Changes In Axonal Excitability Research Articles

Neuroplasticity of peripheral axonal properties after ischemic stroke.

ObjectiveThis study investigated how peripheral axonal excitability changes in ischemic stroke patients with hemiparesis or hemiplegia, reflecting the plasticity of motor axons due to corticospinal tract alterations along the poststroke stage.MethodsEach subject received a clinical evaluation, nerve conduction study, and nerve excitability test. Nerve excitability tests were performed on motor median nerves in paretic and non-paretic limbs in the acute stage of stroke. Control nerve excitability test data were obtained from age-matched control subjects. Some patients underwent excitability examinations several times in subacute or chronic stages.ResultsA total of thirty patients with acute ischemic stroke were enrolled. Eight patients were excluded due to severe entrapment neuropathy in the median nerve. The threshold current for 50% compound muscle action potential (CMAP) was higher in paretic limbs than in control subjects. Furthermore, in the cohort with severe patients (muscle power ≤ 3/5 in affected hands), increased threshold current for 50% CMAP and reduced subexcitability were noted in affected limbs than in unaffected limbs. In addition, in the subsequent study of those severe patients, threshold electrotonus increased in the hyperpolarization direction: TEh (100–109 ms), and the minimum I/V slope decreased. The above findings suggest the less excitable and less accommodation in lower motor axons in the paretic limb caused by ischemic stroke.ConclusionUpper motor neuron injury after stroke can alter nerve excitability in lower motor neurons, and the changes are more obvious in severely paretic limbs. The accommodative changes of axons progress from the subacute to the chronic stage after stroke. Further investigation is necessary to explore the downstream effects of an upper motor neuron insult in the peripheral nerve system.

WE-149. Axonal excitability changes in children with spinal muscular atrophy treated with nusinersen

WE-149. Axonal excitability changes in children with spinal muscular atrophy treated with nusinersen

Role of voltage-gated sodium channels in axonal signal propagation of trigeminal ganglion neurons after infraorbital nerve entrapment

Chronic pain arising from peripheral nerve injuries represents a significant clinical challenge because even the most efficacious anticonvulsant drug treatments are limited by their side effects profile. We investigated pain behavior, changes in axonal signal conduction and excitability of trigeminal neurons, and expression of voltage-gated sodium channels (NaVs) in the infraorbital nerve and trigeminal ganglion (TG) after infraorbital nerve entrapment (IoNE). Compared to Sham, IoNE rats had increased A- and C-fiber compound action potentials (CAPs) and Aδ component of A-CAP area from fibers innervating the vibrissal pad. After IoNE, A- and C-fiber CAPs were more sensitive to blockade by tetrodotoxin (TTX), and those fibers that were TTX-resistant were more sensitive to blockade by the NaV1.8 selective blocker, A-803467. Although NaV1.7 blocker, ICA-121431 alone, did not affect Aδ-fiber signal propagation, cumulative application with A-803467 and 4,9-anhydro-TTX significantly reduced the Aδ-fiber CAP in IoNE rats. In patch clamp recordings from small- and medium-sized TG neurons, IoNE resulted in reduced action potential (AP) depolarizing current threshold, hyperpolarized AP voltage threshold, increased AP duration, and a more depolarized membrane potential. While the transcripts of most NaVs were reduced in the ipsilateral TG after IoNE, NaV1.3, NaV1.7, and NaV1.8 mRNAs, and NaV1.8 protein, were significantly increased in the nerve. Altogether, our data suggest that axonal redistribution of NaV1.8, and to a lesser extent NaV1.3, and NaV1.7 contributes to enhanced nociceptive signal propagation in peripheral nerve after IoNE.

Axonal excitability changes in children with spinal muscular atrophy treated with nusinersen.

