Nerve Excitability Test Research Articles

Increase of HCN current in SOD1-associated amyotrophic lateral sclerosis.

The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is mainly based on clinical presentations, while the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NET) to investigate axonal membrane properties and chemical precipitation, followed by enzyme-linked immunosorbent assay analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-threshold (I/V) curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus (TE) in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the I/V curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72, or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the I/V curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partially prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes as familial ALS patients and ALS mice with mutant SOD1 genes, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the I/V curve was attributable to an elevation in the HCN current in SOD1-associated ALS.

Effects of motor cortical and peripheral axonal hyperexcitability on survival in amyotrophic lateral sclerosis

BackgroundIncreased ‘cortical’ and ‘peripheral’ excitability are reportedly associated with shorter survival in amyotrophic lateral sclerosis (ALS) patients, suggesting that hyperexcitability contributes to motor neuron death. However, whether upper or lower...

Morphofunctional characterisation of axonal damage in different rat models of chemotherapy-induced peripheral neurotoxicity: The role of nerve excitability testing.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and long-lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage. We tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density. NET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement. NET after the first administration demonstrated the ongoing OHP-related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.

Nerve excitability test and lead toxicity: a case-control study

BackgroundAlthough conventional electrophysiological parameters have been proposed as clinical indicators for monitoring lead neuropathies, their correlations with blood lead level are weak. In this study, we investigated the applicability of nerve excitability tests (NETs) to evaluate lead intoxication.MethodsFourteen workers who were exposed to lead with an elevated blood level ranging from 17.8 to 64.9 µg/dL and 20 healthy controls with similar ages and body heights were enrolled. Both workers and controls underwent nerve conduction studies (NCSs), motor evoked potentials (MEPs) with transcranial magnetic stimulation (TMS), and NETs.ResultsNCSs showed prolonged distal latencies and decreased motor nerve conduction velocity of median nerves in the workers but without significant correlation to blood lead level (BLL). Significantly prolonged MEP latency was observed in the workers (+ 6 ms). NETs demonstrated hyperpolarized resting membrane potentials in stimulus-response curves and changes in the property of potassium channels under a hyperpolarized current in threshold electrotonus, implying that lead hyperpolarized nerves by interfering with potassium channels. NETs also showed a better correlation with BLL than conventional electrophysiological parameters.ConclusionsAxonal hyperpolarization and central conduction delay are more apparently reflecting elevated BLL than NCS. NET may have the potential for early detection of lead neuropathy.

Predicting synkinesis caused by Bell's palsy or Ramsay Hunt syndrome using machine learning-based logistic regression.

To investigate whether machine learning (ML)-based algorithms, namely logistic regression (LR), random forest (RF), k-nearest neighbor (k-NN), and gradient-boosting decision tree (GBDT), utilizing early post-onset parameters can predict facial synkinesis resulting from Bell's palsy or Ramsay Hunt syndrome more accurately than the conventional statistics-based LR. This retrospective study included 362 patients who presented to a facial palsy outpatient clinic. Median follow-up of synkinesis-positive and -negative patients was 388 (range, 177-1922) and 198 (range, 190-3021) days, respectively. Electrophysiological examinations were performed, and the rate of synkinesis in Bell's palsy and Ramsay Hunt syndrome was evaluated. Sensitivity and specificity were assessed using statistics-based LR; and electroneurography (ENoG) value, the difference in the nerve excitability test (NET), and scores of the subjective Yanagihara scaling system were evaluated using early post-onset parameters with ML-based LR, RF, k-NN, and GBDT. Synkinesis rate in Bell's palsy and Ramsay Hunt syndrome was 20.2% (53/262) and 40.0% (40/100), respectively. Sensitivity and specificity obtained with statistics-based LR were 0.796 and 0.806, respectively, and the area under the receiver operating characteristic curve (AUC) was 0.87. AUCs measured using ML-based LR of "ENoG," "difference in NET," "Yanagihara," and all three components ("all") were 0.910, 0.834, 0.711, and 0.901, respectively. ML-based LR model shows potential in predicting facial synkinesis probability resulting from Bell's palsy or Ramsay Hunt syndrome and has comparable reliability to the conventional statistics-based LR. 3.

Diagnostic accuracy of nerve excitability and compound muscle action potential scan derived biomarkers in amyotrophic lateral sclerosis.

