Motoneuron Excitability Research Articles

Acute effects of quadriceps muscle versus tendon prolonged local vibration on force production capacities and central nervous system excitability.

The present study aimed to directly compare the effects of 30min muscle (VIBmuscle) vs. tendon (VIBtendon) local vibration (LV) to the quadriceps on maximal voluntary isometric contraction (MVIC) and rate of torque development (RTD) as well as on central nervous system excitability (i.e. motoneuron and cortical excitability). Before (PRE) and immediately after (POST) LV applied to the quadriceps muscle or its tendon, we investigated MVIC and RTD (STUDY #1; n = 20) or vastus lateralis (VL), vastus medialis (VM) and rectus femoris (RF) electromyography responses to thoracic electrical stimulation (TMEPs; motoneuron excitability) and transcranial magnetic stimulation (MEPs; corticospinal excitability) (STUDY #2; n = 17). MEP/TMEP ratios were further calculated to quantify changes in cortical excitability. MVIC decreased at POST (P = 0.017) without any difference between VIBtendon and VIBmuscle, while RTD decreased for VIBtendon (P = 0.013) but not VIBmuscle. TMEP amplitudes were significantly decreased for all muscles (P = 0.014, P < 0.001 and P = 0.004 for VL, VM and RF, respectively) for both LV sites. While no changes were observed for MEP amplitude, MEP/TMEP ratios increased at POST for VM and RF muscles (P = 0.009 and P = 0.013, respectively) for both VIBtendon and VIBmuscle. The present results suggest that prolonged muscle and tendon LV are similarly effective in modulating central nervous system excitability and decreasing maximal force. Yet, altered explosive performance after tendon but not muscle LV suggests greater neural alterations when tendons are vibrated.

Enhanced availability of serotonin limits muscle activation during high-intensity, but not low-intensity, fatiguing contractions.

Serotonin (5-HT) modulates motoneuron excitability during muscle contractions, where the release of 5-HT in the central nervous system (CNS) is linked to the intensity of physical activity. Although there is evidence that enhanced availability of 5-HT can exacerbate fatigue, these effects on the development of fatigue during different contraction intensities are largely unknown. The purpose of this study was to investigate how enhanced 5-HT availability affects voluntary muscle activation and corticospinal excitability during fatigue-inducing contractions. Two experiments were performed. In the first experiment (n = 11), 12 isometric elbow flexions at 20% maximal voluntary contractions (MVCs) were performed for 2 min each with 40-s rest periods. In the second experiment (n = 14), 12 maximal isometric elbow flexions were held for 10 s each with 40-s rest periods. In both experiments, the selective serotonin reuptake inhibitor (20-mg paroxetine), or a placebo, was administered in a two-way crossover design. Muscle responses to transcranial magnetic stimulation (TMS) of the motor cortex (both experiments 1 and 2), as well as motor point stimulation of the elbow flexors (experiment 2) were assessed. Paroxetine reduced both motor cortical (P = 0.018) and motor point voluntary activation (P = 0.036) during the maximal contraction protocol. Paroxetine also reduced exercise-induced lengthening of the TMS silent period during the submaximal (P = 0.037) and maximal (P = 0.002) contraction protocols. Activation of inhibitory 5-HT1A receptors on motoneurons likely exacerbated exercise-induced reductions in voluntary drive to the elbow flexors. However, 5-HT modulation of motor activity also appeared at the supraspinal level.NEW & NOTEWORTHY As serotonin release onto motoneurons may be scaled to the strength of muscle contraction, it may have different effects when neuromuscular fatigue is induced by contractions of different intensities. Enhanced levels of serotonin compromised voluntary activation of muscle when fatigue was induced by strong contractions but not weak contractions. This provides evidence that the serotonergic system has the greatest influence on fatigue that is generated with high neural drive to the target muscle.

The effects of membrane potential oscillations on the excitability of rat hypoglossal motoneurons.

