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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 (7–17 years), young adult (18–28 years) and adult (32–53 years) group, as well as in a separate group of participants taking selective serotonin reuptake inhibitors (SSRIs, aged 11–28 years). Self‐sustained firing, as measured by ΔF, was larger in the young development (∼5.8 Hz, n = 20) compared to the young adult (∼4.9 Hz, n = 13) and adult (∼4.8 Hz, 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 (∼6.5 Hz, n = 9) compared to their age‐matched controls (∼5.3 Hz, 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 7–17 years (young development group) had higher signatures of excitability that included faster firing rates and more self‐sustained activity compared to adults aged ≥18 years.Participants aged 11–28 years 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. [ABSTRACT FROM AUTHOR]

On demand and localized treatment for excessive muscle tone after spinal cord injury (SCI) is currently not available. Here, we examine the reduction in leg hypertonus in a person with mid-thoracic, motor complete SCI using a commercial transcutaneous electrical stimulator (TES) applied at 50 or 150 Hz to the lower back and the possible mechanisms producing this bilateral reduction in leg tone. Hypertonus of knee extensors without and during TES, with both cathode (T11–L2) and anode (L3–L5) placed over the spinal column (midline, MID) or 10 cm to the left of midline (lateral, LAT) to only active underlying skin and muscle afferents, was simultaneously measured in both legs with the pendulum test. Spinal reflexes mediated by proprioceptive (H-reflex) and cutaneomuscular reflex (CMR) afferents were examined in the right leg opposite to the applied LAT TES. Hypertonus disappeared in both legs but only during thoracolumbar TES, and even during LAT TES. The marked reduction in tone was reflected in the greater distance both lower legs first dropped to after being released from a fully extended position, increasing by 172.8% and 94.2% during MID and LAT TES, respectively, compared with without TES. Both MID and LAT (left) TES increased H-reflexes but decreased the first burst, and lengthened the onset of subsequent bursts, in the cutaneomuscular reflex of the right leg. Thoracolumbar TES is a promising method to decrease leg hypertonus in chronic, motor complete SCI without activating spinal cord structures and may work by facilitating proprioceptive inputs that activate excitatory interneurons with bilateral projections that in turn recruit recurrent inhibitory neurons. NEW & NOTEWORTHY: We present proof of concept that surface stimulation of the lower back can reduce severe leg hypertonus in a participant with motor complete, thoracic spinal cord injury (SCI) but only during the applied stimulation. We propose that activation of skin and muscle afferents from thoracolumbar transcutaneous electrical stimulation (TES) may recruit excitatory spinal interneurons with bilateral projections that in turn recruit recurrent inhibitory networks to provide on demand suppression of ongoing involuntary motoneuron activity. [ABSTRACT FROM AUTHOR]

When a muscle is stretched, sensory feedback not only causes reflexes but also leads to a depolarization of sensory afferents throughout the spinal cord (primary afferent depolarization, PAD), readying the whole limb for further disturbances. This sensoryevoked PAD is thought to be mediated by a trisynaptic circuit, where sensory input activates first-order excitatory neurons that activate GABAergic neurons that in turn activate GABAA receptors on afferents to cause PAD, though the identity of these firstorder neurons is unclear. Here, we show that these first-order neurons include propriospinal V3 neurons, as they receive extensive sensory input and in turn innervate GABAergic neurons that cause PAD, because optogenetic activation or inhibition of V3 neurons in mice mimics or inhibits sensory-evoked PAD, respectively. Furthermore, persistent inward sodium currents intrinsic to V3 neurons prolong their activity, explaining the prolonged duration of PAD. Also, local optogenetic activation of V3 neurons at one segment causes PAD in other segments, due to the long propriospinal tracts of these neurons, helping to explain the radiating nature of PAD. This in turn facilitates monosynaptic reflex transmission to motoneurons across the spinal cord. In addition, V3 neurons directly innervate proprioceptive afferents (including Ia), causing a glutamate receptor-mediated PAD (glutamate PAD). Finally, increasing the spinal cord excitability with either GABAA receptor blockers or chronic spinal cord injury causes an increase in the glutamate PAD. Overall, we show the V3 neuron has a prominent role in modulating sensory transmission, in addition to its previously described role in locomotion. NEW & NOTEWORTHY Locomotor-related propriospinal neurons depolarize sensory axons throughout the spinal cord by either direct glutamatergic axoaxonic contacts or indirect innervation of GABAergic neurons that themselves form axoaxonic contacts on sensory axons. This depolarization (PAD) increases sensory transmission to motoneurons throughout the spinal cord, readying the sensorimotor system for external disturbances. The glutamate-mediated PAD is particularly adaptable, increasing with either an acute block of GABA receptors or chronic spinal cord injury, suggesting a role in motor recovery. [ABSTRACT FROM AUTHOR]

