Threshold tracking transcranial magnetic stimulation and neurofilament light chain as diagnostic aids in ALS.

OBJECTIVE: There is a need for sensitive biomarkers in amyotrophic lateral sclerosis (ALS), to enable earlier diagnosis and to help assess potential treatments. The main objective of this study was to compare two potential biomarkers, threshold-tracking short-interval cortical inhibition (T-SICI), which has shown promise as a diagnostic aid, and neurofilament light chains (NfL). METHODS: Ninety-seven patients with ALS (mean age 67.1 ± 11.5 years) and 53 ALS mimics (aged 62.4 ± 12.9) were included. Mean disease duration was 14 months ±14.1. Patients were evaluated with revised ALS functional rating score (ALSFRS-R), Penn upper motor neuron score (UMNS), muscle strength using the Medical Research Council (MRC) score and examined with T-SICI, quantitative electromyography (EMG), and NfL measured in spinal fluid. RESULTS: NfL increased with increasing UMNS (rho = 0.45, p = 8.2 × 10-6) whereas T-SICI at 2.5 ms paradoxically increased toward normal values (rho = 0.53, p = 1.9 × 10-7). However, these two measures were uncorrelated. Discrimination between ALS patients and mimics was best for NfL (area under ROC curve 0.842, sensitivity 84.9%, specificity 83.5%), compared with T-SICI (0.675, 39.6%, 91.8%). For the patients with no UMN signs, NfL also discriminated best (0.884, 89.3%, 82.6%), compared with T-SICI (0.811, 71.4%, 82.6%). However, when combining NfL and T-SICI, higher AUCs of 0.854 and 0.922 and specificities of 93.8 and 100 were found when considering all patients and patients with no UMN signs, respectively. INTERPRETATION: Both T-SICI and NfL correlated with UMN involvement and combined, they provided a strong discrimination between ALS patients and ALS mimics.

Neurophysiological and imaging biomarkers of lower motor neuron dysfunction in motor neuron diseases/amyotrophic lateral sclerosis: IFCN handbook chapter.

This chapter discusses comprehensive neurophysiological biomarkers utilised in motor neuron disease (MND) and, in particular, its commonest form, amyotrophic lateral sclerosis (ALS). These encompass the conventional techniques including nerve conduction studies (NCS), needle and high-density surface electromyography (EMG) and H-reflex studies as well as novel techniques. In the last two decades, new methods of assessing the loss of motor units in a muscle have been developed, that are more convenient than earlier methods of motor unit number estimation (MUNE),and may use either electrical stimulation (e.g. MScanFit MUNE) or voluntary activation (MUNIX). Electrical impedance myography (EIM) is another novel approach for the evaluation that relies upon the application and measurement of high-frequency, low-intensity electrical current. Nerve excitability techniques (NET) also provide insights into the function of an axon and reflect the changes in resting membrane potential, ion channel dysfunction and the structural integrity of the axon and myelin sheath. Furthermore, imaging ultrasound techniques as well as magnetic resonance imaging are capable of detecting the constituents of morphological changes in the nerve and muscle. The chapter provides a critical description of the ability of each technique to provide neurophysiological insight into the complex pathophysiology of MND/ALS. However, it is important to recognise the strengths and limitations of each approach in order to clarify utility. These neurophysiological biomarkers have demonstrated reliability, specificity and provide additional information to validate and assess lower motor neuron dysfunction. Their use has expanded the knowledge about MND/ALS and enhanced our understanding of the relationship between motor units, axons, reflexes and other neural circuits in relation to clinical features of patients with MND/ALS at different stages of the disease. Taken together, the ultimate goal is to aid early diagnosis, distinguish potential disease mimics, monitor and stage disease progression, quantify response to treatment and develop potential therapeutic interventions.

Caffeine and cortical excitability, as measured with paired-pulse transcranial magnetic stimulation.

