Threshold Electrotonus Research Articles

3-2-11. Peripheral nerve excitability changing in spinocerebellar ataxia type 6 (SCA6)

Abstract Motor nerve excitability testing in the median nerve with QtracS program (©Professor H. Bostock, UCL) was compared between 15 spinocerebellar ataxia type 6 (SCA6) patients and 22 age-matched healthy controls. Motor nerve excitability testing in tail nerve of 2 male mice was compared between before and after intraperitoneal injection of ω -agatoxin-IVA. Compared with normal controls, SCA6 showed statistically significant decrease of depolarizing threshold electrotonus (p ω -agatoxin-IVA. The present study indicates that motor nerves of SCA6 increase slow potassium currents derived from dysfunction of mutant protein, P/Q type voltage gated calcium channels.

3-2-01. Decreased motor axonal potassium currents in peripheral nerve hyperexcitability syndrome with negativity for anti-VGKC antibody and positivity for anti-CRMP5 antibody

Peripheral nerve hyperexcitability (PNH) syndromes are caused by spontaneous discharges originating from motor axons. Antibodies against voltage-gated potassium channels (VGKC) are detected in some patients with PNH syndrome, but the cause in the remaining patients has not yet been clarified. The index patient was a 46-year-old female with recurred thymoma and myasthenia gravis. Six month after the start of chemotherapy, she developed myokymia, fasciculations and muscle cramps in both her lower limbs. A nerve conduction studies revealed mild axonal polyneuropathy and a motor F-wave examination showed marked after-discharges. Needle electromyography showed fasciculation potentials and myokymic discharges. From these results, the patient was diagnosed with PNH syndrome. Nerve excitability study showed extremely greater supernormality in the recovery cycle and greater changes in depolarizing threshold electrotonus than control, suggesting decreased slow potassium currents in the motor axons. Serological tests revealed the absence of anti-VGKC antibody and the presence of anti-collapsin response mediator protein 5 (CRMP5) antibody. A recent study reported that CRMP5 plays an important role in axon–Schwann cell cooperation during development and nerve regeneration. The coexistence of nerve regeneration and anti-CRMP5 antibody may cause abnormal axon–Schwann cell interaction, which would result in slow potassium channel dysfunction and associated symptoms such as myokymia.

Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy.

This study investigated sensory and motor nerve excitability properties to elucidate the development of diabetic neuropathy. A total of 109 type 2 diabetes patients were recruited, and 106 were analyzed. According to neuropathy severity, patients were categorized into G0, G1, and G2+3 groups using the total neuropathy score-reduced (TNSr). Patients in the G0 group were asymptomatic and had a TNSr score of 0. Sensory and motor nerve excitability data from diabetic patients were compared with data from 33 healthy controls. Clinical assessment, nerve conduction studies, and sensory and motor nerve excitability testing data were analyzed to determine axonal dysfunction in diabetic neuropathy. In the G0 group, sensory excitability testing revealed increased stimulus for the 50% sensory nerve action potential (P<0.05), shortened strength-duration time constant (P<0.01), increased superexcitability (P<0.01), decreased subexcitability (P<0.05), decreased accommodation to depolarizing current (P<0.01), and a trend of decreased accommodation to hyperpolarizing current in threshold electrotonus. All the changes progressed into G1 (TNSr 1–8) and G2+3 (TNSr 9–24) groups. In contrast, motor excitability only had significantly increased stimulus for the 50% compound motor nerve action potential (P<0.01) in the G0 group. This study revealed that the development of axonal dysfunction in sensory axons occurred prior to and in a different fashion from motor axons. Additionally, sensory nerve excitability tests can detect axonal dysfunction even in asymptomatic patients. These insights further our understanding of diabetic neuropathy and enable the early detection of sensory axonal abnormalities, which may provide a basis for neuroprotective therapeutic approaches.

Burning pain: axonal dysfunction in erythromelalgia.