The lack of reliable early biomarkers still causes substantial diagnostic delays in amyotrophic lateral sclerosis (ALS). The aim was to assess the diagnostic accuracy of a novel electrophysiological protocol in patients with suspected motor neuron disease (MND). Consecutive patients with suspected MND were prospectively recruited at our tertiary referral centre for MND in Utrecht, The Netherlands. Procedures were performed in accordance with the Standards for Reporting of Diagnostic Accuracy. In addition to the standard diagnostic workup, an electrophysiological protocol of compound muscle action potential (CMAP) scans and nerve excitability tests was performed on patients' thenar muscles. The combined diagnostic yield of nerve excitability and CMAP scan based motor unit number estimation was compared to the Awaji and Gold Coast criteria and their added value was determined. In all, 153 ALS or progressive muscular atrophy patients, 63 disease controls and 43 healthy controls were included. Our electrophysiological protocol had high diagnostic accuracy (area under the curve [AUC] 0.85, 95% confidence interval [95% CI] 0.80-0.90), even in muscles with undetectable axon loss (AUC 0.78, 95% CI 0.70-0.85) and in bulbar-onset patients (AUC 0.85, 95% CI 0.73-0.95). Twenty-four of 33 (73%) ALS patients who could not be diagnosed during the same visit were correctly identified, as well as 8/13 (62%) ALS patients not meeting the Gold Coast criteria and 49/59 (83%) ALS patients not meeting the Awaji criteria during this first visit. Our practical and non-invasive electrophysiological protocol may improve early diagnosis in clinically challenging patients with suspected ALS. Routine incorporation may boost early diagnosis, enhance patient selection and generate baseline measures for clinical trials.

D.2 Cross-sectional axonal excitability and motor unit number index profile in early stages of weakness in ALS

Background: What is the number and size of motor units, and axonal excitability profile in the early stages of muscle weakness in ALS compared to controls? Methods: We enrolled ALS patients with APB manual strength testing rated four or four-minus (ALS:4-arm) and four-plus (ALS:4+ arm) and control participants >35 years-old from the University of Toronto, University of Alberta and Universidade Federal de Sao Paulo. Mean±SD, one-way ANOVA and ANCOVA of ALSFRS-R, PUMN Score, MUNIX, MUSIX, and nerve-excitability testing using QTRAC TROND protocol were reported. Results: Twenty-five ALS patients and 63 controls were included. Mean MUNIX was significantly lower (p<0.0001) and MUSIX was significantly higher (p<0.001) in both ALS groups compared to controls. Mean strength-duration time constant in the ALS:4- arm (0.50ms±0.11; p<0.05) and superexcitability in both ALS groups (ALS:4- -29.05%±9.24, ALS:4+ -27.67%±8.03; p<0.05) were relatively increased, supporting axonal hyperexcitability. Conclusions: Significant motor unit loss measured by MUNIX is already present at the earliest detection of muscle weakness in ALS. Increased MUSIX and altered axonal physiology are associated with axonal sprouting and geometry change(1), along with ion channel dysfunction(2). Future trials targeting muscle weakness in ALS should consider the altered neuronal physiology during early disease stages and utilize neurophysiological biomarkers only in normal-to-mildly weak muscles.

Altered flexor carpi radialis motor axon excitability properties after cerebrovascular stroke.