Suppression of the extensor H‐reflex by flexor afferent conditioning is thought to be produced by a long‐lasting inhibition of extensor Ia afferent terminals via GABAA receptor‐activated primary afferent depolarization (PAD). Given the recent finding that PAD does not produce presynaptic inhibition of Ia afferent terminals, we examined in 28 participants if H‐reflex suppression is instead mediated by post‐activation depression of the extensor Ia afferents triggered by PAD‐evoked spikes and/or by a long‐lasting inhibition of the extensor motoneurons. A brief conditioning vibration of the flexor tendon suppressed both the extensor soleus H‐reflex and the tonic discharge of soleus motor units out to 150 ms following the vibration, suggesting that part of the H‐reflex suppression during this period was mediated by postsynaptic inhibition of the extensor motoneurons. When activating the flexor afferents electrically to produce conditioning, the soleus H‐reflex was also suppressed but only when a short‐latency reflex was evoked in the soleus muscle by the conditioning input itself. In mice, a similar short‐latency reflex was evoked when optogenetic or afferent activation of GABAergic (GAD2+) neurons produced a large enough PAD to evoke orthodromic spikes in the test Ia afferents, causing post‐activation depression of subsequent monosynaptic EPSPs. The long duration of this post‐activation depression and related H‐reflex suppression (seconds) was similar to rate‐dependent depression that is also due to post‐activation depression. We conclude that extensor H‐reflex inhibition by brief flexor afferent conditioning is produced by both post‐activation depression of extensor Ia afferents and long‐lasting inhibition of extensor motoneurons, rather than from PAD inhibiting Ia afferent terminals. Key points: Suppression of extensor H‐reflexes by flexor afferent conditioning was thought to be mediated by GABAA receptor‐mediated primary afferent depolarization (PAD) shunting action potentials in the Ia afferent terminal.In line with recent findings that PAD has a facilitatory role in Ia afferent conduction, we show here that when large enough, PAD can evoke orthodromic spikes that travel to the Ia afferent terminal to evoke EPSPs in the motoneuron.These PAD‐evoked spikes also produce post‐activation depression of Ia afferent terminals and may mediate the short‐ and long‐lasting suppression of extensor H‐reflexes in response to flexor afferent conditioning.Our findings highlight that we must re‐examine how changes in the activation of GABAergic interneurons and PAD following nervous system injury or disease affects the regulation of Ia afferent transmission to spinal neurons and ultimately motor dysfunction in these disorders. [ABSTRACT FROM AUTHOR]