Erythromelalgia (EM) is a rare neurovascular disorder characterized by intermittent severe burning pain, erythema, and warmth in the extremities on heat stimuli. To investigate the underlying pathophysiology, peripheral axonal excitability studies were performed and changes with heating and therapy explored. Multiple excitability indices (stimulus-response curve, strength-duration time constant (SDTC), threshold electrotonus, and recovery cycle) were investigated in 23 (9 EMSCN9A+ and 14 EMSCN9A-) genetically characterized patients with EM stimulating median motor and sensory axons at the wrist. At rest, patients with EM showed a higher threshold and rheobase (P < 0.001) compared with controls. Threshold electrotonus and current-voltage relationships demonstrated greater changes of thresholds in both depolarizing and hyperpolarizing preconditioning electrotonus in both EM cohorts compared with controls in sensory axons (P < 0.005). When average temperature was raised from 31.5°C to 36.3°C in EMSCN9A+ patients, excitability changes showed depolarization, specifically SDTC significantly increased, in contrast to the effects of temperature previously established in healthy subjects (P < 0.05). With treatment, 4 EMSCN9A+ patients (4/9) reported improvement with mexiletine, associated with reduction in SDTC in motor and sensory axons. This is the first study of primary EM using threshold tracking techniques to demonstrate alterations in peripheral axonal membrane function. Taken together, these changes may be attributed to systemic neurovascular abnormalities in EM, with chronic postischaemic resting membrane potential hyperpolarization due to Na/K pump overactivity. With heating, a trigger of acute symptoms, axonal depolarization developed, corresponding to acute axonal ischaemia. This study has provided novel insights into EM pathophysiology.

Modification of multiple ion channel functions in vivo by pharmacological inhibition: observation by threshold tracking and modeling.

Maintenance of axonal excitability relies on complex balance by multiple ion currents, but its evaluation is limited by in vitro single channel neurophysiological study on overall behavior. We sought to evaluate behaviors of multiple ion currents by pharmacological blockade. The threshold tracking technique was used to measure multiple excitability indices on tail sensory nerve of normal male mice before and after administration of either BaCl2 or ivabradine. Mathematical modeling was used to identify the interval changes of the channel parameters. After administration of BaCl2 and ivabradine, the following changes were present: greater threshold changes of both depolarizing and hyperpolarizing threshold electrotonus by both; additionally, reduced S2 accommodation, reduced late subexcitability and increased superexcitability by BaCl2, increased S3 accommodation by ivabradine. Mathematical modelling implied reduction of slow K+ conductance, along with reduction of H conductance (Ih) by BaCl2; and reduction of Ih while augmentation of K+ conductances by ivabradine. Pharmacological blockade of a selective ion channel may be compensated by other ion channels. Unintended effects by ion channel modification could be caused by secondary current alteration by multiple ion channels. J. Med. Invest. 64: 30-38, February, 2017.

Membrane properties in small cutaneous nerve fibers in humans

Assessment of membrane properties is important for understanding the mechanisms of painful peripheral neuropathy, developing new diagnostic techniques, and screening/profiling of analgesics that target ion channels. Small cutaneous nerves were activated electrically by small diameter (0.2 mm) cathodes, and large nerves were activated by ordinary patch electrodes. This new perception threshold tracking method combines perception threshold assessment and stimulation paradigms from conventional threshold tracking. The strength-duration time-constant of large fibers (580 µs ± 160 µs) was lower than the time constant of small fibers (1060 µs ± 690 µs; P < 0.01, paired t-test). Threshold electrotonus showed similar threshold reductions to sub-threshold prepulses, except for 80 ms hyperpolarizing prepulses, to which small fibers showed less threshold reduction than large fibers (repeated-measures analysis of variance, Bonferroni, P = 0.006). This is a reliable method to investigate the membrane properties of small cutaneous nerve fibers in humans and may be used in clinical settings as a diagnostic or profiling tool. Muscle Nerve 55: 195-201, 2017.

Nerve excitability in the rat forelimb: a technique to improve translational utility

BackgroundNerve 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 methodWe 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. ResultsNerve 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. ConclusionsUlnar nerves demonstrate a distinct nerve excitability profile than the caudal and tibial nerves which could have functional and pathological implications.