Oscillations in membrane potential induced by synaptic inputs and intrinsic ion channel activity play a role in regulating neuronal excitability, but the precise mechanisms underlying their contributions remain largely unknown. Here we used electrophysiological and modeling approaches to investigate the effects of Gaussian white noise injected currents on the membrane properties and discharge characteristics of hypoglossal (HG) motoneurons in P16-21 day old rats. We found that the noise-induced membrane potential oscillations facilitated spike initiation by hyperpolarizing the cells’ voltage threshold by 3.1 ± 1.0 mV and reducing the recruitment current for the tonic discharges by 0.26 ± 0.1 nA, on average (n = 59). Further analysis revealed that the noise reduced both recruitment and decruitment currents by 0.26 ± 0.13 and 0.33 ± 0.1 nA, respectively, and prolonged the repetitive firing. The noise also increased the slopes of frequency-current (F-I) relationships by 1.1 ± 0.2 Hz/nA. To investigate the potential mechanisms underlying these findings, we constructed a series of HG motoneuron models based on their electrophysiological properties. The models consisted of five compartments endowed with transient sodium (NaT), delayed-rectify potassium [K(DR)], persistent sodium (NaP), calcium-activated potassium [K(AHP)], L-type calcium (CaL) and H-current channels. In general, all our experimental results could be well fitted by the models, however, a modification of standard Hodgkin-Huxley kinetics was required to reproduce the changes in the F-I relationships and the prolonged discharge firing. This modification, corresponding to the noise generated by the stochastic flicker of voltage-gated ion channels (channel flicker, CF), was an adjustable sinusoidal function added to kinetics of the channels that increased their sensitivity to subthreshold membrane potential oscillations. Models with CF added to NaP and CaL channels mimicked the noise-induced alterations of membrane properties, whereas models with CF added to NaT and K(DR) were particularly effective in reproducing the noise-induced changes for repetitive firing observed in the real motoneurons. Further analysis indicated that the modified channel kinetics enhanced NaP- and CaL-mediated inward currents thus increasing the excitability and output of HG motoneurons, whereas they produced relatively small changes in NaT and K(DR), thus balancing these two currents and triggering variability of repetitive firing. This study provided insight into the types of membrane channel mechanisms that might underlie oscillation-induced alterations of neuronal excitability and motor output in rat HG motoneurons.

The effects of loperamide on excitatory and inhibitory neuromuscular function in the human colon.

In most animal species, opioids alter colonic motility via the inhibition of excitatory enteric motor neurons. The mechanisms by which opioids alter human colonic motility are unclear. The aim of this study was to describe the effects of loperamide on neuromuscular function in the human colon. Tissue specimens of human colon from 10 patients undergoing an anterior resection were divided into three inter-taenial circular muscle strips. Separate organ baths were used to assess: (1) excitatory transmission (selective blockade of inhibitory transmission: L-NOARG/MRS2179); (2) inhibitory transmission (selective blockade of excitatory transmission: hyoscine hydrobromide); and (3) a control bath (no drug additions). Neuromuscular function was assessed using force transducer recordings and electrical field stimulation (EFS; 20 V, 10Hz, 0.5ms, 10 s) prior to and following loperamide and naloxone. In human preparations with L-NOARG/MRS2179, loperamide had no significant effects on isometric contractions. In preparations with hyoscine hydrobromide, loperamide reduced isometric relaxation during EFS (median difference +0.60 g post-loperamide, Z=-2.35, p=0.019). Loperamide had no effect on excitatory neuromuscular function in human colonic circular muscle. These findings suggest that loperamide alters colonic function by acting primarily on inhibitory motor neurons, premotor enteric neurons, or via alternative non-opioid receptor pathways.

Differences in motor imagery strategy change behavioral outcome

Kinesthetic motor imagery (KMI) involves imagining the feeling and experience of movements. We examined the effects of KMI, number visualizing, and KMI with number visualizing on the excitability of spinal motor neurons and a behavioral outcome measure in a pinch force task. Healthy participants (13 men and 8 women; mean age: 24.8 ± 5.5 years) were recruited. We compared the F-waves of the left thenar muscles after stimulating the left median nerve at the wrist during each motor imagery condition after a practice session. The KMI condition consisted of imagining muscle contraction, the number visualizing condition consisted of imagining the pinch force increasing numerically, and the KMI with number visualizing consisted of alternating between the KMI and imagining the pinch force increasing numerically. Before and after motor imagery, the time required to adjust to the target pinch force was compared. The time required to adjust the pinch force was shorter in the KMI with number visualizing condition than in the KMI and number visualizing conditions. There was no difference in the F/M amplitude ratio between each MI strategy condition, indicating the excitability of spinal motor neurons. Numerical information helped to improve the ability of participants to perform KMI.

Monosynaptic facilitation of flexor digitorum superficialis motoneurons mediated by Group Ia afferents from the extensor carpi radialis in humans.

