Intrinsic Properties Of Motoneurons Research Articles

Spinal inhibitory neurons degenerate before motor neurons and excitatory neurons in a mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons. A major focus has been directed to motor neuron intrinsic properties as a cause for degeneration, while less attention has been given to the contribution of spinal interneurons. In the present work, we applied multiplexing detection of transcripts and machine learning-based image analysis to investigate the fate of multiple spinal interneuron populations during ALS progression in the SOD1G93A mouse model. The analysis showed that spinal inhibitory interneurons are affected early in the disease, before motor neuron death, and are characterized by a slow progressive degeneration, while excitatory interneurons are affected later with a steep progression. Moreover, we report differential vulnerability within inhibitory and excitatory subpopulations. Our study reveals a strong interneuron involvement in ALS development with interneuron specific degeneration. These observations point to differential involvement of diverse spinal neuronal circuits that eventually may be determining motor neuron degeneration.

Intrinsic motoneuron properties in typical human development.

Motoneuron properties and their firing patterns undergo significant changes throughout development and in response to neuromodulators such as serotonin. Here, we examined the age-related development of self-sustained firing and general excitability of tibialis anterior motoneurons in a young development (7-17years), young adult (18-28years) and adult (32-53years) group, as well as in a separate group of participants taking selective serotonin reuptake inhibitors (SSRIs, aged 11-28years). Self-sustained firing, as measured by ΔF, was larger in the young development (∼5.8Hz, n=20) compared to the young adult (∼4.9Hz, n=13) and adult (∼4.8Hz, n=8) groups, consistent with a developmental decrease in self-sustained firing mediated by persistent inward currents (PIC). ΔF was also larger in participants taking SSRIs (∼6.5Hz, n=9) compared to their age-matched controls (∼5.3Hz, n=26), consistent with increased levels of spinal serotonin facilitating the motoneuron PIC. Participants in the young development and SSRI groups also had higher firing rates and a steeper acceleration in initial firing rates (secondary ranges), consistent with the PIC producing a steeper acceleration in membrane depolarization at the onset of motoneuron firing. In summary, both the young development and SSRI groups exhibited increased intrinsic motoneuron excitability compared to the adults, which, in the young development group, was also associated with a larger unsteadiness in the dorsiflexion torque profiles. We propose several intrinsic and extrinsic factors that affect both motoneuron PICs and cell discharge which vary during development, with a time course similar to the changes in motoneuron firing behaviour observed in the present study. KEY POINTS: Neurons in the spinal cord that activate muscles in the limbs (motoneurons) undergo increases in excitability shortly after birth to help animals stand and walk. We examined whether the excitability of human ankle flexor motoneurons also continues to change from child to adulthood by recording the activity of the muscle fibres they innervate. Motoneurons in children and adolescents aged 7-17years (young development group) had higher signatures of excitability that included faster firing rates and more self-sustained activity compared to adults aged ≥18years. Participants aged 11-28years of age taking serotonin reuptake inhibitors had the highest measures of motoneuron excitability compared to their age-matched controls. The young development group also had more unstable contractions, which might partly be related to the high excitability of the motoneurons.

Postinhibitory excitation in motoneurons can be facilitated by hyperpolarization-activated inward currents: A simulation study.

Postinhibitory excitation is a transient overshoot of a neuron's baseline firing rate following an inhibitory stimulus and can be observed in vivo in human motoneurons. However, the biophysical origin of this phenomenon is still unknown and both reflex pathways and intrinsic motoneuron properties have been proposed. We hypothesized that postinhibitory excitation in motoneurons can be facilitated by hyperpolarization-activated inward currents (h-currents). Using an electrical circuit model, we investigated how h-currents can modulate the postinhibitory response of motoneurons. Further, we analyzed the spike trains of human motor units from the tibialis anterior muscle during reciprocal inhibition. The simulations revealed that the activation of h-currents by an inhibitory postsynaptic potential can cause a short-term increase in a motoneuron's firing probability. This result suggests that the neuron can be excited by an inhibitory stimulus. In detail, the modulation of the firing probability depends on the time delay between the inhibitory stimulus and the previous action potential. Further, the postinhibitory excitation's strength correlates with the inhibitory stimulus's amplitude and is negatively correlated with the baseline firing rate as well as the level of input noise. Hallmarks of h-current activity, as identified from the modeling study, were found in 50% of the human motor units that showed postinhibitory excitation. This study suggests that h-currents can facilitate postinhibitory excitation and act as a modulatory system to increase motoneuron excitability after a strong inhibition.

