Peripheral Nerve Motor Axons Research Articles

Blockage of neuromuscular glutamate receptors impairs reinnervation following nerve crush in adult mice.

Motor axons in peripheral nerves are capable of regeneration following injury. However, complete recovery of motor function is rare, particularly when reinnervation is delayed. We have previously found that glutamate receptors play a crucial role in the successful innervation of muscle during mouse development. In particular, blocking N-methyl-D-aspartate (NMDA) receptor activity delays the normal elimination of excess innervation of each neuromuscular junction. Here, we use behavioral, immunohistochemical, electrophysiological, and calcium imaging methods to test whether glutamate receptors play a similar role in the transition from polyneuronal to mono-innervation and in recovery of function following peripheral nerve injury in mature muscle.

Guillain-Barré Syndrome Variant presenting as Acute Descending Paralysis in Diabetes

Guillain-Barré Syndrome (GBS) is an acute monophasic immune-mediated polyradiculopathy. Neuropathic or radicular pain and dysautonomia are common features in all forms of GBS. Phenotypic variants are hypothesized to be mediated by molecular mimicry targeting peripheral nerve motor axons, with resulting weakness deviating from the classic symmetric “ascending” pattern. Weakness can range from mild to severe flaccid quadriplegia and respiratory failure within days of onset. Urinary retention and gastrointestinal dysfunction are seen in approximately 5% of variant cases. A spectrum of clinical features necessitates the use of laboratory testing and diagnostic modalities to exclude mimics and confirm a diagnosis of GBS. A high clinical suspicion must exist as GBS responds to treatment with plasmapheresis or IVIG. Our patient embodied both a diagnostically challenging presentation and clinical response consistent with variant GBS.

Control of Dynamic Limb Motion Using Fatigue-Resistant Asynchronous Intrafascicular Multi-Electrode Stimulation.

Asynchronous intrafascicular multi-electrode stimulation (aIFMS) of small independent populations of peripheral nerve motor axons can evoke selective, fatigue-resistant muscle forces. We previously developed a real-time proportional closed-loop control method for aIFMS generation of isometric muscle force and the present work extends and adapts this closed-loop controller to the more demanding task of dynamically controlling joint position in the presence of opposing joint torque. A proportional-integral-velocity controller, with integrator anti-windup strategies, was experimentally validated as a means to evoke motion about the hind-limb ankle joint of an anesthetized feline via aIFMS stimulation of fast-twitch plantar-flexor muscles. The controller was successful in evoking steps in joint position with 2.4% overshoot, 2.3-s rise time, 4.5-s settling time, and near-zero steady-state error. Controlled step responses were consistent across changes in step size, stable against external disturbances, and reliable over time. The controller was able to evoke smooth eccentric motion at joint velocities up to 8 deg./s, as well as sinusoidal trajectories with frequencies up to 0.1 Hz, with time delays less than 1.5 s. These experiments provide important insights toward creating a robust closed-loop aIFMS controller that can evoke precise fatigue-resistant motion in paralyzed individuals, despite the complexities introduced by aIFMS.

Do We Have a Channel Solution for ALS?

Amyotrophic lateral sclerosis (ALS) is a dreadful degenerative disorder, characterized by rapidly progressing weakness causing respiratory impairment and death, in spite of moderate benefits from non-invasive ventilation, gastrostomy, riluzole treatment and multidisciplinary care (Andersen et al., 2012). Over the years a large of number of drugs have been tested to deal with this disorder, but all trials have been negative except for riluzole. We can observe that different strategies have been explored in the past, from immunosuppression to neuroprotection, from nerve growth factors to antiglutamatergic compounds (de Carvalho et al., 2005). Threshold tracking has been used to investigate axonal excitability in peripheral nerve motor axons in ALS (Vucic and Kiernan, 2006). Increased persistent Na+ conductance and reduced K+ conductance have been described (Vucic and Kiernan, 2006), which tend to become more marked with disease duration and may be a predictor of survival (Cheah et al., 2012). More recently, it has been suggested that motor neurons have an abnormal function of the membrane ion channels, in ALS (Devlin et al., 2015). These observations have opened a new window of opportunity in clinical trials for ALS, for testing drugs that modulate ion channels in order to stabilize membranes.

Lack of motor recovery after prolonged denervation of the neuromuscular junction is not due to regenerative failure.

Motor axons in peripheral nerves have the capacity to regenerate after injury. However, full functional motor recovery rarely occurs clinically, and this depends on the nature and location of the injury. Recent preclinical findings suggest that there may be a time after nerve injury where, while regrowth to the muscle successfully occurs, there is nevertheless a failure to re-establish motor function, suggesting a possible critical period for synapse reformation. We have now examined the temporal and anatomical determinants for the re-establishment of motor function after prolonged neuromuscular junction (NMJ) denervation in rats and mice. Using both sciatic transection-resuture and multiple nerve crush models in rats and mice to produce prolonged delays in reinnervation, we show that regenerating fibres reach motor endplates and anatomically fully reform the NMJ even after extended periods of denervation. However, in spite of this remarkably successful anatomical regeneration, after 1 month of denervation there is a consistent failure to re-establish functional recovery, as assessed by behavioural and electrophysiological assays. We conclude that this represents a failure in re-establishment of synaptic function, and the possible mechanisms responsible are discussed, as are their clinical implications.

