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 changes in children with spinal muscular atrophy treated with nusinersen.

Spinal muscular atrophy (SMA) is associated with developmental disruption of motor axons in ventral roots of the spinal cord alongside motor axon degeneration. The pathogenesis of peripheral axonal change during development is pertinent to understand treatment response. Nerve excitability techniques, stimulating the median motor nerve at the wrist, were utilised to investigate axonal change during neurodevelopment in 24 children with SMA, compared with 71 age-matched controls. Longitudinal axonal response to nusinersen treatment in 18 children was also investigated. Significant differences in axonal development were noted in the youngest children with SMA, signified by reduced compound muscle action potential (CMAP) (P = 0.030), higher axonal threshold (P = 0.016), rheobase (minimal current amplitude of infinite duration, required to generate an action potential) (P = 0.012) and greater changes in depolarising and hyperpolarising threshold electrotonus. Subexcitability increased in all children with SMA, compared to controls. With treatment, nerve excitability changes were observed prominently in young children, with increases in CMAP, reduction in axonal threshold, fanning-in of threshold electrotonus, increase in resting current-threshold slope and reduction in subexcitability. Whilst motor axons continue to mature in SMA, developmental delays in passive and active membrane properties occur especially in early childhood. Concurrently, motor axons actively undergo degeneration. Nusinersen restores the developmental trajectory of motor axons reducing degeneration, especially in children with early treatment initiation. Our findings move the field forward in understanding the developmental aspect of childhood-onset motor neurone diseases and changes in axonal function associated with disease modification. KEY POINTS: Pathomechanisms in spinal muscular atrophy involve concurrent neurodevelopmental and neurodegenerative processes. The greatest delays in maturation of the passive and active properties of the peripheral motor axon are seen in early childhood. Nusinersen facilitates developmental recovery of the motor axon whilst also reducing neurodegeneration. Axonal dysfunction is reversed with SMN repletion particularly when intervention occurs early in development.

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.

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.

Electrophysiological investigation of motor axonal excitability in a mouse model of nerve constriction injury.

Peripheral nerve injuries caused by focal constriction are characterised by local nerve ischaemia, axonal degeneration, demyelination, and neuroinflammation. The aim of this study was to understand temporal changes in the excitability properties of injured motor axons in a mouse model of nerve constriction injury (NCI). The excitability of motor axons following unilateral sciatic NCI was studied in male C57BL/6J mice distal to the site of injury at the acute (6 hours-1 week) and chronic (up to 20 weeks) phases of injury, using threshold tracking. Multiple measures of nerve excitability, including strength-duration properties, threshold electrotonus, current-threshold relationship, and recovery cycle were examined using the automated nerve excitability protocol (TRONDNF). Acutely, injured motor axons developed a pattern of excitability characteristic of ischemic depolarisation. In most cases, the sciatic nerve became transiently inexcitable. When a liminal compound muscle action potential could again be recorded, it had an increase in threshold and latency, compared to both pre-injury baseline and sham-injured groups. These axons showed a greater threshold change in response to hyperpolarising threshold electrotonus and a significant upward shift in the recovery cycle. Mathematical modelling suggested that the changes seen in chronically injured axons involve shortened internodes, reduced myelination, and exposed juxtaparanodal fast K+ conductances. The findings of this study demonstrate long-term changes in motor excitability following NCI (involving alterations in axonal properties and ion channel activity) and are important for understanding the mechanisms of neurapraxic injuries and traumatic mononeuropathies.

Acute changes in nerve excitability following oxaliplatin treatment in mice.

