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.

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.

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.

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.

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.

In vivo evidence for reduced ion channel expression in motor axons of patients with amyotrophic lateral sclerosis.

KEY POINTS: The progressive loss of motor units in amyotrophic lateral sclerosis (ALS) is initially compensated for by the reinnervation of denervated muscle fibres by surviving motor axons. A disruption in protein homeostasis is thought to play a critical role in the pathogenesis of ALS. The changes in surviving motor neurons were studied by comparing the nerve excitability properties of moderately and severely affected single motor axons from patients with ALS with those from single motor axons in control subjects. A mathematical model indicated that approximately 99% of the differences between the ALS and control units could be explained by a non-selective reduction in the expression of all ion channels. These changes in ALS patients are best explained by a failure in the supply of ion channel and other membrane proteins from the diseased motor neuron. ABSTRACT: Amyotrophic lateral sclerosis (ALS) is characterised by a progressive loss of motor units and the reinnervation of denervated muscle fibres by surviving motor axons. This reinnervation preserves muscle function until symptom onset, when some 60-80% of motor units have been lost. We have studied the changes in surviving motor neurons by comparing the nerve excitability properties of 31 single motor axons from patients with ALS with those from 21 single motor axons in control subjects. ALS motor axons were classified as coming from moderately or severely affected muscles according to the compound muscle action potential amplitude of the parent muscle. Compared with control units, thresholds were increased, and there was reduced inward and outward rectification and greater superexcitability following a conditioning impulse. These abnormalities were greater in axons from severely affected muscles, and were correlated with loss of fine motor skills. A mathematical model indicated that 99.1% of the differences between the moderately affected ALS and control units could be explained by a reduction in the expression of all ion channels. For the severely affected units, modelling required, in addition, an increase in the current leak through and under the myelin sheath. This might be expected if the anchoring proteins responsible for the paranodal seal were reduced. We conclude that changes in axonal excitability identified in ALS patients are best explained by a failure in the supply of ion channel and other membrane proteins from the diseased motor neuron, a conclusion consistent with recent animal and in vitro human data.

In vivo assessment of muscle membrane properties in the sodium channel myotonias.

INTRODUCTION: The gain-of-function mutations that underlie sodium channel myotonia (SCM) and paramyotonia congenital (PMC) produce differing clinical phenotypes. We used muscle velocity recovery cycles (MVRCs) to investigate membrane properties. METHODS: MVRCs and responses to trains of stimuli were compared in patients with SCM (n = 9), PMC (n = 8), and normal controls (n = 26). RESULTS: The muscle relative refractory period was reduced in SCM, consistent with faster recovery of the mutant sodium channels from inactivation. Both SCM and PMC showed an increased early supernormality and increased mean supernormality following multiple conditioning stimuli, consistent with slowed sodium channel inactivation. Trains of fast impulses caused a loss of amplitude in PMC, after which only half of the muscle fibers recovered, suggesting that the remainder stayed depolarized by persistent sodium currents. DISCUSSION: The differing effects of mutations on sodium channel function can be demonstrated in human subjects in vivo using this technique. Muscle Nerve 57: 586-594, 2018.

Muscle membrane properties in A pig sepsis model: Effect of norepinephrine.

INTRODUCTION: Sepsis-induced myopathy and critical illness myopathy are common causes of muscle weakness in intensive care patients. This study investigated the effect of different mean arterial blood pressure (MAP) levels on muscle membrane properties following experimental sepsis. METHODS: Sepsis was induced with fecal peritonitis in 12 of 18 anesthetized and mechanically ventilated pigs. Seven were treated with a high (75-85 mmHg) and 5 were treated with a low (≥60 mmHg) MAP target for resuscitation. In septic animals, resuscitation was started 12 h after peritonitis induction, and muscle velocity recovery cycles were recorded 30 h later. RESULTS: Muscles in the sepsis/high MAP group showed an increased relative refractory period and reduced early supernormality compared with the remaining septic animals and the control group, indicating membrane depolarization and/or sodium channel inactivation. The membrane abnormalities correlated positively with norepinephrine dose. DISCUSSION: Norepinephrine may contribute to sepsis-induced abnormalities in muscle by impairing microcirculation. Muscle Nerve 57: 808-813, 2018.

