Antagonism of 5-HT2 receptors attenuates self-sustained firing of human motor units.

5-HT2 receptors on motoneurones play a critical role in facilitating persistent inward currents (PICs). Although facilitation of PICs can enhance self-sustained firing after periods of excitation, the relationship between 5-HT2 receptor activity and self-sustained firing in human motor units (MUs) has not been resolved. MU activity was assessed from the tibialis anterior of 10 healthy adults (24.9 ± 2.8 years) during two contraction protocols. Both protocols featured steady-state isometric contractions with constant descending drive to the motoneurone pool. However, one protocol also included an additional phase of superimposed descending drive. Adding and then removing descending drive in the middle of steady-state contractions altered MU firing behaviour across the motor pool, where newly recruited units in the superimposed phase were unable to switch off (P = 0.0002), and units recruited prior to additional descending drive reduced their discharge rates (P < 0.0001, difference in estimated marginal means (∆) = 2.24 pulses/s). The 5-HT2 receptor antagonist, cyproheptadine, was then administered to determine whether changes in MU firing were mediated by serotonergic mechanisms. 5-HT2 receptor antagonism caused reductions in MU discharge rate (P < 0.001, ∆ = 1.65 pulses/s), recruitment threshold (P = 0.00112, ∆ = 1.09% maximal voluntary contraction) and self-sustained firing duration (P < 0.0001, ∆ = 1.77s) after the additional descending drive was removed in the middle of the steady-state contraction. These findings indicate that serotonergic neuromodulation plays a key role in facilitating discharge and self-sustained firing of human motoneurones, where adaptive changes in MU recruitment must occur to meet the demands of the contraction. KEY POINTS: Animal and cellular preparations indicate that somato-dendritic 5-HT2 receptors regulate the intrinsic excitability of motoneurones. 5-HT2 receptor antagonism reduces estimates of persistent inward currents in motoneurones, which contribute to self-sustained firing when synaptic inputs are reduced or removed. This human study employed a contraction task that slowly increased (and then removed) the additional descending drive in the middle of a steady-state contraction where marked self-sustained firing occurred when the descending drive was removed. 5-HT2 receptor antagonism caused widespread reductions in motor unit (MU) discharge rates during contractions, which was accompanied by reduced recruitment threshold and attenuation of self-sustained firing duration after the removal of the additional descending drive to motoneurones. These findings support the role that serotonergic neuromodulation is a key facilitator of MU discharge and self-sustained firing of human motoneurones, where adaptative changes in MU recruitment must occur to meet the demands of the contraction.

Motor unit tracking using blind source separation filters and waveform cross-correlations: reliability under physiological and pharmacological conditions.

Recent advancements in the analysis of high-density surface electromyography (HDsEMG) have enabled the identification, and tracking, of motor units (MUs) to study muscle activation. This study aimed to evaluate the reliability of MU tracking using two common methods: blind source separation filters and two-dimensional waveform cross-correlation. An experiment design was developed to assess physiological reliability and reliability for a drug intervention known to reduce the discharge rate of motoneurones (cyproheptadine). HDsEMG signals were recorded from tibialis anterior during isometric dorsiflexions to 10, 30, 50, and 70% of maximal voluntary contraction (MVC). MUs were matched within session (2.5 h) using the filter method, and between sessions (7 days) via the waveform method. Both tracking methods demonstrated similar reliability during physiological conditions [e.g., MU discharge: filter intraclass correlation coefficient (ICC): 10% of MVC = 0.76, to 70% of MVC = 0.86; waveform ICC: 10% of MVC = 0.78, to 70% of MVC = 0.91]. Although reliability slightly reduced after the pharmacological intervention, there were no discernible differences in tracking performance (e.g., MU discharge filter ICC: 10% of MVC = 0.73, to 70% of MVC = 0.75; waveform ICC: 10% of MVC = 0.84, to 70% of MVC = 0.85). The poorest reliability typically occurred at higher contraction intensities, which aligned with the greatest variability in MU characteristics. This study confirms that the tracking method may not impact the interpretation of MU data, provided that an appropriate experiment design is used. However, caution should be used when tracking MUs during higher-intensity isometric contractions.NEW & NOTEWORTHY The most direct way to validate longitudinal tracking of motor unit data extracted from high-density surface electromyography is to contrast findings with intramuscular electromyography. We used pharmacology to induce changes in motor unit discharge properties as a noninvasive alternative to validate the reliability of tracking motor units. This study confirmed that the specific tracking method may not impact interpretation of motor unit data at lower contraction intensities; however, caution should be used when tracking units during higher intensities.

