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The manner in which motoneurons respond to excitatory and inhibitory inputs depends strongly on how their intrinsic properties are influenced by the neuromodulators serotonin and noradrenaline. These neuromodulators enhance the activation of voltage-gated channels that generate persistent (long-lasting) inward sodium and calcium currents (PICs) into the motoneurons. PICs are crucial for initiating, accelerating, and maintaining motoneuron firing. A greater accessibility to state-of-the-art techniques that allows both the estimation and examination of PIC modulation in tens of motoneurons in vivo has rapidly evolved our knowledge of how motoneurons amplify and prolong the effects of synaptic input. We are now in a position to gain substantial mechanistic insight into the role of PICs in motor control at an unprecedented pace. The present review briefly describes the effects of PICs on motoneuron firing and the methods available for estimating them before presenting the emerging evidence of how PICs can be modulated in health and disease. Our rapidly developing knowledge of the potent effects of PICs on motoneuron firing has the potential to improve our understanding of how we move, and points to new approaches to improve motor control. Finally, gaps in our understanding are highlighted and methodological advancements are suggested to encourage readers to explore outstanding questions to further elucidate PIC physiology. [ABSTRACT FROM AUTHOR]

In two papers dated 1928 to 1929 in The Journal of Physiology, Edgar Adrian and Detlev Bronk described recordings from motor nerve and muscle fibres. The recordings from motor nerve fibres required progressive dissection of the nerve until a few fibres remained, from which isolated single fibre activity could be detected. The muscle fibre recordings were performed in humans during voluntary contractions with an intramuscular electrode – the concentric needle electrode – that they describe for the first time in the second paper. They recognised that muscle fibres would respond to each impulse sent by the innervating motor neurone and that therefore muscle fibre recordings provided information on the times of activation of the motor nerve fibres which were as accurate as a direct record from the nerve. These observations and the description of the concentric needle electrode opened the era of motor unit recordings in humans, which have continued for almost a century and have provided a comprehensive view of the neural control of movement at the motor unit level. Despite important advances in technology, many of the principles of motor unit behaviour that would be investigated in the subsequent decades were canvassed in the two papers by Adrian and Bronk. For example, they described the concomitant motor neurones' recruitment and rate coding for force modulation, synchronisation of motor unit discharges, and the dependence of discharge rate on motor unit recruitment threshold. Here, we summarise their observations and discuss the impact of their work. We highlight the advent of the concentric needle, and its subsequent influence on motor control research. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate whether caffeine consumption would change persistent inward current (PIC) contribution to motoneuron firing at increased contraction intensities and after repetitive sustained maximal contractions. Before and after the consumption of 6 mg·kg−1 of caffeine or placebo, 16 individuals performed isometric triangular-shaped ramp dorsiflexion contractions (to 20% and 40% of peak torque), followed by four maximal contractions sustained until torque production dropped to 60% of maximum, and consecutive 20% triangular-shaped contractions. Tibialis anterior motor unit firing frequencies were analyzed from high-density surface electromyograms. PIC contribution to motor unit firing was estimated by calculating the delta frequency (ΔF) using the paired motor unit technique. Motoneuron peak firing frequencies at 20% and 40% contractions and total torque-time integral during the repetitive sustained maximal contractions were also assessed. ΔF increased 0.69 peaks per second (pps) (95% CI = −0.98, −0.405; d = −0.87) from 20% to 40% contraction intensities and reduced 0.85 pps (95% CI = 0.66, 1.05; d = 0.99) after the repetitive sustained maximal contractions, regardless of caffeine consumption. Participants produced 337 Nm·s (95% CI = 49.9, 624; d = 0.63) more torque integral during the repetitive sustained maximal contractions after caffeine consumption. A strong repeated-measures correlation (r = 0.61; 95% CI = 0.49, 0.69) was observed between reductions of ΔF and peak firing frequencies after the repetitive sustained maximal contractions. PIC contribution to motoneuron firing increases from 20% to 40% contraction intensities, with no effect of caffeine (on rested tibialis anterior). Repetitive sustained maximal contractions reduced PIC contribution to motoneuron firing, regardless of caffeine or placebo consumption, evidencing that changes in intrinsic motoneuron properties contributed to performance loss. Caffeine-attenuated reduction of torque production capacity was unlikely mediated by PICs. NEW & NOTEWORTHY Persistent inward current (PIC) contribution to motoneuron firing increases with contraction intensities and is reduced after repetitive sustained maximal contractions, regardless of caffeine consumption. Reductions of PIC contribution to motoneuron firing and peak firing frequencies were largely associated, evidencing a novel mechanism underpinning decrements in maximal torque production capacity following repetitive sustained maximal contractions. Caffeine consumption attenuated neuromuscular performance reductions—allowing higher time-torque integral production during repetitive sustained maximal contractions. This was unlikely mediated by PIC. [ABSTRACT FROM AUTHOR]