Sensory and corticospinal tract (CST) pathways activate spinal GABAergic interneurons that have axoaxonic connections onto proprioceptive (Ia) afferents that cause long‐lasting depolarizations (termed primary afferent depolarization, PAD). In rodents, sensory‐evoked PAD is produced by GABAA receptors at nodes of Ranvier in Ia afferents, rather than at presynaptic terminals, and facilitates spike propagation to motoneurons by preventing branch‐point failures, rather than causing presynaptic inhibition. We examined in 40 human participants whether putative activation of Ia‐PAD by sensory or CST pathways can also facilitate Ia afferent activation of motoneurons via the H‐reflex. H‐reflexes in several leg muscles were facilitated by prior conditioning from low‐threshold proprioceptive, cutaneous or CST pathways, with a similar long‐lasting time course (∼200 ms) to phasic PAD measured in rodent Ia afferents. Long trains of cutaneous or proprioceptive afferent conditioning produced longer‐lasting facilitation of the H‐reflex for up to 2 min, consistent with tonic PAD in rodent Ia afferents mediated by nodal α5‐GABAA receptors for similar stimulation trains. Facilitation of H‐reflexes by this conditioning was likely not mediated by direct facilitation of the motoneurons because isolated stimulation of sensory or CST pathways did not alone facilitate the tonic firing rate of motor units. Furthermore, cutaneous conditioning increased the firing probability of single motor units (motoneurons) during the H‐reflex without increasing their firing rate at this time, indicating that the underlying excitatory postsynaptic potential was more probable, but not larger. These results are consistent with sensory and CST pathways activating nodal GABAA receptors that reduce intermittent failure of action potentials propagating into Ia afferent branches. Key points: Controlled execution of posture and movement requires continually adjusted feedback from peripheral sensory pathways, especially those that carry proprioceptive information about body position, movement and effort.It was previously thought that the flow of proprioceptive feedback from Ia afferents was only reduced by GABAergic neurons in the spinal cord that sent axoaxonic projections to the terminal endings of sensory axons (termed GABAaxo neurons).Based on new findings in rodents, we provide complementary evidence in humans to suggest that sensory and corticospinal pathways known to activate GABAaxo neurons that project to dorsal parts of the Ia afferent also increase the flow of proprioceptive feedback to motoneurons in the spinal cord.These findings support a new role for spinal GABAaxo neurons in facilitating afferent feedback to the spinal cord during voluntary or reflexive movements. [ABSTRACT FROM AUTHOR]

Muscle paralysis after spinal cord injury is partly caused by a loss of brainstem-derived serotonin (5-HT), which normally maintains motoneuron excitability by regulating crucial persistent calcium currents. Here we examine how over time motoneurons compensate for lost 5-HT to regain excitability. We find that, months after a spinal transection in rats, changes in posttranscriptional editing of [5-HT.sub.2C] receptor mRNA lead to increased expression of [5- HT.sub.2C] receptor isoforms that are spontaneously active (constitutively active) without 5-HT. Such constitutive receptor activity restores large persistent calcium currents in motoneurons in the absence of 5-HT. We show that this helps motoneurons recover their ability to produce sustained muscle contractions and ultimately enables recovery of motor functions such as locomotion. However, without regulation from the brain, these sustained contractions can also cause debilitating muscle spasms. Accordingly, blocking constitutively active [5-HT.sub.2C] receptors with SB206553 or cyproheptadine, in both rats and humans, largely eliminates these calcium currents and muscle spasms, providing a new rationale for antispastic drug therapy., Severe spinal cord injury (SCI) causes an immediate paralysis of muscles innervated by motoneurons directly caudal to the injury site. This results not only from a loss of supraspinal tracts [...]

In this update, the authors will discuss evidence for both spinal and brain regulation of walking in humans. They will consider the sensory control of walking in young babies and [...]