KCC3 deficiency-induced disruption of paranodal loops and impairment of axonal excitability in the peripheral nervous system

The autosomal recessive Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum (HMSN/ACC) is associated with the dysfunction of the K+–Cl− cotransporter type 3 (KCC3), which is an electroneutral cotransporter. We previously found that the inhibition of KCC3 cotransporter activity reduces the propagation of action potentials in the peripheral nervous system (PNS). However, the pathogenesis by which KCC3 deficiency impairs peripheral nerve function remains to be examined. Thus, we conducted imaging and electrophysiological studies in the peripheral nerves of KCC3−/− mice at various ages. Analysis using transmission electron microscopy (TEM) revealed an age-dependent progressive swelling of microvilli and disorganization of paranodal loops in KCC3−/− nerves. Yet, no mislocated voltage-dependent channels were observed between the nodes and juxtaparanodes of KCC3−/− nerves. However, electrophysiological studies using the threshold tracking technique indicated a reduced stimulus–response curve slope with an elevated rheobase, a decreased strength–duration time constant, diminished persistent Na+ currents, and an outward deviation of threshold electrotonus in KCC3−/− nerves compared to wild-type nerves. These functional changes indicate an overall reduction in axonal excitability and suggest an increase in paranodal conductance, which was relevant to the pathology at the paranode. Altogether, our findings highlight the importance of KCC3 in maintaining paranodal integrity and in optimizing the propagation of action potentials along peripheral nerves.

Axonal Dysfunction Precedes Motor Neuronal Death in Amyotrophic Lateral Sclerosis.

Wide-spread fasciculations are a characteristic feature in amyotrophic lateral sclerosis (ALS), suggesting motor axonal hyperexcitability. Previous excitability studies have shown increased nodal persistent sodium conductances and decreased potassium currents in motor axons of ALS patients, both of the changes inducing hyperexcitability. Altered axonal excitability potentially contributes to motor neuron death in ALS, but the relationship of the extent of motor neuronal death and abnormal excitability has not been fully elucidated. We performed multiple nerve excitability measurements in the median nerve at the wrist of 140 ALS patients and analyzed the relationship of compound muscle action potential (CMAP) amplitude (index of motor neuronal loss) and excitability indices, such as strength-duration time constant, threshold electrotonus, recovery cycle and current-threshold relationships. Compared to age-matched normal controls (n = 44), ALS patients (n = 140) had longer strength-duration time constant (SDTC: a measure of nodal persistent sodium current; p < 0.05), greater threshold changes in depolarizing threshold electrotonus (p < 0.05) and depolarizing current threshold relationship (i.e. less accommodation; (p < 0.05), greater superexcitability (a measure of fast potassium current; p < 0.05) and reduced late subexcitability (a measure of slow potassium current; p < 0.05), suggesting increased persistent sodium currents and decreased potassium currents. The reduced potassium currents were found even in the patient subgroups with normal CMAP (> 5mV). Regression analyses showed that SDTC (R = -0.22) and depolarizing threshold electrotonus (R = -0.22) increased with CMAP decline. These findings suggest that motor nerve hyperexcitability occurs in the early stage of the disease, and precedes motor neuronal loss in ALS. Modulation of altered ion channel function could be a treatment option for ALS.

Critical illness polyneuropathy in ICU patients is related to reduced motor nerve excitability caused by reduced sodium permeability.

BackgroundReduced motor and sensory nerve amplitudes in critical illness polyneuropathy (CIP) are characteristic features described in electrophysiological studies and due to dysfunction of voltage-gated sodium channels. Yet, faulty membrane depolarization as reported in various tissues of critically ill patients may cause reduced membrane excitability as well. The aim of this study was to compare the pathophysiological differences in motor nerve membrane polarization and voltage-gated sodium channel function between CIP patients and critically ill patients not developing CIP during their ICU stay (ICU controls).MethodsICU patients underwent electrophysiological nerve conduction studies and were categorized as either ICU controls or CIP patients. Subsequently, excitability parameters were recorded as current-threshold relationship, stimulus-response behavior, threshold electrotonus, and recovery of excitability from the abductor pollicis brevis following median nerve stimulation.ResultsTwenty-six critically ill patients were enrolled and categorized as 12 ICU controls and 14 CIP patients. When compared to 31 healthy subjects, the ICU controls exhibited signs of membrane depolarization as shown by reduced superexcitability (p = 0.003), depolarized threshold electrotonus (p = 0.007), increased current-threshold relationship (p = 0.03), and slightly prolonged strength-duration time constant. In contrast, the CIP patients displayed a significantly reduced strength-duration time constant (p < 0.0001), which indicates an increased inactivation of voltage-gated sodium channels.ConclusionsAbnormal motor nerve membrane depolarization is a general finding in critically ill patients whereas voltage-gated sodium channel dysfunction is a characteristic of CIP patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s40635-016-0083-4) contains supplementary material, which is available to authorized users.