Spinal muscular atrophy (SMA) is associated with developmental disruption of motor axons in ventral roots of the spinal cord alongside motor axon degeneration. The pathogenesis of peripheral axonal change during development is pertinent to understand treatment response. Nerve excitability techniques, stimulating the median motor nerve at the wrist, were utilised to investigate axonal change during neurodevelopment in 24 children with SMA, compared with 71 age-matched controls. Longitudinal axonal response to nusinersen treatment in 18 children was also investigated. Significant differences in axonal development were noted in the youngest children with SMA, signified by reduced compound muscle action potential (CMAP) (P=0.030), higher axonal threshold (P=0.016), rheobase (minimal current amplitude of infinite duration, required to generate an action potential) (P=0.012) and greater changes in depolarising and hyperpolarising threshold electrotonus. Subexcitability increased in all children with SMA, compared to controls. With treatment, nerve excitability changes were observed prominently in young children, with increases in CMAP, reduction in axonal threshold, fanning-in of threshold electrotonus, increase in resting current-threshold slope and reduction in subexcitability. Whilst motor axons continue to mature in SMA, developmental delays in passive and active membrane properties occur especially in early childhood. Concurrently, motor axons actively undergo degeneration. Nusinersen restores the developmental trajectory of motor axons reducing degeneration, especially in children with early treatment initiation. Our findings move the field forward in understanding the developmental aspect of childhood-onset motor neurone diseases and changes in axonal function associated with disease modification. KEY POINTS: Pathomechanisms in spinal muscular atrophy involve concurrent neurodevelopmental and neurodegenerative processes. The greatest delays in maturation of the passive and active properties of the peripheral motor axon are seen in early childhood. Nusinersen facilitates developmental recovery of the motor axon whilst also reducing neurodegeneration. Axonal dysfunction is reversed with SMN repletion particularly when intervention occurs early in development.

A Re-evaluation of Whether Non-monosynaptic Homonymous H Reflex Facilitation Tests Propriospinal Circuits.

The C3–C4 propriospinal system is an important pathway mediating movement in cats; it contributes to movements in primates (including humans), and may have a role in recovery after lesion. Validated clinical tests of this system would find many applications, therefore we sought to test whether non-monosynaptic homonymous facilitation of the forearm flexor H reflex is mediated solely via a C3–C4 propriospinal pathway. In one anesthetized macaque monkey, median nerve stimulation elicited an H reflex in the flexor carpi radialis (FCR). Median nerve conditioning stimuli at sub-threshold intensities facilitated the H reflex, for inter-stimulus intervals up to 30 ms. Successive spinal surgical hemisections were then made. C2 lesion left the homonymous facilitation intact, suggesting mediation by spinal, not supraspinal pathways. Facilitation also remained after a second lesion at C5, indicating a major role for segmental (C7–C8) rather than propriospinal (C3–C4) interneurons. In separate experiments in five healthy human subjects, a threshold tracking approach assessed changes in peripheral axon excitability after conditioning stimulation. This was found to be enhanced up to 20 ms after the conditioning stimulus, and could partly, although not completely, underlie the H reflex facilitation seen. We conclude that homonymous facilitation of the H reflex in FCR can be produced by segmental spinal mechanisms, as well as by a supranormal period of nerve excitability. Unfortunately, this straightforward test cannot therefore be used for selective assessment of propriospinal circuits.

Nicotinic receptor modulation of primary afferent excitability with selective regulation of Aδ-mediated spinal actions.

