Maria O. Kovalchuk

Comparing excitability at 37°C versus at 20°C: Differences between motor and sensory axons: Motor Versus Sensory Axons

In some peripheral nervous system disorders, cold induces symptoms of muscle weakness without loss of sensation. To understand this selective effect on motor function, it is first essential to delineate the effects of cooling in motor and sensory axons of healthy subjects.

Excitability tests using high-density surface-EMG: A novel approach to studying single motor units

OBJECTIVEnTo study excitability of single motor units (MUs) using high-density surface-EMG.nnnMETHODSnMotor unit action potentials (MUAPs) were evoked by submaximal stimulation of the median nerve at the wrist and recorded with a 9u202f×u202f14 electrode grid on the skin overlying the thenar muscles. For excitability tests of single MUs, the most optimal specific single-channel surface-EMG signal was selected based on the spatiotemporal profile of single MUs.nnnRESULTSnAxonal excitability measures were successfully obtained from 14 single MUs derived from ten healthy subjects. Selecting the optimal single-channel surface-EMG signals minimized interference from other single MUs and improved signal-to-noise ratio. The muscle fiber conduction velocity (MFCV) could also be derived from the unique spatiotemporal profile of single MUs.nnnCONCLUSIONnHigh-density surface-EMG helps to isolate single MUAP responses, making it a suitable technique for assessing excitability in multiple single motor axons per nerve.nnnSIGNIFICANCEnOur method enables the reliable study of ion-channel dysfunction in single motor axons of nerves without any requirement for specific conditions, such as prominent MU loss or enlarged MUAPs due to collateral sprouting.

Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double‐Blind, Placebo‐Controlled, Crossover Trial

Increased excitability of motor neurons in patients with amyotrophic lateral sclerosis (ALS) may be a relevant factor leading to motor neuron damage. This randomized, double‐blind, three‐way crossover, placebo‐controlled study evaluated peripheral motor nerve excitability testing as a biomarker of hyperexcitability and assessed the effects of riluzole and retigabine in 18 patients with ALS. We performed excitability testing at baseline, and twice after participants had received a single dose of either 100u2009mg riluzole, 300u2009mg retigabine, or placebo. Between‐ and within‐day repeatability was at least acceptable for 14 out of 18 recorded excitability variables. No effects of riluzole on excitability testing were observed, but retigabine significantly decreased strength‐duration time‐constant (9.2%) and refractoriness at 2 ms (10.2) compared to placebo. Excitability testing was shown to be a reliable biomarker in patients with ALS, and the acute reversal of previously abnormal variables by retigabine justifies long‐term studies evaluating the impact on disease progression and survival.

Sodium-potassium pump assessment by submaximal electrical nerve stimulation

OBJECTIVEnSodium-potassium pump dysfunction in peripheral nerve is usually assessed by determining axonal hyperpolarization following maximal voluntary contraction (MVC) or maximal electrical nerve stimulation. As MVC may be unreliable and maximal electrical stimulation too painful, we assessed if hyperpolarization can also be induced by submaximal electrical nerve stimulation.nnnMETHODSnIn 8 healthy volunteers different submaximal electrical stimulus trains were given to the median nerve at the wrist, followed by 5 min assessment of thresholds for compound muscle action potentials of 20%, 40% or 60% of maximal.nnnRESULTSnThreshold increase after submaximal electrical nerve stimulation was most prominent after an 8u202fHz train of at least 5 min duration evoking submaximal CMAPs of 60%. It induced minimal discomfort and was not painful. Threshold increase after MVC was not significantly higher than this stimulus train.nnnCONCLUSIONSnSubmaximal electrical stimulation evokes activity dependent hyperpolarization in healthy test subjects without causing significant discomfort.nnnSIGNIFICANCEnSodium-potassium pump function may be assessed using submaximal electrical stimulation.