Spinal motoneurons may become hyperexcitable after a stroke. Knowledge about motoneuron hyperexcitability remains clinically important as it may contribute to a number of phenomena including spasticity, flexion synergies, and abnormal limb postures. Hyperexcitability seems to occur more often in muscles that flex the wrist and fingers (forearm flexors) compared to other upper limb muscles. The cause of hyperexcitability remains uncertain but may involve plastic changes in motoneurons and their axons. To characterize intrinsic membrane properties of flexor carpi radialis (FCR) motor axons after stroke using nerve excitability testing. Nerve excitability testing using threshold tracking techniques was applied to characterize FCR motor axon properties in persons who suffered a first-time unilateral cortical/subcortical stroke 23 to 308 days earlier. The median nerve was stimulated at the elbow bilaterally in 16 male stroke subjects (51.4 ± 2.9 y) with compound muscle action potentials recorded from the FCR. Nineteen age-matched males (52.7 ± 2.4 y) were also tested to serve as controls. Axon parameters after stroke were consistent with bilateral hyperpolarization of the resting potential. Nonparetic and paretic side axons were modeled by a 2.6-fold increase in pump currents (IPumpNI) together with an increase (38%-33%) in internodal leak conductance (GLkI) and a decrease (23%-29%) in internodal H conductance (Ih) relative to control axons. A decrease (14%) in Na+ channel inactivation rate (Aah) was also needed to fit the paretic axon recovery cycle. "Fanning out" of threshold electrotonus and the resting I/V slope (stroke limbs combined) correlated with blood potassium [K+] (R = -0.61 to 0.62, p< 0.01) and disability (R = -0.58 to 0.55, p < 0.05), but not with spasticity, grip strength, or maximal FCR activity. In contrast to our expectations, FCR axons were not hyperexcitable after stroke. Rather, FCR axons were found to be hyperpolarized bilaterally post stroke, and this was associated with disability and [K+]. Reduced FCR axon excitability may represent a kind of bilateral trans-synaptic homeostatic mechanism that acts to minimize motoneuron hyperexcitability.

Longitudinal prospective cohort study to assess peripheral motor function with extensive electrophysiological techniques in patients with Spinal Muscular Atrophy (SMA): the SMA Motor Map protocol

BackgroundHereditary spinal muscular atrophy (SMA) is a motor neuron disorder with a wide range in severity in children and adults. Two therapies that alter splicing of the Survival Motor Neuron 2 (SMN2) gene, i.e. nusinersen and risdiplam, improve motor function in SMA, but treatment effects vary. Experimental studies indicate that motor unit dysfunction encompasses multiple features, including abnormal function of the motor neuron, axon, neuromuscular junction and muscle fibres. The relative contributions of dysfunction of different parts of the motor unit to the clinical phenotype are unknown. Predictive biomarkers for clinical efficacy are currently lacking. The goals of this project are to study the association of electrophysiological abnormalities of the peripheral motor system in relation to 1) SMA clinical phenotypes and 2) treatment response in patients treated with SMN2-splicing modifiers (nusinersen or risdiplam).MethodsWe designed an investigator-initiated, monocentre, longitudinal cohort study using electrophysiological techniques (‘the SMA Motor Map’) in Dutch children (≥ 12 years) and adults with SMA types 1–4. The protocol includes the compound muscle action potential scan, nerve excitability testing and repetitive nerve stimulation test, executed unilaterally at the median nerve. Part one cross-sectionally assesses the association of electrophysiological abnormalities in relation to SMA clinical phenotypes in treatment-naïve patients. Part two investigates the predictive value of electrophysiological changes at two-months treatment for a positive clinical motor response after one-year treatment with SMN2-splicing modifiers. We will include 100 patients in each part of the study.DiscussionThis study will provide important information on the pathophysiology of the peripheral motor system of treatment-naïve patients with SMA through electrophysiological techniques. More importantly, the longitudinal analysis in patients on SMN2-splicing modifying therapies (i.e. nusinersen and risdiplam) intents to develop non-invasive electrophysiological biomarkers for treatment response in order to improve (individualized) treatment decisions.Trial registrationNL72562.041.20 (registered at https://www.toetsingonline.nl. 26–03-2020).

The test–retest reliability of large and small fiber nerve excitability testing with threshold tracking

ObjectiveStandard nerve excitability testing (NET) predominantly assesses Aα- and Aβ-fiber function, but a method examining small afferents would be of great interest in pain studies. Here, we examined the properties of a novel perception threshold tracking (PTT) method that preferentially activates Aδ-fibers using weak currents delivered by a novel multipin electrode and compared its reliability with NET. MethodsEighteen healthy subjects (mean age:34.06 ± 2.0) were examined three times with motor and sensory NET and PTT in morning and afternoon sessions on the same day (intra-day reliability) and after a week (inter-day reliability). NET was performed on the median nerve, while PTT stimuli were delivered through a multipin electrode located on the forearm. During PTT, subjects indicated stimulus perception via a button press and the intensity of the current was automatically increased or decreased accordingly by Qtrac software. This allowed changes in the perception threshold to be tracked during strength-duration time constant (SDTC) and threshold electrotonus protocols. ResultsThe coefficient of variation (CoV) and interclass coefficient of variation (ICC) showed good–excellent reliability for most NET parameters. PTT showed poor reliability for both SDTC and threshold electrotonus parameters. There was a significant correlation between large (sensory NET) and small (PTT) fiber SDTC when all sessions were pooled (r = 0.29, p = 0.03). ConclusionsThreshold tracking technique can be applied directly to small fibers via a psychophysical readout, but with the current technique, the reliability is poor. SignificanceFurther studies are needed to examine whether Aβ-fiber SDTC may be a surrogate biomarker for peripheral nociceptive signalling.