Oxaliplatin chemotherapy produces acute changes in peripheral nerve excitability in humans by modulating voltage-gated Na+ channel activity. However, there are few animal studies of oxaliplatin-induced neuropathy that demonstrate similar changes in excitability. In the present study, we measured the excitability of motor and sensory caudal nerve in C57BL/6 mice after oxaliplatin injections either systemically (intraperitoneal) or locally (intramuscular at the base of the tail). As opposed to intraperitoneal administration of oxaliplatin, a single intramuscular injection of oxaliplatin produced changes in both motor and sensory axons. In motor axons, oxaliplatin caused a greater change in response to long-lasting depolarization and an upward shift in the recovery cycle, particularly at 24 h [depolarizing threshold electrotonus (TEd) 10-20 ms, P = 0.0095; TEd 90-100 ms, P = 0.0056) and 48 h (TEd 10-20 ms, P = 0.02; TEd 90-100 ms, P = 0.04) posttreatment. Oxaliplatin treatment also stimulated the production of afterdischarges in motor axons. These changes were transient and showed dose dependence. Mathematical modeling demonstrated that these changes could be accounted for by slowing inactivation of voltage-gated Na+ channels by 73.3% and reducing fast K+ conductance by 47% in motor axons. In sensory axons, oxaliplatin caused an increase in threshold, a reduction in peak amplitude, and greater threshold changes to strong hyperpolarizing currents on days 4 and 8. Thus, local administration of oxaliplatin produced clinically relevant changes in nerve excitability in mice and may provide an alternative approach for the study of acute oxaliplatin-induced neurotoxicity.NEW & NOTEWORTHY We present a novel mouse model of acute oxaliplatin-induced peripheral neurotoxicity that is comparable to clinical observations. Intramuscular injection of oxaliplatin produced acute changes in motor nerve excitability that were attributable to alterations in Na+ and K+ channel activity. Conversely, we were unable to show any significant changes in nerve excitability with systemic intraperitoneal injections of oxaliplatin. This study suggests that local intramuscular injection is a valid approach for modelling oxaliplatin-induced peripheral neuropathy in animals.

Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.

OBJECTIVES: To elucidate the motor unit response to intrathecal nusinersen in children with symptomatic spinal muscular atrophy (SMA) using a novel motor unit number estimation technique. METHODS: MScanFit MUNE studies were sequentially undertaken from the abductor pollicis brevis muscle after stimulation of the median nerve in a prospective cohort of symptomatic children with SMA, undergoing intrathecal treatment with nusinersen at a single neuromuscular centre from June 2017 to August 2019. Electrophysiological measures included compound muscle action potential (CMAP), motor unit number estimation (MUNE), motor unit number contributing to 50%-100% of CMAP (N50) and measures of collateral reinnervation including largest single motor unit potential (LSMUP) and amplitude of the smallest unit contributing to N50 (A50). RESULTS: Twenty children (median age 99 months, range 4-193) were followed for a median of 13.8 (4-33.5) months. Therapeutic intervention was an independent and significant contributor to an increase in CMAP (p = 0.005), MUNE (p = 0.001) and N50 (p = 0.04). The magnitude of this electrophysiological response was increased in children with shorter disease durations (p<0.05). Electrophysiological changes delineated children who were functionally stable from those who attained clinically significant gains in motor function. INTERPRETATION: Nusinersen therapy facilitated functional innervation in SMA through recovery of smaller motor units. Delineation of biomechanisms of therapeutic response may be the first step in identifying potential novel targets for disease modification in this and other motor neuropathies. MScanFit MUNE techniques may have a broader role in establishing biomarkers of therapeutic response in similar adult-onset diseases.

Ih contributes to increased motoneuron excitability in restless legs syndrome.

KEY POINTS: Restless legs patients complain about sensory and motor symptoms leading to sleep disturbances. Symptoms include painful sensations, an urge to move and involuntary leg movements. The responsible mechanisms of restless legs syndrome are still not known, although current studies indicate an increased neuronal network excitability. Reflex studies indicate the involvement of spinal structures. Peripheral mechanisms have not been investigated so far. In the present study, we provide evidence of increased hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated inward rectification in motor axons. The excitability of sensory axons was not changed. We conclude that, in restless legs syndrome, an increased HCN current in motoneurons may play a pathophysiological role, such that these channels could represent a valuable target for pharmaceutical intervention. ABSTRACT: Restless legs syndrome is a sensorimotor network disorder. So far, the responsible pathophysiological mechanisms are poorly understood. In the present study, we provide evidence that the excitability of peripheral motoneurons contributes to the pathophysiology of restless legs syndrome. In vivo excitability studies on motor and sensory axons of the median nerve were performed on patients with idiopathic restless legs syndrome (iRLS) who were not currently on treatment. The iRLS patients had greater accommodation in motor but not sensory axons to long-lasting hyperpolarization compared to age-matched healthy subjects, indicating greater inward rectification in iRLS. The most reasonable explanation is that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open at less hyperpolarized membrane potentials, a view supported by mathematical modelling. The half-activation potential for HCN channels (Bq) was the single best parameter that accounted for the difference between normal controls and iRLS data. A 6 mV depolarization of Bq reduced the discrepancy between the normal control model and the iRLS data by 92.1%. Taken together, our results suggest an increase in the excitability of motor units in iRLS that could enhance the likelihood of leg movements. The abnormal axonal properties are consistent with other findings indicating that the peripheral system is part of the network involved in iRLS.