Caffeine does not influence persistent inward current contribution to motoneuron firing.

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.

Estimates of persistent inward currents in lower limb motoneurons are larger in females than in males.

Noninvasive recordings of motor unit (MU) spike trains help us understand how the nervous system controls movement and how it adapts to various physiological conditions. The majority of participants in human and nonhuman animal physiology studies are male, and it is assumed that mechanisms uncovered in these studies are shared between males and females. However, sex differences in neurological impairment and physical performance warrant the study of sex as a biological variable in human physiology and performance. To begin addressing this gap in the study of biophysical properties of human motoneurons, we quantified MU discharge rates and estimates of persistent inward current (PIC) magnitude in both sexes. We decomposed MU spike trains from the tibialis anterior (TA), medial gastrocnemius (MG), and soleus (SOL) using high-density surface electromyography and blind source separation algorithms. Ten participants of each sex performed slow triangular (10 s up and down) isometric contractions to a peak of 30% of their maximum voluntary contraction. We then used linear mixed-effects models to determine if peak discharge rate and estimates of PICs were predicted by the fixed effects of sex, muscle, and their interaction. Despite a lack of sex-differences in peak discharge rates across all muscles, estimates of PICs were larger [χ2(1) = 6.26, P = 0.012] in females [4.73 ± 0.242 pulses per second (pps)] than in males (3.81 ± 0.240 pps). These findings suggest that neuromodulatory drive, inhibitory input, and/or biophysical properties of motoneurons differ between the sexes and may contribute to differences in MU discharge patterns.NEW & NOTEWORTHY Sex-related differences in motoneuron analyses have emerged with greater inclusion of female participants, however, mechanisms for these differences remain unclear. Estimates of persistent inward currents (i.e., ΔF) in motoneurons of the lower limb muscles were larger in females than in males. This suggests neuromodulatory drive, monoaminergic signaling, intrinsic motoneuron properties, and/or descending motor commands may differ between the sexes, which provides a potential mechanism underlying previously reported sex-related differences in motoneuron discharge patterns.

5‐HT2 receptor antagonism reduces human motoneuron output to antidromic activation but not to stimulation of corticospinal axons

The intrinsic electrical properties of motoneurons strongly affect motoneuron excitability to fast‐acting excitatory ionotropic inputs. Serotonin (5‐HT) is a neurochemical that alters the intrinsic properties of motoneurons, whereby animal models and in vitro experiments indicate that 5‐HT increases motoneuron excitability by activating 5‐HT2 receptors on the somato‐dendritic compartment. In the current study, we examined how antagonism of the 5‐HT2 receptor affects motoneuron excitability in humans. We hypothesised that motoneuron excitability would be reduced. The 5‐HT2 antagonist cyproheptadine was administered to 10 healthy participants in a double‐blinded, placebo‐controlled, crossover trial. Electrical cervicomedullary stimulation was used to deliver a synchronised excitatory volley to motoneurons to elicit cervicomedullary motor evoked potentials (CMEPs) in the surface electromyography (EMG) signal of the resting biceps brachii. Likewise, electrical peripheral nerve stimulation was used to generate antidromic spikes in motoneurons and cause recurrent discharges, which were recorded with surface EMG as F‐waves in a resting hand muscle. Compared with placebo, we found that 5‐HT2 antagonism reduced the amplitude and persistence of F‐waves but did not affect CMEP amplitude. 5‐HT2 antagonism also reduced maximal contraction strength. The reduced recurrent discharge of motoneurons with 5‐HT2 antagonism suggests that 5‐HT2 receptors modulate the electrical properties of the initial segment or soma to promote excitability. Conversely, as cyproheptadine did not affect motoneuron excitability to brief synaptic input, but affected maximal contractions requiring sustained input, it seems likely that the 5‐HT2‐mediated amplification of synaptic input at motoneuron dendrites is functionally significant only when excitatory input activates persistent inward currents.

