Activation Of Persistent Inward Currents Research Articles

Persistent inward currents in tibialis anterior motoneurons can be reliably estimated within the same session

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 (rrm = 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 (rrm = 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.

Effects of jaw clenching and mental stress on persistent inward currents estimated by two different methods.

Spinal motoneuron firing depends greatly on persistent inward currents (PICs), which in turn are facilitated by the neuromodulators serotonin and noradrenaline. The aim of this study was to determine whether jaw clenching (JC) and mental stress (MS), which may increase neuromodulator release, facilitate PICs in human motoneurons. The paired motor unit (MU) technique was used to estimate PIC contribution to motoneuron firing. Surface electromyograms were collected using a 32-channel matrix on gastrocnemius medialis (GM) during voluntary, ramp, plantar flexor contractions. MU discharges were identified, and delta frequency (ΔF), a measure of recruitment-derecruitment hysteresis, was calculated. Additionally, another technique was used (VibStim) that evokes involuntary contractions that persist after cessation of combined Achilles tendon vibration and triceps surae neuromuscular electrical stimulation. VibStim measures of plantar flexor torque and soleus activity may reflect PIC activation. ΔF was not significantly altered by JC (p = .679, n = 18, 9 females) or MS (p = .147, n = 14, 5 females). However, all VibStim variables quantifying involuntary torque and muscle activity during and after vibration cessation were significantly increased in JC (p < .011, n = 20, 10 females) and some, but not all, increased in MS (p = .017-.05, n = 19, 10 females). JC and MS significantly increased the magnitude of involuntary contractions (VibStim) but had no effect on GM ΔF during voluntary contractions. Effects of increased neuromodulator release on PIC contribution to motoneuron firing might differ between synergists or be context dependent. Based on these data, the background level of voluntary contraction and, hence, both neuromodulation and ionotropic inputs could influence neuromodulatory PIC enhancement.

Can local vibration alter the contribution of persistent inward currents to human motoneuron firing?

The response of spinal motoneurons to synaptic input greatly depends on the activation of persistent inward currents (PICs), which in turn are enhanced by the neuromodulators serotonin and noradrenaline. Local vibration (LV) induces excitatory Ia input onto motoneurons and may alter neuromodulatory inputs. Therefore, we investigated whether LV influences the contribution of PICs to motoneuron firing. This was assessed in voluntary contractions with concurrent, ongoing LV, as well as after a bout of prolonged LV. High-density surface electromyograms (HD-EMG) of the tibialis anterior were recorded with a 64-electrode matrix. Twenty males performed isometric, triangular, dorsiflexion contractions to 20% and 50% of maximal torque at baseline, during LV of the tibialis anterior muscle, and after 30-min of LV. HD-EMG signals were decomposed, and motor units tracked across time points to estimate PICs through a paired motor unit analysis, which quantifies motor unit recruitment-derecruitment hysteresis (ΔF). During ongoing LV, ΔF was lower for both 20% and 50% ramps. Although significant changes in ΔF were not observed after prolonged LV, a differential effect across the motoneuron pool was observed. This study demonstrates that PICs can be non-pharmacologically modulated by LV. Given that LV leads to reflexive motor unit activation, it is postulated that lower PIC contribution to motoneuron firing during ongoing LV results from decreased neuromodulatory inputs associated with lower descending corticospinal drive. A differential effect in motoneurons of different recruitment thresholds after prolonged LV is provocative, challenging the interpretation of previous observations and motivating future investigations. KEY POINTS: Neuromodulatory inputs from the brainstem influence motoneuron intrinsic excitability through activation of persistent inward currents (PICs). PICs make motoneurons more responsive to excitatory input. We demonstrate that vibration applied on the muscle modulates the contribution of PICs to motoneuron firing, as observed through analysis of the firing of single motor units. The effects of PICs on motoneuron firing were lower when vibration was concurrently applied during voluntary ramp contractions, likely due to lower levels of neuromodulation. Additionally, prolonged exposure to vibration led to differential effects of lower- vs. higher-threshold motor units on PICs, with lower-threshold motor units tending to present an increased and higher-threshold motor units a decreased contribution of PICs to motoneuron firing. These results demonstrate that muscle vibration has the potential to influence the effects of neuromodulation on motoneuron firing. The potential of using vibration as a non-pharmacological neuromodulatory intervention should be further investigated.