Cerebral palsy (CP) is caused by a variety of factors attributed to early brain damage, resulting in permanently impaired motor control, marked by weakness and muscle stiffness. To find out if altered physiology of spinal motoneurons (MNs) could contribute to movement deficits, we performed whole-cell patch-clamp in neonatal rabbit spinal cord slices after developmental injury at 79% gestation. After preterm hypoxia-ischemia (HI), rabbits are born with motor deficits consistent with a spastic phenotype including hypertonia and hyperreflexia. There is a range in severity, thus kits are classified as severely affected, mildly affected, or unaffected based on modified Ashworth scores and other behavioral tests. At postnatal day (P)0–5, we recorded electrophysiological parameters of 40 MNs in transverse spinal cord slices using whole-cell patch-clamp. We found significant differences between groups (severe, mild, unaffected and sham control MNs). Severe HI MNs showed more sustained firing patterns, depolarized resting membrane potential, and fired action potentials at a higher frequency. These properties could contribute to muscle stiffness, a hallmark of spastic CP. Interestingly altered persistent inward currents (PICs) and morphology in severe HI MNs would dampen excitability (depolarized PIC onset and increased dendritic length). In summary, changes we observed in spinal MN physiology likely contribute to the severity of the phenotype, and therapeutic strategies for CP could target the excitability of spinal MNs. [ABSTRACT FROM AUTHOR]

Cerebral palsy (CP) is the most common motor disability in children. Much of the previous research on CP has focused on reducing the severity of brain injuries, whereas very few researchers have investigated the cause and amelioration of motor symptoms. This research focus has had an impact on the choice of animal models. Many of the commonly used animal models do not display a prominent CP-like motor phenotype. In general, rodent models show anatomically severe injuries in the central nervous system (CNS) in response to insults associated with CP, including hypoxia, ischemia, and neuroinflammation. Unfortunately, most rodent models do not display a prominent motor phenotype that includes the hallmarks of spasticity (muscle stiffness and hyperreflexia) and weakness. To study motor dysfunction related to developmental injuries, a larger animal model is needed, such as rabbit, pig, or nonhuman primate. In this work, we describe and compare various animal models of CP and their potential for translation to the human condition. [ABSTRACT FROM AUTHOR]

The neural plasticity of spinal reflexes after two contrasting forms of walking training was determined in individuals with chronic, motor-incomplete spinal cord injury (SCI). Endurance Training involved treadmill walking for as long as possible, and Precision Training involved walking precisely over obstacles and onto targets overground. Twenty participants started either Endurance or Precision Training for 2 months and then crossed over after a 2-month rest period to the other form of training for 2 months. Measures were taken before and after each phase of training and rest. The cutaneomuscular reflex (CMR) during walking was evoked in the soleus (SOL) and tibialis anterior muscles by stimulating the posterior tibial nerve at the ankle. Clonus was estimated from the EMG power in the SOL during unperturbed walking. The inhibitory component of the SOL CMR was enhanced after Endurance but not Precision Training. Clonus did not change after either form of training. Participants with lower reflex excitability tended to be better walkers (i.e., faster walking speeds) prior to training, and the reduction in clonus was significantly correlated with the improvement in walking speed and distance. Thus, reflex excitability responded in a training-specific way, with the reduction in reflex excitability related to improvements in walking function. Trial registration number is NCT01765153. [ABSTRACT FROM AUTHOR]

Inhibitory feedback from sensory pathways is important for controlling movement. Here, we characterize, for the first time, a longlatency, inhibitory spinal pathway to ankle flexors that is activated by low-threshold homonymous afferents. To examine this inhibitory pathway in uninjured, healthy participants, we suppressed motorevoked potentials (MEPs), produced in the tibialis anterior (TA), by a prior stimulation to the homonymous common peroneal nerve (CPN). The TA MEP was suppressed by a triple-pulse stimulation to the CPN, applied 40, 50, and 60 ms earlier and at intensities of 0.5- 0.7 times motor threshold (average suppression of test MEP was 33%). Whereas the triple-pulse stimulation was below M-wave and H-reflex threshold, it produced a long-latency inhibition of background muscle activity, approximately 65-115 ms after the CPN stimulation, a time period that overlapped with the test MEP. However, not all of the MEP suppression could be accounted for by this decrease in background muscle activity. Evoked responses from direct activation of the corticospinal tract, at the level of the brain stem or thoracic spinal cord, were also suppressed by low-threshold CPN stimulation. Our findings suggest that low-threshold muscle and cutaneous afferents from the CPN activate a long-latency, homonymous spinal inhibitory pathway to TA motoneurons. We propose that inhibitory feedback from spinal networks, activated by low-threshold homonymous afferents, helps regulate the activation of flexor motoneurons by the corticospinal tract. [ABSTRACT FROM AUTHOR]

