Strength-duration Time Constant Research Articles

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...

Nerve excitability measured with the TROND protocol in amyotrophic lateral sclerosis: a systematic review and meta-analysis.

This meta-analysis assessed the 30+ nerve excitability indices generated by the TROND protocol to identify potential biomarkers for amyotrophic lateral sclerosis (ALS). A comprehensive search was conducted in multiple databases to identify human studies that tested median motor axons. Forest plot analyses were performed using a random-effects model to determine the pooled effect (Z-score), heterogeneity (I2), and Cohen's d for potential biomarker identification. Out of 2,866 studies, 23 studies met the inclusion criteria, incorporating data from 719 controls and 942 patients with ALS. Seven indices emerged as potential biomarkers: depolarizing threshold electrotonus (TEd) 90-100 ms, strength-duration time constant (SDTC), superexcitability, TEd 40-60 ms, resting I/V slope, 50% depolarizing I/V, and subexcitability (ranked by the magnitude of the difference between patients and controls from largest to smallest). In a sensitivity analysis focusing on patients with larger compound muscle action potentials (CMAPs), only four indices were potential biomarkers: TEd 10-20 ms, TEd 90-100 ms, superexcitability, and SDTC. Among the extensive range of 30+ excitability indices generated by the TROND protocol, we have identified seven indices that effectively differentiate patients with ALS from healthy controls. Furthermore, a smaller subset of four indices shows promise as potential biomarkers when the CMAP remains relatively large. However, most studies were considered to be at moderate risk of bias due to case-control designs and absence of sensitivity and specificity calculations, underscoring the need for more prospective diagnostic test-accuracy studies with appropriate disease controls.NEW & NOTEWORTHY This meta-analysis uncovers seven potential axonal excitability biomarkers for lower motor neuron pathology in ALS, shedding light on ion channel dysfunction. The identified dysfunction aligns with the primary pathology-protein homeostasis disruption. These biomarkers could fill a gap to detect presymptomatic spread of the disease in the spinal cord and monitor treatments targeting protein homeostasis and limiting spread, toward enhancing patient care.

High-dose pharmaceutical-grade biotin in patients with demyelinating neuropathies: a phase 2b open label, uncontrolled, pilot study

BackgroundWe proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept.MethodsPhase IIb open label, uncontrolled, single center, pilot study in 15 patients (three groups of five patients) with chronic demyelinating peripheral neuropathy, i.e. chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelin-associated glycoprotein neuropathy and Charcot-Marie-Tooth 1a or 1b. The investigational product was high-dose pharmaceutical-grade biotin (100 mg taken orally three times a day over a maximum of 52 weeks.The primary endpoint was a 10% relative improvement in 2 of the following 4 electrophysiological variables: motor nerve conduction velocity, distal motor latency, F wave latency, duration of the compound muscle action potential. The secondary endpoints included Overall Neuropathy Limitations Scale (ONLS) score, Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sum score, 10-m walk test, 6-min walk test, posturography parameters, and nerve excitability variables.ResultsThe primary endpoint was reached in one patient. In the full population analysis, some secondary endpoints parameters improved: MRC score, INCAT sensory sum score, 6-min walk distance, strength-duration time constant, and rheobase. There was a positive correlation between the improvement in the 6-min walk distance and the strength-duration time constant. Regarding the safety results, 42 adverse events occurred, of which three were of severe intensity but none was considered as related to the investigational product.ConclusionsEven if the primary endpoint was not met, administration of high-dose pharmaceutical-grade biotin led to an improvement in various sensory and motor parameters, gait abilities, and nerve excitability parameters. The tolerance of the treatment was satisfactory.Trial registrationClinicalTrials.gov Identifier: NCT02967679; date 2016/12/05.