INTRODUCTION/AIMS: The transcranial magnetic stimulation tests of short-interval intracortical inhibition (SICI) by both conventional amplitude measurements (A-SICI) and threshold-tracking (T-SICI) are important methods to investigate intracortical inhibitory circuits, and T-SICI has been proposed to aid the diagnosis of amyotrophic lateral sclerosis. Beverages containing caffeine are widely consumed, and caffeine has been reported to affect cortical excitability. The aim of this study was to determine whether these SICI tests are affected by caffeine. METHODS: Twenty-four healthy subjects (13 females, 11 males, aged from 19 to 31, mean: 26.2 ± 2.4 years) were studied in a single fixed-dose randomized double-blind placebo-controlled cross-over trial of 200 mg caffeine or placebo ingested as chewing gum. A-SICI and T-SICI, using parallel tracking (T-SICIp), were performed before and after chewing gum. RESULTS: There was no significant change in SICI parameters after placebo in A-SICI (p > .10) or T-SICIp (p > .30), and no significant effect of caffeine was found on A-SICI (p > .10) or T-SICIp (p > .50) for any of the interstimulus intervals. DISCUSSION: There is no need for caffeine abstention before measurements of SICI by either the T-SICI or A-SICI measurements.

Three different short-interval intracortical inhibition methods in early diagnosis of amyotrophic lateral sclerosis.

Objectives: To compare the utility of conventional amplitude measurements of short-interval intracortical inhibition (A-SICI) with two threshold-tracking (T-SICI) methods, as aids to early diagnosis of amyotrophic lateral sclerosis (ALS). The new parallel threshold-tracking method (T-SICIp) was compared with the previously used serial tracking method (T-SICIs). Methods: 112 consecutive patients referred with the suspicion of ALS and 40 healthy controls were prospectively included. Based on clinical follow-up, patients were divided into 67 patients with motor neuron disease (MND) comprising progressive muscular atrophy (PMA) as well as ALS, and 45 patient controls. SICI was recorded from first dorsal interosseus muscle using the three different protocols. Results: MND patients had significantly reduced T-SICIp, T-SICIs and A-SICI, compared with healthy controls and patient controls, while healthy and patient controls were similar. Paradoxically, T-SICIp was least affected in MND patients with the most upper motor neuron (UMN) signs (Spearman ρ = 0.537, P < 0.0001) whereas there was no correlation for T-SICIs or A-SICI. T-SICIp also provided the best discrimination between patient controls and MND as determined by the receiver operating characteristic (ROC) curves. For patients with no UMN signs, area under ROC curve for 2-3ms inter-stimulus intervals was 0.931 for T-SICIp, 0.771 for T-SICIs and 0.786 for A-SICI. Conclusions: SICI is a sensitive measure for detection of cortical involvement in ALS patients. T-SICIp has higher sensitivity and specificity than T-SICIs and A-SICI, particularly in patients without any upper motor neuron signs.

Development and early diagnosis of critical illness myopathy in COVID-19 associated acute respiratory distress syndrome.

BACKGROUND: The COVID-19 pandemic has greatly increased the incidence and clinical importance of critical illness myopathy (CIM), because it is one of the most common complications of modern intensive care medicine. Current diagnostic criteria only allow diagnosis of CIM at an advanced stage, so that patients are at risk of being overlooked, especially in early stages. To determine the frequency of CIM and to assess a recently proposed tool for early diagnosis, we have followed a cohort of COVID-19 patients with acute respiratory distress syndrome and compared the time course of muscle excitability measurements with the definite diagnosis of CIM. METHODS: Adult COVID-19 patients admitted to the Intensive Care Unit of the University Hospital Bern, Switzerland requiring mechanical ventilation were recruited and examined on Days 1, 2, 5, and 10 post-intubation. Clinical examination, muscle excitability measurements, medication record, and laboratory analyses were performed on all study visits, and additionally nerve conduction studies, electromyography and muscle biopsy on Day 10. Muscle excitability data were compared with a cohort of 31 age-matched healthy subjects. Diagnosis of definite CIM was made according to the current guidelines and was based on patient history, results of clinical and electrophysiological examinations as well as muscle biopsy. RESULTS: Complete data were available in 31 out of 44 recruited patients (mean [SD] age, 62.4 [9.8] years). Of these, 17 (55%) developed CIM. Muscle excitability measurements on Day 10 discriminated between patients who developed CIM and those who did not, with a diagnostic precision of 90% (AUC 0.908; 95% CI 0.799-1.000; sensitivity 1.000; specificity 0.714). On Days 1 and 2, muscle excitability parameters also discriminated between the two groups with 73% (AUC 0.734; 95% CI 0.550-0.919; sensitivity 0.562; specificity 0.857) and 82% (AUC 0.820; CI 0.652-0.903; sensitivity 0.750; specificity 0.923) diagnostic precision, respectively. All critically ill COVID-19 patients showed signs of muscle membrane depolarization compared with healthy subjects, but in patients who developed CIM muscle membrane depolarization on Days 1, 2 and 10 was more pronounced than in patients who did not develop CIM. CONCLUSIONS: This study reports a 55% prevalence of definite CIM in critically ill COVID-19 patients. Furthermore, the results confirm that muscle excitability measurements may serve as an alternative method for CIM diagnosis and support its use as a tool for early diagnosis and monitoring the development of CIM.