Effects of reciprocal inhibition and whole-body relaxation on persistent inward currents estimated by two different methods.

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.

Spinal motoneurones are intrinsically more responsive in the adult G93A SOD1mouse model of amyotrophic lateral sclerosis.

Although in vitro recordings using neonatal preparations from mouse models of amyotrophic lateral sclerosis (ALS) suggest increased motoneurone excitability, in vivo recordings in adult ALS mouse models have been conflicting. In adult G93A SOD1models, spinal motoneurones have previously been shown to have deficits in repetitive firing, in contrast to the G127X SOD1mouse model. Our in vivo intracellular recordings in barbiturate-anaesthetized adult male G93A SOD1mice reveal that the incidence of failure to fire with current injection was equally low in control and ALS mice (∼2%). We show that failure to fire repetitively can be a consequence of experimental protocol and should not be used alone to classify otherwise normal motoneurones as hypo-excitable. Motoneurones in the G93A SOD1mice showed an increased response to inputs, with lower rheobase, higher input-output gains and increased activation of persistent inward currents. In vitro studies from transgenic amyotrophic lateral sclerosis models have suggested an increased excitability of spinal motoneurones. However, in vivo intracellular recordings from adult amyotrophic lateral sclerosis mice models have produced conflicting findings. Previous investigations using barbiturate anaesthetized G93A SOD1mice have suggested that some motoneurones are hypo-excitable, defined by deficits in repetitive firing. Our own previous recordings in G127X SOD1mice using different anaesthesia, however, showed no repetitive firing deficits and increased persistent inward currents at symptom onset. These discrepancies may be a result of differences between models, symptomatic stage, anaesthesia or technical differences. To investigate this, we repeated our original experiments, but in adult male G93A SOD1mice, at both presymptomatic and symptomatic stages, under barbiturate anaesthesia. In vivo intracellular recordings from antidromically identified spinal motoneurones revealed that the incidence of failure to fire with current injection was equally low in control and G93A SOD1mice (∼2%). Motoneurones in G93A SOD1mice fired significantly more spontaneous action potentials. Rheobase was significantly lower and the input resistance and input-output gain were significantly higher in both presymptomatic and symptomatic G93A SOD1mice. This was despite a significant increase in the duration of the post-spike after-hyperpolarization in both presymptomatic and symptomatic G93A SOD1mice. Finally, evidence of increased activation of persistent inward currents was seen in both presymptomatic and symptomatic G93A SOD1mice. Our results do not confirm previous reports of hypo-excitability of spinal motoneurones in the G93A SOD1mouse and demonstrate that the motoneurones show an increased response to inputs.

Linking Motoneuron PIC Location to Motor Function in Closed-Loop Motor Unit System Including Afferent Feedback: A Computational Investigation.

The goal of this study is to investigate how the activation location of persistent inward current (PIC) over motoneuron dendrites is linked to motor output in the closed-loop motor unit. Here, a physiologically realistic model of a motor unit including afferent inputs from muscle spindles was comprehensively analyzed under intracellular stimulation at the soma and synaptic inputs over the dendrites during isometric contractions over a full physiological range of muscle lengths. The motor output of the motor unit model was operationally assessed by evaluating the rate of force development, the degree of force potentiation and the capability of self-sustaining force production. Simulations of the model motor unit demonstrated a tendency for a faster rate of force development, a greater degree of force potentiation, and greater capacity for self-sustaining force production under both somatic and dendritic stimulation of the motoneuron as the PIC channels were positioned farther from the soma along the path of motoneuron dendrites. Interestingly, these effects of PIC activation location on force generation significantly differed among different states of muscle length. The rate of force development and the degree of force potentiation were systematically modulated by the variation of PIC channel location for shorter-than-optimal muscles but not for optimal and longer-than-optimal muscles. Similarly, the warm-up behavior of the motor unit depended on the interplay between PIC channel location and muscle length variation. These results suggest that the location of PIC activation over motoneuron dendrites may be distinctively reflected in the motor performance during shortening muscle contractions.

