Increased Motor Neuron Excitability Research Articles

Intrinsic motor neuron excitability is increased after resistance training in older adults.

This study investigated the effects of high-intensity resistance training on estimates of the motor neuron persistent inward current (PIC) in older adults. Seventeen participants (68.5 ± 2.8 yr) completed a 2-wk nonexercise control period followed by 6 wk of resistance training. Surface electromyographic signals were collected with two 32-channel electrodes placed over soleus to investigate motor unit discharge rates. Paired motor unit analysis was used to calculate delta frequency (ΔF) as an estimate of PIC amplitudes during 1) triangular-shaped contractions to 20% of maximum torque capacity and 2) trapezoidal- and triangular-shaped contractions to 20% and 40% of maximum torque capacity, respectively, to understand their ability to modulate PICs as contraction intensity increases. Maximal strength and functional capacity tests were also assessed. For the 20% triangular-shaped contractions, ΔF [0.58-0.87 peaks per second (pps); P ≤ 0.015] and peak discharge rates (0.78-0.99 pps; P ≤ 0.005) increased after training, indicating increased PIC amplitude. PIC modulation also improved after training. During the control period, mean ΔF differences between 20% trapezoidal-shaped and 40% triangular-shaped contractions were 0.09-0.18 pps (P = 0.448 and 0.109, respectively), which increased to 0.44 pps (P < 0.001) after training. Also, changes in ΔF showed moderate to very large correlations (r = 0.39-0.82) with changes in peak discharge rates and broad measures of motor function. Our findings indicate that increased motor neuron excitability is a potential mechanism underpinning training-induced improvements in motor neuron discharge rate, strength, and motor function in older adults. This increased excitability is likely mediated by enhanced PIC amplitudes, which are larger at higher contraction intensities.NEW & NOTEWORTHY Resistance training elicited important alterations in soleus intrinsic motor neuronal excitability, likely mediated by enhanced persistent inward current (PIC) amplitude, in older adults. Estimates of PICs increased after the training period, accompanied by an enhanced ability to increase PIC amplitudes at higher contraction intensities. Our data also suggest that changes in PIC contribution to self-sustained discharging may contribute to increases in motor neuron discharge rates, maximal strength, and functional capacity in older adults after resistance training.

Interfering with lysophosphatidic acid receptor edg2/lpa1 signalling slows down disease progression in SOD1-G93A transgenic mice.

Alterations in excitability represent an early hallmark in Amyotrophic Lateral Sclerosis (ALS). Therefore, deciphering the factors that impact motor neuron (MN) excitability offers an opportunity to uncover further aetiopathogenic mechanisms, neuroprotective agents, therapeutic targets, and/or biomarkers in ALS. Here, we hypothesised that the lipokine lysophosphatidic acid (lpa) regulates MN excitability via the G-protein-coupled receptor lpa1 . Then, modulating lpa1 -mediated signalling might affect disease progression in the ALS SOD1-G93A mouse model. The influence of lpa-lpa1 signalling on the electrical properties, Ca2+ dynamic and survival of MNs was tested in vitro. Expression of lpa1 in cultured MNs and in the spinal cord of SOD1-G93A mice was analysed. ALS mice were chronically treated with a small-interfering RNA against lpa1 (siRNAlpa1 ) or with the lpa1 inhibitor AM095. Motor skills, MN loss, and lifespan were evaluated. AM095 reduced MN excitability. Conversely, exogenous lpa increased MN excitability by modulating task1 'leak' potassium channels downstream of lpa1 . Lpa-lpa1 signalling evoked an excitotoxic response in MNs via voltage-sensitive calcium channels. Cultured SOD1-G93A MNs displayed lpa1 upregulation and heightened vulnerability to lpa. In transgenic mice, lpa1 was upregulated mostly in spinal cord MNs before cell loss. Chronic administration of either siRNAlpa1 or AM095 reduced lpa1 expression at least in MNs, delayed MN death, improved motor skills, and prolonged life expectancy of ALS mice. These results suggest that stressed lpa-lpa1 signalling contributes to MN degeneration in SOD1-G93A mice. Consequently, disrupting lpa1 slows down disease progression. This highlights LPA1 signalling as a potential target and/or biomarker in ALS.