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

OBJECTIVE: Axonal 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. METHODS: Two 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). RESULTS: Participants 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. INTERPRETATION: Axonal 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.

Short latency afferent inhibition: comparison between threshold-tracking and conventional amplitude recording methods.

Short-latency afferent inhibition (SAI), which is conventionally measured as a reduction in motor evoked potential amplitude (A-SAI), is of clinical interest as a potential biomarker for cognitive impairment. Since threshold-tracking has some advantages for clinical studies of short-interval cortical inhibition, we have compared A-SAI with a threshold-tracking alternative method (T-SAI). In the T-SAI method, inhibition was calculated by tracking the required TMS intensity for the targeted MEP amplitude (200 uV) both for the test (TMS only) and paired (TMS and peripheral stimulation) stimuli. A-SAI and T-SAI were recorded from 31 healthy subjects using ten stimuli at each of 12 inter-stimulus intervals, once in the morning and again in the afternoon. There were no differences between morning and afternoon recordings. When A-SAI was normalized by log conversion it was closely related to T-SAI. Between subjects, variability was similar for the two techniques, but within-subject variability was significantly smaller for normalized A-SAI. Conventional amplitude measurements appear more sensitive for detecting changes within-subjects, such as in interventional studies, but threshold-tracking may be as sensitive as detecting abnormal SAI in a patient.

Short interval intracortical inhibition: Variability of amplitude and threshold-tracking measurements with 6 or 10 stimuli per point.

Reduced short-interval intracortical inhibition (SICI) in motor neuron disease has been demonstrated by amplitude changes (A-SICI) and threshold-tracking (T-SICI) using 10 stimuli per inter-stimulus interval (ISI). To test whether fewer stimuli would suffice, A-SICI and T-SICI were recorded twice from 30 healthy subjects using 6 and 10 stimuli per ISI. Using fewer stimuli increased mean A-SICI variances by 23.8% but the 7.3% increase in T-SICI variance was not significant. We conclude that our new parallel threshold-tracking SICI protocol, with 6 stimuli per ISI, can reduce time and stimulus numbers by 40% without appreciable loss of accuracy.

A test to determine the site of abnormal neuromuscular refractoriness.

OBJECTIVE: The 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). METHODS: Twenty-four healthy subjects aged 37.8 ±â€¯2.4 years (mean ±â€¯SE) were examined with median nerve excitability testing using RC and RCSM protocols at normal temperature (34.1 ±â€¯0.2 °C). The recordings were repeated in 12 subjects after selective cooling of the thenar muscle (25.2 ±â€¯0.7 °C) and in 12 subjects after cooling the nerve trunk at the wrist (24.9 ±â€¯0.3 °C). RESULTS: After 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). CONCLUSIONS: A difference between RC and RCSM indicates abnormal excitability distal to the axonal membrane under the stimulating electrode. SIGNIFICANCE: Combining RCSM with the conventional RC protocol should help to localize the site of abnormal neuromuscular refractoriness.