Involvement of 5-HT1 and 5-HT5A Receptors in Modulation of Synaptic Transmission and Intrinsic Membrane Properties of Spinal Motoneurons of the Frog (Rana ridibunda)

Involvement of 5-HT1 and 5-HT5A Receptors in Modulation of Synaptic Transmission and Intrinsic Membrane Properties of Spinal Motoneurons of the Frog (Rana ridibunda)

Developmentally Regulated Modulation of Lumbar Motoneurons by Metabotropic Glutamate Receptors: A Cellular and Behavioral Analysis in Newborn Mice.

The present study explores the impact of metabotropic glutamate receptor (mGluR) activation on activity-dependent synaptic plasticity (ADSP) and the intrinsic membrane properties of lumbar motoneurons (MNs) using a combination of biochemical, pharmacological, electrophysiological and behavioral techniques. Using spinal cord slices from C57BL/6JRJ mice at two developmental stages, 1-3 and 8-12 postnatal days (P1-P3; P8-P12, respectively), we found that ADSP expressed at glutamatergic synapses between axons conveyed in the ventrolateral funiculus (VLF) and MNs, involved mGluR activation. Using specific agonists of the three groups of mGluRs, we observed that mGluR stimulation causes subtype-specific and developmentally regulated modulation of the ADSP and synaptic transmission at VLF-MN synapses as well as the intrinsic membrane properties of MNs. RT-qPCR analysis revealed a downregulation of mGluR gene expression with age in the ventral part of the lumbar spinal cord. Interestingly, the selective harvest by laser microdissection of MNs innervating the Gastrocnemius and Tibialis anterior muscles unraveled that the level of Grm2 expression is higher in Tibialis MNs compared to Gastrocnemius MNs suggesting a specific mGluR gene expression profile in these two MN pools. Finally, we assessed the functional impact of mGluR modulation on electrically induced bouts of fictive locomotion in the isolated spinal cord preparation of P1-P3 mice, and in vivo during spontaneous episodes of swimming activity in both P1-P3 and P8-P12 mouse pups. We observed that the mGluR agonists induced distinct and specific effects on the motor burst amplitudes and period of the locomotor rhythms tested and that their actions are function of the developmental stage of the animals. Altogether our data show that the metabotropic glutamatergic system exerts a complex neuromodulation in the developing spinal lumbar motor networks and provide new insights into the expression and modulation of ADSP in MNs.

Mechanisms modulating spinal excitability after nerve stimulation inducing extra torque

The study included three experiments aiming to examine the mechanisms responsible for spinal excitability modulation, as assessed by the H-reflex, following stimulation trains delivered at two different frequencies (20 and 100 Hz) inducing extra torque (ET). A first experiment (n = 15) was conducted to evaluate changes in presynaptic inhibition acting on Ia afferents induced by these electrical stimulation trains, assessed by conditioning the soleus H-reflex (tibial nerve stimulation) with stimulation of the common peroneal nerve (D1 inhibition) and of the femoral nerve (heteronymous Ia facilitation, HF). A second experiment (n = 12) permitted to investigate homosynaptic postactivation depression (HPAD) changes after the stimulation trains. A third experiment (n = 14) analyzed changes in motoneuron intrinsic properties after the stimulation trains, by electrically stimulating the descending corticospinal tract at the thoracic level, evoking thoracic motor-evoked potentials (TMEP). Main results showed that in all experiments, spinal excitability decreased after the 20-Hz train (P < 0.05), whereas this parameter significantly increased after the 100-Hz stimulation (P < 0.05). D1 and HF were not significantly modified after either stimulation. HPAD was significantly decreased only after the 20-Hz train, whereas TMEP was significantly increased only after the 100-Hz train (P < 0.05). It is concluded that the decreased spinal excitability observed after the 20-Hz train cannot be attributed to D1 presynaptic inhibition but rather to increased HPAD of the Ia afferents terminals, whereas the increase of this parameter obtained after the 100-Hz train can be assigned to changes in intrinsic motoneuron properties allowing to maintain Ia-α-motoneurons transmission efficacy.NEW & NOTEWORTHY Using different electrophysiological techniques, results show that the downregulation of spinal excitability observed after the 20-Hz train could be ascribed to homosynaptic postactivation depression of the Ia afferents terminals, whereas changes in intrinsic motoneuron properties could explain the increased spinal excitability observed after the 100-Hz train. A novel methodology for assessing soleus D1 presynaptic inhibition and heteronymous Ia facilitation, accounting for eventual modulations of test reflex amplitude throughout the session, was developed.

Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry.

Despite the rising prevalence of methadone treatment in pregnant women with opioid use disorder, the effects of methadone on neurobehavioral development remain unclear. We developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. We investigated the effects of PME on physical development, sensorimotor behavior, and motor neuron properties using a multidisciplinary approach of physical, biochemical, and behavioral assessments along with brain slice electrophysiology and in vivo magnetic resonance imaging. Methadone accumulated in the placenta and fetal brain, but methadone levels in offspring dropped rapidly at birth which was associated with symptoms and behaviors consistent with neonatal opioid withdrawal. PME produced substantial impairments in offspring physical growth, activity in an open field, and sensorimotor milestone acquisition. Furthermore, these behavioral alterations were associated with reduced neuronal density in the motor cortex and a disruption in motor neuron intrinsic properties and local circuit connectivity. The present study adds to the limited body of work examining PME by providing a comprehensive, translationally relevant characterization of how PME disrupts offspring physical and neurobehavioral development.

Rapid activity-dependent modulation of the intrinsic excitability through up-regulation of KCNQ/Kv7 channel function in neonatal spinal motoneurons.

Activity-dependent changes in the properties of the motor system underlie the necessary adjustments in its responsiveness on the basis of the environmental and developmental demands of the organism. Although plastic changes in the properties of the spinal cord have historically been neglected because of the archaic belief that the spinal cord is constituted by a hardwired network that simply relays information to muscles, plenty of evidence has been accumulated showing that synapses impinging on spinal motoneurons undergo short- and long-term plasticity. In the brain, brief changes in the activity level of the network have been shown to be paralleled by changes in the intrinsic excitability of the neurons and are suggested to either reinforce or stabilize the changes at the synaptic level. However, rapid activity-dependent changes in the intrinsic properties of spinal motoneurons have never been reported. In this study, we show that in neonatal mice the intrinsic excitability of spinal motoneurons is depressed after relatively brief but sustained changes in the spinal cord network activity. Using electrophysiological techniques together with specific pharmacological blockers of KCNQ/Kv7 channels, we demonstrate their involvement in the reduction of the intrinsic excitability of spinal motoneurons. This action results from an increased M-current, the product of the activation of KCNQ/Kv7 channels, which leads to a hyperpolarization of the resting membrane potential and a decrease in the input resistance of spinal motoneurons. Computer simulations showed that specific up-regulations in KCNQ/Kv7 channels functions lead to a modulation of the intrinsic excitability of spinal motoneurons as observed experimentally. These results indicate that KCNQ/Kv7 channels play a fundamental role in the activity-dependent modulation of the excitability of spinal motoneurons.

Correlation between discharge timings of pairs of motor units reveals the presence but not the proportion of common synaptic input to motor neurons.