Progression of motor axon dysfunction and ectopic Nav1.8 expression in a mouse model of Charcot-Marie-Tooth disease 1B

Mice heterozygously deficient for the myelin protein P0 gene (P0+/−) develop a slowly progressing neuropathy modeling demyelinating Charcot-Marie-Tooth disease (CMT1B). The aim of the study was to investigate the long-term progression of motor dysfunction in P0+/− mice at 3, 7, 12 and 20months. By comparison with WT littermates, P0+/− showed a decreasing motor performance with age. This was associated with a progressive reduction in amplitude and increase in latency of the plantar compound muscle action potential (CMAP) evoked by stimulation of the tibial nerve at ankle. This progressive functional impairment was in contrast to the mild demyelinating neuropathy of the tibial nerve revealed by histology. “Threshold-tracking” studies showed impaired motor axon excitability in P0+/− from 3months. With time, there was a progressive reduction in threshold deviations during both depolarizing and hyperpolarizing threshold electrotonus associated with increasing resting I/V slope and increasing strength-duration time constant. These depolarizing features in excitability in P0+/− as well as the reduced CMAP amplitude were absent in P0+/− NaV1.8 knockouts, and could be acutely reversed by selective pharmacologic block of NaV1.8 in P0+/−. Mathematical modeling indicated an association of altered passive cable properties with a depolarizing shift in resting membrane potential and increase in the persistent Na+ current in P0+/−. Our data suggest that ectopic NaV1.8 expression precipitates depolarizing conduction failure in CMT1B, and that motor axon dysfunction in demyelinating neuropathy is pharmacologically reversible.

The Relationship between Dyslipidemia and Acute Axonal Function in Type 2 Diabetes Mellitus In Vivo.

ObjectivesDiabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes mellitus. Treatment largely consists of symptom alleviation and there is a need to identify therapeutic targets for prevention and treatment of DPN. The objective of this study was to utilise novel neurophysiological techniques to investigate axonal function in patients with type 2 diabetes and to prospectively determine their relationship to serum lipids in type 2 diabetic patients.MethodsSeventy-one patients with type 2 diabetes were consecutively recruited and tested. All patients underwent thorough clinical neurological assessments including nerve conduction studies, and median motor axonal excitability studies. Studies were also undertaken in age matched normal control subjects(n = 42). Biochemical studies, including serum lipid levels were obtained in all patients. Patient excitability data was compared to control data and linear regression analysis was performed to determine the relationship between serum triglycerides and low density lipoproteins and excitability parameters typically abnormal in type 2 diabetic patients.ResultsPatient mean age was 64.2±2.3 years, mean glycosylated haemoglobin (HbA1c%) was 7.8±0.3%, mean triglyceride concentration was 1.6±0.1 mmol/L and mean cholesterol concentration was 4.1±0.2mmol/L. Compared to age matched controls, median motor axonal excitability studies indicated axonal dysfunction in type 2 diabetic patients as a whole (T2DM) and in a subgroup of the patients without DPN (T2DM-NN). These included reduced percentage threshold change during threshold electrotonus at 10–20ms depolarising currents (TEd10–20ms)(controls 68.4±0.8, T2DM63.9±0.8, T2DM-NN64.8±1.6%,P<0.05) and superexcitability during the recovery cycle (controls-22.5±0.9, T2DM-17.5±0.8, T2DM-NN-17.3±1.6%,P<0.05). Linear regression analysis revealed no associations between changes in axonal function and either serum triglyceride or low density lipoprotein concentration when adjusted for renal function, a separate risk factor for neuropathy development. Our findings indicate that acutely, serum lipids do not exert an acute effect on axonal function in type 2 diabetic patients: TEd(10–20ms)(1.2(-1.4,3.8);P = 0.4) and superexcitability (2.4(-0.05, 4.8);P = 0.06).ConclusionsThese findings suggest that serum triglyceride levels are not related to axonal function in type 2 diabetic patients. Additional pathogenic mechanisms may play a more substantial role in axonal dysfunction prior to DPN development.