Somatosensory input strength can be modulated by primary afferent depolarization (PAD) generated predominantly via presynaptic GABAA receptors on afferent terminals. We investigated whether ionotropic nicotinic acetylcholine receptors (nAChRs) also provide modulatory actions, focusing on myelinated afferent excitability in in vitro murine spinal cord nerve-attached models. Primary afferent stimulation-evoked synaptic transmission was recorded in the deep dorsal horn as extracellular field potentials (EFPs), whereas concurrently recorded dorsal root potentials (DRPs) were used as an indirect measure of PAD. Changes in afferent membrane excitability were simultaneously measured as direct current (DC)-shifts in membrane polarization recorded in dorsal roots or peripheral nerves. The broad nAChR antagonist d-tubocurarine (d-TC) selectively and strongly depressed Aδ-evoked synaptic EFPs (36% of control) coincident with similarly depressed A-fiber DRP (43% of control), whereas afferent electrical excitability remained unchanged. In comparison, acetylcholine (ACh) and the nAChR agonists, epibatidine and nicotine, reduced afferent excitability by generating coincident depolarizing DC-shifts in peripheral axons and intraspinally. Progressive depolarization corresponded temporally with the emergence of spontaneous axonal spiking and reductions in the DRP and all afferent-evoked synaptic actions (31%-37% of control). Loss of evoked response was long-lasting, independent of DC repolarization, and likely due to mechanisms initiated by spontaneous C-fiber activity. DC-shifts were blocked with d-TC but not GABAA receptor blockers and retained after tetrodotoxin block of voltage-gated Na+ channels. Notably, actions tested were comparable between three mouse strains, in rat, and when performed in different labs. Thus, nAChRs can regulate afferent excitability via two distinct mechanisms: by central Aδ-afferent actions, and by transient extrasynaptic axonal activation of high-threshold primary afferents.NEW & NOTEWORTHY Primary afferents express many nicotinic ACh receptor (nAChR) subtypes but whether activation is linked to presynaptic inhibition, facilitation, or more complex and selective activity modulation is unknown. Recordings of afferent-evoked responses in the lumbar spinal cord identified two nAChR-mediated modulatory actions: 1) selective control of Aδ afferent transmission and 2) robust changes in axonal excitability initiated via extrasynaptic shifts in DC polarization. This work broadens the diversity of presynaptic modulation of primary afferents by nAChRs.

Decreased excitability of motor axons contributes substantially to contraction fatigability during neuromuscular electrical stimulation.

The present study was designed to (i) determine the time course of changes in motor axon excitability during and after neuromuscular electrical stimulation (NMES); and (ii) characterize the relationship between contraction fatigability, NMES frequency, and changes at the axon, neuromuscular junction, and muscle. Eight neurologically intact participants attended 3 sessions. NMES was delivered over the common peroneal nerve at 20, 40, or 60 Hz for 8 min (0.3 s "on", 0.7 s "off"). Threshold tracking was used to measure changes in axonal excitability. Supramaximal stimuli were used to assess neuromuscular transmission and force-generating capacity of the tibialis anterior muscle. Torque decreased by 49% and 62% during 8 min of 40 and 60 Hz NMES, respectively. Maximal twitch torque decreased only during 60 Hz NMES. Motor axon excitability decreased by 14%, 27%, and 35% during 20, 40, and 60 Hz NMES, respectively. Excitability recovered to baseline immediately (20 Hz) and at 2 min (40 Hz) and 4 min (60 Hz) following NMES. Overall, decreases in axonal excitability best predicted how torque declined over 8 min of NMES. During NMES, motor axons become less excitable and motor units "drop out" of the contraction, contributing substantially to contraction fatigability and its dependence on NMES frequency. Novelty: The excitability of motor axons decreased during NMES in a frequency-dependent manner. As excitability decreased, axons failed to reach threshold and motor units dropped out of the contraction. Overall, decreased excitability best predicted how torque declined and thus is a key contributor to fatigability during NMES.

Split hand and motor axonal hyperexcitability in spinal and bulbar muscular atrophy

ObjectiveThe ‘split hand’ sign refers to preferential wasting of the thenar and first dorsal interosseous muscles with relatively sparing of the hypothenar muscles in amyotrophic lateral sclerosis (ALS) and both...

Changes in long term peripheral nerve biophysical properties in childhood cancer survivors following neurotoxic chemotherapy

ObjectiveIn the context of increasing numbers of childhood cancer survivors (CCS), this study aimed to enhance understanding of the biophysical basis for long term chemotherapy induced peripheral neuropathy from different chemotherapy agents in CCS. MethodsDetailed cross-sectional neurophysiological examination, using median nerve axonal excitability studies, alongside clinical assessments, in 103 long term CCS (10.5 ± 0.6 years post-treatment). ResultsCisplatin treated CCS (n = 16) demonstrated multiple sensory axonal excitability changes including increased threshold (P < 0.05), alterations in depolarising and hyperpolarising threshold electrotonus (P < 0.05) and reduction in resting and minimum IV slope (P < 0.01). Vincristine treated CCS (n = 73) were comparable to controls, except for prolonged distal motor latency (P = 0.001). No differences were seen in the non-neurotoxic chemotherapy group (n = 14). Abnormalities were more evident in the cisplatin subgroup with greater clinical neuropathy manifestations. ConclusionPersistent long term changes in axonal biophysical properties vary with different chemotherapy agents, most evident after cisplatin exposure. Longitudinal studies of nerve function during chemotherapy treatment are required to further evaluate these differences and their mechanistic basis. SignificanceThis study provides a unique biophysical perspective for persistent cisplatin related neurotoxicity in children, previously under recognised.

