriched conventional mathematical teaching, a fine motor math group (FMM) and a gross motor math group (GMM), which received mathematical teaching enriched with fine and gross motor activity, respectively. The children were tested before (T0), immediately after (T1) and 8 weeks after the intervention (T2). A standardized mathematical test (50 tasks) was used to evaluate mathematical performance. Furthermore, it was investigated whether motor-enriched math was accompanied by different effects in low and normal math performers. Additionally, the study investigated the potential contribution of cognitive functions and motor skills on mathematical performance. Results: All groups improved their mathematical performance from T0 to T1. However, from T0 to T1, the improvement was significantly greater in GMM compared to FMM (1.87 ± 0.71 correct answers) (p = 0.02). At T2 no significant differences in mathematical performance were observed. A subgroup analysis revealed that normal math-performers benefitted from GMM compared to both CON 1.78 ± 0.73 correct answers (p = 0.04) and FMM 2.14 ± 0.72 correct answers (p = 0.008). These effects were not observed in low math-performers. The effects were partly accounted for by visuo-spatial short-term memory and gross motor skills. Conclusion: The study demonstrates that motor enriched learning activities can improve mathematical performance. In normal math performers GMM led to larger improvements than FMM and CON. This was not the case for the low math performers. Future studies should further elucidate the neurophysiological mechanisms underlying the observed behavioral effects.

Short-latency crossed responses in the human biceps femoris muscle.

KEY POINTS: The present study is the first to show short-latency crossed-spinal reflexes in the human upper leg muscles following mechanical rotations to the ipsilateral knee (iKnee) joint. The short-latency reflex in the contralateral biceps femoris (cBF) was inhibitory following iKnee extension perturbations, and facilitatory following iKnee flexion perturbations. The onset latency was 44 ms, indicating that purely spinal pathways mediate the cBF reflexes. The short-latency cBF inhibitory and facilitatory reflexes followed the automatic gain control principle, becoming larger as the level of background contraction in the cBF increased. The short-latency cBF reflexes were observed at the motor unit level using i.m. electromyography recordings, and the same population of cBF motor units that was inhibited following iKnee extensions was facilitated following iKnee flexions. Parallel interneuronal pathways from ipsilateral afferents to common motoneurons in the contralateral leg can therefore probably explain the perturbation direction-dependent reversal in the sign of the short-latency cBF reflex. ABSTRACT: Interlimb reflexes contribute to the central neural co-ordination between different limbs in both humans and animals. Although commissural interneurons have only been directly identified in animals, spinally-mediated interlimb reflexes have been discovered in a number of human lower limb muscles, indicating their existence in humans. The present study aimed to investigate whether short-latency crossed-spinal reflexes are present in the contralateral biceps femoris (cBF) muscle following ipsilateral knee (iKnee) joint rotations during a sitting task, where participants maintained a slight pre-contraction in the cBF. Following iKnee extension joint rotations, an inhibitory reflex was observed in the surface electromyographic (EMG) activity of the cBF, whereas a facilitatory reflex was observed in the cBF following iKnee flexion joint rotations. The onset latency of both cBF reflexes was 44 ms, which is too fast for a transcortical pathway to contribute. The cBF inhibitory and facilitatory reflexes followed the automatic gain control principle, with the size of the response increasing as the level of background pre-contraction in the cBF muscle increased. In addition to the surface EMG, both short-latency inhibitory and facilitatory cBF reflexes were recorded directly at the motor unit level by i.m. EMG, and the same population of cBF motor units that were inhibited following iKnee extension joint rotations were facilitated following iKnee flexion joint rotations. Therefore, parallel interneuronal pathways (probably involving commissural interneurons) from ipsilateral afferents to common motoneurons in the contralateral leg can probably explain the perturbation direction-dependent reversal in the sign of the short-latency cBF reflex.

Interlimb communication following unexpected changes in treadmill velocity during human walking.