Assessing inter-rater reproducibility in MScanFit MUNE in a 6-subject, 12-rater "Round Robin" setup.

OBJECTIVE: To assess the inter-rater reliability of MScanFit MUNE using a "Round Robin" research design. METHODS: Twelve raters from different centres examined six healthy study participants over two days. Median, ulnar and common peroneal nerves were stimulated, and compound muscle action potential (CMAP)-scans were recorded from abductor pollicis brevis (APB), abductor digiti minimi (ADM) and anterior tibial (TA) muscles respectively. From this we calculated the Motor Unit Number Estimation (MUNE) and "A50", a motor unit size parameter. As statistical analysis we used the measures Limits of Agreement (LOA) and Coefficient of Variation (COV). Study participants scored their perception of pain from the examinations on a rating scale from 0 (no pain) to 10 (unbearable pain). RESULTS: Before this study, 41.6% of the raters had performed MScanFit less than five times. The mean MUNE-values were: 99.6 (APB), 131.4 (ADM) and 126.2 (TA), with LOA: 19.5 (APB), 29.8 (ADM) and 20.7 (TA), and COV: 13.4 (APB), 6.3 (ADM) and 5.6 (TA). MUNE-values correlated to CMAP max amplitudes (R2-values were: 0.463 (APB) (p<0.001), 0.421 (ADM) (p<0.001) and 0.645 (TA) (p<0.001)). The average perception of pain was 4. DISCUSSION: MScanFit indicates a high level of inter-rater reliability, even with only limited rater experience and is overall reasonably well tolerated by patients. These results may indicate MScanFit as a reliable MUNE method with potential as a biomarker in drug trials.

The role of potassium in muscle membrane dysfunction in end-stage renal disease.

OBJECTIVE: Uremic myopathy is a condition seen in end-stage renal disease (ESRD), characterized by muscle weakness and muscle fatigue, in which the pathophysiology is uncertain. The aim of this study was to assess the role of abnormal serum constituents in ESRD patients by relating them to the excitability properties of the tibialis anterior muscle, at rest and during electrically induced muscle activation, by recording muscle velocity recovery cycles (MVRC) and frequency ramp responses. METHODS: Eighteen ESRD patients undergoing hemodialysis were evaluated by blood sample, MVRC, and frequency ramp (before and near the end of dialysis treatment), quantitative electromyography, and nerve conduction studies. Patients were compared to 24 control subjects. RESULTS: In patients, muscle relative refractory period, early supernormality, late supernormality after 5 conditioning stimuli, and latency of the last of 15 and 30 frequency ramp pulses were strongly associated with potassium levels (p < 0.01), showing depolarization before and normalization in the end of hemodialysis. CONCLUSIONS: In ESRD patients, the muscle membrane is depolarized, mainly due to hyperkalemia. SIGNIFICANCE: Since normal muscle fatigue has been attributed to potassium-induced depolarization, it seems likely that this mechanism is also a major cause of the exaggerated muscle fatigue and weakness in ESRD patients.

Conventional and Threshold-Tracking Transcranial Magnetic Stimulation Tests for Single-handed Operation.

Most single-pulse transcranial magnetic stimulation (TMS) parameters (e.g., motor threshold, stimulus-response function, cortical silent period) are used to examine corticospinal excitability. Paired-pulse TMS paradigms (e.g., short- and long-interval intracortical inhibition (SICI/LICI), short-interval intracortical facilitation (SICF), and short- and long-latency afferent inhibition (SAI/LAI)) provide information about intracortical inhibitory and facilitatory networks. This has long been done by the conventional TMS method of measuring changes in the size of the motor-evoked potentials (MEPs) in response to stimuli of constant intensity. An alternative threshold-tracking approach has recently been introduced whereby the stimulus intensity for a target amplitude is tracked. The diagnostic utility of threshold-tracking SICI in amyotrophic lateral sclerosis (ALS) has been shown in previous studies. However, threshold-tracking TMS has only been used in a few centers, in part due to the lack of readily available software but also perhaps due to uncertainty over its relationship to conventional single- and paired-pulse TMS measurements. A menu-driven suite of semi-automatic programs has been developed to facilitate the broader use of threshold-tracking TMS techniques and to enable direct comparisons with conventional amplitude measurements. These have been designed to control three types of magnetic stimulators and allow recording by a single operator of the common single- and paired-pulse TMS protocols. This paper shows how to record a number of single- and paired-pulse TMS protocols on healthy subjects and analyze the recordings. These TMS protocols are fast and easy to perform and can provide useful biomarkers in different neurological disorders, particularly neurodegenerative diseases such as ALS.