We investigated whether correlation measures derived from pairs of motor unit (MU) spike trains are reliable indicators of the degree of common synaptic input to motor neurons. Several 50-s isometric contractions of the biceps brachii muscle were performed at different target forces ranging from 10 to 30% of the maximal voluntary contraction relying on force feedback. Forty-eight pairs of MUs were examined at various force levels. Motor unit synchrony was assessed by cross-correlation analysis using three indexes: the output correlation as the peak of the cross-histogram (ρ) and the number of synchronous spikes per second (CIS) and per trigger (E). Individual analysis of MU pairs revealed that ρ, CIS, and E were most often positively associated with discharge rate (87, 85, and 76% of the MU pairs, respectively) and negatively with interspike interval variability (69, 65, and 62% of the MU pairs, respectively). Moreover, the behavior of synchronization indexes with discharge rate (and interspike interval variability) varied greatly among the MU pairs. These results were consistent with theoretical predictions, which showed that the output correlation between pairs of spike trains depends on the statistics of the input current and motor neuron intrinsic properties that differ for different motor neuron pairs. In conclusion, the synchronization between MU firing trains is necessarily caused by the (functional) common input to motor neurons, but it is not possible to infer the degree of shared common input to a pair of motor neurons on the basis of correlation measures of their output spike trains.NEW & NOTEWORTHY The strength of correlation between output spike trains is only poorly associated with the degree of common input to the population of motor neurons. The synchronization between motor unit firing trains is necessarily caused by the (functional) common input to motor neurons, but it is not possible to infer the degree of shared common input to a pair of motor neurons on the basis of correlation measures of their output spike trains.

Electrophysiological properties of abdominal muscle‐projecting expiratory motoneurons of rats

Expiration is considered a passive process during resting breathing condition. There is a lack of information about the intrinsic electrophysiological properties of expiratory motoneurons and their possible changes in conditions in which the expiration becomes an active process, such as hypoxia. Considering that abdominal expiratory muscle activity depends on excitability of these motoneurons, here we aimed to characterize the electrophysiological properties of abdominal muscle‐projecting expiratory motoneurons combining retrograde tracer, immunofluorescence and whole cell patch clamp, in thoraco‐lumbar spinal cord slices from juvenile Wistar rats. Three different types of cholinergic expiratory motoneurons with similar capacitance were recorded: neurons with spontaneous action potentials whose resting potential hyperpolarizes (−65 ± 5 mV vs −69.7 ± 4 mV, n=9) and firing frequency decreases (8.5 ± 2 Hz vs 1.7 ± 1.3 Hz, n=9) after synaptic blockade. The passive properties of these motoneurons, such as input resistance and excitability, did not change after synaptic blockade (Ri = 0.16 ± 0.03 GΩ vs 0.13 ± 0.03 GΩ; Excitability = 40 ± 10 Hz vs 32 ± 11 Hz, n=9). The second group of motoneurons also exhibited spontaneous action potentials, but showed spike frequency adaptation, slowing or ceasing firing frequency during a maintained stimulus. Their membrane potential also hyperpolarized (−60 ± 1 mV vs −66 ± 1 mV, n=4) and firing frequency was abolished by synaptic blockade. On the other hand, no differences in the input resistance was observed (0.13 ± 0.01 GΩ vs 0.11 ± 0.01 GΩ, n=4). The third group did not show spontaneous action potential and synaptic blockade did not change membrane potential (−72.2 ± 2 mV vs −76 ± 3 mV, n=6) or input resistance (0.1 ± 0.04 GΩ vs 0.06 ± 0.02 GΩ, n=6). However, synaptic blockade decreased their intrinsic excitability. Overall, our data show that there are three different populations of abdominal muscle‐projecting expiratory motoneurons in rats, which may contribute to recruitment of expiratory muscles in different physiological and pathophysiological conditions.Support or Funding InformationFAPESP, CAPES, CNPQ

Cadence-dependent changes in corticospinal excitability of the biceps brachii during arm cycling.