Mutant HSPB1 overexpression in neurons is sufficient to cause age-related motor neuronopathy in mice

The small heat shock protein HSPB1 is a multifunctional, α-crystallin-based protein that has been shown to be neuroprotective in animal models of motor neuron disease and peripheral nerve injury. Missense mutations in HSPB1 result in axonal Charcot–Marie–Tooth disease with minimal sensory involvement (CMT2F) and distal hereditary motor neuropathy type 2 (dHMN-II). These disorders are characterized by a selective loss of motor axons in peripheral nerve resulting in distal muscle weakness and often severe disability. To investigate the pathogenic mechanisms of HSPB1 mutations in motor neurons in vivo, we have developed and characterized transgenic PrP-HSPB1 and PrP-HSPB1(R136W) mice. These mice express the human HSPB1 protein throughout the nervous system including in axons of peripheral nerve. Although both mouse strains lacked obvious motor deficits, the PrP-HSPB1(R136W) mice developed an age-dependent motor axonopathy. Mutant mice showed axonal pathology in spinal cord and peripheral nerve with evidence of impaired neurofilament cytoskeleton, associated with organelle accumulation. Accompanying these findings, increases in the number of Schmidt–Lanterman incisures, as evidence of impaired axon–Schwann cell interactions, were present. These observations suggest that overexpression of HSPB1(R136W) in neurons is sufficient to cause pathological and electrophysiological changes in mice that are seen in patients with hereditary motor neuropathy.

Toxin Induced Continuous Muscle Fiber Activity Syndrome

Continuous Muscle Fiber Activity Syndrome describes rare heterogeneous group of conditions that exhibit sustained, diffuse motor unit activity due to hyperactivity of peripheral nerve motor axons. The disorder, which has both inherited and acquired forms, is characterized by muscular stiffness, cramps, fasciculation and weakness particularly in the limbs. We report a case 42 year old male who presented with easy fatigability and insidious onset gradually progressive difficulty in walking due to muscle stiffness in both lower limbs along with continuous twitching of muscles of all 4 limbs and chin. EMG study showed spontaneous, continuous, irregular rapid discharges of motor-unit potentials. doi: 10.5214/ans.0972.7531.2008.150405 Competing interests: None. Source of Funding: None Received Date: 25 Sept 2008 Revised Date: 15 Oct 2008 Accepted Date: 27 Oct 2008

Plasticity of inwardly rectifying conductances following a corticospinal lesion in human subjects

This study investigated whether there are changes in the excitability of motor axons in peripheral nerves of patients with corticospinal lesions, reflecting plasticity of the motoneuron due to altered descending drives and/or changes in afferent feedback. The excitability of motor and sensory axons in peripheral nerves of the affected limb of 11 patients with unilateral hemiparesis due to stroke was compared with that for the unaffected limbs and with data for 12 age-matched controls. There was significantly less accommodation to hyperpolarizing currents in motor axons on the affected side. There were small differences between the data for the unaffected side and that of the control subjects but these were not statistically significant. Other findings indicate that there was no change in resting membrane potential. There was no comparable alteration in the excitability of sensory axons. The changes in response of motor axons to hyperpolarizing currents could be reproduced in a computer model of the human motor axon by reducing the hyperpolarization-activated conductance, IH, by 30% and the quantitatively small leak conductance by 77%. The data for the uninvolved side matched the data for control subjects best when IH was increased. These findings are consistent with modulation of IH by activity. They demonstrate a change in the biophysical properties of motor axons not directly affected by the pathology and synaptically remote from the lesion, and have implications for 'trans-synaptic' changes in central nervous system pathways. In human subjects studies of motor axon properties may allow insight into processes affecting the motoneuron.

Higher-order non-linear phenomena in Renshaw cell responses to random motor axon stimulation

Renshaw cell responses to random motor axon stimulation exhibit second-order non-linearities in that they depend on the occurrence of a preceding stimulus, although these non-linearities are not strong enough to significantly depress the coherence. However, higher-order non-linearities have not been checked for so far. This is carried out here. Lumbosacral Renshaw cells were recorded with micropipettes in anaesthetized cats. Their responses to random (pseudo-Poisson) stimulation of motor axons in peripheral nerves or ventral roots were quantified by calculating peristimulus-time histograms of various sorts, conventional and conditional. Conventional peristimulus-time histograms were computed with respect to all the stimuli in a train. Conditional peristimulus-time histograms were calculated with respect to “test” stimuli which were sorted out (by computer) from the original stimulus train when they were preceded by “conditional” stimuli at average intervals of δ 1 or δ 2 or both. These conditioned responses were compared with those to be expected from hypothetical linear superposition. Renshaw cell responses showed small third-order non-linearities to pairs of conditioning stimuli at small intervals (up to some tens of milliseconds before the test stimuli). These third-order effects were smaller than each of the second-order non-linearities elicited by any of the single-conditioning stimuli. Also, further higher-order non-linearities were apparent, but of little average significance. Hence, the non-linearities in Renshaw cell responses to random inputs are essentially of second-order and fairly small.

Field potentials of alpha and gamma motoneurons and Renshaw cells in response to activation of motor axons

The antidromic action potentials evoked in alpha and gamma motoneurons by stimulation of motor axons in peripheral nerves were located with reference to the histology of the ventral horn of the deafferented cat spinal cord using a contour mapping technique. The regions of the maximum sinks of alpha and gamma motoneurons were essentially co-extensive, indicating that the motoneurons of a given muscle nerve, whether of alpha or gamma size, are located in the same part of the gray matter. The Renshaw-cell field potentials studied in the same animals showed a maximum sink in the ventral part of lamina VII, the same region in which most single Renshaw cells have been found.