Blockade of 5-HT2 receptors suppresses motor unit firing and estimates of persistent inward currents during voluntary muscle contraction in humans.

Serotonergic neuromodulation contributes to enhanced voluntary muscle activation. However, it is not known how the likely motoneurone receptor candidate (5-HT2 ) influences the firing rate and activation threshold of motor units (MUs) in humans. The purpose of this study was to determine whether 5-HT2 receptor activity contributes to human MU behaviour during voluntary ramped contractions of differing intensity. High-density surface EMG (HDsEMG) of the tibialis anterior was assessed during ramped isometric dorsiflexions at 10, 30, 50 and 70% of maximal voluntary contraction (MVC). MU characteristics were successfully extracted from HDsEMG of 11 young adults (four female) pre- and post-ingestion of 8 mg cyproheptadine or a placebo. Antagonism of 5-HT2 receptors caused a reduction in MU discharge rate during steady-state muscle activation that was independent of the level of contraction intensity [P < 0.001; estimated mean difference (∆) = 1.06 pulses/s], in addition to an increase in MU derecruitment threshold (P < 0.013, ∆ = 1.23% MVC), without a change in force during MVC (P = 0.652). A reduction in estimates of persistent inward current amplitude was observed at 10% MVC (P < 0.001, ∆ = 0.99 Hz) and 30% MVC (P = 0.003, ∆ = 0.75 Hz) that aligned with 5-HT changes in MU firing behaviour attributable to 5-HT2 antagonism. Overall, these findings indicate that 5-HT2 receptor activity has a role in regulating the discharge rate in populations of spinal motoneurones when performing voluntary contractions. This study provides evidence of a direct link between MU discharge properties, persistent inward current activity and 5-HT2 receptor activity in humans. KEY POINTS: Activation of 5-HT receptors on the soma and dendrites of motoneurones regulates their excitability. Previous work using chlorpromazine and cyproheptadine has demonstrated that the 5-HT2 receptor regulates motoneurone activity in humans with chronic spinal cord injury and non-injured control subjects. It is not known how the 5-HT2 receptor directly influences motor unit (MU) discharge and MU recruitment in larger populations of human motoneurones during voluntary contractions of differing intensity. Despite the absence of change in force during maximal voluntary dorsiflexions, 5-HT2 receptor antagonism caused a reduction in MU discharge rate during submaximal steady-state muscle contraction, in addition to an increase in MU derecruitment threshold, irrespective of the submaximal contraction intensity. Reductions in estimates of persistent inward currents after 5-HT2 receptor antagonism support the viewpoint that the 5-HT2 receptor plays a crucial role in regulating motor activity, whereby a persistent inward current-based mechanism is involved in regulating the excitability of human motoneurones.

A qualitative analysis of the experiences of children with cerebral palsy and their caregivers in a goal-directed cycling programme.

PURPOSE: This qualitative thematic analysis aimed to capture the experiences of children with cerebral palsy (CP) and caregivers who completed an 8-week goal-directed cycling programme, to provide insights on engagement and programme feasibility. METHODS: Children with CP (6-18 years, Gross Motor Function Classification Scale (GMFCS) levels II-IV) and caregivers completed semi-structured interviews at the end of the training programme. Interview transcripts were coded by two investigators and systematically organised into themes. A third investigator reviewed the final thematic map. RESULTS: 17 interviews were conducted with 29 participants (11 children: 7-14 years). Four themes emerged: facilitators and challenges to programme engagement; perceived outcomes; the functional-electrical stimulation (FES) cycling experience; and previous cycling participation. Engagement was facilitated by the "therapist's connection," "cycling is fun" and "participant driven goal setting," while "getting there" and "time off school" were identified as challenges. Participants positively linked improved physical function to greater independence. The FES-experience was "fun and challenging," and participants had mixed feelings about electrode "stickiness." Previous cycling participation was limited by access to adapted bikes. CONCLUSIONS: Children with CP enjoy riding bikes. Facilitators and challenges to engagement were identified that hold practical relevance for clinicians. Environmental and personal factors should be carefully considered when developing future programs, to maximise opportunities for success. CLINICAL TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry - ACTRN12617000644369pIMPLICATIONS FOR REHABILITATIONAdapted cycling is a fun and engaging activity for young people with cerebral palsy.Environmental and personal factors should be carefully considered when prescribing adapted or FES cycling programs to this group.Engagement in adapted and FES-cycling programs can be facilitated by access to loan equipment, a goal-directed focus, and positive therapist-child relationship.Participation in adapted cycling is limited by access to adapted cycling equipment.