This is the first study to report the influence of different cadences on the modulation of supraspinal and spinal excitability during arm cycling. Supraspinal and spinal excitability were assessed using transcranial magnetic stimulation of the motor cortex and transmastoid electrical stimulation of the corticospinal tract, respectively. Transcranial magnetic stimulation-induced motor evoked potentials and transmastoid electrical stimulation-induced cervicomedullary evoked potentials (CMEPs) were recorded from the biceps brachii at two separate positions corresponding to elbow flexion and extension (6 and 12 o'clock relative to a clock face, respectively) while arm cycling at 30, 60 and 90 rpm. Motor evoked potential amplitudes increased significantly as cadence increased during both elbow flexion (P < 0.001) and extension (P = 0.027). CMEP amplitudes also increased with cadence during elbow flexion (P < 0.01); however, the opposite occurred during elbow extension (i.e., decreased CMEP amplitude; P = 0.01). The data indicate an overall increase in the excitability of corticospinal neurons which ultimately project to biceps brachii throughout arm cycling as cadence increased. Conversely, changes in spinal excitability as cadence increased were phase dependent (i.e., increased during elbow flexion and decreased during elbow extension). Phase- and cadence-dependent changes in spinal excitability are suggested to be mediated via changes in the balance of excitatory and inhibitory synaptic input to the motor pool, as opposed to changes in the intrinsic properties of spinal motoneurons.

Single-motor-unit discharge characteristics in human lumbar multifidus muscle.

The underlying neurophysiology of postural control of the lower back in humans is poorly understood. We have characterized motor unit (MU) discharge activity in the deep lumbar multifidus (LM) muscle in nine healthy subjects (20-40 yr, 3 females). Bilateral fine wire electrodes were implanted at L4 spinal level using ultrasound guidance. EMG was recorded during spontaneous sitting and standing and during voluntary force production. Individual MUs were analyzed with regard to instantaneous discharge rate, interspike interval variability, alternation of activity between MUs, and cross correlation between concurrently active MUs quantified by the common drive coefficient (CDC). Significant effects of sitting vs. standing were seen on median discharge rate and interspike interval variability. Median discharge rate in 71 units was 5.4 and 6.9 pulses/s during spontaneous sitting and standing and 7.4 pulses/s during voluntary force production. Several MUs fired doublets. CDC analysis of 87 MU pairs showed a significantly higher common drive in spontaneous than in voluntary activity and significant differences between unilateral and bilateral pairs, although not when spontaneously active in standing. In spite of common drive, MUs were recruited from inactivity to tonic discharge lasting for several minutes without changes in discharge rate in already active MUs, and several instances were documented where activity was rotated between MUs. We argue that this behavior is indicative of self-sustained discharge in LM motoneurons, establishing intrinsic motoneuron properties as a central mechanism for postural control of deep back muscles.

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.

Asynchronous recruitment of low-threshold motor units during repetitive, low-current stimulation of the human tibial nerve.

Motoneurons receive a barrage of inputs from descending and reflex pathways. Much of our understanding about how these inputs are transformed into motor output in humans has come from recordings of single motor units during voluntary contractions. This approach, however, is limited because the input is ill-defined. Herein, we quantify the discharge of soleus motor units in response to well-defined trains of afferent input delivered at physiologically-relevant frequencies. Constant frequency stimulation of the tibial nerve (10–100 Hz for 30 s), below threshold for eliciting M-waves or H-reflexes with a single pulse, recruited motor units in 7/9 subjects. All 25 motor units recruited during stimulation were also recruited during weak (<10% MVC) voluntary contractions. Higher frequencies recruited more units (n = 3/25 at 10 Hz; n = 25/25 at 100 Hz) at shorter latencies (19.4 ± 9.4 s at 10 Hz; 4.1 ± 4.0 s at 100 Hz) than lower frequencies. When a second unit was recruited, the discharge of the already active unit did not change, suggesting that recruitment was not due to increased synaptic drive. After recruitment, mean discharge rate during stimulation at 20 Hz (7.8 Hz) was lower than during 30 Hz (8.6 Hz) and 40 Hz (8.4 Hz) stimulation. Discharge was largely asynchronous from the stimulus pulses with “time-locked” discharge occurring at an H-reflex latency with only a 24% probability. Motor units continued to discharge after cessation of the stimulation in 89% of trials, although at a lower rate (5.8 Hz) than during the stimulation (7.9 Hz). This work supports the idea that the afferent volley evoked by repetitive stimulation recruits motor units through the integration of synaptic drive and intrinsic properties of motoneurons, resulting in “physiological” recruitment which adheres to Henneman’s size principle and results in relatively low discharge rates and asynchronous firing.