Early diagnosis of amyotrophic lateral sclerosis by threshold tracking and conventional transcranial magnetic stimulation.

BACKGROUND AND PURPOSE: Short-interval intracortical inhibition by threshold tracking (T-SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS) but has not been compared directly with conventional amplitude measurements (A-SICI). This study compared A-SICI and T-SICI for sensitivity and clinical usefulness as biomarkers for ALS. METHODS: In all, 104 consecutive patients referred with suspicion of ALS were prospectively included and were subsequently divided into 62 patients with motor neuron disease (MND) and 42 patient controls (ALS mimics) by clinical follow-up. T-SICI and A-SICI recorded in the first dorsal interosseus muscle (index test) were compared with recordings from 53 age-matched healthy controls. The reference standard was the Awaji criteria. Clinical scorings, conventional nerve conduction studies and electromyography were also performed on the patients. RESULTS: Motor neuron disease patients had significantly reduced T-SICI and A-SICI compared with the healthy and patient control groups, which were similar. Sensitivity and specificity for discriminating MND patients from patient controls were high (areas under the receiver operating characteristic curves 0.762 and 0.810 for T-SICI and A-SICI respectively at 1-3.5 ms). Paradoxically, T-SICI was most reduced in MND patients with the fewest upper motor neuron (UMN) signs (Spearman ρ = 0.565, p = 4.3 × 10-6 ). CONCLUSIONS: Amplitude-based measure of cortical inhibition and T-SICI are both sensitive measures for the detection of cortical involvement in MND patients and may help early diagnosis of ALS, with T-SICI most abnormal before UMN signs have developed. The gradation in T-SICI from pathological facilitation in patients with minimal UMN signs to inhibition in those with the most UMN signs may be due to progressive degeneration of the subset of UMNs experiencing facilitation.

Effect of intermittent high-frequency stimulation on muscle velocity recovery cycle recordings.

The technique of multifiber muscle velocity recovery cycle recordings was developed as a diagnostic tool to assess muscle membrane potential changes and ion channel function in vivo. This study was undertaken to assess the impact of intermittent high-frequency stimulation on muscle velocity recovery cycle components and to study whether the changes can be modified by endurance training. We recorded muscle velocity recovery cycles with 1 and 2 conditioning stimuli in the left tibialis anterior muscle in 15 healthy subjects during intermittent 37-Hz stimulation and analyzed its effects on the different phases of supernormality. Recordings were conducted before and after 2-wk endurance training. Training effect was assessed by measuring the difference in endurance time, peak force, and limb circumference. Muscle velocity recovery cycle recordings during intermittent high-frequency stimulation were successfully recorded in 12 subjects. Supernormality for interstimulus intervals shorter than 15 ms (early supernormality) was maximally reduced at the beginning of repetitive stimulation and recovered during stimulation. Supernormality for interstimulus intervals between 50 and 150 ms (late supernormality) showed a delayed decrease and stayed significantly reduced after high-frequency stimulation. Training had no significant effect on any of the measured parameters, but we found that training induced changes in peak force correlated positively with baseline changes of early supernormality. Our results support the hypothesis that early supernormality represents membrane potential, which depolarizes in the beginning of high-frequency stimulation. Late supernormality probably reflects transverse tubular function and shows progressive changes during high-frequency stimulation with delayed normalization.NEW & NOTEWORTHY A conditioning impulse in human muscle fibers induces a prolonged phase of increased velocity (also called supernormality) with two phases related to an early and late afterpotential. We investigated the effects of intermittent 37-Hz stimulation on muscle fiber supernormality and found that the early and late phases of supernormality changed differently, and that the late phase may reflect the ionic interactions responsible for the counter-regulation of muscle fatigue.