Interlimb reflexes play an important role in human walking, particularly when dynamic stability is threatened by external perturbations or changes in the walking surface. Interlimb reflexes have recently been demonstrated in the contralateral biceps femoris (cBF) following knee joint rotations applied to the ipsilateral leg (iKnee) during the late stance phase of human gait (Stevenson AJ, Geertsen SS, Andersen JB, Sinkjær T, Nielsen JB, Mrachacz-Kersting N. J Physiol 591: 4921-4935, 2013). This interlimb reflex likely acts to slow the forward progression of the body to maintain dynamic stability following the perturbations. We examined this hypothesis by unexpectedly increasing or decreasing the velocity of the treadmill before (-100 and -50 ms), at the same time, or following (+50 ms) the onset of iKnee perturbations in 12 healthy volunteers. We quantified the cBF reflex amplitude when the iKnee perturbation was delivered alone, the treadmill velocity change was delivered alone, or when the two perturbations were combined. When the treadmill velocity was suddenly increased (or decreased) 100 or 50 ms before the iKnee perturbations, the combined cBF reflex was significantly larger (or smaller) than the algebraic sum of the two perturbations delivered separately. Furthermore, unexpected changes in treadmill velocity increased the incidence of reflexes in other contralateral leg muscles when the iKnee perturbations were elicited alone. These results suggest a context dependency for interlimb reflexes. They also show that the cBF reflex changed in a predictable manner to slow the forward progression of the body and maintaining dynamic stability during walking, thus signifying a functional role for interlimb reflexes.

Interlimb communication to the knee flexors during walking in humans.

A strong coordination between the two legs is important for maintaining a symmetric gait pattern and adapting to changes in the external environment. In humans as well as animals, receptors arising from the quadriceps muscle group influence the activation of ipsilateral muscles. Moreover, strong contralateral spinal connections arising from quadriceps and hamstring afferents have been shown in animal models. Therefore, the aims of the present study were to assess if such connections also exist in humans and to elucidate on the possible pathways. Contralateral reflex responses were investigated in the right leg following unexpected unilateral knee joint rotations during locomotion in either the flexion or extension direction. Strong reflex responses in the contralateral biceps femoris (cBF) muscle with a mean onset latency of 76 ± 6 ms were evoked only from ipsilateral knee extension joint rotations in the late stance phase. To investigate the contribution of a transcortical pathway to this response, transcranial magnetic and electrical stimulation were applied. Motor evoked potentials elicited by transcranial magnetic stimulation, but not transcranial electrical stimulation, were facilitated when elicited at the time of the cBF response to a greater extent than the algebraic sum of the cBF reflex and motor evoked potentials elicited separately, indicating that a transcortical pathway probably contributes to this interlimb reflex. The cBF reflex response may therefore be integrated with other sensory input, allowing for responses that are more flexible. We hypothesize that the cBF reflex response may be a preparation of the contralateral leg for early load bearing, slowing the forward progression of the body to maintain dynamic equilibrium during walking.

Assessment of a portable device for the quantitative measurement of ankle joint stiffness in spastic individuals.

OBJECTIVE: Spasticity is a common complication with neurological diseases and CNS lesions. Instrumented systems to evaluate spasticity often cannot provide an immediate result, thus limiting their clinical usefulness. In this study we investigated the accuracy and reliability of the portable Neurokinetics RA1 Ridgidity Analyzer to measure stiffness of the ankle joint in 46 controls, 14 spinal cord injured (SCI) and 23 multiple sclerosis (MS) participants. METHODS: Ankle stiffness measures were made twice by two raters, at speeds above and below the expected stretch reflex threshold. Ankle torque was measured with the portable device and a stationary torque motor. Inter- and intra-rater reliability was assessed with the intra-class correlation coefficient (ICC). RESULTS: Stiffness measures with the portable and stationary devices were significantly correlated for controls and MS participants (p < 0.01). Intra-rater reliability for the portable device ranged from 0.60-0.89 (SCI) and 0.63-0.67 (control) and inter-rater reliability ranged from 0.70-0.73 (SCI) and 0.61-0.77 (control). Ankle stiffness measures in SCI and MS participants were significantly larger than in controls for both slow (p < 0.05) and fast movements (p < 0.01), with stiffness being larger for fast compared to slow movements in SCI and MS participants (p < 0.05), but not in controls (p = 0.5). CONCLUSION: The portable device correlated well with measures obtained by a torque motor in both controls and MS participants, showed high intra- and inter-rater reliability for the SCI participants, and could easily distinguish between stiff and control ankle joints. However, the device, in its current form, may be less accurate during rapid movements when inertia contributes to stiffness and the shape of the air-filled pads did not provide a good interface with the foot. SIGNIFICANCE: This study demonstrates that a portable device can potentially be a useful diagnostic tool to obtain reliable information of stiffness for the ankle joint.