T106. Warming nerves for excitability-testing

Introduction Temperature affects excitability-variables measured from peripheral nerve. Excitability studies provide valuable insights into disease mechanisms in motor neuron disease and various neuropathies. Warming the nerve prior to the investigation helps to compensate for temperature variability, facilitates reproducibility, and improves the certainty of ascribing changes to pathophysiological mechanisms. For clinical purposes, therefore, it is important to determine how long a nerve has to be warmed for an excitability-variable to reach a stable value. We investigated which method of warming the nerve was quickest in reaching stable excitability variables. Methods In five healthy subjects, we compared three methods of warming the median nerve to 37u202f°C: (i) infrared lamp, (ii) water blanket, and (iii) water bath. Prior to warming the nerve, an excitability test was performed in all three methods to assess baseline values for distal motor latency (DML) and multiple excitability variables (strength duration time constant, rheobase, minimal and resting I/V slope, relative refractory period and super-excitability). During a one-hour warming period, the excitability-tests were repeated every 10u202fmin from which the values for DML and excitability variables were determined. To asses which were affected by temperature in our subjects, we first investigated the temperature relation for all recorded variables. Temperature dependent variables were fitted by an exponential function from which the time-constant and asymptotic end-value were determined. A variable was considered to be stable when it had reached 95% of the asymptotic end-value. Results Temperature-dependency was found for DML, refractory period and super-excitability. Of the three warming methods, the water bath was the quickest in reaching stable values for DML (29u202fmin, IQR 22–30), refractory period (25u202fmin, IQR 23–33), and super-excitability (43u202fmin, IQR 43–49). For the infrared lamp, DML reached stable values at 36u202fmin (IQR 30–42), refractory period at 28u202fmin, IQR 27–32), and super-excitability at 45u202fmin, IQR 36–51). For the water blanket stable values were reached for DML at 36u202fmin (IQR 23 – 52), for refractory period at 34u202fmin (IQR 29–35), and for super-excitability at 45u202fmin (IQR 25–71). Conclusion Warming the median nerve in a water bath is the most efficient way to warm the nerve for excitability-testing.

F128. Excitability-tests using multi-channel contraction force recordings: Development of a novel setup to study distal motor excitability properties

Introduction In animal models of motor neuron disease downstream pathophysiological events were shown to occur at distal nerve terminal branches. Recently, distal excitability-tests were developed which have the potential to assess changes in ion-channel activity in these branches. In these tests, electrical conditioning and test stimuli are delivered to distal motor axon branches near the muscle. The muscle responses are then recorded by assessing threshold-changes for eliciting a given muscle force as CMAP-recording would be too much affected by electrical stimulus artifacts. With current methods insight into direction of force remains unknown when using a single force transducer. Therefore, we present a novel method to study distal excitability by monitoring force in multiple directions. Methods Excitability properties were obtained by stimulating the median nerve at wrist level and the motor point over the thenar muscles. Thumb contraction force was recorded using four transducers, which were configured in such a way to measure force in left–right and up–down direction. With this configuration the transducers enclosed a square in the middle which was used to position the interphalangeal joint of the thumb. Using multiple force transducers the optimal recording direction was determined by rotating the transducers to maximize the response in a single-channel and minimize the response in the others. For excitability testing, the single-channel with the maximum response was selected. Results Five excitability recordings were successfully performed in the median nerve at wrist level (nu202f=u202f3) and motor point (nu202f=u202f2) in a single test subject. The maximum baseline to peak force during supramaximal nerve and motor point stimulation was approximately 2–3u202fN. The mean threshold for 50% maximum force was 2.4u202fmA at wrist level, and right-shifted for the motor point with a mean threshold of 10.2u202fmA. The mean strength-duration time constant was 0.476u202fms at the wrist level and 0.211u202fms at the motor point. At the motor point, the current-threshold relationship could not be completed for hyperpolarizing conditioning stimuli over 50%, most likely due to high currents. In the recovery cycle, the thresholds from 2.5u202fms to 100u202fms were lower for motor point stimulation than stimulation at wrist level. Although minimal, small force responses were also observed perpendicular to main recording direction. Conclusion Measuring excitability with multiple force transducers is potentially useful to optimize distal excitability recording.