Strength-duration time constant and rheobase measurements: Comparison of the threshold tracking method and a manual procedure

ObjectiveTo compare the strength-duration time constant (SDTC) and rheobase measurements obtained by the threshold tracking method (TT) and by a non-automated method (MM). MethodsThe MM procedure involved measuring, using a routine electrodiagnostic device, the intensity required to evoke a motor response whose amplitude corresponds to 40% of the maximum amplitude for four stimulus duration (1.0, 0.7, 0.5, 0.2 ms), and studying the linear relationship between stimulus charge and stimulus duration (slope = rheobase, intercept on the x-axis = SDTC). Using TT and MM, 30 successive healthy subjects (mean age = 38 years old) underwent a prospective evaluation of SDTC and rheobase of the median nerve motor axons at the wrist. Nerve stimulation and bipolar recording of evoked motor responses were performed with disposable self-adhesive surface electrodes. ResultsThe Spearman correlations between the two methods were 0.78 (p < 0.0001) for SDTC and 0.96 (p < 0.0001) for the rheobase. The Bland-Altman analysis did not reveal any systematic bias of MM compared to TT. ConclusionsThe MM procedure was reliable for strength-duration relationship analysis. SignificanceWe encourage neurophysiologists, who do not have dedicated threshold tracking equipment, not to hesitate to use these simple tools to assess peripheral nerve excitability.

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 &gt;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&lt;0.0001) and MUSIX was significantly higher (p&lt;0.001) in both ALS groups compared to controls. Mean strength-duration time constant in the ALS:4- arm (0.50ms±0.11; p&lt;0.05) and superexcitability in both ALS groups (ALS:4- -29.05%±9.24, ALS:4+ -27.67%±8.03; p&lt;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.

Strength-duration properties and excitability of motor and sensory axons across different target thresholds.

The present series of studies aimed to investigate the biophysical basis underlying differences in behavior between motor and sensory axons at different target response levels. In 24 healthy individuals, axonal excitability protocols measured strength-duration properties and latent addition across several axonal populations, with target amplitudes set at 10%, 20%, 40%, and 60%. Strength-duration time constants (SDTCs) were typically longer at lower target levels for both motor and sensory axons. Threshold change at 0.2 ms during assessment of latent addition, representing a persistent Na+ current (Nap), was higher in sensory axons. Passive membrane properties were not different across target levels. Significant relationships were evident between the threshold change at 0.2 ms and SDTC across all target levels for motor and sensory axons. These differences were explored using mathematical modeling of excitability data. With decreasing target size, as the internodal leak conductance increased in sensory axons, the Barrett-Barrett conductance decreased, whereas the hyperpolarization-activated cation current (Ih) channels became more depolarized. A similar pattern was observed in motor axons. As such, it was concluded that Nap was not responsible for the differences observed in SDTC between different target levels, although within specific target levels, Nap changes contributed to the variability of SDTC. This study provides a comprehensive assessment of Nap current, SDTC, and outlines key factors operating at different target levels in motor and sensory axons. Findings from the present study may point to the contributing factors of symptom development in human neuropathy.NEW & NOTEWORTHY This study provides a comprehensive assessment concerning the strength-duration behavior of motor and sensory axons at differing target levels of the compound nerve response. Strength-duration time constant was increased at lower target response levels particularly for sensory axons, whereas threshold change at 0.2 ms and passive membrane properties were not different. The results have established templates for axonal behavior in normal human axons, demonstrating altered adaptive responses, presumably secondary to different patterns of nerve activation.

Age-related changes in sensory and motor components of the Hoffmann-reflex pathway of the flexor carpi radialis.