Spinal inhibition of descending command to soleus motoneurons is removed prior to dorsiflexion.

It has recently been demonstrated that soleus motor-evoked potentials (MEPs) are facilitated prior to the onset of dorsiflexion. The purpose of this study was to examine if this could be explained by removal of spinal inhibition of the descending command to soleus motoneurons. To test this, we investigated how afferent inputs from the tibialis anterior muscle modulate the corticospinal activation of soleus spinal motoneurons at rest, during static contraction and prior to movement. MEPs activated by transcranial magnetic stimulation (TMS) and Hoffmann reflexes (H-reflexes), activated by electrical stimulation of the posterior tibial nerve (PTN), were conditioned by prior stimulation of the common peroneal nerve (CPN) at a variety of conditioning-test (CT) intervals. MEPs in the precontracted soleus muscle were inhibited when the TMS pulse was preceded by CPN stimulation with a CT interval of 35 ms, and they were facilitated for CT intervals of 50-55 ms. A similar inhibition of the soleus H-reflex was not observed. To investigate which descending pathways might be responsible for the afferent-evoked inhibition and facilitation, we examined the effect of CPN stimulation on short-latency facilitation (SLF) and long-latency facilitation (LLF) of the soleus H-reflex induced by a subthreshold TMS pulse at different CT intervals. SLF is known to reflect the excitability of the fastest conducting, corticomotoneuronal cells whereas LLF is believed to be caused by more indirect descending pathways. At CT intervals of 40-45 ms, the LLF was significantly more inhibited compared to the SLF when taking the effect on the H-reflex into account. Finally, we investigated how the CPN-induced inhibition and facilitation of the soleus MEP were modulated prior to dorsiflexion. Whereas the late facilitation (CT interval: 55 ms) was similar prior to dorsiflexion and at rest, no inhibition could be evoked at the earlier latency (CT interval: 35 ms) prior to onset of dorsiflexion. The observation that the CPN-induced inhibition of soleus MEPs disappears prior to onset of dorsiflexion may explain why soleus MEPs are facilitated prior to onset of dorsiflexion contraction. A possible mechanism involves the removal of inhibition of the descending command to the motoneurons at a spinal interneuronal level because the inhibition was seen in LLF and not in SLF, and the MEP inhibition was not observed in the H-reflex. The data illustrate that spinal interneuronal pathways modify descending commands to human spinal motoneurons and influence the size of MEPs elicited by TMS.

Reciprocal Ia inhibition contributes to motoneuronal hyperpolarisation during the inactive phase of locomotion and scratching in the cat.