T35. Developing a mathematical model of the human peripheral myelinated axon: Effects of segmental demyelination and impaired sodium channel conductance

Introduction Immune-mediated neuropathies affect myelinated nerve fibers, including Schwann cells, axons, and the complex array of ion-channels and other proteins in their membrane. The downstream events leading to damage or dysfunction of these structures in human neuropathies are often impossible to investigate because the available experimental methods cannot assess the consequences of a single pathophysiological mechanism and are only applicable to lower mammalian myelinated axons. Knowledge of these mechanisms is essential for the development of treatments aimed at prevention of irreversible nerve damage. The present study is a first step in the development of a complex forward mathematical model of the human peripheral myelinated axon which should incorporate all available functional knowledge on higher mammalian or human myelinated axons obtained, for instance, by patch-clamp studies. Here we assessed activation threshold for electrical stimulation and conduction behavior by focussing on segmental demyelination and sodium channel dysfunction in human motor and sensory axons. Methods We applied an established peripheral myelinated axon model consisting of 40 nodes. To simulate human motor axons, we modified the nodal membrane dynamics to those used in human peripheral motor nerve excitability tests in the median nerve. Sensory axons were simulated by doubling the percentage of persistent sodium channels. Focal segmental demyelination was simultaneously applied on the paranodal, juxtaparanodal, and internodal regions surrounding the three middle nodes by gradually increasing myelin capacitance and conductance until conduction failure occurred. Subsequently, impaired nodal sodium channel function on the three middle nodes was simulated by gradually decreasing the nodal transient and persistent sodium conductance. Results Normal motor and sensory conduction velocity was approximately 53u202fm/s and 54u202fm/s. The activation threshold in the motor axon model was 2% higher than for the sensory axon model. At 70% demyelination, the motor and sensory conduction velocity dropped to 37u202fm/s. Conduction block occurred for both at 97% of segmental demyelination. With decreasing sodium channel conductance motor axons showed conduction block at a decrease of 94% and sensory axons at 95%. At the site of demyelination the activation threshold increased up to approximately 4-fold in motor and sensory axon model before conduction block occurred. For impaired sodium channel conductance the activation threshold increase was approximately a factor of 3. Conclusion Using the longitudinal myelinated axon model, we successfully explored the increase in activation threshold and conduction slowing and block due to demyelination and decrease in sodium channel conductance.

Comparing excitability at 37°C versus at 20°C: Differences between motor and sensory axons

In some peripheral nervous system disorders, cold induces symptoms of muscle weakness without loss of sensation. To understand this selective effect on motor function, it is first essential to delineate the effects of cooling in motor and sensory axons of healthy subjects.

Comparing excitability at 37°C with 20°C: differences between motor and sensory axons

In some peripheral nervous system disorders, cold induces symptoms of muscle weakness without loss of sensation. To understand this selective effect on motor function, it is first essential to delineate the effects of cooling in motor and sensory axons of healthy subjects.

O122 Nerve excitability at different target levels in multifocal motor neuropathy

Objectives To determine if different types of motor axons in multifocal motor neuropathy (MMN) are affected differently. Methods In 17 MMN patients we performed excitability tests of the median nerve motor axons at three target levels (20%, 40%, and 60% of the maximum CMAP). Motor responses were recorded from the thenar muscle. Nerve conduction findings included motor conduction block, demyelinative slowing, or normal values in the forearm region of the median nerve. Mann-Whitney test was used for statistical analysis between groups. Results Excitability parameters between 20% and 40% target levels did not demonstrate any difference. Depolarizing threshold electrotonus peak (TEdpeak) and S2 accommodation differed significantly between 40% and 60% target levels. Largest differences were observed between 20% and 60% target levels: fanning out of threshold electrotonus ( p xa0=xa00.008) was more pronounced at 60% target level, resting ( p xa0=xa00.029) and minimal ( p xa0=xa00.017) current-voltage slopes were steeper at 20% target level, TEd peak ( p xa0=xa00.007) and S2 accommodation ( p xa0=xa00.024) were greater at 20% target level. Discussion Discrepancies in the excitability parameters among axons with different thresholds may highlight selective nerve abnormalities in MMN, which renders them more vulnerable to develop axon damage along the course of MMN. Conclusions Current technique showed that motor excitability-abnormalities in MMN differ betweenxa0axons with different thresholds. Significance Excitability tests applied at different target levels may reveal specific ion-channel disfunction in different types of motor axons in MMN.