Nonlinear Input-Output Functions of Motoneurons.

All movements are generated by the activation of motoneurons, and hence their input-output properties define the final step in processing of all motor commands. A major challenge to understanding this transformation has been the striking nonlinear behavior of motoneurons conferred by the activation of persistent inward currents (PICs) mediated by their voltage-gated Na+ and Ca2+ channels. In this review, we focus on the contribution that these PICs make to motoneuronal discharge and how the nonlinearities they engender impede the construction of a comprehensive model of motor control.

Investigating the Effect of Persistent Inward Currents on Motor Unit Firing Rates and Beta-Band Coherence in a Model of the First Dorsal Interosseous Muscle.

Neuromodulatory drive resulting in the generation of persistent inward currents (PICs) within motoneuron dendrites has been demonstrated to introduce nonlinearities into the motoneuron input-output function for a given motor command. It is less understood, however, as to what role PICs play during voluntary contractions or on the correlation between motoneuron firings arising as a result of common synaptic inputs to the motoneuron pool. To examine this, a biophysical model of the motoneuron pool representing the first dorsal interosseous (FDI) muscle was used to simulate the effects of PICs on motor unit firing patterns and beta-band (15-30 Hz) motor unit coherence at 20, 30, and 40 percent of maximum voluntary contraction (MVC). The contribution of PICs at each MVC was quantified by calculating the difference in the mean firing rate of each motoneuron within the pool and assessing changes in the mean firing rate distribution and motor unit coherence with and without PICs present. The results of the current study demonstrated that increased activation of PICs progressively reduced motor unit coherence, however, changes in coherence were modest when investigating activation levels consistent with experimentally observed mean motor unit firing rates in the FDI muscle during isometric voluntary contraction.

Postnatal development of persistent inward currents in rat XII motoneurons and their modulation by serotonin, muscarine and noradrenaline.

Persistent inward currents (PICs) in spinal motoneurons are long-lasting, voltage-dependent currents that increase excitability; they are dramatically potentiated by serotonin, muscarine, and noradrenaline (norepinephrine). Loss of these modulators (and the PIC) during sleep is hypothesized as a major contributor to REM sleep atonia. Reduced excitability of XII motoneurons that drive airway muscles and maintain airway patency is causally implicated in obstructive sleep apnoea (OSA), but whether XII motoneurons possess a modulator-sensitive PIC that could be a factor in the reduced airway tone of sleep is unknown. Whole-cell recordings from rat XII motoneurons in brain slices indicate that PIC amplitude increases ∼50% between 1 and 23days of age, when potentiation of the PIC by 5HT2 , muscarinic, or α1 noradrenergic agonists peaks at <50%, manyfold lower than the potentiation observed in spinal motoneurons. α1 noradrenergic receptor activation produced changes in XII motoneuron firing behaviour consistent with PIC involvement, but indicators of strong PIC activation were never observed; in vivo experiments are needed to determine the role of the modulator-sensitive PIC in sleep-dependent reductions in airway tone. Hypoglossal (XII) motoneurons play a key role in maintaining airway patency; reductions in their excitability during sleep through inhibition and disfacilitation, i.e. loss of excitatory modulation, is implicated in obstructive sleep apnoea. In spinal motoneurons, 5HT2 , muscarinic and α1 noradrenergic modulatory systems potentiate persistent inward currents (PICs) severalfold, dramatically increasing excitability. If the PICs in XII and spinal motoneurons are equally sensitive to modulation, loss of the PIC secondary to reduced modulatory tone during sleep could contribute to airway atonia. Modulatory systems also change developmentally. We therefore characterized developmental changes in magnitude of the XII motoneuron PIC and its sensitivity to modulation by comparing, in neonatal (P1-4) and juvenile (P14-23) rat brainstem slices, the PIC elicited by slow voltage ramps in the absence and presence of agonists for 5HT2 , muscarinic, and α1 noradrenergic receptors. XII motoneuron PIC amplitude increased developmentally (from -195±12 to -304±19pA). In neonatal XII motoneurons, the PIC was only potentiated by α1 receptor activation (5±4%). In contrast, all modulators potentiated the juvenile XII motoneurons PIC (5HT2 , 5±5%; muscarine, 22±11%; α1 , 18±5%). These data suggest that the influence of the PIC and its modulation on XII motoneuron excitability will increase with postnatal development. Notably, the modulator-induced potentiation of the PIC in XII motoneurons was dramatically smaller than the 2- to 6-fold potentiation reported for spinal motoneurons. In vivo measurements are required to determine if the modulator-sensitive, XII motoneuron PIC is an important factor in sleep-state dependent reductions in airway tone.