Comparison of figure-of-8 and circular coils for threshold tracking transcranial magnetic stimulation measurements.

OBJECTIVES: The transcranial magnetic stimulation (TMS) technique of threshold-tracking short-interval intracortical inhibition (T-SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS). Most of these studies have used a circular coil, whereas a figure-of-8 coil is usually recommended for paired-pulse TMS measurements. The aim of this study was to compare figure-of-8 and circular coils for T-SICI in the upper limb, with special attention to reproducibility, and the pain or discomfort experienced by the subjects. METHODS: Twenty healthy subjects (aged: 45.5 ±â€¯6.7, mean ±â€¯SD, 9 females, 11 males) underwent two examinations with each coil, in morning and afternoon sessions on the same day, with T-SICI measured at interstimulus intervals (ISIs) from 1-7 ms. After each examination the subjects rated degree of pain/discomfort from 0 to 10 using a numerical rating scale (NRS). RESULTS: Mean T-SICI was higher for the figure-of-8 than for the circular coil at ISI of 2 ms (p < 0.05) but did not differ at other ISIs. Intra-subject variability did not differ between coils, but mean inhibition from 1-3.5 ms was less variable between subjects with the figure-of-8 coil (SD 7.2% vs. 11.2% RMT, p < 0.05), and no such recordings were without inhibition (vs. 6 with the circular coil). The subjects experienced less pain/discomfort with the figure-of-8 coil (mean NRS: 1.9 ±â€¯1.28 vs 2.8 ±â€¯1.60, p < 0.005). DISCUSSION: The figure-of-8 coil may have better applicability in patients, due to the lower incidence of lack of inhibition in healthy subjects, and the lower experience of pain or discomfort.

Short-interval intracortical inhibition as a function of inter-stimulus interval: Three methods compared.

BACKGROUND: Short-interval intracortical inhibition (SICI), as measured by threshold-tracking as a function of inter-stimulus interval (ISI), has been proposed as a useful biomarker for amyotrophic lateral sclerosis (ALS), but its relationship to conventional amplitude measurements has not been established. METHODS: Serial tracking of SICI at increasing ISIs from 1 to 7 ms (T-SICIs) was compared in 50 healthy control subjects with the same ISIs tracked in parallel (T-SICIp), and with conventional amplitude measurements (A-SICI). For T-SICIp and A-SICI, pairs of conditioning and test stimuli with different ISIs were pseudo-randomised and interspersed with test-alone stimuli given at regular intervals. Thresholds were estimated by regression of log peak-to-peak amplitude on stimulus. RESULTS: T-SICIp and A-SICI were closely related: a ten-fold reduction in amplitude corresponding to an approximately 18% increase in threshold. Threshold increases were greater for T-SICIs than for T-SICIp at 3.5-5 ms (P < 0.001). This divergence depended on the initial settings and whether ISIs were progressively increased or decreased, and was attributed to the limitations of the serial tracking protocol. SICI variability between subjects was greatest for T-SICIs estimates and least for A-SICI, and only A-SICI estimates revealed a significant decline in inhibition with age. CONCLUSIONS: The serial tracking protocol did not accurately show the dependence of inhibition on ISI. Randomising ISIs gives corresponding SICI measures, whether tracking thresholds or measuring amplitude measurements. SICI variability suggested that A-SICI measurements may be the most sensitive to loss of inhibition.

Muscle Velocity Recovery Cycles to Examine Muscle Membrane Properties.