Wrist position is known to affect the grip strength. We focused on the spinal reflex arc, which would support the movement, and investigated the effects of low-threshold afferents from the extensor carpi radialis (ECR) on the excitability of the flexor digitorum superficialis (FDS) motoneurons using the post-stimulus time-histogram (PSTH) and electromyogram-averaging (EMG-A) methods. Electrical conditioning stimulation of an intensity below the motor threshold was applied to the radial nerve branch innervating the ECR. In the PSTH study, changes in the firing probability of single motor units after electrical conditioning stimulation were investigated in seven subjects. An early and significant peak (increase in the firing probability: facilitation) was recorded for 36/60 FDS motor units. The remaining 24 motor units did not show any effects. Weak mechanical conditioning stimulation of the ECR muscle belly induced a similar peak. The central latency of the facilitation was equivalent to that of the homonymous monosynaptic facilitation. In the EMG-A study, changes in the rectified and averaged electromyograms of FDS induced by conditioning stimulation were examined in 12 subjects. An early and significant peak (facilitation) was induced by both electrical and mechanical conditioning stimulations. The facilitation decreased after withdrawal of the vibration to the ECR muscle belly. The facilitation was never induced by cutaneous nerve stimulation in the PSTH and EMG-A studies. These findings suggest that Group Ia afferents from the ECR increase the excitability of FDS motoneurons through a monosynaptic path in the spinal cord. These reflex arcs likely facilitate hand grasping movements.

Acute retigabine-induced effects on myelinated motor axons in amyotrophic lateral sclerosis.

Altered motor neuron excitability in patients with amyotrophic lateral sclerosis (ALS) has been suggested to be an early pathophysiological mechanism associated with motor neuron death. Compounds that affect membrane excitability may therefore have disease‐modifying effects. Through which mechanism(s), these compounds modulate membrane excitability is mostly provided by preclinical studies, yet remains challenging to verify in clinical studies. Here, we investigated how retigabine affects human myelinated motor axons by applying computational modeling to interpret the complex excitability changes in a recent trial involving 18 ALS patients. Compared to baseline, the post‐dose excitability differences were modeled well by a hyperpolarizing shift of the half‐activation potential of slow potassium (K+)‐channels (till 2 mV). These findings verify that retigabine targets slow K+‐channel gating and highlight the usefulness of computational models. Further developments of this approach may facilitate the identification of early target engagement and ultimately aid selecting responders leading to more personalized treatment strategies.

Detecting motor unit abnormalities in amyotrophic lateral sclerosis using high-density surface EMG

ObjectiveThe purpose of this study was to detect specific motor unit (MU) abnormalities in people with amyotrophic lateral sclerosis (ALS) compared to controls using high-density surface electromyography (HD-SEMG). MethodsSixteen people with ALS and 16 control subjects. The participants performed ramp up and sustained contractions at 30% of their maximal voluntary contraction. HD-SEMG signals were recorded in the vastus lateralis muscle and decomposed into individual MU firing behavior using a convolution blind source separation method. ResultsIn total, 339 MUs were detected (people with ALS; n = 93, control subjects; n = 246). People with ALS showed significantly higher mean firing rate, recruitment threshold, coefficient of variation of the MU firing rate, MU firing rate at recruitment, and motoneurons excitability than those of control subjects (p < 0.001). The number of MU, MU firing rate, recruitment threshold, and MU firing rate at recruitment were significantly correlated with disease severity (p < 0.001). Multivariable analysis revealed that an increased MU firing rate at recruitment was independently associated with ALS. ConclusionsThese results suggest increased excitability at recruitment, which is consistent with neurodegeneration results in a compensatory increase in MU activity. SignificanceAbnormal MU firing behavior provides an important physiological index for understanding the pathophysiology of ALS.

Altered excitability of motor neuron pathways after stroke: more than upper motor neuron impairments

BackgroundPrevious studies have suggested that impairment occurs in the lower motor neuron (LMN) pathway after stroke, but more research remains to be supported.ObjectiveIn this study, we tested the hypotheses: (1)...