Increased motor axonal persistent sodium currents predict rapid functional declines in amyotrophic lateral sclerosis

AbstractBackgroundPrevious studies have shown that increased motor axonal excitability is associated with shorter survival in amyotrophic lateral sclerosis patients.AimTo study the axonal excitability properties related with motor functional decline.MethodsA total of 60 amyotrophic lateral sclerosis patients were prospectively evaluated at baseline, 3 months and 6 months. Motor function was evaluated with the revised amyotrophic lateral sclerosis functional rating scale. Multiple axonal excitability indices, such as strength‐duration time constant (a measure of persistent sodium currents), supernormality and threshold electrotonus, were measured in median nerve motor axons at the wrist. Univariate and multivariate mixed model analyses were used to examine whether clinical and neurophysiological factors were associated with a decline of revised amyotrophic lateral sclerosis functional rating scale scores.ResultsIn univariate analyses, revised amyotrophic lateral sclerosis functional rating scale changes were significantly worse in patients with longer strength‐duration time constant (P = 0.034) and lower vital capacity (P = 0.012). Age, sex, onset site and other excitability indices did not relate with speed of motor decline. Multivariate analysis also showed the longer strength‐duration time constant (P = 0.021) and decreased vital capacity (P = 0.020) groups were significantly associated with rapid revised amyotrophic lateral sclerosis functional rating scale declines.ConclusionsGreater axonal persistent sodium currents in motor axons are presumably associated with more rapid functional declines in amyotrophic lateral sclerosis patients. Suppression of persistent sodium currents could be a treatment option for amyotrophic lateral sclerosis.

18. Dysfunctional properties of single motor units in ALS

Background Abnormalities in the excitability of lower motor neurons in amyotrophic lateral sclerosis have been extensively examined using threshold tracking techniques. Several studies have found evidence for a down-regulation of K+, and an up-regulation of Na+ conductances. The results as a whole however have been somewhat mixed. Threshold-tracking studies test the excitability of a fixed fraction of the maximal compound action potential, and for most disease processes this accurately reflects the excitability of all axons of the same modality within a nerve. However, in ALS such a relationship is unreliable. The slow inexorable process of degeneration of individual motor units is likely to change their excitability, with hyperexcitability and reinnervation believed to impact on their viability. In ALS the disease process itself presents the opportunity to study single motor units identifiable in the recruitment curve, and in particular the large units which result from reinnervation of muscle fibres from motor units that have undergone degeneration. Such measurements provide an unequivocal snapshot of the excitability of an individual motor unit. Methods Measurements of the excitability of single motor units in the intrinsic muscles of the split hand were undertaken in 7 subjects, and mathematical modelling was performed to examine the nature of changes in individual motor units. Results As expected, the ALS single motor unit recordings were more varied in nature when compared to normal single motor units from a previous study. Significant differences were observed with a greater rheobasic current and lower resting I/V slope, relative refractory period and ‘fanned out’ threshold electrotonus in the ALS single motor units compared to the normal controls. Conclusions The excitability of individual motor units in ALS is heterogeneous in nature, with axonal abnormalities correlated with disease progression. The underlying biophysical mechanisms of these abnormal motor units were best modelled by an increase in the Na+/K+-ATPase pump current, and a near halving of slow K+ conductances. The relative proportions of changes to the Na+/K+-ATPase pump and slow K+ conductances are likely to vary between individual motor units, and with disease progression.

10. Neurophysiological profile of multifocal motor neuropathy

Introduction Multifocal motor neuropathy (MMN) is a rare immune-mediated neuropathy, typically presenting with asymmetrical, and slowly progressive, distal upper limb wasting and weakness without sensory abnormalities. The disorder is associated with GM1 antibodies in approximately 50% of cases but the pathogenic role of such antibodies along with the mechanism of conduction block remains unclear. Methods Nerve conduction studies and motor axonal excitability studies were undertaken in 7 patients with MMN (mean age: 52.3). Axonal excitability studies were undertaken in the median nerve at the wrist and compared to 70 healthy controls (mean age: 49.6). Results When compared healthy controls, patients with MMN had greater threshold changes in threshold electrotonus in both depolarizing (TEd 90–100 ms: 54.09 ± 1.3 vs 45.0 ± 0.5; p 0.01) and hyperpolarizing directions (TEh 90–100 ms: −157.7 ± 9.1 vs −117.8 ± 2.0; p 0.01). In addition, they demonstrated greater superexcitability (−40.2 ± 2.1 vs −23.7 ± 0.7; p 0.01) and reduced refractoriness at 2.5 msec (−6.7 ± 7.4 vs 28.2 ± 2.1; p 0.01). Conclusion Patients with MMN have a unique neurophysiological profile demonstrated on axonal excitability studies which are consistent with axonal hyperpolarization.