Effect of standing posture on inhibitory postsynaptic potentials in gastrocnemius motoneurons.

This study examined the task dependence of sensory inputs on motoneuron excitability by comparing the inhibitory postsynaptic potential (IPSP) evoked by stimulation of the sural nerve between a standing postural task (Free Standing) and a comparable voluntary isometric contraction performed in a supine position (Lying Supine). We hypothesized that there would be a smaller IPSP in standing than in the supine position, based on the task dependence of the ankle plantarflexor activity on the standing task. Ten healthy participants participated in a total of 15 experiments. Single motor unit (MU) firings were recorded with both intramuscular fine-wire electrodes and high-density surface electromyography. Participants maintained the MU discharge at 6-8 Hz in Free Standing or Lying Supine while the right sural nerve was stimulated at random intervals between 1 and 3 s. To evaluate the reflex response, the firing times of the discriminated MUs were used to construct peristimulus time histograms and peristimulus frequencygrams. The sural nerve stimulation resulted in weaker inhibition in Free Standing than in Lying Supine. This finding is discussed in relation to the putative activation of persistent inward currents in standing posture and the task-dependent advantages of overriding inhibitory synaptic inputs to the plantarflexors to maintain the standing posture. NEW & NOTEWORTHY The task-dependent modulation of sensory inputs on motoneuron excitability in standing is not well understood. Evoking an inhibitory postsynaptic potential (IPSP) resulted in a smaller IPSP in gastrocnemius motoneurons in standing than in the supine position. Mildly painful sensory inputs produced weaker motoneuron inhibition in standing, suggesting an imperative to maintain ankle plantarflexion activity for the task of upright stance.

Muscle length-dependent contribution of motoneuron Cav1.3 channels to force production in model slow motor unit

Persistent inward current (PIC)-generating Cav1.3 channels in spinal motoneuron dendrites are thought to be actively recruited during normal behaviors. However, whether and how the activation of PIC channels influences force output of motor unit remains elusive. Here, building a physiologically realistic model of slow motor unit I demonstrated that force production induced by the PIC activation is much smaller for short than lengthened muscles during the regular firing of the motoneuron that transitions from the quiescent state by either a brief current pulse at the soma or a brief synaptic excitation at the dendrites. By contrast, the PIC-induced force potentiation was maximal for short muscles when the motoneuron switched from a stable low-frequency firing state to a stable high-frequency firing state by the current pulse at the soma. Under the synaptic excitation at the dendrites, however, the force could not be potentiated by the transitioning of the motoneuron from a low- to a high-frequency firing state due to the simultaneous onset of PIC at the dendrites and firing at the soma. The strong dependency of the input-output relationship of the motor unit on the neuromodulation and Ia afferent inputs for the PIC channels was further shown under static variations in muscle length. Taken together, these findings suggest that the PIC activation in the motoneuron dendrites may differentially affect the force production of the motor unit, depending not only on the firing state history of the motoneuron and the variation in muscle length but also on the mode of motor activity.NEW & NOTEWORTHY Cav1.3 channels in motoneuron dendrites are actively involved during normal motor activities. To investigate the effects of the activation of motoneuron Cav1.3 channels on force production, a model motor unit was built based on best-available data. The simulation results suggest that force potentiation induced by Cav1.3 channel activation is strongly modulated not only by firing history of the motoneuron but also by length variation of the muscle as well as neuromodulation inputs from the brainstem.