Combined effects of dry needling and exercises therapy on muscle spasticity and motor function in chronic stroke: a pretest-posttest pilot study

Aim: Spasticity is one of the most common symptoms in post-stroke patients. Dry needling (DN) is a relatively new method for the management of muscle spasticity. A multimodal treatment may be more effective in spasticity management. The purpose of this study was to explore the short-term combined effects of DN and exercise therapy on wrist flexor spasticity, motor function, and motor neuron excitability in patients with chronic stroke. Methods: Ten patients with stroke and a mean age of 52 ± 4.9 years participated in this pretest-posttest pilot study. Patients received four sessions of DN and exercise therapy. Affected flexor carpi radialis and flexor carpi ulnaris muscles were needled each for 1 min. Patients underwent exercise therapy for about 30 min, once a week after DN. The outcome measures were the Modified Modified Ashworth Scale (MMAS), the maximal amplitude of H wave/maximal amplitude of M wave ratio (Hmax/Mmax Ratio), H-reflex latency, wrist extension active and passive range of motion (ROM), Action Research Arm Test (ARAT), and Fugl-Meyer Assessment (FMA). Assessments were performed at baseline, after four sessions of treatment, and three weeks after treatment. Results: After treatment, significant improvements in MMAS, wrist passive ROM, ARAT, and FMA were obtained (P ≤ 0.05). Conclusions: DN combined with exercise therapy improved muscle spasticity and motor function in patients with chronic stroke. Further investigations with a randomized controlled trial design with a comparator group of DN only are warranted (https://www.irct.ir/; IRCT ID: IRCT20180611040061N1).

The control and training of single motor units in isometric tasks are constrained by a common input signal.

Recent developments in neural interfaces enable the real-time and non-invasive tracking of motor neuron spiking activity. Such novel interfaces could provide a promising basis for human motor augmentation by extracting potentially high-dimensional control signals directly from the human nervous system. However, it is unclear how flexibly humans can control the activity of individual motor neurons to effectively increase the number of degrees of freedom available to coordinate multiple effectors simultaneously. Here, we provided human subjects (N = 7) with real-time feedback on the discharge patterns of pairs of motor units (MUs) innervating a single muscle (tibialis anterior) and encouraged them to independently control the MUs by tracking targets in a 2D space. Subjects learned control strategies to achieve the target-tracking task for various combinations of MUs. These strategies rarely corresponded to a volitional control of independent input signals to individual MUs during the onset of neural activity. Conversely, MU activation was consistent with a common input to the MU pair, while individual activation of the MUs in the pair was predominantly achieved by alterations in de-recruitment order that could be explained by history-dependent changes in motor neuron excitability. These results suggest that flexible MU recruitment based on independent synaptic inputs to single MUs is unlikely, although de-recruitment might reflect varying inputs or modulations in the neuron's intrinsic excitability.

The influence of experimental low back pain on neural networks involved in the control of lumbar erector spinae muscles.

Low back pain (LBP) often modifies spine motor control, but the neural origin of these motor control changes remains largely unexplored. This study aimed to determine the impact of experimental low back pain on the excitability of cortical, subcortical, and spinal networks involved in the control of back muscles. Thirty healthy subjects were recruited and allocated to pain (capsaicin and heat) or control (heat) groups. Corticospinal excitability (motor-evoked potential; MEP) and intracortical networks were assessed by single- and paired-pulse transcranial magnetic stimulation, respectively. Electrical vestibular stimulation was applied to assess vestibulospinal excitability (vestibular MEP; VMEP) and the stretch reflex for excitability of the spinal or supraspinal loop (R1 and R2, respectively). Evoked back motor responses were measured before, during, and after pain induction. Nonparametric rank-based ANOVA determined if pain modulated motor neural networks. A decrease of R1 amplitude was present after the pain disappearance (P = 0.01) whereas an increase was observed in the control group (P = 0.03) compared with the R1 amplitude measured at prepain and preheat period, respectively (group × time interaction, P < 0.001). No difference in MEP and VMEP amplitude was present during and after pain (P > 0.05). During experimental LBP, no change in cortical, subcortical, or spinal networks was observed. After pain disappearance, the reduction of the R1 amplitude without modification of MEP and VMEP amplitude suggests a reduction in spinal excitability potentially combined with an increase in descending drives. The absence of effect during pain needs to be further explored.NEW & NOTEWORTHY In the presence of experimental low back pain, spinal, subcortical, and cortical motor networks involved in the control of back muscles were not modified. However, once the pain disappeared, a reduction in motoneuronal excitability was observed without change in corticospinal and vestibulospinal excitability, suggesting a reduction in descending drive. Experimental low back pain may elicit long-term plasticity even after pain extinction.