The state of areflexia and muscle weakness that immediately follows a spinal cord injury (SCI) is gradually replaced by the recovery of neuronal and network excitability, leading to both improvements in residual motor function and the development of spasticity. In this review we summarize recent animal and human studies that describe how motoneurons and their activation by sensory pathways become hyperexcitable to compensate for the reduction of functional activation of the spinal cord and the eventual impact on the muscle. Specifically, decreases in the inhibitory control of sensory transmission and increases in intrinsic motoneuron excitability are described. We present the idea that replacing lost patterned activation of the spinal cord by activating synaptic inputs via assisted movements, pharmacology or electrical stimulation may help to recover lost spinal inhibition. This may lead to a reduction of uncontrolled activation of the spinal cord and thus, improve its controlled activation by synaptic inputs to ultimately normalize circuit function. Increasing the excitation of the spinal cord with spared descending and/or peripheral inputs by facilitating movement, instead of suppressing it pharmacologically, may provide the best avenue to improve residual motor function and manage spasticity after SCI. [ABSTRACT FROM AUTHOR]

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 (∆F = 4.6 ± 1.5 imp/s). The F, 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 ∆F 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. [ABSTRACT FROM AUTHOR]

Activation of receptors by serotonin (5-HT1) and norepinephrine (-2) on primary afferent terminals and excitatory interneurons reduces transmission in spinal sensory pathways. Loss or reduction of descending sources of serotonin and norepinephrine after spinal cord injury (SCI) and the subsequent reduction of 5-HT1/-2 receptor activity contributes, in part, to the emergence of excessive motoneuron activation from sensory afferent pathways and the uncontrolled triggering of persistent inward currents that depolarize motoneurons during muscle spasms. We tested in a double-blind, placebocontrolled study whether facilitating 5-HT1B/D receptors with the agonist zolmitriptan reduces the sensory activation of motoneurons during an H-reflex in both noninjured control and spinal cord-injured participants. In both groups zolmitriptan, but not placebo, reduced the size of the maximum soleus H-reflex with a peak decrease to 59% (noninjured) and 62% (SCI) of predrug values. In SCI participants we also examined the effects of zolmitriptan on the cutaneomuscular reflex evoked in tibialis anterior from stimulation to the medial arch of the foot. Zolmitriptan, but not placebo, reduced the long-latency, polysynaptic component of the cutaneomuscular reflex (first 200 ms of reflex) by ~50%. This ultimately reduced the triggering of the long-lasting component of the reflex (500 ms poststimulation to end of reflex) known to be mediated by persistent inward currents in the motoneuron. These results demonstrate that facilitation of 5-HT1B/D receptors reduces sensory transmission in both monosynaptic and polysynaptic reflex pathways to ultimately reduce long-lasting reflexes (spasms) after SCI. [ABSTRACT FROM AUTHOR]

Muscle paralysis after spinal cord injury is partly caused by a loss of brainstem-derived serotonin (5-HT), which normally maintains motoneuron excitability by regulating crucial persistent calcium currents. Here we examine how over time motoneurons compensate for lost 5-HT to regain excitability. We find that, months after a spinal transection in rats, changes in post-transcriptional editing of 5-HT2C receptor mRNA lead to increased expression of 5-HT2C receptor isoforms that are spontaneously active (constitutively active) without 5-HT. Such constitutive receptor activity restores large persistent calcium currents in motoneurons in the absence of 5-HT. We show that this helps motoneurons recover their ability to produce sustained muscle contractions and ultimately enables recovery of motor functions such as locomotion. However, without regulation from the brain, these sustained contractions can also cause debilitating muscle spasms. Accordingly, blocking constitutively active 5-HT2C receptors with SB206553 or cyproheptadine, in both rats and humans, largely eliminates these calcium currents and muscle spasms, providing a new rationale for antispastic drug therapy. [ABSTRACT FROM AUTHOR]