A 15-minute session of direct current stimulation does not produce lasting changes in axonal excitability

To assess the applicability and lasting effects on axonal membrane excitability of transcutaneous peripheral nerve direct current stimulation (pDCS). We included 15 healthy subjects. pDCS was performed with the active electrode placed over the left forearm and the reference electrode on the back of the hand. We used 5×5cm rubber electrodes and the current applied was 2.5mA during 15minutes. Three pDCS sessions were performed on the same day with a 20-minute interval between them: first a sham stimulation, followed by cathodal and anodal stimulations in random order. Motor nerve excitability measurements were performed immediately after each pDCS session using the TRONDNF nerve excitability protocol of the QTRAC program. The protocol was completed and well tolerated in all subjects. There were no consistent significant differences in excitability measurements between the three sessions. No consistent long-lasting effects were noted on peripheral nerve excitability beyond the period of application of pDCS. We showed that a 15-minute session of DCS is not able to produce lasting changes in axonal excitability, supporting the hypothesis that the functional and clinical impact of DCS protocols applied to the central nervous system is related to long-term synaptic changes rather sustained local changes in axonal rest membrane potential.

In vivo evidence for reduced ion channel expression in motor axons of patients with amyotrophic lateral sclerosis.

The progressive loss of motor units in amyotrophic lateral sclerosis (ALS) is initially compensated for by the reinnervation of denervated muscle fibres by surviving motor axons. A disruption in protein homeostasis is thought to play a critical role in the pathogenesis of ALS. The changes in surviving motor neurons were studied by comparing the nerve excitability properties of moderately and severely affected single motor axons from patients with ALS with those from single motor axons in control subjects. A mathematical model indicated that approximately 99% of the differences between the ALS and control units could be explained by a non-selective reduction in the expression of all ion channels. These changes in ALS patients are best explained by a failure in the supply of ion channel and other membrane proteins from the diseased motor neuron. Amyotrophic lateral sclerosis (ALS) is characterised by a progressive loss of motor units and the reinnervation of denervated muscle fibres by surviving motor axons. This reinnervation preserves muscle function until symptom onset, when some 60-80% of motor units have been lost. We have studied the changes in surviving motor neurons by comparing the nerve excitability properties of 31 single motor axons from patients with ALS with those from 21 single motor axons in control subjects. ALS motor axons were classified as coming from moderately or severely affected muscles according to the compound muscle action potential amplitude of the parent muscle. Compared with control units, thresholds were increased, and there was reduced inward and outward rectification and greater superexcitability following a conditioning impulse. These abnormalities were greater in axons from severely affected muscles, and were correlated with loss of fine motor skills. A mathematical model indicated that 99.1% of the differences between the moderately affected ALS and control units could be explained by a reduction in the expression of all ion channels. For the severely affected units, modelling required, in addition, an increase in the current leak through and under the myelin sheath. This might be expected if the anchoring proteins responsible for the paranodal seal were reduced. We conclude that changes in axonal excitability identified in ALS patients are best explained by a failure in the supply of ion channel and other membrane proteins from the diseased motor neuron, a conclusion consistent with recent animal and in vitro human data.

Altered motor axonal excitability in patients with cervical spondylotic amyotrophy

ObjectiveTo investigate the changes in motor axonal excitability properties in cervical spondylotic amyotrophy (CSA). MethodsThreshold tracking was used to measure the median motor axons in 21 patients with CSA, 10 patients with cervical spondylotic radiculopathy (CSR) and 16 normal controls. ResultsCompared with normal controls, patients with distal-type CSA showed increased threshold electrotonus hyperpolarization (TEh [90–100]) and increased superexcitability on the symptomatic side (P < 0.05), which are suggestive of distal motor axonal hyperpolarization, presumably due to motor axonal regeneration. More importantly, compared with normal controls and CSR cases, both distal- and proximal-type CSA cases showed lower accommodation during depolarising currents (reduced S2 accommodation, decreased TEd [undershoot] and/or lower subexcitability) (P < 0.05), indicating that slow K+ conductance may be less active in motor axons in patients with CSA. ConclusionsThe present study demonstrated changes in motor axonal excitability in patients with CSA compared with both normal controls and patients with CSR. SignificanceLess expression of slow K+ conductance may confer greater instability in membrane potential in CSA, thereby presumably contributing to the increased vulnerability of motor axons in patients with CSA.