Chronic Hypoxemia Triggers a Neuropathic Process in Chronic Obstructive Pulmonary Disease: Insight From In Vivo Neurophysiological Assessments.

Peripheral neuropathies (PNs) are a common but poorly understood complication of chronic obstructive pulmonary disease (COPD). To clarify the initial trigger of a PN in COPD, we investigated the excitability of peripheral nerves in patients with COPD. The automated nerve excitability test (NET) using the threshold-tracking paradigm was applied to 20 COPD patients. The recording protocol calculated the strength-duration time constant, threshold electrotonus (TE), current-threshold relationship, and recovery cycle (RC). Each NET parameter was compared with two control groups: normal controls group (NC group) and smokers without COPD group (smoker group). In the motor NETs, the change in the threshold in the mid-depolarizing phase of TE (40-60 ms) was smaller in the COPD group (50.7%±1.2%, mean±SEM; n=20) than in the NC group (54.5%±0.7%, n=25; p<0.01), as was the prominence of superexcitability in the RC (-22.6%±1.5% and -26.4%±1.1%, respectively; p=0.04). There were no significant differences in the sensory NETs. Comparisons between the COPD and smoker groups (n=25) also showed no differences in either the motor or sensory NETs. The pattern of excitability in COPD revealed a membrane depolarization attributable to Na+-K+-ATPase failure in the axolemma of distal motor nerves. This finding suggests that chronic hypoxemia and adaptative process can alter axonal excitability and trigger a resultant neuropathic process that is antecedent to PN in COPD.

Feasibility and tolerability of multimodal peripheral electrophysiological techniques in a cohort of patients with spinal muscular atrophy

ObjectiveElectrophysiological techniques are emerging as an aid in identifying prognostic or therapeutic biomarkers in patients with spinal muscular atrophy (SMA), but electrophysiological assessments may be burdensome for patients. We, therefore, assessed feasibility and tolerability of multimodal peripheral non-invasive electrophysiological techniques in a cohort of patients with SMA. MethodsWe conducted a single center, longitudinal cohort study investigating the feasibility and tolerability of applying multimodal electrophysiological techniques to the median nerve unilaterally. Techniques consisted of the compound muscle action potential scan, motor nerve excitability tests, repetitive nerve stimulation and sensory nerve action potential. We assessed tolerability using the numeric rating scale (NRS), ranging from 0 (no pain) to 10 (worst possible pain), and defined the protocol to be tolerable if the NRS score ≤ 3. The protocol was considered feasible if it could be performed according to test and quality standards. ResultsWe included 71 patients with SMA types 1–4 (median 39 years; range 13–67) and 63 patients at follow-up. The protocol was feasible in 98% of patients and was well-tolerated in up to 90% of patients. Median NRS score was 2 (range 0–6 at baseline and range 0–4 at follow-up (p < 0.01)). None of the patients declined follow-up assessment. ConclusionsMultimodal, peripheral, non-invasive, electrophysiological techniques applied to the median nerve are feasible and well-tolerated in adolescents and adults with SMA types 1–4. SignificanceOur study supports the use of non-invasive multimodal electrophysiological assessments in adolescents and adults with SMA types 1–4.

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.

TH-237. Diagnostic utility of nerve excitability tests in amyotrophic lateral sclerosis

TH-237. Diagnostic utility of nerve excitability tests in amyotrophic lateral sclerosis

In vivo neurophysiological assessment of in silico predictions of neurotoxicity: Citronellal, 3,4-dichloro-1-butene, and benzyl bromoacetate