Inhibition linearizes firing rate responses in human motor units: implications for the role of persistent inward currents.

Motor neurons are the output neurons of the central nervous system and are responsible for controlling muscle contraction. When initially activated during voluntary contraction, firing rates of motor neurons increase steeply but then level out at modest rates. Activation of an intrinsic source of excitatory current at recruitment onset may underlie the initial steep increase in firing rate in motor neurons. We attempted to disable this intrinsic excitatory current by artificially activating an inhibitory reflex. When motor neuron activity was recorded while the inhibitory reflex was engaged, firing rates no longer increased steeply, suggesting that the intrinsic excitatory current was probably responsible for the initial sharp rise in motor neuron firing rate. During graded isometric contractions, motor unit (MU) firing rates increase steeply upon recruitment but then level off at modest rates even though muscle force continues to increase. The mechanisms underlying such firing behaviour are not known although activation of persistent inward currents (PICs) might be involved. PICs are intrinsic, voltage-dependent currents that activate strongly when motor neurons (MNs) are first recruited. Such activation might cause a sharp escalation in depolarizing current and underlie the steep initial rise in MU firing rate. Because PICs can be disabled with synaptic inhibition, we hypothesized that artificial activation of an inhibitory pathway might curb this initial steep rise in firing rate. To test this, human subjects performed slow triangular ramp contractions of the ankle dorsiflexors in the absence and presence of tonic synaptic inhibition delivered to tibialis anterior (TA) MNs by sural nerve stimulation. Firing rate profiles (expressed as a function of contraction force) of TA MUs recorded during these tasks were compared for control and stimulation conditions. Under control conditions, during the ascending phase of the triangular contractions, 93% of the firing rate profiles were best fitted by rising exponential functions. With stimulation, however, firing rate profiles were best fitted with linear functions or with less steeply rising exponentials. Firing rate profiles for the descending phases of the contractions were best fitted with linear functions for both control and stimulation conditions. These results seem consistent with the idea that PICs contribute to non-linear firing rate profiles during ascending but not descending phases of contractions.

Contribution of intrinsic motoneuron properties to discharge hysteresis and its estimation based on paired motor unit recordings: a simulation study.

Motoneuron activity is strongly influenced by the activation of persistent inward currents (PICs) mediated by voltage-gated sodium and calcium channels. However, the amount of PIC contribution to the activation of human motoneurons can only be estimated indirectly. Simultaneous recordings of pairs of motor units have been used to provide an estimate of the PIC contribution by using the firing rate of the lower threshold unit to provide an estimate of the common synaptic drive to both units, and the difference in firing rate (ΔF) of this lower threshold unit at recruitment and de-recruitment of the higher threshold unit to estimate the PIC contribution to activation of the higher threshold unit. It has recently been suggested that a number of factors other than PIC can contribute to ΔF values, including mechanisms underlying spike frequency adaptation and spike threshold accommodation. In the present study, we used a set of compartmental models representing a sample of 20 motoneurons with a range of thresholds to investigate how several different intrinsic motoneuron properties can potentially contribute to variations in ΔF values. We drove the models with linearly increasing and decreasing noisy conductance commands of different rate of rise and duration and determined the influence of different intrinsic mechanisms on discharge hysteresis (the difference in excitatory drive at recruitment and de-recruitment) and ΔF. Our results indicate that, although other factors can contribute, variations in discharge hysteresis and ΔF values primarily reflect the contribution of dendritic PICs to motoneuron activation.

Estimates of persistent inward current in human motor neurons during postural sway.