Axonal excitability changes and acute symptoms of oxaliplatin treatment: In vivo evidence for slowed sodium channel inactivation

ObjectiveNeurotoxicity is the most frequent dose-limiting side effect of the anti-cancer agent oxaliplatin, but the mechanisms are not well understood. This study used nerve excitability testing to investigate the pathophysiology of the acute neurotoxicity. MethodsQuestionnaires, quantitative sensory tests, nerve conduction studies and nerve excitability testing were undertaken in 12 patients with high-risk colorectal cancer treated with adjuvant oxaliplatin and in 16 sex- and age-matched healthy controls. Examinations were performed twice for patients: once within 3 days after oxaliplatin treatment (post-infusion examination) and once shortly before the following treatment (recovery examination). ResultsThe most frequent post-infusion symptoms were tingling paresthesias and cold allodynia. The most prominent nerve excitability change was decreased superexcitability of motor axons which correlated with the average intensity of abnormal sensations (Spearman Rho = 0.80, p < .01). The motor nerve excitability changes were well modeled by a slowing of sodium channel inactivation, and were proportional to dose/m2 with a half-life of about 10d. ConclusionsOxaliplatin induces reversible slowing of sodium channel inactivation in motor axons, and these changes are closely related to the reversible cold allodynia. However, further studies are required due to small sample size in this study. SignificanceNerve excitability data provide an index of sodium channel dysfunction: an objective biomarker of acute oxaliplatin neurotoxicity.

S48 Axonal excitability, Schwann cells and the ‘Barrett-Barrett conductance’

In 1982, Ellen and John Barret published a paper on the depolarizing afterpotential in lizard axons which showed that it was due to passive spread of current from the nodal action potential to the internodal axolemma. The revolutionary electrical model of myelinated axons that they proposed was later found crucial to understanding the excitability changes recordable from human axons in the recovery cycle and threshold electrotonus. A key parameter in their new model was a resistive path across the Schwann cells, between the internodal periaxonal space and the external medium, and its conductance is known in their honour as the ‘Barrett-Barrett conductance’ (GBB). In recent years it has proved possible to understand quite well, by mathematical modelling,the changes in axonal excitability produced by changes in axonal membrane potential, and in the conductances of the major axonal voltage-dependent ion channels (sodium, fast and slow potassium, and HCN), such as in toxic and genetic channelopathies. Less well understood, however, are the complex excitability changes occurring in most demyelinating and other neuropathies that affect Schwann cells and the structure of myelinated axons. This review will bring together a few disparate genetic and auto-immune conditions in which modelling suggests that axonal excitability abnormalities are primarily due to Schwann cell dysfunction and an increase in the ‘Barrett-Barrett’ conductance. In some cases only, this increase appears to be accompanied by an increase in nodal fast potassium conductance, as might be expected for paranodal demyelination with exposure of juxtaparanodal potassium channels.

S49 Changes in the final common path in CMT1A and RLS

Patients suffering from Charcot-Marie-Tooth disease complain about various so called positive and negative symptoms. Positive symptoms include e.g. paraesthesia, pain, fasciculations, muscle cramps and restless legs syndrome, whereby negative symptoms represent a loss of function, e.g. hypaesthesia or muscle weakness. There is growing knowledge about disease specific molecular pathomechanisms, which does not necessarily explain symptoms patients are complaining about. Currently there is no mechanism based treatment of any symptom. In this presentation I will give an overview about recent findings in Charcot-Marie-Tooth disease type 1A patients deciphering the mechanisms of motor symptoms, e.g. fasciculations, muscle cramps and regarding restless legs syndrome: leg movements and the urge to move. By combining axonal excitability studies with multi-unit electromyography recordings it is possible to decipher the role of changes in axonal excitability for the output of individual motor units and consequently also for motor symptoms. Our findings suggest that ion channel modulators may be beneficial to influence both positive and negative motor symptoms in CMT1A.