Neurotoxicants may be widespread in the environment and can produce serious health impacts in the human population. Screening programs that use in vitro methods have generated data for thousands of chemicals. However, these methods often do not evaluate repeated or prolonged exposures, which are required for many neurotoxic outcomes. Additionally, the data produced by such screening methods may not include mechanisms which play critical biological roles necessary for in vivo neurotoxicity. The Hard and Soft Acids and Bases (HSAB) in silico model focuses on chemical structure and electrophilic properties which are important to the formation of protein adducts. A group of structurally diverse chemicals have been evaluated with an in silico screening approach incorporating HSAB parameters. However, the predictions from the expanded chemical space have not been evaluated using in vivo methods. Three chemicals predicted to be cumulative toxicants were selected for in vivo neurotoxicological testing. Adult male Long-Evans rats were treated orally with citronellal (CIT), 3,4-dichloro-1-butene (DCB), or benzyl bromoacetate (BBA) for 8 weeks. Behavioral observations were recorded weekly to assess motor function. Peripheral neurophysiological measurements were derived from nerve excitability (NE) tests which involved compound muscle action potentials (CMAPs) in the tail and foot, and mixed nerve action potentials (MNAPs) in the tail. Compound nerve action potentials (CNAPs) and nerve conduction velocity (NCV) in the tail were also quantified. Peripheral inputs into the central nervous system were examined using somatosensory evoked potentials recorded from the cortex (SEPCTX) and cerebellum (SEPCEREB). CIT or BBA did not result in significant alterations to peripheral nerve or somatosensory function. DCB reduced grip-strength and altered peripheral nerve function. The MNAPs required less current to reach 50% amplitude and had a lower calculated rheobase, suggesting increased excitability. Increased CNAP amplitudes and greater NCV were also observed. Novel changes were found in the SEPCTX with an abnormal peak forming in the early portion of the waveforms of treated rats, and decreased latencies and increased amplitudes were observed in SEPCEREB recordings. These data contribute to testing an expanded chemical space from an in silico HSAB model for predicting cumulative neurotoxicity and may assist with prioritizing chemicals to protect human health.

IMI2-PainCare-BioPain-RCT1: study protocol for a randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by peripheral nerve excitability testing (NET)

BackgroundFew new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system.MethodsThis is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na+ conductance) of large sensory fibers and SDTC of large motor fibers comparing lacosamide and placebo. The key secondary endpoint is the SDTC measured in small sensory fibers. Remaining treatment arm effects on key NET outcomes and PK modelling are other prespecified secondary or exploratory analyses.DiscussionMeasurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.Trial registrationThis trial was registered 25/06/2019 in EudraCT (2019-000942-36).

The additional diagnostic value of motor nerve excitability testing in chronic axonal neuropathy

ObjectiveTo explore potential differences in motor nerve excitability testing (NET) variables at group levels between patients with a clinical diagnosis of polyneuropathy (PNP), which did not fulfil diagnostic criteria of conventional nerve conduction studies (NCS) and patients without polyneuropathy. Such differences could support a role for NET in increasing the diagnostic sensitivity of NCS in chronic axonal PNP. MethodsMotor NET was performed using the median nerve in patients with a clinical suspicion of PNP in addition to conventional NCS, skin biopsies, corneal confocal microscopy and structured clinical evaluation including scoring of neuropathy symptoms and signs. ResultsOf the 57 patients included, 32 had PNP, half of which had NCS, which fulfilled criteria for PNP (NCS+ PNP). There were no significant differences for any of the NET variables between PNP patients with non-diagnostic conventional NCS (NCS− PNP) and patients without PNP. Rheobase was increased, and Ted (undershoot) and subexcitability were decreased in NCS+ PNP. Sural amplitude, peroneal nerve F-wave latency and tibial nerve F-wave-latency were correlated with subexcitability, and tibial nerve motor amplitude was correlated with rheobase. ConclusionsNET was correlated with conventional NCS and no differences were found between NCS− PNP patients and patients without PNP. SignificanceNET does not seem to offer any additional diagnostic value in chronic mixed etiology neuropathy.