Soleus H and Lower Limb Posterior Root Muscle Reflexes During Stepping After Incomplete SCI.

The goal of this study was to examine and compare the step cycle related modulation of the soleus H and posterior root muscle (PRM) reflexes in subjects with and without spinal cord injury. Ten subjects without neurological injury and fifteen subjects with spinal cord injury (SCI) underwent soleus H reflex and lower limb PRM reflex testing while standing and stepping in a robotic gait orthosis. Reflex amplitudes were evaluated during standing, mid stance and mid swing to determine if speed and/or injury altered step cycle related neuromodulation. H and PRM reflexes in the soleus underwent step cycle related modulation in injured and uninjured subjects though the degree of modulation differed between the two reflexes with the H reflex showing more step cycle related modulation. We found in the SCI group that both the soleus H and soleus PRM reflex amplitudes were higher relative to the non-injured group and modulated less during the step cycle. We also found that modulation of the soleus H reflex, but not soleus PRM reflex, correlated to the lower extremity motor scores in individuals with SCI. Our evidence suggests that the inability to provide appropriate step cycle related reflex modulation may be due to decreased supra-spinal regulation of motoneuron and spinal excitability and could be an indicator of the severity of injury as it relates to clinically measured lower extremity motor scores.

Effects of different modalities of afferent stimuli of the lumbo-sacral area on control of lumbar paravertebral muscles.

Somatosensory feedback to the central nervous system is essential to plan, perform and refine spine motor control. However, the influence of somatosensory afferent input from the trunk on the motor output to trunk muscles has received little attention. The objective was to compare the effects of distinct modalities of afferent stimulation on the net motoneuron and corticomotor excitability of paravertebral muscles. Fourteen individuals were recruited. Modulation of corticospinal excitability (motor-evoked potential [MEP]) of paravertebral muscles was measured when afferent stimuli (cutaneous noxious and non-noxious, muscle contraction) were delivered to the trunk at 10 intervals prior to transcranial magnetic stimulation. Each peripheral stimulation was applied alone, and subsequent electromyography (EMG) modulation was measured to control for net motoneuron excitability. MEP modulation and MEP/EMG ratio were used as measures of corticospinal excitability with and without control of net motoneuron excitability, respectively. MEP and EMG modulation were smaller after evoked muscle contraction than after cutaneous noxious and non-noxious stimuli. MEP/EMG ratio was not different between stimulation types. Both MEP and EMG amplitudes were reduced after evoked muscle contraction, but not when expressed as MEP/EMG ratio. Noxious and non-noxious stimulation had limited impact on all variables. Distinct modalities of peripheral afferent stimulation of the lumbo-sacral area differently modulated responses of paravertebral muscles, but without an influence on corticospinal excitability with control of net motoneuron excitability. Muscle stimulation reduced paravertebral activity and was best explained by spinal mechanisms. The impact of afferent stimulation on back muscles differs from the effects reported for limb muscles.

Effects of dry needling and exercise therapy on post-stroke spasticity and motor function– protocol of randomized clinical trial

BackgroundSpasticity is one of the most common problems after the first stroke. Dry needling (DN) has been presented as a new therapeutic approach used by physiotherapists for the management of post-stroke spasticity. This study aimed to determine whether the addition of exercise therapy to the DN results in better outcomes in wrist flexors spasticity, motor neuron excitability, motor function and range of motion (ROM) in patients with chronic stroke. MethodsWe will use a single-blind randomized controlled trial (RCT) in accordance with the CONSORT guidelines. A total of 24 patients with stroke will be included from the University Rehabilitation Clinics. The outcome measures will include Modified Modified Ashworth Scale, Hmax/Mmax ratio, H-reflex latency, Action Research Arm Test, Fugl-Meyer Assessment, and wrist extension active and passive range of motion. Patients in the DN and exercise therapy group will undergo 4 sessions of deep DN in flexor carpi radialis and flexor carpi ulnaris muscles on the affected upper limb and exercise therapy. Participants in the DN group will only receive DN for target muscles. Clinical and neurophysiological tests will be performed at baseline, after four therapy sessions, and at three weeks’ follow-up. DiscussionThis study will provide evidence for additional effects of exercise therapy to DN in comparison to DN alone on wrist flexors spasticity, motor neuron excitability, upper-limb motor function, and ROM in patients with chronic stroke.