Introduction: We tested two strategies that hypothetically increase serotonin availability (α-lactalbumin consumption and a remote submaximal handgrip contraction) on estimates of persistent inward currents (PICs) amplitude of soleus muscle in healthy participants. Methods: With a randomised, double-blind, and cross-over design, 13 healthy participants performed triangular-shaped ramp contractions with their plantar flexors (20% of maximal torque), followed by a 30-s handgrip sustained contraction (40% of maximal force) and consecutive repeated triangular-shaped contractions. This was performed before and after the consumption of either 40 g of α-lactalbumin, an isonitrogenous beverage (Zein) or an isocaloric beverage (Corn-starch). Soleus motor units discharge rates were analysed from high-density surface electromyography signals. PICs were estimated by calculating the delta frequency (ΔF) of motor unit train spikes using the paired motor unit technique. Results: ΔF (0.19 pps; p = 0.001; d = 0.30) and peak discharge rate (0.20 pps; p < 0.001; d = 0.37) increased after the handgrip contraction, irrespective of the consumed supplement. No effects of α-lactalbumin were observed. Conclusions: Our results indicate that 40 g of α-lactalbumin was unable to modify intrinsic motoneuron excitability. However, performing a submaximal handgrip contraction before the plantar flexion triangular contraction was capable of increasing ΔF and discharge rates on soleus motor units. These findings highlight the diffused effects of serotonergic input, its effects on motoneuron discharge behaviour, and suggest a cross-effector effect within human motoneurons. [ABSTRACT FROM AUTHOR]

The response of spinal motoneurons to synaptic input greatly depends on the activation of persistent inward currents (PICs), the contribution of which can be estimated through the paired motor unit technique. Yet, the intra-session test–retest reliability of this measurement remains to be fully established. Twenty males performed isometric triangular dorsiflexion contractions to 20 and 50 % of maximal torque at baseline and after a 15-min resting period. High-density electromyographic signals (HD-EMG) of the tibialis anterior were recorded with a 64-electrode matrix. HD-EMG signals were decomposed, and motor units tracked across time points to estimate the contribution of PICs to motoneuron firing through quantification of motor unit recruitment-derecruitment hysteresis (ΔF). A good intraclass correlation coefficient (ICC = 0.75 [0.63, 0.83]) and a large repeated measures correlation coefficient (r rm = 0.65 [0.49, 0.77]; p < 0.001) were found between ΔF values obtained at both time points for 20 % MVC ramps. For 50 % MVC ramps, a good ICC (0.77 [0.65, 0.85]) and a very large repeated measures correlation coefficient (r rm = 0.73 [0.63, 0.80]; p < 0.001) were observed. Our data suggest that ΔF scores can be reliably investigated in tibialis anterior motor units during both low- and moderate-intensity contractions within a single experimental session. [ABSTRACT FROM AUTHOR]

Persistent inward currents (PICs) are crucial for initiation, acceleration, and maintenance of motoneuron firing. As PICs are highly sensitive to synaptic inhibition and facilitated by serotonin and noradrenaline, we hypothesised that both reciprocal inhibition (RI) induced by antagonist nerve stimulation and whole‐body relaxation (WBR) would reduce PICs in humans. To test this, we estimated PICs using the well‐established paired motor unit (MU) technique. High‐density surface electromyograms were recorded from gastrocnemius medialis during voluntary, isometric 20‐s ramp, plantarflexor contractions and decomposed into MU discharges to calculate delta frequency (ΔF). Moreover, another technique (VibStim), which evokes involuntary contractions proposed to result from PIC activation, was used. Plantarflexion torque and soleus activity were recorded during 33‐s Achilles tendon vibration and simultaneous 20‐Hz bouts of neuromuscular electrical stimulation (NMES) of triceps surae. ΔF was decreased by RI (n = 15, 5 females) and WBR (n = 15, 7 females). In VibStim, torque during vibration at the end of NMES and sustained post‐vibration torque were reduced by WBR (n = 19, 10 females), while other variables remained unchanged. All VibStim variables remained unaltered in RI (n = 20, 10 females). Analysis of multiple human MUs in this study demonstrates the ability of local, focused inhibition to attenuate the effects of PICs on motoneuron output during voluntary motor control. Moreover, it shows the potential to reduce PICs through non‐pharmacological, neuromodulatory interventions such as WBR. The absence of a consistent effect in VibStim might be explained by a floor effect resulting from low‐magnitude involuntary torque combined with the negative effects of the interventions. Key points: Spinal motoneurons transmit signals to skeletal muscles to regulate their contraction. Motoneuron firing partly depends on their intrinsic properties such as the strength of persistent (long‐lasting) inward currents (PICs) that make motoneurons more responsive to excitatory input.In this study, we demonstrate that both reciprocal inhibition onto motoneurons and whole‐body relaxation reduce the contribution of PICs to human motoneuron firing. This was observed through analysis of the firing of single motor units during voluntary contractions.However, an alternative technique that involves tendon vibration and neuromuscular electrical stimulation to evoke involuntary contractions showed less effect. Thus, it remains unclear whether this alternative technique can be used to estimate PICs under all physiological conditions.These results improve our understanding of the mechanisms of PIC depression in human motoneurons. Potentially, non‐pharmacological interventions such as electrical stimulation or relaxation could attenuate unwanted PIC‐induced muscle contractions in conditions characterised by motoneuron hyperexcitability. [ABSTRACT FROM AUTHOR]