Fatigue and activity-dependent conduction block in neuromuscular disorders

ObjectiveFatigue is a major disabling problem in patients with neuromuscular disorders. Both nerve demyelination and increased axonal branching associated with collateral sprouting reduce the safety factor for impulse transmission and could cause activity-dependent hyperpolarization and conduction block during voluntary contraction, and thus fatigue. This study aimed to investigate whether activity-dependent conduction block is associated with fatigue in demyelinating neuropathies and lower motor neuron disorders. MethodsThis study included 31 patients (17 with chronic inflammatory demyelinating polyneuropathy [CIDP] and 14 with spinal and bulbar muscular atrophy [SBMA]). Sixteen healthy subjects served as normal controls. Fatigue was assessed using the Fatigue Scale for Motor and Cognitive Functions (FSMC). Compound muscle action potential (CMAP) recording and nerve excitability testing after median nerve stimulation in the wrist were performed before and after maximal voluntary contraction of the abductor pollicis brevis for 1 min. ResultsPatients with CIDP/SBMA had prominent fatigue with higher FSMC motor scores (P < 0.0001) than normal controls. After voluntary contractions, CMAP amplitudes decreased significantly in four of the 17 patients with CIDP and one of the 14 patients with SBMA. The reduction in CMAP amplitude was associated with the fatigue score in the motor but not in the cognitive domain. After voluntary contraction, excitability testing showed axonal hyperpolarization in the normal and CIDP/SBMA groups. ConclusionsIn CIDP or SBMA, fatigue is caused by voluntary contraction-induced membrane hyperpolarization and conduction block, presumably due to the critically lowered safety factor due to demyelination or increased axonal branching. SignificancePeripheral fatigue can be objectively assessed using CMAP amplitudes and nerve excitability testing.

A test to determine the site of abnormal neuromuscular refractoriness

ObjectiveThe relative refractory period (RRP) of motor axons is an important parameter in nerve excitability tests of the recovery cycle (RC). Abnormalities may have a site in the axonal membrane, the neuromuscular junction, or in a dysfunction of the muscle. We aimed in this study to determine the site of abnormality, using a modified protocol of the conventional RC test, whereby an additional supramaximal stimulus is added at the same interstimulus interval as in RC recordings (RCSM). MethodsTwenty-four healthy subjects aged 37.8 ± 2.4 years (mean ± SE) were examined with median nerve excitability testing using RC and RCSM protocols at normal temperature (34.1 ± 0.2 °C). The recordings were repeated in 12 subjects after selective cooling of the thenar muscle (25.2 ± 0.7 °C) and in 12 subjects after cooling the nerve trunk at the wrist (24.9 ± 0.3 °C). ResultsAfter cooling the nerve, RRP measured with RC and RCSM were prolonged similarly (medians by 1.8 ms, and 2.1 ms respectively). In contrast, cooling the muscle prolonged RRP measured with RC (by 1.3 ms), but did not significantly prolong RRP measured with RCSM. RRPs measured by RC and RCSM were significantly different when cooling was at the muscle (P = 5.10-4), but not when cooling was at the nerve (P = 0.57). ConclusionsA difference between RC and RCSM indicates abnormal excitability distal to the axonal membrane under the stimulating electrode. SignificanceCombining RCSM with the conventional RC protocol should help to localize the site of abnormal neuromuscular refractoriness.

WS3.4. Electrodiagnostic Approach to Motor Neuron Disease: Split Hand in ALS

Amyotrophic lateral sclerosis (ALS) is characterized by involvement of both upper and lower motor neurons. Electrophysiologic approach includes EMG (denervation potentials and fasciculation potentials) and nerve conduction studies (NCS; low CMAP, decreased motor unit number, and axonal hyperexcitability on nerve excitability testing) for lower motor neuron involvement, and transcranial magnetic stimulation with threshold tracking (decreased short- latency intracortical inhibition) for upper motoneuronal hyperexcitability. Of these, routine NCS can detect the “split hand” pattern, which is a very important indicator for diagnosis, because this symptom has been recognized as being specific to ALS; the thenar and first dorsal interosseous (FDI) muscles are preferentially affected. In contrast, the hypothenar muscle (abductor digiti minimi, ADM) is relatively preserved. FDI and ADM muscles are innervated by the same C8/Th1 spinal segments and the same ulnar nerve. The split hand indicates a potentially specific pathological mechanism, suggesting hyperexcitability of both upper and lower motor neuron/axons. Along with this symptom, wide-spread fasciculations are prominent clinical features in patients with ALS, specifically seen in ALS among disorders with neurogenic muscle atrophy. Fasciculations frequently arise from the motor nerve terminals, and the hyperexcitability of motor axons appears to constitute the pathophysiology of the disease. Neurophysiologic investigations of the upper and lower motor neurons/axons have shown increased excitability. The altered excitability is supposed to relate to motor neuron death.