Simulating progressive motor neuron degeneration and collateral reinnervation in motor neuron diseases using a dynamic muscle model based on human single motor unit recordings

Objective.To simulate progressive motor neuron loss and collateral reinnervation in motor neuron diseases (MNDs) by developing a dynamic muscle model based on human single motor unit (MU) surface-electromyography (EMG) recordings. Approach.Single MU potentials recorded with high-density surface-EMG from thenar muscles formed the basic building blocks of the model. From the baseline MU pool innervating a muscle, progressive MU loss was simulated by removal of MUs, one-by-one. These removed MUs underwent collateral reinnervation with scenarios varying from 0% to 100%. These scenarios were based on a geometric variable, reflecting the overlap in MU territories using the spatiotemporal profiles of single MUs and a variable reflecting the efficacy of the reinnervation process. For validation, we tailored the model to generate compound muscle action potential (CMAP) scans, which is a promising surface-EMG method for monitoring MND patients. Selected scenarios for reinnervation that matched observed MU enlargements were used to validate the model by comparing markers (including the maximum CMAP and a motor unit number estimate (MUNE)) derived from simulated and recorded CMAP scans in a cohort of 49 MND patients and 22 age-matched healthy controls. Main results.The maximum CMAP at baseline was 8.3 mV (5th-95th percentile: 4.6 mV-11.8 mV). Phase cancellation caused an amplitude drop of 38.9% (5th-95th percentile, 33.0%-45.7%). To match observations, the geometric variable had to be set at 40% and the efficacy variable at 60%-70%. The Δ maximum CMAP between recorded and simulated CMAP scans as a function of fitted MUNE was -0.4 mV (5th-95th percentile = -4.0 - +2.4 mV). Significance.The dynamic muscle model could be used as a platform to train personnel in applying surface-EMG methods prior to their use in clinical care and trials. Moreover, the model may pave the way to compare biomarkers more efficiently, without directly posing unnecessary burden on patients

Motor Unit Integrity in Multifocal Motor Neuropathy: A Systematic Evaluation with CMAP Scans

Introduction/Aims: Progressive axonal loss in multifocal motor neuropathy (MMN) is often assessed with nerve conduction studies (NCS), by recording maximum compound muscle action potentials (CMAPs). However, reinnervation maintains the CMAP amplitude until a significant portion of the motor unit (MU) pool is lost. Therefore, we performed more informative CMAP scans to study MU characteristics in a large cohort of patients with MMN. Methods: We derived the maximum CMAP amplitude (CMAP max), an MU number estimate (MUNE), and the largest MU amplitude stimulus current required to elicit 5%, 50%, and 95% of CMAP max (S5, S50, S95) and relative ranges ([S95 − S5] × 100 / S50) from the scans. These metrics were compared with clinical, laboratory, and NCS results. Results: Forty MMN patients and 24 healthy controls were included in the study. CMAP max and MUNE were reduced in MMN patients (both P <.001). Largest MU amplitude as a percentage of CMAP max was increased in MMN patients (P <.001). Disease duration and treatment duration were not associated with MUNE. Relative range was larger in patients with anti-GM1 antibodies than in those without anti-GM1 antibodies (P =.016) and controls (P <.001). The largest MU amplitudes were larger in patients without anti-GM1 antibodies than in patients with anti-GM1 antibodies (P =.037) and controls (P =.044). Discussion: We found that MU loss is common in MMN and accompanied by enlarged MUs. Presence of anti-GM1 antibodies was associated with increased relative range of MU thresholds and reduction in largest MU amplitude. Our findings indicate that CMAP scans complement routine NCS, and may have potential for practical monitoring of treatment efficacy and disease progression

Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial

BackgroundGiven the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A. MethodsA randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between -6.0 and -2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events. DiscussionLithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup

Excitability of motor and sensory axons in multifocal motor neuropathy

OBJECTIVE: To assess excitability differences between motor and sensory axons of affected nerves in patients with multifocal motor neuropathy (MMN). METHODS: We performed motor and sensory excitability tests in affected median nerves of 20 MMN patients and in 20 age-matched normal subjects. CMAPs were recorded from the thenar and SNAPs from the 3rd digit. Clinical tests included assessment of muscle strength, two-point discrimination and joint position. RESULTS: All MMN patients had weakness of the thenar muscle and normal sensory tests. Motor excitability testing in MMN showed an increased threshold for a 50% CMAP, increased rheobase, decreased stimulus-response slope, fanning-out of threshold electrotonus, decreased resting I/V slope, shortened refractory period, and more pronounced superexcitability. Sensory excitability testing in MMN revealed decreased accommodation half-time and S2-accommodation and less pronounced subexcitability. Mathematical modeling indicated increased Barrett-Barrett conductance for motor fibers and increase in internodal fast potassium conductance for sensory fibers. CONCLUSIONS: Excitability findings in MMN suggest myelin sheath or paranodal seal involvement in motor fibers and, possibly, paranodal detachment in sensory fibers. SIGNIFICANCE: Excitability properties of affected nerves in MMN differ between motor and sensory nerve fibers

Sodium-potassium pump assessment by submaximal electrical nerve stimulation

OBJECTIVE: Sodium-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. METHODS: In 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. RESULTS: Threshold increase after submaximal electrical nerve stimulation was most prominent after an 8 Hz 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. CONCLUSIONS: Submaximal electrical stimulation evokes activity dependent hyperpolarization in healthy test subjects without causing significant discomfort. SIGNIFICANCE: Sodium-potassium pump function may be assessed using submaximal electrical stimulation

Sodium-potassium pump assessment by submaximal electrical nerve stimulation

OBJECTIVE: Sodium-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. METHODS: In 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. RESULTS: Threshold increase after submaximal electrical nerve stimulation was most prominent after an 8 Hz 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. CONCLUSIONS: Submaximal electrical stimulation evokes activity dependent hyperpolarization in healthy test subjects without causing significant discomfort. SIGNIFICANCE: Sodium-potassium pump function may be assessed using submaximal electrical stimulation

Warming nerves for excitability testing

Introduction: The aim of this study was to find the best method of warming the median nerve before excitability testing to a standard temperature. Methods: In 5 healthy subjects, the forearm and hand were warmed for 1 h to 37°C by infrared lamp, water blanket, or water bath. Recordings were performed before and during warming every 10 min. Excitability indices were fitted by exponential relations, thereby calculating the time needed to reach 95% of their asymptotic end value. Results: Distal motor latency, refractory period, and superexcitability at 10 ms changed exponentially with time. Warming by water bath took the shortest time (24 min); this was followed by warming by infrared lamp (34 min) and water blanket (35 min). Conclusions: Warming by water bath is the quickest way. The other methods took only moderately more time. Future studies need to specify both warming method and warming time before excitability testing. Muscle Nerve, 2019