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• Conventional nerve conduction studies, H-reflex studies, and needle electromyography are important tools for the diagnosis of Motor Neuron Disease (MND) • High-density surface EMG, nerve excitability testing, electrical impedance myography, MUNIX, and MScanFit are potential biomarkers for MND. • Neuromuscular ultrasonography can detect changes in nerve and muscle architecture including dynamic changes such as fasciculations. 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. [ABSTRACT FROM AUTHOR]

Background and Aims: Chemotherapy‐induced peripheral neurotoxicity (CIPN) is a common and long‐lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage. Methods: We tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density. Results: NET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement. Interpretation: NET after the first administration demonstrated the ongoing OHP‐related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage. [ABSTRACT FROM AUTHOR]

Background and Aims: Intravenous immunoglobulin (IVIg) has a rapid clinical effect which cannot be explained by remyelination during each treatment cycle in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). This study aimed to investigate axonal membrane properties during the IVIg treatment cycle and their potential correlation with clinically relevant functional measurements. Methods: Motor nerve excitability testing (NET) of the median nerve was performed before and 4 and 18 days after initiation of an IVIg treatment cycle in 13 treatment‐naïve (early) CIDP patients and 24 CIDP patients with long term (late) IVIg treatment, 12 CIDP patients treated with subcutaneous immunoglobulin (SCIg) and 55 healthy controls. Clinical function was measured extensively using the Six Spot Step test, 10‐Meter Walk test, 9‐Hole Peg test, grip strength, MRC sum score, Overall Neuropathy Limitations Score and Patient Global Impression of Change. Results: Superexcitability and S2 accommodation decreased significantly in the early treatment group from baseline to day 4 and returned to baseline levels at day 18, suggesting temporary depolarization of the axonal membrane. A similar trend was observed for the late IVIg group. Substantial clinical improvement was observed in both early and late IVIg groups during the entire treatment cycle. No statistically significant correlation was found between clinical and NET changes. No change was found in NET or clinical function in the SCIg group or controls. Interpretation: NET suggested temporary depolarization of the axonal membrane during IVIg treatment in treatment naïve CIDP patients. The relation to clinical improvement, however, remains speculative. [ABSTRACT FROM AUTHOR]

Abstract Background Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system. Methods This is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na+ conductance) of large sensory fibers and SDTC of large motor fibers comparing lacosamide and placebo. The key secondary endpoint is the SDTC measured in small sensory fibers. Remaining treatment arm effects on key NET outcomes and PK modelling are other prespecified secondary or exploratory analyses. Discussion Measurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. Trial registration This trial was registered 25/06/2019 in EudraCT ( 2019-000942-36 ).

Objective: To explore potential differences in motor nerve excitability testing (NET) variables at group levels between patients with a clinical diagnosis of polyneuropathy (PNP), which did not fulfil diagnostic criteria of conventional nerve conduction studies (NCS) and patients without polyneuropathy. Such differences could support a role for NET in increasing the diagnostic sensitivity of NCS in chronic axonal PNP. Methods: Motor NET was performed using the median nerve in patients with a clinical suspicion of PNP in addition to conventional NCS, skin biopsies, corneal confocal microscopy and structured clinical evaluation including scoring of neuropathy symptoms and signs. Results: Of the 57 patients included, 32 had PNP, half of which had NCS, which fulfilled criteria for PNP (NCS+ PNP). There were no significant differences for any of the NET variables between PNP patients with non-diagnostic conventional NCS (NCS− PNP) and patients without PNP. Rheobase was increased, and Ted (undershoot) and subexcitability were decreased in NCS+ PNP. Sural amplitude, peroneal nerve F-wave latency and tibial nerve F-wave-latency were correlated with subexcitability, and tibial nerve motor amplitude was correlated with rheobase. Conclusions: NET was correlated with conventional NCS and no differences were found between NCS− PNP patients and patients without PNP. Significance: NET does not seem to offer any additional diagnostic value in chronic mixed etiology neuropathy.