Could motor unit control strategies be partially preserved after stroke?

There is considerable evidence on the impairments that a cerebral stroke will have down-stream of the stroke, i.e., in the spinal motoneuron and the muscle. Motor impairment following stroke has been documented as force production that is slow, weak, and lacking in precision (Garland et al., 2009) and is associated with difficulty in fully activating the muscle (Klein et al., 2013). Furthermore, in functional tasks such as standing balance and gait, there is evidence of deficits in intra-limb coordination of muscles even on the non-paretic side (Marigold and Eng, 2006; Raja et al., 2012). In this opinion paper, we will first briefly review the changes observed at the level of the motor unit (MU) after stroke and second reflect upon whether some changes in the intrinsic properties of motoneurons, typically considered to be maladaptive, might also reflect a positive adaptation that could assist in force production. Lastly, this paper will explore the control of MUs between limbs during standing balance and suggest that, while some impairment may exist, there remains the possibility of a preservation of fundamental motor control strategies after stroke that might be a target for rehabilitation.

Locomotor training modifies soleus monosynaptic motoneuron responses in human spinal cord injury.

The objective of this study was to assess changes in monosynaptic motoneuron responses to stimulation of Ia afferents after locomotor training in individuals with chronic spinal cord injury (SCI). We hypothesized that locomotor training modifies the amplitude of the soleus monosynaptic motoneuron responses in a body position-dependent manner. Fifteen individuals with chronic clinical motor complete or incomplete SCI received an average of 45 locomotor training sessions. The soleus H-reflex and M-wave recruitment curves were assembled using data collected in both the right and left legs, with subjects seated and standing, before and after training. The soleus H-reflexes and M-waves, measured as peak-to-peak amplitudes, were normalized to the maximal M-wave (M(max)). Stimulation intensities were normalized to 50% M(max) stimulus intensity. A sigmoid function was also fitted to the normalized soleus H-reflexes on the ascending limb of the recruitment curve. After training, soleus H-reflex excitability was increased in both legs in AIS C subjects, and remained unchanged in AIS A-B and AIS D subjects during standing. When subjects were seated, soleus H-reflex excitability was decreased after training in many AIS C and D subjects. Changes in reflex excitability coincided with changes in stimulation intensities at H-threshold, 50% maximal H-reflex, and at maximal H-reflex, while an interaction between leg side and AIS scale for the H-reflex slope was also found. Adaptations of the intrinsic properties of soleus motoneurons and Ia afferents, the excitability profile of the soleus motoneuron pool, oligosynaptic inputs, and corticospinal inputs may all contribute to these changes. The findings of this study demonstrate that locomotor training impacts the amplitude of the monosynaptic motoneuron responses based on the demands of the motor task in people with chronic SCI.

Gain control mechanisms in spinal motoneurons.

Motoneurons provide the only conduit for motor commands to reach muscles. For many years, motoneurons were in fact considered to be little more than passive “wires”. Systematic studies in the past 25 years however have clearly demonstrated that the intrinsic electrical properties of motoneurons are under strong neuromodulatory control via multiple sources. The discovery of potent neuromodulation from the brainstem and its ability to change the gain of motoneurons shows that the “passive” view of the motor output stage is no longer tenable. A mechanism for gain control at the motor output stage makes good functional sense considering our capability of generating an enormous range of forces, from very delicate (e.g., putting in a contact lens) to highly forceful (emergency reactions). Just as sensory systems need gain control to deal with a wide dynamic range of inputs, so to might motor output need gain control to deal with the wide dynamic range of the normal movement repertoire. Two problems emerge from the potential use of the brainstem monoaminergic projection to motoneurons for gain control. First, the projection is highly diffuse anatomically, so that independent control of the gains of different motor pools is not feasible. In fact, the system is so diffuse that gain for all the motor pools in a limb likely increases in concert. Second, if there is a system that increases gain, probably a system to reduce gain is also needed. In this review, we summarize recent studies that show local inhibitory circuits within the spinal cord, especially reciprocal and recurrent inhibition, have the potential to solve both of these problems as well as constitute another source of gain modulation.