Ageing is accompanied by numerous changes within the sensory and motor components of the muscle spindle pathway. To further document these age-related changes, this study compared the characteristics of the Hoffmann (H) reflex and M wave, evoked with several pulse durations, between young and old adults. The H-reflex and M-wave recruitment curves were recorded at rest in the flexor carpi radialis of 12 young (21-36 years) and 12 older adults (62-80 years). For each pulse duration (0.05, 0.2 and 1ms), the maximal M-wave (MMAX ) and H-reflex (HMAX ) amplitude, the M-wave amplitude associated with HMAX (MHmax ) and the H-reflex amplitude for a stimulus intensity evoking an M-wave of 5% MMAX (HM5% ) were measured. The strength-duration time constant and response threshold were estimated from the charge/stimulus-duration relation for the H reflex and M wave. Results indicate that varying pulse duration mainly induces a similar effect on H-reflex and M-wave recruitment curves between young and older adults. Regardless of pulse duration, old adults had lesser HMAX (p = 0.029) and HM5% (p < 0.001) but greater MHmax (p < 0.001). The H-reflex and M-wave response thresholds were greater in old than young adults (p = 0.003), but the strength-duration time constant was lesser in old than young adults for the H reflex (p = 0.048) but not the M wave (p = 0.21). These results suggest greater age-related changes in the sensory than the motor component of the H-reflex pathway, which may be indicative of a greater loss of sensory than motor axons or alterations of synapses between Ia afferents and motor neurones.

Dependence of cortical neuronal strength-duration properties on TMS pulse shape

ObjectiveThe aim of present study was to explore the effects of different combinations of transcranial magnetic stimulation (TMS) pulse width and pulse shape on cortical strength-duration time constant (SDTC) and rheobase measurements. MethodsResting motor thresholds (RMT) at pulse widths (PW) of 30, 45, 60, 90 and 120 µs and M−ratios of 0.2, 0.1 and 0.025 were determined using figure-of-eight coil with initial posterior-to-anterior induced current. The M−ratio indicates the relative phases of the induced current with lower values signifying a more unidirectional stimulus. Strength-duration time constant (SDTC) and rheobase were estimated for each M−ratio and various PW combinations. Simulations of biophysically realistic cortical neuron models assessed underlying neuronal populations and physiological mechanisms mediating pulse shape effects on strength-duration properties. ResultsThe M−ratio exerted significant effect on SDTC (F(2,44) = 4.386, P = 0.021), which was longer for M−ratio of 0.2 (243.4 ± 61.2 µs) compared to 0.025 (186.7 ± 52.5 µs, P = 0.034). Rheobase was significantly smaller when assessed with M−ratio 0.2 compared to 0.025 (P = 0.026). SDTC and rheobase values were most consistent with pulse width sets of 30/45/60/90/120 µs, 30/60/90/120 µs, and 30/60/120 µs. Simulation studies indicated that isolated pyramidal neurons in layers 2/3, 5, and large basket-cells in layer 4 exhibited SDTCs comparable to experimental results. Further, simulation studies indicated that reducing transient Na+ channel conductance increased SDTC with larger increases for higher M−ratios. ConclusionsCortical strength-duration curve properties vary with pulse shape, and the modulating effect of the hyperpolarising pulse phase on cortical axonal transient Na+ conductances could account for these changes, although a shift in the recruited neuronal populations may contribute as well. SignificanceThe dependence of the cortical strength-duration curve properties on the TMS pulse shape and pulse width selection underscores the need for consistent measurement methods across studies and the potential to extract information about pathophysiological processes.

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.

Plasma taurine is an axonal excitability-translatable biomarker for amyotrophic lateral sclerosis

Although various body fluid biomarkers for amyotrophic lateral sclerosis (ALS) have been reported, no biomarkers specifically reflecting abnormalities in axonal excitability indices have currently been established. Capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry were used to perform a comprehensive metabolome analysis of plasma from seven ALS patients and 20 controls, and correlation analysis with disease phenotypes was then performed in 22 other ALS patients. Additionally, electrophysiological studies of motor nerve axonal excitability were performed in all ALS patients. In the ALS and control groups, levels of various metabolites directly associated with skeletal muscle metabolism, such as those involved in fatty acid β-oxidation and the creatine pathway, were detected. Receiver operating characteristic curve analysis of the top four metabolites (ribose-5-phosphate, N6-acetyllysine, dyphylline, 3-methoxytyrosine) showed high diagnostic accuracy (area under the curve = 0.971) in the ALS group compared with the control group. Furthermore, hierarchical cluster analysis revealed that taurine levels were correlated with the strength-duration time constant, an axonal excitability indicator established to predict survival. No significant effects of diabetes mellitus and treatment (Riluzole and Edaravone) on this relationship were detected in the study. Therefore, plasma taurine is a potential novel axonal excitability-translatable biomarker for ALS.