Motor and Sensory Axon Excitability Properties From the Median and Ulnar Nerves and the Effects of Age on These Properties.

Threshold tracking is a new noninvasive approach for detecting axonal excitability changes in vivo. In this study, the authors compared the excitability indices of motor and sensory axons of median and ulnar nerves to determine whether the two nerves behave in a similar or a noninterchangeable way. They also examined whether age affects these indices. Seventy normal subjects aged 22-70 years (mean, 36.7 ± 12.5 years) were recruited. Multiple excitability indices were measured in both motor and sensory axons from median and ulnar nerves. The threshold and rheobase were significantly higher for the ulnar motor axons recorded at the first dorsal interosseous muscle than for the median motor axons at the abductor pollicis brevis muscle. In contrast, the strength-duration time constant was decreased, threshold electrotonus reduction (in both depolarizing and hyperpolarizing directions) was significantly smaller, I/V slope was decreased, and subexcitability was reduced for the ulnar motor axons. Excitability indices measured in the sensory axons of both nerves were not overtly different. In R-square analysis, age had a homogeneous influence on sensory axon excitability but heterogeneous influence on motor axon excitability. The excitability indices may be interchangeable for sensory axons but not motor axons. The authors therefore recommend recording motor axonal excitability in various muscle groups rather than a single muscle group.

Torque decrease during submaximal evoked contractions of the quadriceps muscle is linked not only to muscle fatigue.

The aim of this study was to analyze the neuromuscular mechanisms involved in the torque decrease induced by submaximal electromyostimulation (EMS) of the quadriceps muscle. It was hypothesized that torque decrease after EMS would reflect the fatigability of the activated motor units (MUs), but also a reduction in the number of MUs recruited as a result of changes in axonal excitability threshold. Two experiments were performed on 20 men to analyze 1) the supramaximal twitch superimposed and evoked at rest during EMS (Experiment 1, n = 9) and 2) the twitch response and torque-frequency relation of the MUs activated by EMS (Experiment 2, n = 11). Torque loss was assessed by 15 EMS-evoked contractions (50 Hz; 6 s on/6 s off), elicited at a constant intensity that evoked 20% of the maximal voluntary contraction (MVC) torque. The same stimulation intensity delivered over the muscles was used to induce the torque-frequency relation and the single electrical pulse evoked after each EMS contraction (Experiment 2). In Experiment 1, supramaximal twitch was induced by femoral nerve stimulation. Torque decreased by ~60% during EMS-evoked contractions and by only ~18% during MVCs. This was accompanied by a rightward shift of the torque-frequency relation of MUs activated and an increase of the ratio between the superimposed and posttetanic maximal twitch evoked during EMS contraction. These findings suggest that the torque decrease observed during submaximal EMS-evoked contractions involved muscular mechanisms but also a reduction in the number of MUs recruited due to changes in axonal excitability.

Axonal ion channel dysfunction in c9orf72 familial amyotrophic lateral sclerosis.