Advanced Technology or Manual Skills: Evidence That The Accuracy of Corticospinal Responsiveness Is Not Ameliorated by Neuronavigation

PurposeTranscranial magnetic stimulation (TMS) is a noninvasive technique to assess corticospinal excitability and inhibition. TMS over the motor cortex during a voluntary contraction elicits short‐latency excitatory (motor‐evoked potential, MEP) and inhibitory (silent period, SP) responses in the target muscle. However, the technique for searching and determining the optimal site to elicit MEPs (“hotspot”), an essential component in order to correctly place the TMS coil, is not unanimously standardized. This can be a problem since changes in coil position and/or orientation may influence the magnitude of MEP and SP responses. Usually, the “hotspot” is marked either on a swim cap or on the scalp and the investigator holds the coil manually during the entire testing session. However, the capacity to maintain the coil placement within and between sessions may be limited. To reduce variability in coil position and orientation in space and over time, neuronavigated TMS (nTMS) is used. However, no studies investigated the accuracy of the assessment of corticospinal excitability and inhibition using nTMS versus a traditional manual approach for the maintenance of coil positioning.Methods18 healthy participants (10W/8M) volunteered in two identical and randomized sessions ~30 days apart. Maximal and submaximal neuromuscular evaluations were performed with TMS six times before (PRE), and at the end (POST) of a 2‐min sustained maximal voluntary isometric contraction (MVIC) (100%, 75%, 50% MVIC and 25%isoEMG). The “hotspot” was maintained either with a grid demarcated on the participants’ scalp or with visual feedback provided by nTMS on a computer screen. In both sessions, “hotspot” was considered as the site where the largest MEPs in the rectus femoris were elicited.ResultsThere were not a “hotspot” technique × contraction intensities × time points interactions for both MEP (P = 0.217) and SP (P = 0.627). Bland‐Altman plots display adequate agreements between the difference in the two “hotspot” techniques and the means of the two “hotspot” techniques. The slopes of the resulting regression lines were not significantly different from zero (horizontal to x‐axis) for both MEP (all r ≤ 0.335, all P ≥ 0.162) and SP (all r ≤ 0.382, all P ≥ 0.131), indicating a uniformity of systematic error at all contraction intensities and time points.ConclusionsSpatial stability of the TMS coil position over the motor cortex did not influence corticospinal excitability and inhibition responses in unfatigued and fatigued knee extensors. This is because the variability in MEP and SP responses is due to spontaneous fluctuations in corticospinal and motoneuron excitability and inhibition; and this variability is not affected by spatial accuracy. Therefore, nTMS or a traditional manual approach could be interchangeably use in order to maintain the TMS coil position in the exact “hotspot”.

Role of the Dopamine Subtype 1 Receptor (D1R) Modulation of the Ih Current in Rhythmic Spinal Mammalian Motor Networks

Restless Legs Syndrome (RLS) is a chronic sensorimotor disorder that has been recently associated with decreased expression of inhibitory Gi‐coupled adenosine A1 receptors (A1Rs), leading to increased dopamine release (hyperdopaminergic signaling) within the central nervous system. Previous studies have shown that A1Rs specifically inhibit the Gs‐coupled dopamine D1 receptor (D1R) subtype through a functional A1R‐D1R heteromer receptor complex. Furthermore, D1Rs control spinal motor neuron (MN) excitability by increasing cyclic adenosine monophosphate (cAMP) concentration and opening hyperpolarization‐activated cyclic nucleotide‐gated non‐selective cation channel (HCN). This finding raises the possibility of increased HCN activity underlying some of the motor dysfunctions associated with periodic leg movements (PLMS) during sleep in RLS. Thus, this study aims to elucidate the importance of the D1 receptor subtype on modulating the hyperpolarization‐activated cation current (Ih) in spinal mammalian motor networks. I hypothesized that blocking Ih in the presence of a D1R agonist (enhanced dopaminergic modulation) would slow locomotor activity and disrupt MN bursting stability. Neonatal (P0‐P5; n = 7) mouse spinal cord preparations were used to measure MN bursting activity patterns including amplitude, duration, and cycle period of extracellular ventral root (L2 and L5) recordings via suction electrodes. Treatment conditions include serotonin (9‐15 μM 5‐HT) and N‐methyl‐D‐aspartate (6 μM NMDA) with and without a D1R agonist (10 μM SKF38393) to assess the effect of D1R on rhythmic bursting. Subsequently, an Ih blocker (1 μM ZD7288) was added to observe the importance of Ih in modulating MN burst activity. For both L2 and L5 roots, blocking the Ih current led to increases in burst amplitude, duration, and cycle period in respect to the control 5‐HT/NMDA condition. Our results propose that D1Rs play a significant role in modulating Ih by increasing cAMP levels and opening HCN1 channels at a more depolarized membrane potential. Future experiments involve: 1) using TM5 transmembrane disrupting peptide to disrupt A1R‐D1R heteromers in spinal MNs (and use TM7 as a negative control) to confirm if dopamine modulation of Ih activity is linked to the A1R‐D1R heteromer complexes and 2) applying adenyl cyclase activators and blockers to verify that the modulation of the Ih current is through the D1R‐mediated Gs second messenger pathway.