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a frequent adverse event of colorectal cancer treatment. OIPN encompasses a chronic and an acute syndrome. The latter consists of transient axonal hyperexcitability, due to unbalance in Na+ voltage-operated channels (Na+VOC). This leads to sustained depolarisation which can activate the reverse mode of the Na+/Ca2+ exchanger 2 (NCX2), resulting in toxic Ca2+ accumulation and axonal damage (ADa). We explored the role of NCX2 in in vitro and in vivo settings. Embryonic rat Dorsal Root Ganglia (DRG) organotypic cultures treated with SEA0400 (SEA), a NCX inhibitor, were used to assess neuroprotection in a proof-of-concept and pilot study to exploit NCX modulation to prevent ADa. In vivo, OHP treated mice (7 mg/Kg, i.v., once a week for 8 weeks) were compared with a vehicle-treated group (n = 12 each). Neurophysiological and behavioural testing were performed to characterise acute and chronic OIPN, and morphological analyses were performed to detect ADa. Immunohistochemistry, immunofluorescence, and western blotting (WB) analyses were also performed to demonstrate changes in NCX2 immunoreactivity and protein expression. In vitro, NCX inhibition was matched by ADa mitigation. In the in vivo part, after verifyingboth acute and chronic OIPN had ensued, we confirmed via immunohistochemistry, immunofluorescence, and WB that a significant NCX2 alteration had ensued in the OHP group. Our data suggest NCX2 involvement in ADa development, paving the way to a new line of research to prevent OIPN. [ABSTRACT FROM AUTHOR]

Background: Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system.Methods: This is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na+ conductance) of large sensory fibers and SDTC of large motor fibers comparing lacosamide and placebo. The key secondary endpoint is the SDTC measured in small sensory fibers. Remaining treatment arm effects on key NET outcomes and PK modelling are other prespecified secondary or exploratory analyses.Discussion: Measurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.Trial Registration: This trial was registered 25/06/2019 in EudraCT ( 2019-000942-36 ). [ABSTRACT FROM AUTHOR]

Introduction: Cold allodynia is often seen in the acute phase of oxaliplatin treatment, but the underlying pathophysiology remains unclear.Methods: Patients scheduled for adjuvant oxaliplatin for colorectal cancer were examined with quantitative sensory testing and nerve excitability tests at baseline and after the second or third oxaliplatin cycle at different skin temperatures.Results: Seven patients were eligible for examination. All patients felt evoked pain and tingling when touching something cold after oxaliplatin infusion. Oxaliplatin decreased motor nerve superexcitability (P < .001), increased relative refractory period (P = .011), and caused neuromyotonia-like after-activity. Cooling exacerbated these changes and prolonged the accommodation half-time.Discussion: The findings suggest that a combined effect of oxaliplatin and cooling facilitates nerve excitability changes and neuromyotonia-like after-activity in peripheral nerve axons. A possible mechanism is the slowing in gating of voltage-dependent fast sodium and slow potassium channels, which results in symptoms of cold allodynia. [ABSTRACT FROM AUTHOR]

Objective Neurotoxicity is the most frequent dose-limiting side effect of the anti-cancer agent oxaliplatin, but the mechanisms are not well understood. This study used nerve excitability testing to investigate the pathophysiology of the acute neurotoxicity. Methods Questionnaires, quantitative sensory tests, nerve conduction studies and nerve excitability testing were undertaken in 12 patients with high-risk colorectal cancer treated with adjuvant oxaliplatin and in 16 sex- and age-matched healthy controls. Examinations were performed twice for patients: once within 3 days after oxaliplatin treatment (post-infusion examination) and once shortly before the following treatment (recovery examination). Results The most frequent post-infusion symptoms were tingling paresthesias and cold allodynia. The most prominent nerve excitability change was decreased superexcitability of motor axons which correlated with the average intensity of abnormal sensations (Spearman Rho = 0.80, p  < .01). The motor nerve excitability changes were well modeled by a slowing of sodium channel inactivation, and were proportional to dose/m 2 with a half-life of about 10d. Conclusions Oxaliplatin induces reversible slowing of sodium channel inactivation in motor axons, and these changes are closely related to the reversible cold allodynia. However, further studies are required due to small sample size in this study. Significance Nerve excitability data provide an index of sodium channel dysfunction: an objective biomarker of acute oxaliplatin neurotoxicity. [ABSTRACT FROM AUTHOR]