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.

Sarcolemmal excitability in the myotonic dystrophies.

INTRODUCTION: Chloride conductance disturbances contribute to sarcolemmal dysfunction in myotonic dystrophy type 1 (DM1) and type 2 (DM2). Studies using muscle velocity recovery cycles (MVRCs) suggest Na+ /K+ -adenosine triphosphatase activation becomes defective in advanced DM1. We used MVRCs to investigate muscle excitability in DM1 and DM2. METHODS: MVRCs were measured for patients with mild (n = 8) and advanced (n = 11) DM1, DM2 (n = 4), and normal controls (n = 30). RESULTS: Residual supernormality after multiple conditioning stimuli was increased in DM2 and advanced DM1. Advanced DM1 was distinguished by increases in muscle relative refractory period (MRRP) and reduced early supernormality as well as peak amplitude decrements for the first and last responses in train during repetitive stimulation. DISCUSSION: Prolongation of the MRRP indicates that depolarization of the resting muscle membrane potential occurs in advanced DM1, with possible implications for future therapeutic approaches. Muscle Nerve 57: 595-602, 2018.

Neurofascin-155 IGG4 Neuropathy: Pathophysiological Insights, Spectrum of Clinical Severity and Response To treatment.

INTRODUCTION: Sensorimotor neuropathy associated with IgG4 antibodies to neurofascin-155 (NF155) was recently described. The clinical phenotype is typically associated with young onset, distal weakness, and in some cases, tremor. METHODS: From a consecutive cohort of 55 patients diagnosed with chronic inflammatory demyelinating polyneuropathy, screening for anti-NF155 antibodies was undertaken. Patients underwent clinical assessment, diagnostic neurophysiology, including peripheral axonal excitability studies and nerve ultrasound. RESULTS: Three of 55 chronic inflammatory demyelinating polyneuropathy patients (5%) tested positive for anti-NF155 IgG4. Patients presenting with more severe disease had higher antibody titers. Ultrasound demonstrated diffuse nerve enlargement. Axonal excitability studies were markedly abnormal, with subsequent mathematical modeling of the results supporting disruption of the paranodal seal. DISCUSSION: A broad spectrum of disease severity and treatment response may be observed in anti-NF155 neuropathy. Excitability studies support the pathogenic role of anti-NF155 IgG4 antibodies targeting the paranodal region. Muscle Nerve 57: 848-851, 2018.

A unified model of the excitability of mouse sensory and motor axons.

Non-invasive nerve excitability techniques have provided valuable insight into the understanding of neurological disorders. The widespread use of mice in translational research on peripheral nerve disorders and by pharmaceutical companies during drug development requires valid and reliable models that can be compared to humans. This study established a novel experimental protocol that enables comparative assessment of the excitability properties of motor and sensory axons at the same site in mouse caudal nerve, compared the mouse data to data for motor and sensory axons in human median nerve at the wrist, and constructed a mathematical model of the excitability of mouse axons. In a separate study, ischaemia was employed as an experimental manoeuvre to test the translational utility of this preparation. The patterns of mouse sensory and motor excitability were qualitatively similar to human studies under normal and ischaemic conditions. The most conspicuous differences between mouse and human studies were observed in the recovery cycle and the response to hyperpolarization. Modelling showed that an increase in temperature in mouse axons could account for most of the differences in the recovery cycle. The modelling also suggested a larger hyperpolarization-activated conductance in mouse axons. The kinetics of this conductance appeared to be much slower raising the possibility that an additional or different hyperpolarization-activated cyclic-nucleotide gated (HCN) channel isoform underlies the accommodation to hyperpolarization in mouse axons. Given a possible difference in HCN isoforms, caution should be exercised in extrapolating from studies of mouse motor and sensory axons to human nerve disorders.

Diuretic-sensitive electroneutral Na+ movement and temperature effects on central axons.