Persistent inward current (PIC) plays a critical role in setting the gain of spinal motor neurons. In humans, most estimates of PIC are made from plantarflexor or dorsiflexor motor units in a seated position. This seated and static posture negates the task-dependent nature of the monoaminergic drive and afferent inhibition that modulate PIC activation. Our purpose was to estimate PIC during both the conventional seated posture and in a more functionally relevant anterior postural sway. We hypothesized that paired motor unit estimates of PIC would be greater when during standing compared with sitting. Soleus motor neuron PIC was estimated via the paired motor unit (PMU) technique. For each motor unit pair, difference in reference unit firing frequency (ΔF) estimates of PIC were made during isometric ramps in plantarflexion force during sitting (conventional approach) and during standing anterior postural sway (new approach). Baseline reciprocal inhibition (RI) was also measured in each posture using the poststimulus time histogram technique. ΔF estimates during standing postural sway were not different [2.64 ± 0.95 pulses/s (pps), P = 0.098] from seated PIC estimates (3.15 ± 1.45 pps) measured from the same motor unit pair. Similarly, reciprocal inhibition at the onset of each task was the same in standing (-0.60 ± 0.32, P = 0.301) and seated (-0.86 ± 0.82) postures. PMU recordings made during standing postural sway met all assumptions that underlay the PMU technique, including rate modulation ≥0.5 pps (3.11 ± 1.90 pps), rate-rate correlation r ≥ 0.7 (0.84 ± 0.13), and time between reference and test unit recruitment ≥1 s (1.83 ± 0.81 s). This study presents a novel, functionally relevant standing method for investigating PIC in humans.NEW & NOTEWORTHY Paired motor unit (PMU) estimates of persistent inward current (PIC) in human soleus motor units are typically made in seated posture. Our study demonstrates that these estimates can be made during standing forward sway, a task that more accurately reflects the postural role of human soleus muscle. PMU recordings made during standing postural sway were validated using all previously published criteria used to test the assumptions of the PMU technique. Standing estimates of PIC did not differ from seated estimates made from the same motor unit pairs.

Neuromodulation impact on nonlinear firing behavior of a reduced model motoneuron with the active dendrite.

Neuromodulatory inputs from brainstem systems modulate the normal function of spinal motoneurons by altering the activation properties of persistent inward currents (PICs) in their dendrites. However, the effect of the PIC on firing outputs also depends on its location in the dendritic tree. To investigate the interaction between PIC neuromodulation and PIC location dependence, we used a two-compartment model that was biologically realistic in that it retains directional and frequency-dependent electrical coupling between the soma and the dendrites, as seen in multi-compartment models based on full anatomical reconstructions of motoneurons. Our two-compartment approach allowed us to systematically vary the coupling parameters between the soma and the dendrite to accurately reproduce the effect of location of the dendritic PIC on the generation of nonlinear (hysteretic) motoneuron firing patterns. Our results show that as a single parameter value for PIC activation was either increased or decreased by 20% from its default value, the solution space of the coupling parameter values for nonlinear firing outputs was drastically reduced by approximately 80%. As a result, the model tended to fire only in a linear mode at the majority of dendritic PIC sites. The same results were obtained when all parameters for the PIC activation simultaneously changed only by approximately ±10%. Our results suggest the democratization effect of neuromodulation: the neuromodulation by the brainstem systems may play a role in switching the motoneurons with PICs at different dendritic locations to a similar mode of firing by reducing the effect of the dendritic location of PICs on the firing behavior.