Muscle action potential scans and ultrasound imaging in neurofibromatosis type 2.

INTRODUCTION: The neuropathy in patients with neurofibromatosis type 2 (NF2) is difficult to quantify and follow up. In this study we compared 3 methods that may help assess motor axon pathology in NF2 patients. METHODS: Nerve conduction studies in median nerves were supplemented by deriving motor unit number estimates (MUNEs) from compound muscle action potential (CMAP) scans and by high-resolution ultrasound (US) peripheral nerve imaging. RESULTS: CMAP amplitudes and nerve conduction velocity were normal in the vast majority of affected individuals, but CMAP scan MUNE revealed denervation and reinnervation in many peripheral nerves. In addition, nerve US imaging enabled monitoring of the size and number of schwannoma-like fascicular enlargements in median nerve trunks. CONCLUSION: In contrast to conventional nerve conduction studies, CMAP scan MUNE in combination with US nerve imaging can quantify the NF2-associated neuropathy and may help to monitor disease progression and drug treatments. Muscle Nerve 55: 350-358, 2017.

In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2.

Ion channel dysfunction causes a range of neurological disorders by altering transmembrane ion fluxes, neuronal or muscle excitability, and neurotransmitter release. Genetic neuronal channelopathies affecting peripheral axons provide a unique opportunity to examine the impact of dysfunction of a single channel subtype in detail in vivo. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the neuronal voltage-gated calcium channel Cav2.1. In peripheral motor axons, this channel is highly expressed at the presynaptic neuromuscular junction where it contributes to action potential-evoked neurotransmitter release, but it is not expressed mid-axon or thought to contribute to action potential generation. Eight patients from five families with genetically confirmed episodic ataxia type 2 underwent neurophysiological assessment to determine whether axonal excitability was normal and, if not, whether changes could be explained by Cav2.1 dysfunction. New mutations in the CACNA1A gene were identified in two families. Nerve conduction studies were normal, but increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission in two patients. Excitability properties of median motor axons were compared with those in 30 age-matched healthy control subjects. All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing (P < 0.00007) and depolarizing currents (P < 0.001) in threshold electrotonus. In the recovery cycle, refractoriness (P < 0.0002) and superexcitability (P < 0.006) were increased. Cav2.1 dysfunction in episodic ataxia type 2 thus has unexpected effects on axon excitability, which may reflect an indirect effect of abnormal calcium current fluxes during development.

Accommodation to hyperpolarization of human axons assessed in the frequency domain.

Human axons in vivo were subjected to subthreshold currents with a threshold impedance amplitude profile to allow the use of frequency domain techniques to determine the propensity for resonant behavior and to clarify the relative contributions of different ion channels to their low-frequency responsiveness. Twenty-four studies were performed on the motor and sensory axons of the median nerve in six subjects. The response to oscillatory currents was tested between direct current (DC) and 16 Hz. A resonant peak at ∼2-2.5 Hz was found in the response of hyperpolarized axons, but there was only a small broad response in axons at resting membrane potential (RMP). A mathematical model of axonal excitability developed using DC pulses provided a good fit to the frequency response for human axons and indicated that the hyperpolarization-activated current Ih and the slow potassium current IKs are principally responsible for the resonance. However, the results indicate that if axons are hyperpolarized by more than -60% of resting threshold, the only conductances that are appreciably active are Ih and the leak conductance, i.e., that the activity of these conductances can be studied in vivo virtually in isolation at hyperpolarized membrane potentials. Given that the leak conductance dampens resonance, it is suggested that the -60% hyperpolarization used here is optimal for Ih As expected, differences between the frequency responses of motor and sensory axons were present and best explained by reduced slow potassium conductance GKs, up-modulation of Ih, and increased persistent Na(+) current INaP (due to depolarization of RMP) in sensory axons.

Estimating motor unit numbers from a CMAP scan.