Axonal Excitability Does Not Differ between Painful and Painless Diabetic or Chemotherapy-Induced Distal Symmetrical Polyneuropathy in a Multicenter Observational Study.

ObjectiveAxonal excitability reflects ion channel function, and it is proposed that this may be a biomarker in painful (vs painless) polyneuropathy. Our objective was to investigate the relationship between axonal excitability parameters and chronic neuropathic pain in deeply phenotyped cohorts with diabetic or chemotherapy‐induced distal symmetrical polyneuropathy.MethodsTwo hundred thirty‐nine participants with diabetic polyneuropathy were recruited from sites in the UK and Denmark, and 39 participants who developed chemotherapy‐induced polyneuropathy were recruited from Denmark. Participants were separated into those with probable or definite neuropathic pain and those without neuropathic pain. Axonal excitability of large myelinated fibers was measured with the threshold tracking technique. The stimulus site was the median nerve, and the recording sites were the index finger (sensory studies) and abductor pollicis brevis muscle (motor studies).ResultsParticipants with painless and painful polyneuropathy were well matched across clinical variables. Sensory and motor axonal excitability measures, including recovery cycle, threshold electrotonus, strength–duration time constant, and current–threshold relationship, did not show differences between participants with painful and painless diabetic polyneuropathy, and there were only minor changes for chemotherapy‐induced polyneuropathy.InterpretationAxonal excitability did not significantly differ between painful and painless diabetic or chemotherapy‐induced polyneuropathy in a multicenter observational study. Threshold tracking assesses the excitability of myelinated axons; the majority of nociceptors are unmyelinated, and although there is some overlap of the "channelome" between these axonal populations, our results suggest that alternative measures such as microneurography are required to understand the relationship between sensory neuron excitability and neuropathic pain. ANN NEUROL 2022;91:506–520

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).

HP58 : Effects of sodium channel blockers on “nerve exciatability threshold tracking“

Selective voltage gated sodium channel blockers are of growing interest as treatment for pain. For drug development of such compounds, it would be critical to have a biomarker that can be used for proof-of-mechanism. We aimed to evaluate whether drug-induced changes in sodium conductance can be detected using nerve excitability threshold tracking in 18 healthy subjects. In a randomized, double-blind, three-way crossover study, effects of single doses of mexiletine and lacosamide were compared to placebo. On each study visit, motor- and sensory nerve excitability measurements of the median nerve were performed (pre-dose; 2- and 5-hours post-dose). Stimulation was guided by QTRAC-S. Treatment effects were calculated using an ANCOVA, with baseline as covariate. Mexiletine and lacosamide had significant effects on a multitude of motor- and sensory nerve excitability parameters. In motor nerves, TEd 40-60ms was significantly decreased when compared to placebo, with an estimated difference -1.37% (95%CI:-2.20,-0.55;p=0.002) after mexiletine and -1.27% (95%CI:-2.0968,-0.4430; p=0.004) after lacosamide. Moreover, mexiletine and lacosamide significantly increased superexcitability in motor nerves, with an estimated difference of 1.74% (95%CI:0.61,2.87; p=0.004) and 1.47% (95%CI:0.34, 2.60;p=0.013), respectively. The strength-duration time constant decreased after lacosamide in both motor nerves -0.03ms (95%CI:-0.06,-0.01;p=0.005) and sensory nerves -0.08ms (95%CI:-0.12,-0.05;p<0.001). Mexiletine and lacosamide significantly decrease excitability of motor and sensory nerves, in line with the mechanism of action. This study shows that threshold tracking can be an effective biomarker in pharmacological studies. The method would therefore be a valuable tool in drug development, to help identifying target engagement in healthy subjects.