Activation properties of trigeminal motoneurons in participants with and without bruxism

In animals, sodium- and calcium-mediated persistent inward currents (PICs), which produce long-lasting periods of depolarization under conditions of low synaptic drive, can be activated in trigeminal motoneurons following the application of the monoamine serotonin. Here we examined if PICs are activated in human trigeminal motoneurons during voluntary contractions and under physiological levels of monoaminergic drive (e.g., serotonin and norepinephrine) using a paired motor unit analysis technique. We also examined if PICs activated during voluntary contractions are larger in participants who demonstrate involuntary chewing during sleep (bruxism), which is accompanied by periods of high monoaminergic drive. In control participants, during a slowly increasing and then decreasing isometric contraction, the firing rate of an earlier-recruited masseter motor unit, which served as a measure of synaptic input to a later-recruited test unit, was consistently lower during derecruitment of the test unit compared with at recruitment (ΔF = 4.6 ± 1.5 imp/s). The ΔF, therefore, is a measure of the reduction in synaptic input needed to counteract the depolarization from the PIC to provide an indirect estimate of PIC amplitude. The range of ΔF values measured in the bruxer participants during similar voluntary contractions was the same as in controls, suggesting that abnormally high levels of monoaminergic drive are not continually present in the absence of involuntary motor activity. We also observed a consistent "onion skin effect" during the moderately sized contractions (<20% of maximal), whereby the firing rate of higher threshold motor units discharged at slower rates (by 4-7 imp/s) compared with motor units with relatively lower thresholds. The presence of lower firing rates in the more fatigue-prone, higher threshold trigeminal motoneurons, in addition to the activation of PICs, likely facilitates the activation of the masseter muscle during motor activities such as eating, nonnutritive chewing, clenching, and yawning.

Individual and collective properties of computationally efficient motoneuron models of types S and F with active dendrites

The input–output properties of motoneurons (MNs) and motor units (MUs) may be modulated by different physiological variables, including neuromodulators released by presynaptic neurons from the brainstem. Monoamines, such as serotonin and norepinephrine, act on MNs mainly by activating dendritic L-type Ca++ channels, generating a persistent inward current (PIC), which may change the input–output properties of the MU. If the firing properties of individual MNs and also the features of the force generated by the MUs can be changed, it follows that the descending monoaminergic systems may modulate the overall dynamics of motor control. The purpose of the present study is to investigate the effects of neuromodulation on the input–output properties of mathematically modeled type-specified MUs. Computationally efficient models are presented for S- and F-type mammalian MNs as well as a MN pool commanding muscle units of the Soleus muscle. The single models have a dendritic L-type Ca++ channel, generating a PIC, along with somatic currents that are responsible for spike-generating mechanisms and the afterhyperpolarization. The S-type active-dendrite (AD) MN model resulted highly excitable and discharged in a self-sustained manner after an excitatory input (bistability). An inhibitory activity turned off this self-sustained discharge. In addition, this low-threshold MN model showed a significant reduction in interspike interval (ISI) variability in comparison with an equivalent passive-dendrite (PD) MN model discharging at a similar mean rate. The frequency response gain from presynaptic spike train rate modulation to output spike train modulation had a clear valley from about 1–10Hz for the S-type AD MN model, whereas the PD model showed a gain increase instead. On the other hand, the frequency responses of PD and AD F-type models were similarly shaped, with the AD model having a higher gain at high frequencies. These results suggest that in motor behaviors where steady or low frequency activity is required, such as posture, PICs would aid low-threshold MNs to respond with regular spikes, reducing output variability, and would attenuate the effects of high-frequency input disturbances, helping maintain system steadiness. At the same time, high-threshold MNs being more responsive to high-frequency disturbances would contribute with the necessary activity to correct for postural deviations from a desired position. Simulation results from the neuromuscular model have shown that the PIC activation profoundly affects muscle force generation, with the neuromodulatory activity acting in the adjustment of the motor output. Both individual and collective results presented here expand the understanding of the versatility of monoaminergic neuromodulation in adjusting both the MN input–output coding and the control of force generation.

Voltage-dependent amplification of synaptic inputs in respiratory motoneurones.