Recruitment and repetitive firing of spinal motoneurons depend on the activation of persistent inward calcium and sodium currents (PICs) that are in turn facilitated by serotonin and norepinephrine that arise primarily from the brain stem. Considering that in rats motoneuron PICs are greatly facilitated by increasing the presynaptic release of norepinephrine with amphetamine, we sought similar evidence for the modulation of PICs in human motoneurons. Pairs of motor units were recorded during a gradually increasing and then decreasing voluntary contraction. The firing frequency (F) of the lower-threshold (control) motor unit was used as an estimate of the synaptic input to the higher-threshold (test) motor unit. Generally, PICs are initiated during the recruitment of a motoneuron and subsequently provide a fixed depolarizing current that helps the synaptic input maintain firing until derecruitment. Thus the amplitude of the PIC in the test motor unit was estimated from the difference in synaptic input (🜂F) needed to maintain minimal firing once the PIC was fully activated (measured at the time of test unit derecruitment) compared with the larger synaptic input required to initiate firing prior to full PIC activation (measured at the time of test unit recruitment; 🜂F Frecruit Fderecruit). Moreover, the activation time of the PIC was estimated as the minimal contraction duration needed to produce a maximal PIC (🜂F). In five subjects, oral administration of amphetamine, but not placebo, increased the 🜂F by 62% [from 3.7 ～ 0.6 to 6.0 0.8 (SD) imp/s, P 0.001] and decreased the time needed to activate a maximal 🜂F from ～2 to 0.5 s. Both findings suggest that the endogenous facilitation of PICs from brain stem derived norepinephrine plays an important role in modulating human motoneuron excitability, readying motoneurons for rapid and sustained activity during periods of high arousal such as stress or fear. [ABSTRACT FROM AUTHOR]

Stroke survivors often exhibit abnormal motoneuron excitability, manifested clinically as spasticity with exaggerated stretch reflexes in resting muscles. We examined whether this abnormal excitability is a result of increased activation of intrinsic voltage-dependent persistent inward currents (PICs) or whether it is a result of enhanced synaptic inputs to the motoneuron. This distinction was made by recording firing rate profiles of pairs of motor units during isometric contractions of elbow flexor muscles. To estimate PIC amplitude, the discharge of the lower-threshold (reporter) motor unit of the pair was used to estimate the synaptic input to the higher-threshold (test) motor unit. The estimated synaptic input required to recruit the test unit was compared with the synaptic input when the test unit was derecruited (ΔF) and this served as an estimate of the intrinsic (PIC) contribution to motoneuron firing. We found that PIC estimates were not larger in spastic-paretic motoneurons (ΔF = 4.0 ± 1.6 pps) compared with contralateral (4.6 ± 1.4 pps) and age-matched healthy control motoneurons (3.8 ± 1.7, all P > 0.1). Instead, following the voluntary contractions, the majority of lower-threshold motor units in spasticparetic muscles (83%) exhibited spontaneous discharge, compared with 14% of contralateral and 0% of control motor units. Furthermore, there was strong co-modulation of simultaneously active units in spastic muscle. The presence of ongoing, correlated unit activity at "rest," coupled with firing behavior at recruitment unique to lowerthreshold motor units in spastic muscles, suggested that firing changes are likely a result of a low-level depolarizing synaptic drive to the resting motoneuron pool. [ABSTRACT FROM AUTHOR]