Blockade of 5-HT2 receptors suppresses rate of torque development and motor unit discharge rate during rapid contractions.

Serotonin (5-HT) is a neuromodulator that is critical for regulating the excitability of spinal motoneurons and the generation of muscle torque. However, the role of 5-HT in modulating human motor unit activity during rapid contractions has yet to be assessed. Nine healthy participants (23.7 ± 2.2 yr) ingested 8 mg of the competitive 5-HT2 antagonist cyproheptadine in a double-blinded, placebo-controlled, repeated-measures experiment. Rapid dorsiflexion contractions were performed at 30%, 50%, and 70% of maximal voluntary contraction (MVC), where motor unit activity was assessed by high-density surface electromyographic decomposition. A second protocol was performed where a sustained, fatigue-inducing dorsiflexion contraction was completed before undertaking the same 30%, 50%, and 70% MVC rapid contractions and motor unit analysis. Motor unit discharge rate (P < 0.001) and rate of torque development (RTD; P = 0.019) for the unfatigued muscle were both significantly lower for the cyproheptadine condition. Following the fatigue inducing contraction, cyproheptadine reduced motor unit discharge rate (P < 0.001) and RTD (P = 0.024), whereas the effects of cyproheptadine on motor unit discharge rate and RTD increased with increasing contraction intensity. Overall, these results support the viewpoint that serotonergic effects in the central nervous system occur fast enough to regulate motor unit discharge rate during rapid powerful contractions.NEW & NOTEWORTHY We have shown that serotonin activity in the central nervous system plays a role in regulating human motor unit discharge rate during rapid contractions. Our findings support the viewpoint that serotonergic effects in the central nervous system are fast and are most prominent during contractions that are characterized by high motor unit discharge rates and large amounts of torque development.

Machine learning to quantify habitual physical activity in children with cerebral palsy.

AIM: To investigate whether activity-monitors and machine learning models could provide accurate information about physical activity performed by children and adolescents with cerebral palsy (CP) who use mobility aids for ambulation. METHOD: Eleven participants (mean age 11y [SD 3y]; six females, five males) classified in Gross Motor Function Classification System (GMFCS) levels III and IV, completed six physical activity trials wearing a tri-axial accelerometer on the wrist, hip, and thigh. Trials included supine rest, upper-limb task, walking, wheelchair propulsion, and cycling. Three supervised learning algorithms (decision tree, support vector machine [SVM], random forest) were trained on features in the raw-acceleration signal. Model-performance was evaluated using leave-one-subject-out cross-validation accuracy. RESULTS: Cross-validation accuracy for the single-placement models ranged from 59% to 79%, with the best performance achieved by the random forest wrist model (79%). Combining features from two or more accelerometer placements significantly improved classification accuracy. The random forest wrist and hip model achieved an overall accuracy of 92%, while the SVM wrist, hip, and thigh model achieved an overall accuracy of 90%. INTERPRETATION: Models trained on features in the raw-acceleration signal may provide accurate recognition of clinically relevant physical activity behaviours in children and adolescents with CP who use mobility aids for ambulation in a controlled setting. WHAT THIS PAPER ADDS: Machine learning may assist clinicians in evaluating the efficacy of surgical and therapy-based interventions. Machine learning may help researchers better understand the short- and long-term benefits of physical activity for children with more severe motor impairments.