Although conventional nerve conduction studies (NCS) and electromyography (EMG) are suitable for the diagnosis of neuromuscular disorders, they provide limited information about muscle fiber membrane properties and underlying disease mechanisms. Muscle velocity recovery cycles (MVRCs) illustrate how the velocity of a muscle action potential depends on the time after a preceding action potential. MVRCs are closely related to changes in membrane potential that follow an action potential, thereby providing information about muscle fiber membrane properties. MVRCs may be recorded quickly and easily by direct stimulation and recording from multi-fiber bundles in vivo. MVRCs have been helpful in understanding disease mechanisms in several neuromuscular disorders. Studies in patients with channelopathies have demonstrated the different effects of specific ion channel mutations on muscle excitability. MVRCs have been previously tested in patients with neurogenic muscles. In this prior study, muscle relative refraction period (MRRP) was prolonged, and early supernormality (ESN) and late supernormality (LSN) were reduced in patients compared to healthy controls. Thereby, MVRCs can provide in vivo evidence of membrane depolarization in intact human muscle fibers that underlie their reduced excitability. The protocol presented here describes how to record MVRCs and analyze the recordings. MVRCs can serve as a fast, simple, and useful method for revealing disease mechanisms across a broad range of neuromuscular disorders.

In vivo assessment of interictal sarcolemmal membrane properties in hypokalaemic and hyperkalaemic periodic paralysis.

OBJECTIVE: Hypokalaemic periodic paralysis (HypoPP) is caused by mutations of Cav1.1, and Nav1.4 which result in an aberrant gating pore current. Hyperkalaemic periodic paralysis (HyperPP) is due to a gain-of-function mutation of the main alpha pore of Nav1.4. This study used muscle velocity recovery cycles (MVRCs) to investigate changes in interictal muscle membrane properties in vivo. METHODS: MVRCs and responses to trains of stimuli were recorded in tibialis anterior and compared in patients with HyperPP(n = 7), HypoPP (n = 10), and normal controls (n = 26). RESULTS: Muscle relative refractory period was increased, and early supernormality reduced in HypoPP, consistent with depolarisation of the interictal resting membrane potential. In HyperPP the mean supernormality and residual supernormality to multiple conditioning stimuli were increased, consistent with increased inward sodium current and delayed repolarisation, predisposing to spontaneous myotonic discharges. CONCLUSIONS: The in vivo findings suggest the interictal resting membrane potential is depolarized in HypoPP, and mostly normal in HyperPP. The MVRC findings in HyperPP are consistent with presence of a window current, previously proposed on the basis of in vitro expression studies. Although clinically similar, HyperPP was electrophysiologically distinct from paramyotonia congenita. SIGNIFICANCE: MVRCs provide important in vivo data that complements expression studies of ion channel mutations.

Measurement of axonal excitability: Consensus guidelines.

Measurement of axonal excitability provides an in vivo indication of the properties of the nerve membrane and of the ion channels expressed on these axons. Axonal excitability techniques have been utilised to investigate the pathophysiological mechanisms underlying neurological diseases. This document presents guidelines derived for such studies, based on a consensus of international experts, and highlights the potential difficulties when interpreting abnormalities in diseased axons. The present manuscript provides a state-of-the-art review of the findings of axonal excitability studies and their interpretation, in addition to suggesting guidelines for the optimal performance of excitability studies.

Following disease progression in motor neuron disorders with 3 motor unit number estimation methods.

INTRODUCTION: The objective of this study was to evaluate a recently developed motor unit number estimation (MUNE) method, MScanFit MUNE (MScan), as a measure of disease progression in amyotrophic lateral sclerosis (ALS) compared with compound muscle action potential (CMAP) amplitude and 2 traditional MUNE methods. METHODS: ALS patients were evaluated clinically using the ALS Functional Rating Scale-Revised (ALSFRS-R). MScan, multiple-point stimulation MUNE (MPS), and motor unit number index (MUNIX) were performed in the abductor pollicis brevis (APB) muscle at baseline (27 patients), 4 months (23 patients), and 8 months (16 patients). RESULTS: Of the 5 measures, MScan registered the largest decline (8.7% per month), compared with MPS (3.4%), MUNIX (4.8%), CMAP amplitude (2.0%), and ALSFRS-R (1.9%). Only MScan and ALSFRS-R registered significant decrements over 4 and 8 months. DISCUSSION: MScan may be useful as a sensitive, objective tool for quantifying motor unit loss in ALS. Muscle Nerve 59:82-87, 2019.