The role of persistent inward currents (PICs) in cat respiratory motoneurones (phrenic inspiratory and thoracic expiratory) was investigated by studying the voltage-dependent amplification of central respiratory drive potentials (CRDPs), recorded intracellularly, with action potentials blocked with the local anaesthetic derivative, QX-314. Decerebrate unanaesthetized or barbiturate-anaesthetized preparations were used. In expiratory motoneurones, plateau potentials were observed in the decerebrates, but not under anaesthesia. For phrenic motoneurones, no plateau potentials were observed in either state (except in one motoneurone after the abolition of the respiratory drive by means of a medullary lesion), but all motoneurones showed voltage-dependent amplification of the CRDPs, over a wide range of membrane potentials, too wide to result mainly from PIC activation. The measurements of the amplification were restricted to the phase of excitation, thus excluding the inhibitory phase. Amplification was found to be greatest for the smallest CRDPs in the lowest resistance motoneurones and was reduced or abolished following intracellular injection of the NMDA channel blocker, MK-801. Plateau potentials were readily evoked in non-phrenic cervical motoneurones in the same (decerebrate) preparations. We conclude that the voltage-dependent amplification of synaptic excitation in phrenic motoneurones is mainly the result of NMDA channel modulation rather than the activation of Ca2+ channel mediated PICs, despite phrenic motoneurones being strongly immunohistochemically labelled for CaV1.3 channels. The differential PIC activation in different motoneurones, all of which are CaV1.3 positive, leads us to postulate that the descending modulation of PICs is more selective than has hitherto been believed.

Evaluating a possible role for persistent inward currents in firing rate saturation

During increasing isometric force contractions, motor unit firing rates (FRs) tend to increase rapidly and then saturate (that is, reach a plateau), despite continued augmentation in force and, presumably, synaptic drive. The mechanism underlying this behavior is presently unknown, although persistent inward current (PIC) activation may provide one possible explanation. PICs contribute a non‐synaptic excitation source that activates around recruitment threshold and boosts synaptic input. Furthermore, PICs appear to be inactivated by inhibitory input. Therefore, we reasoned that if we artificially delivered synaptic inhibition to motor neurons before a ramp contraction, then this might prevent full expression of PICs and prevent the initial rapid increase in FR. To test this hypothesis, human subjects performed isometric triangular ramp contractions using tibialis anterior in the absence and presence of additional inhibition provided by surface sural nerve stimulation. We compared single motor unit FR profiles, expressed as a function of force, by fitting the data with rising exponential and linear functions. During control trials, ascending FR profiles were best fit by a rising exponential function but became more linearly related to force with sural nerve stimulation. Overall, our results are consistent with the hypothesis that PIC activation contributes to FR saturation. Funding from NIH NS070897

Firing patterns of spontaneously active motor units in spinal cord‐injured subjects

Involuntary motor unit activity at low rates is common in hand muscles paralysed by spinal cord injury. Our aim was to describe these patterns of motor unit behaviour in relation to motoneurone and motor unit properties. Intramuscular electromyographic activity (EMG), surface EMG and force were recorded for 30 min from thenar muscles of nine men with chronic cervical SCI. Motor units fired for sustained periods (>10 min) at regular (coefficient of variation ≤ 0.15, CV, n =19 units) or irregular intervals (CV>0.15, n =14). Regularly firing units started and stopped firing independently suggesting that intrinsic motoneurone properties were important for recruitment and derecruitment. Recruitment (3.6 Hz, SD 1.2), maximal (10.2 Hz, SD 2.3, range: 7.5-15.4 Hz) and derecruitment frequencies were low (3.3 Hz, SD 1.6), as were firing rate increases after recruitment (~20 intervals in 3 s). Once active, firing often covaried, promoting the idea that units received common inputs.Half of the regularly firing units showed a very slow decline (>40 s) in discharge before derecruitment and had interspike intervals longer than their estimated after hyperpolarisation potential (AHP) duration (estimated by death rate and breakpoint analyses). The other units were derecruited more abruptly and had shorter estimated AHP durations. Overall, regularly firing units had longer estimated AHP durations and were weaker than irregularly firing units, suggesting they were lower threshold units. Sustained firing of units at regular rates may reflect activation of persistent inward currents, visible here in the absence of voluntary drive, whereas irregularly firing units may only respond to synaptic noise.