Age-related deterioration within both motoneuron and monoaminergic systems should theoretically reduce neuromodulation by weakening motoneuronal persistent inward current (PIC) amplitude. However, this assumption remains untested. Surface electromyographic signals were collected using two 32-channel electrode matrices placed on soleus and tibialis anterior of 25 older adults (70 ± 4 years) and 17 young adults (29 ± 5 years) to investigate motor unit discharge behaviors. Participants performed triangular-shaped plantar and dorsiflexion contractions to 20% of maximum torque at a rise-decline rate of 2%/s of each participant's maximal torque. Pairwise and composite paired-motor unit analyses were adopted to calculate delta frequency (ΔF), which has been used to differentiate between the effects of synaptic excitation and intrinsic motoneuronal properties and is assumed to be proportional to PIC amplitude. Soleus and tibialis anterior motor units in older adults had lower ΔFs calculated with either the pairwise [-0.99 and -1.46 pps; -35.4 and -33.5%, respectively] or composite (-1.18 and -2.28 pps; -32.1 and -45.2%, respectively) methods. Their motor units also had lower peak discharge rates (-2.14 and -2.03 pps; -19.7 and -13.9%, respectively) and recruitment thresholds (-1.50 and -2.06% of maximum, respectively) than young adults. These results demonstrate reduced intrinsic motoneuron excitability during low-force contractions in older adults, likely mediated by decreases in the amplitude of persistent inward currents. Our findings might be explained by deterioration in the motoneuron or monoaminergic systems and could contribute to the decline in motor function during aging; these assumptions should be explicitly tested in future investigations. [ABSTRACT FROM AUTHOR]

Purpose: Simultaneous application of tendon vibration and neuromuscular electrical stimulation (NMES) induces an involuntary sustained torque. We examined the effect of different NMES parameters (intensity, pattern of stimulation and pulse width) on the magnitude of the evoked involuntary torque.Methods: Plantar flexor torque was recorded during 33-s Achilles tendon vibration with simultaneous 20-Hz NMES bouts on triceps surae (n = 20; 13 women). Intensity was set to elicit 10, 20 or 30% of maximal voluntary contraction torque (MVC), pulse width was narrow (0.2 ms) or wide (1 ms), and the stimulus pattern varied (5 × 2-s or 10 × 1-s). Up to 12 different trials were performed in a randomized order, and then repeated in those who produced a sustained involuntary torque after the cessation of vibration.Results: Six of 7 men and 5 of 13 women produced a post-vibration sustained torque. Eight of 20 participants did not complete the 30% trials, as they were perceived as painful. Torque during vibration at the end of NMES and the increase in torque throughout the trial were significantly higher in 20 than 10% trials (n = 11; 9.7 ± 9.0 vs 7.1 ± 6.1% MVC and 4.3 ± 4.5 vs 3.6 ± 3.5% MVC, respectively). Post-vibration sustained torque was higher in wide pulse-width trials (5.4 ± 5.9 vs 4.1 ± 4.3% MVC). Measures of involuntary torque were not different between 20 and 30% trials (n = 8).Conclusion: Bouts of 5 × 2-s NMES with wide pulse width eliciting 20% MVC provides the most robust responses and could be used to maximise the production of involuntary torque in triceps surae. [ABSTRACT FROM AUTHOR]

Findings from mice that had their Smn gene deleted and some copies of the human SMN2 gene introduced to produce SMN protein are summarized. Symptoms due to this manipulation can be corrected only by restoring the SMN protein expression in neurones and not in muscle. The changes in muscle and neuromuscular junction (NMJ) in these mutant mice are probably due to the malfunction of the neuronal component of the NMJ i.e. the nerve terminal. The reduction of transmitter release by nerve terminals in animals with reduced SMN protein supports this notion. There is a critical period during which the presence of the SMN protein is mandatory for the survival of the motor unit and the individual. This period coincides with the most important events involved in the development of the motor unit. Results from normal genetically unaffected rats and mice show that during a critical period of development the function of the nerve terminal and the release of transmitter play a crucial role in the development of the motor neurone and muscle. The possibility that targeting the function of the nerve terminal to overcome its inability to release transmitter could benefit patients with the deletion of the SMN gene. [ABSTRACT FROM AUTHOR]