Inverse modulation of motor neuron cellular and synaptic properties can maintain the same motor output

Although often examined in isolation, a single neuromodulator typically has multiple cellular and synaptic effects. Here, we have examined the interaction of the cellular and synaptic effects of 5-HT in the lamprey spinal cord.5-HT reduces the amplitude of glutamatergic synaptic inputs and the slow post-spike afterhyperpolarization (sAHP) in motor neurons. We examined the interaction between these effects using ventral root activity evoked by stimulation of the spinal cord. While 5-HT reduced excitatory glutamatergic synaptic inputs in motor neurons to approximately 60% of control, ventral root activity was not significantly affected. The reduction of the sAHP by 5-HT increased motor neuron excitability by reducing spike frequency adaptation, an effect that could in principle have opposed the reduction of the excitatory synaptic input. Support for this was sought by reducing the amplitude of the sAHP by applying the toxin apamin before 5-HT application. In these experiments, 5-HT reduced the ventral root response, presumably because the reduction of the synaptic input now dominated. This was supported by computer simulations that showed that the motor output could be maintained over a wide range of synaptic input values if they were matched by changes in postsynaptic excitability. The effects of 5-HT on ventral root responses were altered by spinal cord lesions: 5-HT significantly increased ventral root responses in animals that recovered good locomotor function, consistent with a lesion-induced reduction in the synaptic effects of 5-HT, which thus biases its effects to the increase in motor neuron excitability.

Spatiotemporal correlation of spinal network dynamics underlying spasms in chronic spinalized mice.

Spasms after spinal cord injury (SCI) are debilitating involuntary muscle contractions that have been associated with increased motor neuron excitability and decreased inhibition. However, whether spasms involve activation of premotor spinal excitatory neuronal circuits is unknown. Here we use mouse genetics, electrophysiology, imaging and optogenetics to directly target major classes of spinal interneurons as well as motor neurons during spasms in a mouse model of chronic SCI. We find that assemblies of excitatory spinal interneurons are recruited by sensory input into functional circuits to generate persistent neural activity, which interacts with both the graded expression of plateau potentials in motor neurons to generate spasms, and inhibitory interneurons to curtail them. Our study reveals hitherto unrecognized neuronal mechanisms for the generation of persistent neural activity under pathophysiological conditions, opening up new targets for treatment of muscle spasms after SCI.

Post-activation potentiation: The neural effects of post-activation depression.

Our knowledge of the neurophysiology of post-activation potentiation (PAP) is limited. The purpose of this study was to examine the effect of PAP on twitch torque and H-reflex amplitude after a 10-s maximal voluntary contraction (MVC). PAP measurements were assessed with the plantarflexors in a relaxed state and during a tonic contraction at 10% MVC. The H-reflex/maximum M-wave ratio (H/M) decreased significantly (P<0.05) and returned to baseline levels after 1 min. The decrement in H/M was depressed when the plantarflexors were active at 10% MVC, and the depression was more obvious in the lateral gastrocnemius than in the soleus muscle. The inhibition induced immediately after contraction could be attributed to post-activation depression. We conclude that PAP after a 10-s MVC cannot be attributed to increased motor neuron excitability through the reflex pathway as assessed by the H-reflex technique.