Abnormalities of axonal excitability characterized by upregulation of persistent sodium (Na+) conductances and reduced potassium (K+) currents have been reported in sporadic amyotrophic lateral sclerosis (SALS) phenotypes and linked to the development of clinical features such as fasciculations and neurodegeneration. To investigate whether abnormalities of axonal ion channel function, particularly upregulation of persistent Na+ conductances and reduced K+ currents, form the pathophysiological basis of chromosome 9 open reading frame 72 (c9orf72) familial amyotrophic lateral sclerosis (FALS). This was a prospective study. Clinical and functional assessment, along with motor-nerve excitability studies, were undertaken in 10 clinically affected patients with c9orf72 FALS, 9 asymptomatic c9orf72 mutation carriers, and 21 patients with SALS from 3 hospitals and 2 outpatient clinics. Axonal excitability variables were measured in patients with c9orf72 ALS and results compared with matched patients with SALS and healthy control participants. Strength-duration time constant (τSD) was significantly increased in the patients with c9orf72 FALS and those with SALS (mean [SD], c9orf72 FALS: 0.50 [0.02] milliseconds; SALS: 0.52 [0.02] milliseconds; P < .01) when compared with control participants (mean [SD], 0.44 [0.01] milliseconds). In contrast, there were no significant changes of τSD in asymptomatic c9orf72 mutation carriers (P = .42). An accompanying increase in depolarizing threshold electrotonus at 90 to 100 milliseconds (TEd 90-100 milliseconds) was also evident in the c9orf72 FALS (P < .05) and SALS (P < .01) cohorts. Mathematical modeling suggested that an increase in persistent Na+ conductances, along with reduced K+ currents, best explained the changes in axonal excitability. Importantly, these abnormalities in axonal excitability correlated with the motor amplitude (τSD: R = -0.38, P < .05 and TEd 90-100 milliseconds: R = -0.44, P < .01), muscle weakness (TEd 90-100 milliseconds: R = -0.32, P < .05), and the ALS Functional Rating Scale (TEd 90-100 milliseconds: R = -0.34, P < .05). Findings from the present study establish that upregulation of persistent Na+ conductances and reduced K+ currents were evident in both c9orf72 FALS and SALS cohorts, and these changes in axonal excitability were associated with motor neuron degeneration.

Acquired and genetic channelopathies: In vivo assessment of axonal excitability

Neuronal or axonal ion channel function can be impaired or altered in a number of disorders, such as acquired (autoantibody-mediated, toxic, and metabolic) and genetic channelopathies, and even neurodegenerative (motor neuron disease) or inflammatory diseases (multiple sclerosis, immune-mediated neuropathies). When specific channels are affected, axonal/neuronal excitability primarily alters according to original function of the corresponding channels. Separately, in the 1990s, axonal excitability testing was developed to assess ion channel function, membrane potential, and passive membrane properties non-invasively in human subjects. Using this technique, numerous papers on altered axonal excitability in a variety of disorders have been published since 2000. In a recent issue of Experimental Neurology, Park et al. demonstrated changes in peripheral axonal excitability in limbic encephalitis and acquired neuromyotonia with anti-voltage gated potassium channel antibodies. Unexpectedly, the results were not consistent with those caused by simple potassium channel blockade, suggesting that multiple other factors contribute to altered axonal excitability. In contrast it was reported that patients with episodic ataxia type 1 (genetic channelopathy with mutation of Kv1.1 channel gene) show prominent excitability changes exactly compatible with fast potassium channel blockade. This commentary aims to highlight findings of this study in a broader context, and provides possible explanations for the discrepancy of patterns of axonal excitability changes in acquired and genetic potassium channelopathies.

Arginine butyrate per os protects mdx mice against cardiomyopathy, kyphosis and changes in axonal excitability

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by lack of dystrophin, a sub-sarcolemmal protein, which leads to dramatic muscle deterioration. We studied in mdx mice, the effects of oral administration of arginine butyrate (AB), a compound currently used for the treatment of sickle cell anemia in children, on cardiomyopathy, vertebral column deformation and electromyographic abnormalities.Monthly follow-up by echocardiography from the 8th month to the 14th month showed that AB treatment protected the mdx mice against drastic reduction (20–23%) of ejection fraction and fractional shortening, and also against the ≈20% ventricular dilatation and 25% cardiac hypertrophy observed in saline-treated mdx mice. The phenotypic improvement was corroborated by the decrease in serum CK level and by better fatigue resistance. Moreover, AB treatment protected against the progressive spinal deformity observed in mdx mice, another similarity with DMD patients. The value of the kyphosis index in AB-treated mice reached 94% of the value in C57BL/10 mice. Finally, axonal excitability parameters such as the membrane resting potential, the threshold and amplitude of the action potential, the absolute and relative refractory periods and the supernormal and subnormal periods, recorded from caudal and plantar muscles in response to excitability tests, that were modified in saline-treated mdx mice were not significantly changed, compared with wild-type animals, in AB-treated mdx mice. All of these results suggest that AB could be a potential treatment for DMD patients.