Background Nerve excitability testing by threshold-tracking is the only available method to study axonal ion channel function and membrane potential in the clinical setting. The measures are, however, indirect and the interpretation of neuropathic changes remains challenging. The same multiple measures of axonal excitability were adapted to further explore the pathophysiological changes in rodent disease models under pharmacologic and genetic manipulations. These studies are typically limited to the investigation of the “long nerves” such as the tail or the tibial nerves. New method We introduce a novel setup to explore the ulnar nerve excitability in rodents. We provide normative ulnar data in 11 adult female Long Evans rats under anaesthesia by comparison with tibial and caudal nerves. Additionally, these measures were repeated weekly on 3 occasions to determine the repeatability of these tests. Results Nerve excitability assessment of ulnar nerve proved to be a longitudinally repeatable measure of axonal function mature in rats, as were measures in tibial and caudal nerves. Comparison with existing method: Ulnar nerve motor excitability measures were different from the caudal and tibial excitability measures. Most notably, ulnar nerve showed the largest threshold changes during both depolarizing and hyperpolarizing threshold electrotonus. Conclusions Ulnar nerves demonstrate a distinct nerve excitability profile than the caudal and tibial nerves which could have functional and pathological implications. [ABSTRACT FROM AUTHOR]

Abstract: Upon peripheral nerve injury (caused by trauma or disease process) axons of the dorsal root ganglion (DRG) somatosensory neurons have the ability to sprout and regrow/remyelinate to reinnervate distant target tissue or form a tangled scar mass called a neuroma. This regenerative response can become maladaptive leading to a persistent and debilitating pain state referred to as chronic pain corresponding to the clinical description of neuropathic/chronic inflammatory pain. There is little agreement to what causes peripheral chronic pain other than hyperactivity of the nociceptive DRG neurons which ultimately depends on the function of voltage-gated ion channels. This review focuses on the pharmacological modulators of voltage-gated ion channels known to be present on axonal membrane which represents by far the largest surface of DRG neurons. Blockers of voltage-gated Na+ channels, openers of voltage-gated K+ channels and blockers of hyperpolarization-activated cyclic nucleotide-gated channels that were found to reduce neuronal activity were also found to be effective in neuropathic and inflammatory pain states. The isoforms of these channels present on nociceptive axons have limited specificity. The rationale for considering axonal voltage-gated ion channels as targets for pain treatment comes from the accumulating evidence that chronic pain states are associated with a dysregulation of these channels that could alter their specificity and make them more susceptible to pharmacological modulation. This drives the need for further development of subtype-specific voltage-gated ion channels modulators, as well as clinically available neurophysiological techniques for monitoring axonal ion channel function in peripheral nerves. [Copyright &y& Elsevier]

Abstract: We sought to investigate the peripheral nerve excitability property of early diabetic neuropathy (DN) and provide a logical hypothesis regarding the pathophysiology of subclinical/early stage of DN. The automated nerve excitability test (NET) utilizing the threshold tracking technique (TTT) was performed to measure multiple excitability indices in 30 early DN and 30 normal subjects. Early DN was defined as N0 or N1 stage of Dyck''s staging method. The protocols calculated strength-duration time constant (SDTC) from duration–charge curve, parameters of threshold electrotonus (TE) and current–threshold relationship (CTR) from sequential sub-threshold current, and recovery cycle (RC) from double supra-threshold stimulation. Each parameter of test was co-analyzed with clinical and laboratory data including age, sex, BMI, HgbA1c, lipid profile, and estimated glomerular filtration rate (eGFR). Compared to normal or N0 groups, N1 group had ‘fanning-in’ phenomenon in TE, increased refractory period, and decreased supernormality/subnormality. Linear regression showed that parameters associated with vascular factor were significantly related with STDC: absolute TG values were positively associated with STDC, whereas eGFR values were inversely related with STDC. Nerve excitability can be altered even in the early mild DN. The pattern of alteration suggests depolarizing nerve or nerve ischemia in pathophysiology of subclinical/early DN. [Copyright &y& Elsevier]

Abstract: Objective: The threshold tracking technique is a new approach to non-invasively assess biophysical properties of axonal membrane in human subjects. The aim of this study was to evaluate the effects of age and gender on excitability properties of human motor axons. Methods: Computerized threshold tracking was used to measure multiple excitability indices in median motor axons of 93 normal subjects (50 men; age, 20–86 years). Results: Regression analyses showed that the higher age was associated with longer strength-duration time constant (p =0.03), smaller threshold changes in depolarizing threshold electrotonus (p =0.02), smaller supernormality (p =0.01), and steeper slope of the current–threshold relationship for hyperpolarizing currents (p <0.001). There were slight sex differences in rheobase, threshold electrotonus, supernormality, late subnormality, and current–threshold slope, though they were significant only in the subgroup with age <50 years. Conclusions: Aging may increase persistent sodium currents, inward rectification, and possibly, outward potassium currents. The combination of changes raises the possibility of slight membrane depolarization in elderly people. For the sex-related differences, further studies will be required with the evaluation of sex hormonal effects. Significance: Age-related effects on excitability properties are subtle, but should be taken into consideration in the clinical application of nerve excitability testing, particularly in elderly subjects. [Copyright &y& Elsevier]