Influence of Rest Intervals After Assisted Jumping on Bodyweight Vertical Jump Performance

Assisted jumping (an overspeed concept) is a method used to improve vertical jump performance. However, research is lacking on the optimal program design to maximize performance outcomes. The purpose of this study was to determine the influence of rest intervals after assisted jumping on bodyweight (BW) vertical jumps. Twenty healthy recreationally trained men (age: 22.85 ± 1.84 years; height: 179.44 ± 5.99 cm; mass: 81.73 ± 9.51 kg) attended 5 sessions. For all sessions, subjects performed the same dynamic warm-up and then executed 1 set of 5 consecutive assisted jumps at 30% BW reduction. They then rested for 30 seconds (C30), 1 minute (C1), 2 minutes (C2), or 4 minutes (C4), followed by 3 BW jumps with no assistance. Baseline (CB) jump height was measured without preceding assisted jumps. Analyses of variance revealed a main effect for takeoff velocity, with 1 and 4 minutes being greater than baseline (C1: 3.36 ± 0.40 m·s(-1); C4: 3.27 ± 0.41 m·s(-1); CB: 3.13 ± 0.32 m·s(-1)). Relative peak power also demonstrated a main effect, with 1 minute being greater than all other conditions (C1: 75.22 ± 10.83 W·kg(-1)). Jump height and relative ground reaction force demonstrated no differences between conditions. These results indicate overspeed jumping acutely enhances explosive BW jumping velocity and power. This acute performance enhancement is probably a result of increased motor neuron excitability and motor unit synchronization.

A PI3-Kinase–Mediated Negative Feedback Regulates Neuronal Excitability

Use-dependent downregulation of neuronal activity (negative feedback) can act as a homeostatic mechanism to maintain neuronal activity at a particular specified value. Disruption of this negative feedback might lead to neurological pathologies, such as epilepsy, but the precise mechanisms by which this feedback can occur remain incompletely understood. At one glutamatergic synapse, the Drosophila neuromuscular junction, a mutation in the group II metabotropic glutamate receptor gene (DmGluRA) increased motor neuron excitability by disrupting an autocrine, glutamate-mediated negative feedback. We show that DmGluRA mutations increase neuronal excitability by preventing PI3 kinase (PI3K) activation and consequently hyperactivating the transcription factor Foxo. Furthermore, glutamate application increases levels of phospho-Akt, a product of PI3K signaling, within motor nerve terminals in a DmGluRA-dependent manner. Finally, we show that PI3K increases both axon diameter and synapse number via the Tor/S6 kinase pathway, but not Foxo. In humans, PI3K and group II mGluRs are implicated in epilepsy, neurofibromatosis, autism, schizophrenia, and other neurological disorders; however, neither the link between group II mGluRs and PI3K, nor the role of PI3K-dependent regulation of Foxo in the control of neuronal excitability, had been previously reported. Our work suggests that some of the deficits in these neurological disorders might result from disruption of glutamate-mediated homeostasis of neuronal excitability.

A PI3K-mediated negative feedback regulates Drosophila motor neuron excitability

AbstractNegative feedback can act as a homeostatic mechanism to maintain neuronal activity at a particular specified value. At the Drosophila neuromuscular junction, a mutation in the type II metabotropic glutamate receptor gene (mGluRA) increased motor neuron excitability by disrupting an autocrine, glutamate-mediated negative feedback. We show that mGluRA mutations increase neuronal excitability by preventing PI3 kinase (PI3K) activation and consequently hyperactivating the transcription factor Foxo. Furthermore, glutamate application increases levels of phospho-Akt, a product of PI3K signaling, within motor nerve terminals in an mGluRA-dependent manner. In humans, PI3K and type II mGluRs are implicated in epilepsy, neurofibromatosis, autism, schizophrenia and other neurological disorders; however, neither the link between type II mGluRs and PI3K, nor the role of Foxo in the control of neuronal excitability, had been previously reported. Our work suggests that some of the deficits in these neurological disorders might result from disruption of glutamate-mediated homeostasis of neuronal excitability.

The Drosophila melanogaster translational repressor pumilio regulates neuronal excitability.