Despite decades of research, the classical idea that 'reciprocal inhibition' is involved in the hyperpolarisation of motoneurones in their inactive phase during rhythmic activity is still under debate. Here, we investigated the contribution of reciprocal Ia inhibition to the hyperpolarisation of motoneurones during fictive locomotion (evoked either by electrical stimulation of the brainstem or by l-DOPA administration following a spinal transection at the cervical level) and fictive scratching (evoked by stimulation of the pinna) in decerebrate cats. Simultaneous extracellular recordings of Ia inhibitory interneurones and intracellular recordings of lumbar motoneurones revealed the interneurones to be most active when their target motoneurones were hyperpolarised (i.e. in the inactive phase of the target motoneurones). To date, these results are the most direct evidence that Ia inhibitory interneurones contribute to the hyperpolarisation of motoneurones during rhythmic behaviours. We also estimated the amount of Ia inhibition as the amplitude of Ia IPSC in voltage-clamp mode. In both flexor and extensor motoneurones, Ia IPSCs were always larger in the inactive phase than in the active phase during locomotion (n = 14) and during scratch (n = 11). Results obtained from spinalised animals demonstrate that the spinal rhythm-generating network simultaneously drives the motoneurones of one muscle group and the Ia interneurones projecting to motoneurones of the antagonist muscles in parallel. Our results thus support the classical view of reciprocal inhibition as a basis for relaxation of antagonist muscles during flexion-extension movements.

Voluntary activation of ankle muscles is accompanied by subcortical facilitation of their antagonists.

Flexion and extension movements are organized reciprocally, so that extensor motoneurones in the spinal cord are inhibited when flexor muscles are active and vice versa. During and just prior to dorsiflexion of the ankle, soleus motoneurones are thus inhibited as evidenced by a depression of the soleus H-reflex. It is therefore surprising that soleus motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) have been found not to be reduced and even facilitated during a voluntary dorsiflexion. The objective of this study was to investigate if MEPs, evoked by TMS, show a similar facilitation prior to and at the onset of contraction of muscles that are antagonists to the muscle in which the MEP is evoked and if so, examine the origin of such a facilitatory motor programme. Eleven seated subjects reacted to an auditory cue by contracting either the tibialis anterior (TA) or soleus muscle of the left ankle. TMS was applied to the hotspot of TA and soleus muscles on separate days. Stimuli were delivered prior to and at the beginning of contraction. Soleus MEPs were significantly facilitated when TMS was applied 50 ms prior to onset of plantar flexion. Surprisingly, soleus MEPs were also facilitated (although to a lesser extent) at a similar time in relation to the onset of dorsiflexion. TA MEPs were facilitated 50 ms prior to onset of dorsiflexion and neither depressed nor facilitated prior to plantar flexion. No difference was found between the facilitation of the soleus MEP and motor evoked responses to cervicomedullary stimulation prior to dorsiflexion, suggesting that the increased soleus MEPs were not caused by changes at a cortical level. This was confirmed by the observation that short-latency facilitation of the soleus H-reflex by subthreshold TMS was increased prior to plantar flexion, but not prior to dorsiflexion. These findings suggest that voluntary contraction at the ankle is accompanied by preceding facilitation of antagonists by a subcortical motor programme. This may help to ensure that the direction of movement may be changed quickly and efficiently during functional motor tasks.

Increased central facilitation of antagonist reciprocal inhibition at the onset of dorsiflexion following explosive strength training.

At the onset of dorsiflexion disynaptic reciprocal inhibition (DRI) of soleus motoneurons is increased to prevent activation of the antagonistic plantar flexors. This is caused by descending facilitation of transmission in the DRI pathway. Because the risk of eliciting stretch reflexes in the ankle plantar flexors at the onset of dorsiflexion is larger the quicker the movement, it was hypothesized that DRI may be increased when subjects are trained to perform dorsiflexion movements as quickly as possible For this purpose, 14 healthy human subjects participated in explosive strength training of the ankle dorsiflexor muscles 3 times a week for 4 wk. Test sessions were conducted before, shortly after, and 2 wk after the training period. The rate of torque development measured at 30, 50, 100, and 200 ms after onset of voluntary explosive isometric dorsiflexion increased by 24-33% (P < 0.05). DRI was measured as the depression of the soleus H reflex following conditioning stimulation of the peroneal nerve (1.1 x motor threshold) at an interval of 2-3 ms. At the onset of dorsiflexion the amount of DRI measured relative to DRI at rest increased significantly from 6% before the training to 22% after the training (P < 0.05). We speculate that DRI at the onset of movement may be increased in healthy subjects following explosive strength training to ensure efficient suppression of the antagonist muscles as the dorsiflexion movement becomes faster.