INTRODUCTION: Compound muscle action potential (CMAP) scans are detailed stimulus-response curves which provide information about motor unit properties in neuromuscular disorders. This study assessed a method of automatic motor unit number estimation (MUNE) from 5-min CMAP scans. METHODS: A preliminary model, derived from the variance and slope of the scan, is refined to fit the CMAP scan more closely. The method was tested by application to 60 simulated scans, generated from between 5 and 160 motor unit potentials. RESULTS: The fitting procedure took an average of 1.5 min on a standard personal computer. Small unit numbers (5-20) were on average correctly estimated, but large unit numbers (>40) were slightly underestimated. Overall, the absolute MUNE error averaged 6.9%. CONCLUSIONS: This new MUNE method takes all excitable motor units into account and provides realistic estimates of unit numbers over the range 5 to 160. Validation as a clinical tool awaits further study. Muscle Nerve 53: 889-896, 2016.

Force training induces changes in human muscle membrane properties.

INTRODUCTION: Human muscle membrane properties can be assessed in vivo by recording muscle velocity recovery cycles (MVRCs). This study was undertaken to study the effect of muscle force training on MVRC parameters. METHODS: MVRCs with 1 to 5 conditioning stimuli were recorded from brachioradialis muscle before and after 2 weeks of muscle force training in 12 healthy subjects. The effects of training on relative refractory period and early and late supernormality were quantified. RESULTS: Force training induced a reduction of relative refractory period (P < 0.0001), while early supernormality was increased (P < 0.02) and peaked earlier (P < 0.01). Late supernormality and the increases in late supernormality due to 2 and 5 conditioning stimuli remained unchanged. CONCLUSIONS: Muscle force training leads to hyperpolarization of the resting muscle membrane potential, probably caused by an increase in the number of sodium pump sites. Muscle Nerve 54: 144-146, 2016.

Muscle velocity recovery cycles: Comparison between surface and needle recordings.

INTRODUCTION: Recording of muscle velocity recovery cycles (MVRCs) has been developed as a technique to investigate the pathophysiology of muscle diseases. MVRCs have been measured by direct muscle stimulation and concentric electromyographic needle recording. This study was undertaken to determine whether recordings can be made with surface electrodes. METHODS: MVRCs with 1 and 2 conditioning stimuli were recorded simultaneously with concentric needle and surface electrodes from the brachioradialis muscle in 12 healthy volunteers. Muscle relative refractory period, early and late supernormality, and extra-late supernormality were compared between the recording techniques. RESULTS: Surface recordings were possible in all subjects. The multifiber action potentials recorded with surface electrodes were smaller than those recorded with needles, but there was no significant difference between any of their MVRC properties. CONCLUSIONS: MVRCs can be recorded with surface electrodes in healthy subjects. The use of surface electrodes may facilitate the technique of recording MVRCs.

In vivo assessment of muscle membrane properties in myotonic dystrophy.

INTRODUCTION: Myotonia in myotonic dystrophy types 1 (DM1) and 2 (DM2) is generally attributed to reduced chloride-channel conductance. We used muscle velocity recovery cycles (MVRCs) to investigate muscle membrane properties in DM1 and DM2, using comparisons with myotonia congenita (MC). METHODS: MVRCs and responses to repetitive stimulation were compared between patients with DM1 (n = 18), DM2 (n = 5), MC (n = 18), and normal controls (n = 20). RESULTS: Both DM1 and DM2 showed enhanced late supernormality after multiple conditioning stimuli, indicating delayed repolarization as in MC. Contrary to MC, however, DM1 showed reduced early supernormality after multiple conditioning stimuli, and weak DM1 patients also showed abnormally slow latency recovery after repetitive stimulation. CONCLUSIONS: These findings support the presence of impaired chloride conductance in both DM1 and DM2. The early supernormality changes indicate that sodium currents were reduced in DM1, whereas the weakness-associated slow recovery after repetitive stimulation may provide an indication of reduced Na(+) /K(+) -ATPase activation. Muscle Nerve 54: 249-257, 2016.

Hyperexcitable C nociceptors in fibromyalgia.