Influence of age and gender in the sensory nerve fibers excitability.

ObjectivesTo assess the influence of age and gender on sensory nerve axonal excitability parameters.MethodsThirty‐three healthy subjects (21 women) were included, with a mean age of 34.6 (range 21–76). Median sensory nerve excitability measurements (index finger) were performed using the TRONDNF nerve excitability protocol of the QTRAC program.ResultsPeak sensory nerve action potential (SNAP) amplitude was significantly higher among women (27.1 vs. 9.2 μV; p = .022), and strength–duration time constant (SDTC) was significantly higher in men (0.7 vs. 0.5; p = .011), not dependent on age. Greater age was negatively correlated with resting I/V slope, not dependent on gender (r = –0.4; p = .024). No other changes in excitability properties with increasing age were found.ConclusionsPhysiological features like as age and gender do not have a relevant impact on sensory nerve excitability measurements, which can have implications regarding pharmacological treatments.

WS4.3. Overview of Axonal Excitability Studies

Nerve excitability testing is a non-invasive neurophysiological technique, which investigates nerve functions in vivo . While nerve conduction studies deliver supramaximal stimuli to measure conduction velocities and the number of large myelinated fibres, nerve excitability studies use weaker stimuli and measure strength of stimuli, which evoke target compound muscle action potential or sensory nerve action potential amplitudes. The combination of conditioning and test stimuli, with various strength and duration, can examine functions of various types of ion channels and ion pumps and exchangers, which are located in peripheral nerve axons, and membrane potential. Several paradigms, such as strength-duration properties, threshold electrotonus, current-threshold relationship and recovery cycle, are assessed in this testing, and alterations of parameters in these paradigms indicate changes in those functions. This technique has disclosed various pathophysiological alterations mainly in genetic and acquired channelopathies. A famous study, using this technique, disclosed an effect of puffer fish poisoning for nerve excitability. Tetrodotoxin is known to block sodium channels, and salient reductions of strength-duration time constant and refractoriness in recovery cycle, makers of persistent and transient sodium channel functions, respectively, were disclosed in patients with tetrodotoxin intoxation. This study firstly visualized an effect of tetrodotoxin for the human peripheral nerve. In another study, increased strength-duration time constant, i.e. increased excitability, was revealed in patients with neuropathic pain and muscle cramps. Mexiletine treatment, a sodium channel blocker, for these patients relieved those symptoms and decreased strength-duration time constant. As those studies, recent studies, using this testing, have disclosed an impact of altered ion channel functions for neurological diseases and utility of this technique as a treatment biomarker. In this session, I plan to introduce the principle of this testing and recent advances in clarification of pathophysiology in neurological diseases and treatment developments, using this testing.

The Effects of Menstrual Cycle on Sympathetic Skin Response and Strength–Duration Properties