Changes in the strength of corticospinal projections to muscles in the upper and lower limbs are induced in conscious humans after paired associative stimulation (PAS) to the motor cortex. We tested whether an intervention of PAS consisting of 90 low-frequency (0.1-Hz) stimuli to the common peroneal nerve combined with suprathreshold transcranial magnetic stimulation (TMS) produces specific changes to the motor-evoked potentials (MEPs) in lower leg muscles if the afferent volley from peripheral stimulation is timed to arrive at the motor cortex after TMS-induced firing of corticospinal neurons. Unlike PAS in the hand, MEP facilitation in the leg was produced when sensory inputs were estimated to arrive at the motor cortex over a range of 15 to 90 ms after cortical stimulation. We examined whether this broad range of facilitation occurred as a result of prolonged subthreshold excitability of the motor cortex after a single pulse of suprathreshold TMS so that coincident excitation from sensory inputs arriving many milliseconds after TMS can occur. We found that significant facilitation of MEP responses (>200%) occurred when the motor cortex was conditioned with suprathreshold TMS tens of milliseconds earlier. Likewise, it was possible to induce strong MEP facilitation (85% at 60 min) when afferent inputs were directly paired with subthreshold TMS. We argue that in the leg motor cortex, facilitation of MEP responses from PAS occurred over a large range of interstimulus intervals as a result of the paired activation of sensory inputs with sustained, subthreshold activity of cortical neurons that follow a pulse of suprathreshold TMS. [ABSTRACT FROM AUTHOR]

After chronic spinal injury, motoneurons spontaneously develop two persistent inward currents (PICs): a TTX-sensitive persistent sodium current (sodium PIC) and a nimodipine-sensitive persistent calcium current (calcium PIC). In the present paper, we examined how these PICs contributed to motoneuron firing. Adult rats were spinalized at the S(2) sacral level, and after 2 months intracellular recordings were made from sacrocaudal motoneurons in vitro. The PICs and repetitive firing were measured with slow triangular voltage and current ramps, respectively. The sodium PIC was examined after blocking the calcium PIC with nimodipine (20 microM; n = 12). It was always activated subthreshold, and during current ramps in nimodipine, it produced a sodium plateau that assisted in initiating and maintaining firing (self-sustained firing). The sodium PIC oscillated off and on during firing and helped initiate each spike, and near threshold this caused abnormally slow firing (2.82 +/- 1.21 Hz). A low dose of TTX (0.5 microM) blocked the sodium PIC, sodium plateau, and very slow firing prior to affecting the spike itself. The calcium PIC was estimated as the current blocked by nimodipine or current remaining in TTX (2 microM; n = 13). In 59% of motoneurons, the calcium PIC was activated subthreshold to firing and produced a plateau that assisted in initiating and sustaining firing because nimodipine significantly increased the firing threshold current and decreased the self-sustained firing. In the remaining motoneurons (41%), the calcium PIC was activated suprathreshold to firing and during current ramps did not initially affect firing but eventually was activated and caused an acceleration in firing followed by self-sustained firing, which were blocked by nimodipine. The frequency-current (F-I) slope was 3.0 +/- 1.0 Hz/nA before the calcium PIC activation (primary range), 6.3 +/- 3.6 Hz/nA during the calcium PIC onset (secondary range; acceleration), and 2.1 +/- 1.3 Hz/nA with the calcium PIC steadily activated (tertiary range). Nimodipine eliminated the secondary and tertiary ranges, leaving a linear F-I slope of 3.7 +/- 1.0 Hz/nA. A single low-threshold shock to the dorsal root evoked a many-second-long discharge, the counterpart of a muscle spasm in the awake chronic spinal rat. This long-lasting reflex was caused by the motoneuron PICs because when the activation of the voltage-dependent PICs was prevented by hyperpolarization, the same dorsal root stimulation only produced a brief excitatory postsynaptic potential (<1 s). Both the calcium and sodium PIC were involved because nimodipine only partly reduced the reflex and there remained very slow firing mediated by the sodium PIC. [ABSTRACT FROM AUTHOR]