OBJECTIVE: To test the hypothesis that peripheral C nociceptor function may be abnormal in fibromyalgia and that C nociceptor dysfunction may contribute to the symptoms reported by these patients. METHODS: Microneurography was used to record C nociceptors of 30 female patients meeting criteria for fibromyalgia and compared with recordings from 17 female patients with small-fiber neuropathy and 9 female controls. RESULTS: We obtained stable recordings of 186 C nociceptors in the fibromyalgia group, 114 from small-fiber neuropathy patients, and 66 from controls. The mechanosensitive nociceptors in the fibromyalgia patients behaved normally, but the silent nociceptors in 76.6% of fibromyalgia patients exhibited abnormalities. Spontaneous activity was detected in 31% of silent nociceptors in fibromyalgia, 34% in small-fiber neuropathy, and 2.2% in controls. Sensitization to mechanical stimulation was found in 24.2% of silent nociceptors in fibromyalgia, 22.7% in small-fiber neuropathy, and 3.7% in controls. Abnormally high slowing of conduction velocity when first stimulated at 0.25Hz was more common in fibromyalgia. INTERPRETATION: We show for the first time that the majority of fibromyalgia patients have abnormal C nociceptors. Many silent nociceptors exhibit hyperexcitability resembling that in small-fiber neuropathy, but high activity-dependent slowing of conduction velocity is more common in fibromyalgia patients, and may constitute a distinguishing feature. We infer that abnormal peripheral C nociceptor ongoing activity and increased mechanical sensitivity could contribute to the pain and tenderness suffered by patients with fibromyalgia.

Chloride channels in myotonia congenita assessed by velocity recovery cycles.

INTRODUCTION: Myotonia congenita (MC) is caused by congenital defects in the muscle chloride channel CLC-1. This study used muscle velocity recovery cycles (MVRCs) to investigate how membrane function is affected. METHODS: MVRCs and responses to repetitive stimulation were compared between 18 patients with genetically confirmed MC (13 recessive, 7 dominant) and 30 age-matched, normal controls. RESULTS: MC patients exhibited increased early supernormality, but this was prevented by treatment with sodium channel blockers. After multiple conditioning stimuli, late supernormality was enhanced in all MC patients, indicating delayed repolarization. These abnormalities were similar between the MC subtypes, but recessive patients showed a greater drop in amplitude during repetitive stimulation. CONCLUSIONS: MVRCs indicate that chloride conductance only becomes important when muscle fibers are depolarized. The differential responses to repetitive stimulation suggest that, in dominant MC, the affected chloride channels are activated by strong depolarization, consistent with a positive shift of the CLC-1 activation curve.

Early changes of muscle membrane properties in porcine faecal peritonitis.

INTRODUCTION: Sepsis-induced myopathy and critical illness myopathy (CIM) are possible causes of muscle weakness in intensive care patients. They have been attributed to muscle membrane dysfunction. The aim of this study was to investigate membrane properties in the early stage of experimental sepsis by evaluating muscle excitability. METHODS: In total, 20 anesthetized and mechanically ventilated pigs were randomized to either faecal peritonitis (n = 10) or to non-septic controls (n = 10). Resuscitation with fluids and vasoactive drugs was started 3 hours after peritonitis induction. Muscle membrane properties were investigated by measuring muscle velocity recovery cycles before induction of peritonitis as well as 6, 18 and 27 hours thereafter. Muscle relative refractory period (MRRP) and early supernormality (ESN) were assessed. RESULTS: Peritonitis lasting 27 hours was associated with an increase of MRRP by 28% from 2.38 ± 0.18 ms (mean ± SD) to 3.47 ± 1.79 ms (P <0.01) and a decrease of ESN by 31% from 9.64 ± 2.82% to 6.50 ± 2.64% (P <0.01). ESN reduction was already apparent 6 hours after induction of peritonitis. Values in controls did not show any significant alterations. CONCLUSIONS: Muscle membrane abnormalities consistent with membrane depolarization and/or sodium channel inactivation occurred within 6 hours of peritonitis induction. This indicates that changes that have been described in established sepsis-induced myopathy and/or CIM start early in the course of sepsis. Muscle excitability testing facilitates evaluation of the time course of these changes.

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.