Background: Sympathetic control of the circulation is considerably affected by female reproductive hormones. Sudomotor function can be easily evaluated with sympathetic skin response (SSR). Although studies reveal that SSR amplitude decreases with hormone replacement therapy, the effect of estrogen on SSR is unclear. Measuring axonal excitability provides information about the physiological and physical properties of axonal ion channels and nerves. Axonal excitability tests may also give valuable information about the pathophysiology underlying neuronal disorders. In this study, we investigate the influence of female hormones, especially estrogen, on neuronal excitability and the sympathetic nervous system. Methods: SSR and strength–duration time constant (SDTC) tests were conducted on healthy women with a mean age of 26 ± 4 years with regular menstrual cycles. The tests were performed during the first 3 days of the menstrual cycle when the level of estrogen is at its lowest and 2 days before ovulation when the estrogen is at its highest level. Results: SDTC, rheobase, and the latency of SSR were found to be relatively shorter at 2 days before ovulation when compared with the values of the first 3 days of the menstrual cycle. However, the difference was not statistically significant (P &gt; 0.05). Discussion: The SDTC and SSR values in the 2 days before ovulation and the first 3 days of the menstrual cycle did not show any significant differences. We suggested that these parameters do not affect neuronal excitability associated with varied estrogen levels. Conclusion: Further research will be required to fully understand the influence of sex hormones on the nervous system in menstrual cycles, which can suggest underlying mechanisms of various diseases that are linked with autonomic and hormonal alterations.

Impact of stimulus duration on motor unit thresholds and alternation in compound muscle action potential scans

ObjectiveTo investigate the impact of stimulus duration on motor unit (MU) thresholds and alternation within compound muscle action potential (CMAP) scans. MethodsThe stimulus duration (0.1, 0.2, 0.6, and 1.0 ms) in thenar CMAP scans and individual MUs of 14 healthy subjects was systematically varied. We quantified variability of individual MU’s thresholds by relative spread (RS), MU thresholds by stimulus currents required to elicit target CMAPs of 5% (S5), 50% (S50) and 95% (S95) of the maximum CMAP, and relative range (RR) by 100*[S95-S5]/S50. We further assessed the strength-duration time constant (SDTC). Experimental observations were subsequently simulated to quantify alternation. ResultsRS, unaffected by stimulus duration, was 1.65% averaged over all recordings. RR increased for longer stimulus duration (11.4% per ms, p < 0.001). SDTC shortened with higher target CMAPs (0.007 ms per 10% CMAP, p < 0.001). Experiments and simulations supported that this may underlie the increased RR. A short compared to long stimulus duration recruited relative more MUs at S50 (more alternation) than at the tails (less alternation). ConclusionsThe stimulus duration significantly affects MU threshold distribution and alternation within CMAP scans. SignificanceStimulation settings can be further optimized and their standardization is preferred when using CMAP scans for monitoring neuromuscular diseases.

Does Essential Tremor Alter the Axonal Excitability Properties of Lower Motor Neurons?

Automated nerve excitability testing has identified that the altered excitability of lower motor neuron (LMN) axons in central diseases is because of trans-synaptic plasticity. Essential tremor (ET) is considered a central disorder caused by an altered cerebellar circuit. This study aimed to identify alterations in the excitability of distal motor axons in subjects with ET, with the intention of clarifying whether a trans-synaptic mechanism or LMN adaptation for tremor affects the LMNs of subjects with ET. Twenty-one consecutive patients diagnosed with ET underwent a clinical and electrophysiological evaluation. For the enrolled cases and 45 age- and gender-matched healthy controls, automated nerve excitability testing with threshold tracking techniques (QTRACS software with TRONDF multiple-excitability protocol) was used to evaluate multiple nerve excitability indices in distal median nerve motor axons. The automated protocol calculated the strength-duration time constant, parameters of threshold electrotonus and current-threshold relationship, and the recovery cycle of excitability. Comparisons of the automated nerve excitability testing parameters revealed no significant differences between the ET and control groups in any of strength-duration time constant, threshold electrotonus, current-threshold relationship, and recovery cycle, whereas the rheobase was higher in the ET group (3.4 ± 1.1 vs. 2.3 ± 1.1, mean ± standard error mean; P < 0.01). With the exception of an increased rheobase in ET subjects, no significant differences were observed in LMN excitability between the ET subjects and their controls. The extent of plasticity or adaptation in LMNs may be limited to a major change in central processes that exert marked effects on the pool of LMNs.

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials.To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS.This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements.Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks.The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001).Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.ClinicalTrials.gov Identifier: NCT02450552.