KEY POINTS: Optic nerve axons get less excitable with warming. F-fibre latency does not shorten at temperatures above 30°C. Action potential amplitude falls when the Na+ -pump is blocked, an effect speeded by warming. Diuretics reduce the rate of action potential fall in the presence of ouabain. Our data are consistent with electroneutral entry of Na+ occurring in axons and contributing to setting the resting potential. ABSTRACT: Raising the temperature of optic nerve from room temperature to near physiological has effects on the threshold, refractoriness and superexcitability of the shortest latency (fast, F) nerve fibres, consistent with hyperpolarization. The temperature dependence of peak impulse latency was weakened at temperatures above 30°C suggesting a temperature-sensitive process that slows impulse propagation. The amplitude of the supramaximal compound action potential gets larger on warming, whereas in the presence of bumetanide and amiloride (blockers of electroneutral Na+ movement), the action potential amplitude consistently falls. This suggests a warming-induced hyperpolarization that is reduced by blocking electroneutral Na+ movement. In the presence of ouabain, the action potential collapses. This collapse is speeded by warming, and exposure to bumetanide and amiloride slows the temperature-dependent amplitude decline, consistent with a warming-induced increase in electroneutral Na+ entry. Blocking electroneutral Na+ movement is predicted to be useful in the treatment of temperature-dependent symptoms under conditions with reduced safety factor (Uhthoff's phenomenon) and provide a route to neuroprotection.

Differentiating lower motor neuron syndromes.

Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features.

Laterality of motor cortical function measured by transcranial magnetic stimulation threshold tracking.

INTRODUCTION: Threshold tracking paired-pulse transcranial magnetic stimulation (TTTMS) examines cortical function and is useful for diagnosis of motor neuron disorders. Differences in cortical function have been identified between dominant and non-dominant limbs using constant stimulus methods, but they remain unclear, potentially due to methodological differences. In this study we aimed to clarify differences in cortical function between dominant and non-dominant limbs using TTTMS. METHODS: Single-pulse TMS, TTTMS, and nerve conduction studies were performed in 25 healthy, right-handed participants by recording from the abductor pollicis brevis muscle. RESULTS: There were no side-to-side differences observed in resting motor threshold, motor evoked potential (MEP) amplitude, MEP latency, central motor conduction time, cortical silent period, short-interval intracortical inhibition and facilitation, compound muscle action potential (CMAP) amplitude, CMAP latency, F-wave latency, or neurophysiological index. CONCLUSIONS: These findings suggest that, when using TTTMS, there are no differences in cortical function between dominant and non-dominant hemispheres. Muscle Nerve 55: 424-427, 2017.

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.

Increased HCN channel driven inward rectification in benign cramp fasciculation syndrome.

Muscle cramps are a common complaint associated with sudden painful involuntary contractions of a muscle. The mechanisms responsible for muscle cramps are still not clear. Axonal excitability and multi-unit electromyography studies were performed in 20 patients suffering from benign cramp fasciculation syndrome, not currently on medication. The measures of axonal excitability suggested greater inward rectification, indicative of an increase in Ih. Mathematical modelling suggested that the data were best explained by depolarization of the voltage dependence of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Parameters associated with polarization of resting membrane potential were not changed. These findings suggest that a role for HCN channels may become apparent during the rhythmic discharge associated with a voluntary contraction. Consistent with this view, patients had higher motor unit discharge rates than healthy controls during maximal voluntary effort.

Long-interval afferent inhibition measurement using two different methods: Normative values, repeatability and reliability.

BACKGROUND: The mechanism of Short-Latency Afferent Inhibition (SAI) is relatively well understood. In contrast, Long-Latency Afferent Inhibition (LAI) has not been as extensively studied as SAI, and its underlying mechanism remains unclear. OBJECTIVE/HYPOTHESIS: This study had two primary objectives: first, to determine the optimal ISIs for LAI measured by amplitude changes (A-LAI) using high-resolution ISI ranges; and second, to compare measurements of LAI by threshold-tracking (T-LAI). METHODS: Twenty-eight healthy volunteers (12 males aged 24- 45 years) participated in the study. Paired peripheral electrical and transcranial magnetic stimulation (TMS) stimuli (TS1mv) were applied at varying (ISIs)- 100, 200, 250, 300, 350, 400, 450, 500, 550, 600, 700, 800, 900, 1000 ms. RESULTS: Both A-LAI and T-LAI showed that LAI decreased progressively from a peak at 200 or 250 ms to 1000 ms. Using the A-LAI method, pronounced inhibition was observed at three specific ISIs: 100 ms, 250 ms and 450 ms. When A-LAI values were converted to equivalent threshold changes, they did not differ significantly from T-LAI. Reliability at distinguishing individuals, as indicated by intraclass correlation coefficient (ICC) was greater for A-LAI, with a peak value of 0.82 at 250 ms. CONCLUSION(S): The study demonstrates that ISIs of 100 ms and 250 ms can be reliably used in amplitude measurement LAI. The study demonstrates that both LAI measurements record a similar decline of inhibition with increasing ISI.

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.

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.