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.

Propulsive colonic contractions are mediated by inhibition-driven poststimulus responses that originate in interstitial cells of Cajal

The peristaltic reflex is a fundamental behavior of the gastrointestinal (GI) tract in which mucosal stimulation activates propulsive contractions. The reflex occurs by stimulation of intrinsic primary afferent neurons with cell bodies in the myenteric plexus and projections to the lamina propria, distribution of information by interneurons, and activation of muscle motor neurons. The current concept is that excitatory cholinergic motor neurons are activated proximal to and inhibitory neurons are activated distal to the stimulus site. We found that atropine reduced, but did not block, colonic migrating motor complexes (CMMCs) in mouse, monkey, and human colons, suggesting a mechanism other than one activated by cholinergic neurons is involved in the generation/propagation of CMMCs. CMMCs were activated after a period of nerve stimulation in colons of each species, suggesting that the propulsive contractions of CMMCs may be due to the poststimulus excitation that follows inhibitory neural responses. Blocking nitrergic neurotransmission inhibited poststimulus excitation in muscle strips and blocked CMMCs in intact colons. Our data demonstrate that poststimulus excitation is due to increased Ca2+ transients in colonic interstitial cells of Cajal (ICC) following cessation of nitrergic, cyclic guanosine monophosphate (cGMP)-dependent inhibitory responses. The increase in Ca2+ transients after nitrergic responses activates a Ca2+-activated Cl− conductance, encoded by Ano1, in ICC. Antagonists of ANO1 channels inhibit poststimulus depolarizations in colonic muscles and CMMCs in intact colons. The poststimulus excitatory responses in ICC are linked to cGMP-inhibited cyclic adenosine monophosphate (cAMP) phosphodiesterase 3a and cAMP-dependent effects. These data suggest alternative mechanisms for generation and propagation of CMMCs in the colon.

Locomotor Exercise Enhances Supraspinal Control of Lower-Urinary-Tract Activity to Improve Micturition Function after Contusive Spinal-Cord Injury.

The recovery of lower-urinary-tract activity is a top priority for patients with spinal-cord injury. Historically, locomotor training improved micturition function in both patients with spinal cord injury and animal models. We explore whether training augments such as the supraspinal control of the external urethral sphincter results in enhanced coordination in detrusor-sphincter activity. We implemented a clinically relevant contusive spinal-cord injury at the 12th thoracic level in rats and administered forced wheel running exercise for 11 weeks. Awake rats then underwent bladder cystometrogram and sphincter electromyography recordings to examine the micturition reflex. Subsequently, pseudorabies-virus-encoding red fluorescent protein was injected into the sphincter to trans-synaptically trace the supraspinal innervation of Onuf’s motoneurons. Training in the injury group reduced the occurrence of bladder nonvoiding contractions, decreased the voiding threshold and peak intravesical pressure, and shortened the latency of sphincter bursting during voiding, leading to enhanced voiding efficiency. Histological analysis demonstrated that the training increased the extent of spared spinal-cord tissue around the epicenter of lesions. Compared to the group of injury without exercise, training elicited denser 5-hydroxytryptamine-positive axon terminals in the vicinity of Onuf’s motoneurons in the cord; more pseudorabies virus-labeled or c-fos expressing neurons were detected in the brainstem, suggesting the enhanced supraspinal control of sphincter activity. Thus, locomotor training promotes tissue sparing and axon innervation of spinal motoneurons to improve voiding function following contusive spinal-cord injury.