Objective: To explore potential differences in motor nerve excitability testing (NET) variables at group levels between patients with a clinical diagnosis of polyneuropathy (PNP), which did not fulfil diagnostic criteria of conventional nerve conduction studies (NCS) and patients without polyneuropathy. Such differences could support a role for NET in increasing the diagnostic sensitivity of NCS in chronic axonal PNP., Methods: Motor NET was performed using the median nerve in patients with a clinical suspicion of PNP in addition to conventional NCS, skin biopsies, corneal confocal microscopy and structured clinical evaluation including scoring of neuropathy symptoms and signs., Results: Of the 57 patients included, 32 had PNP, half of which had NCS, which fulfilled criteria for PNP (NCS+ PNP). There were no significant differences for any of the NET variables between PNP patients with non-diagnostic conventional NCS (NCS- PNP) and patients without PNP. Rheobase was increased, and Ted (undershoot) and subexcitability were decreased in NCS+ PNP. Sural amplitude, peroneal nerve F-wave latency and tibial nerve F-wave-latency were correlated with subexcitability, and tibial nerve motor amplitude was correlated with rheobase., Conclusions: NET was correlated with conventional NCS and no differences were found between NCS- PNP patients and patients without PNP., Significance: NET does not seem to offer any additional diagnostic value in chronic mixed etiology neuropathy., (© 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Oxaliplatin (OHP) Induced Peripheral Neurotoxicity (OIPN) is one of the dose-limiting toxicities of the drug and these adverse effects limit cancer therapy with L-OHP, used for colorectal cancer treatment. Acute neurotoxicity consists of symptoms that are the hallmarks of a transient axonal hyperexcitability; chronic neurotoxicity has a clinical picture compatible with a length-dependent sensory neuropathy. Acute OIPN pathogenesis has been linked to sodium voltage-operated channels (Na + VOC) dysfunction and it has been advocated as a possible predisposing factor to chronic neurotoxicity. We tested if topiramate (TPM), a well-known Na + VOC modulator, was able to modify acute as well as chronic OIPN. The project was divided into two parts. In Experiment 1 we tested by means of Nerve Excitability Testing (NET) a cohort of female Wistar rats to assess TPM effects after a single OHP administration (5 mg/kg, iv). In Experiment 2 we assessed TPM effects after chronic OHP treatment (5 mg/kg, 2qw4ws, iv) using NET, nerve conduction studies (NCS), behavioral tests and neuropathology (caudal nerve morphometry and morphology and Intraepidermal Nerve Fiber [IENF] density). In Experiment 1 TPM was able to prevent OHP effects on Na + VOC: OHP treatment induced a highly significant reduction of the sensory nerve's threshold, during the superexcitability period (p-value = 0.008), whereas TPM co-administration prevented this effect. In Experiment 2 we verified that TPM was able to prevent not only acute phenomena, but also to completely prevent chronic OIPN. This latter observation was supported by a multimodal approach: in fact, only OHP group showed altered findings compared to CTRL group at a neurophysiological (proximal caudal nerve sensory nerve action potential [SNAP] amplitude, p-value = 0.001; distal caudal nerve SNAP amplitude, p-value<0.001, distal caudal nerve sensory conduction velocity, p-value = 0.04), behavioral (mechanical threshold, p-value 0.003) and neuropathological levels (caudal nerve fibers density, p-value 0.001; IENF density, p-value <0.001). Our data show that TPM is a promising drug to prevent both acute and chronic OIPN. These findings have a high translational potential, since they were obtained using outcome measures that match clinical practice and TPM is already approved for clinical use being free from detrimental interaction with OHP anticancer properties. • Oxaliplatin Induced Peripheral Neurotoxicity (OIPN) is a detrimentallate event. No treatment is available. • Topiramate (TPM) in animals modulated acute OIPN and prevented chronic OIPN • TPM is approved for clinical use and compatible with chemotherapy:its efficacy, given prior to chemotherapy and continued during the treatment, could be tested in a clinical setting. [ABSTRACT FROM AUTHOR]