Maintenance of proper neuronal excitability is vital to nervous system function and normal behavior. A subset of Drosophila mutants that exhibit altered behavior also exhibit defective motor neuron excitability, which can be monitored with electrophysiological methods. One such mutant is the P-element insertion mutant bemused (bem). The bem mutant exhibits female sterility, sluggishness, and increased motor neuron excitability. The bem P element is located in the large intron of the previously characterized translational repressor gene pumilio (pum). Here, by several criteria, we show that bem is a new allele of pum. First, ovary-specific expression of pum partially rescues bem female sterility. Second, pum null mutations fail to complement bem female sterility, behavioral defects, and neuronal hyperexcitability. Third, heads from bem mutant flies exhibit greatly reduced levels of Pum protein and the absence of two pum transcripts. Fourth, two previously identified pum mutants exhibit neuronal hyperexcitability. Fifth, overexpression of pum in the nervous system reduces neuronal excitability, which is the opposite phenotype to pum loss of function. Collectively, these findings describe a new role of pum in the regulation of neuronal excitability and may afford the opportunity to study the role of translational regulation in the maintenance of proper neuronal excitability.

Hyperreflexia in axonal Guillain–Barré syndrome subsequent to Campylobacter jejuni enteritis

We describe a patient with the acute motor axonal neuropathy (AMAN) form of Guillain–Barré syndrome (GBS), who showed generalized hyperreflexia. A 24-year-old man developed acute paralysis following Campylobacter jejuni enteritis. He showed exaggerated tendon reflexes with abnormal reflex spread to other segments, and was initially diagnosed as having post-infectious myelitis. Nerve conduction studies showed motor axonal degeneration (the AMAN pattern), and increased soleus H-reflex amplitudes. His serum was positive for IgG antibodies to gangliosides GM1b and GalNAc-GD1a. He was treated with plasmapheresis, resulting in rapid recovery. Hyperreflexia was still present 12 months after onset when muscle strength was completely normal. This case provides further evidence that patients with AMAN can develop increased motor neuron excitability, and possible mechanisms for the hyperreflexia are discussed.

Physiologic and Clinical Monitoring of Spastic Hypertonia

Spasticity has been defined as "a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex, as one component of the upper motor neuron syndrome." Increased motor neuron excitability and enhanced stretch-evoked synaptic excitation of motor neurons are potential neurophysiologic mechanisms to explain this phenomenon. The relative contribution of these two distinct mechanisms likely varies depending on the location of the lesion in the central nervous system. The patient history is an important component of the clinical evaluation focusing on potential nociceptive inputs that can worsen spasticity (e.g., urinary tract infections, skin breakdown). Assessment of the impact of the spasticity on function (positive and negative), position, care of the patient, and pain should be pursued. Clinical examination of spasticity is performed using methods to evoke and quantify spastic reflex responses to muscle stretch stimuli and to observe the patient performing functional tasks to note the impact of spasticity on their performance. Treatment is based on the negative impact of the spasticity on the patient, severity of the problems, and whether the hypertonicity is focal or diffuse in distribution (see article by Elovic elsewhere in this issue). First-line treatments include elimination of nociceptive stimuli, range of motion, seating and positioning, and other physical modalities. If additional intervention is necessary, oral medications are implemented for widespread spasticity, whereas focal problems are treated with prolonged stretching and splinting or casting to maintain muscle stretch and optimal positioning. In more severe cases, invasive procedures may be needed to supplement other treatments. Neurolytic procedures are pursued for focal tone problems. For generalized hypertonicity, intrathecal pump administration of medications or surgical interruption of reflex pathways has been helpful. Ultimately, the clinician must systematically approach the evaluation and treatment of spasticity. As decisions regarding moving from less to more invasive treatments are discussed, the potential risks and side effects of treatment options must be weighed versus the potential benefits that the patient might receive to maintain a rational approach to the management of spasticity.

Hyperreflexia in Guillain-Barré syndrome: relation with acute motor axonal neuropathy and anti-GM1 antibody

OBJECTIVESTo investigate the incidence of hyperreflexia in patients with Guillain-Barré syndrome (GBS), and its relation with electrodiagnosis of acute motor axonal neuropathy (AMAN), antiganglioside GM1 antibody, and Campylobacter jejuni infection....