14. Haemodialysis alters nerve morphology in chronic kidney disease

Introduction Peripheral neuropathy is highly prevalent in chronic kidney disease (CKD), occurring in 90–100% of patients receiving dialysis. Previous neurophysiological studies using nerve excitability techniques have demonstrated changes in axonal function following a single session of dialysis. The present study was undertaken to examine whether there were morphological changes that may accompany these alterations in nerve function. Methods 15 CKD patients on thrice-weekly high-flux haemodialysis were recruited and studies were conducted before and after a single session of haemodialysis. Serial measurements of median nerve cross-sectional area (CSA), echogenicity and intraneural blood flow were also performed at a non-entrapment site (distal forearm) using high resolution ultrasonography (10–18 MHz probe). Intraneural blood flow was measured by obtaining 5 twenty-second clips of Power Doppler sonograms. Intraneural blood flow and echogenicity data were semi-quantitatively analyzed using a specialized and well-validated software to obtain the median nerve perfusion intensity (PI) and the percentage of hypoechoic area (pHA) respectively. Corresponding nerve excitability studies were undertaken on median motor axons. Results Overall, there was a significant decrease in CSA and PI post-dialysis (p 0.05). A reduction in CSA occurred in 90% of patients (9.05 ± 0.89 mm2 vs 8.51 ± 0.98 mm2), while 80% and 75% had a decrease in PI (0.79 ± 0.47 cm/s vs 0.47 ± 0.24 cm/s) and pHA (56.0 ± 1.0% vs 55.0 ± 1.6) respectively. Furthermore, the change in morphological measures was significantly correlated with excitability indices of membrane potential (PI and depolarising threshold electrotonus r = 0.67 p 0.05). Conclusion This study demonstrates morphological changes in peripheral nerves following a single session of dialysis. These changes correlate with the extent of change in measures of axonal function and may contribute to the development of axonal injury in CKD.

7. Pathophysiological basis of motor neuronal hyperexcitability in amyotrophic lateral sclerosis

Objective Motor neuronal hyperexcitability potentially contributes to motor neuron death in amyotrophic lateral sclerosis (ALS). We aimed to reveal pathomechanisms of motor neuron hyperexcitability in ALS. Methods Threshold tracking transcranial magnetic stimulation and multiple excitability measurements were performed in 130 healthy controls (HC), 83 sporadic ALS (sALS) patients, 11 patients with superoxide dismutase-1 (SOD-1) mutations, 16 C9orf72 hexanucleotide repeat expansions and 2 FUS mutations. Results Compared to HC, in peripheral nerve excitability sALS had greater strength-duration time constant (p 0.05), depolarizing threshold electrotonus (p 0.0001) and superexcitability (p 0.05) and smaller late subexcitability (p 0.05). In cortical excitability, sALS had reduced short interval intracortical inhibition (p 0.0001). These indices were not significantly different in SOD-1 and C9orf72, compared to sALS. Conclusion These findings suggest both sALS and familial ALS have increased sodium currents, decreased potassium currents, rendering to peripheral nerve hyperexcitability. In addition, all ALS patients demonstrated decreased intracortical inhibition. Significance Motor neuronal hyperexcitability may be a common feature in both sALS and familial ALS associated with different pathological bases.

9. Subclinical peripheral neuropathy prior to chemotherapy in colorectal cancer patients – Myth or reality?

Background Several studies have reported subclinical deficits in sensory nerve function, as evidenced by quantitative sensory testing, in adult patients with colorectal cancer prior to any exposure to neurotoxic chemotherapy. These studies, however, have not correlated the quantitative sensory testing with objective neurophysiological studies. If present, this could be an important risk factor for developing chemotherapy induced peripheral neuropathy. Aim To determine whether patients with colorectal cancer have subclinical peripheral neuropathy, before commencing neurotoxic chemotherapy. Method Assessments were undertaken in 87 participants with colorectal cancer prior to initiation of chemotherapy. Clinical and functional findings were correlated with conventional nerve conduction studies and specialised nerve excitability techniques. Data were compared to normal controls or normative reference ranges. Results Mean lower limb sural sensory amplitude for colorectal patients aged ⩽ 39, 40–59 and ⩾ 60years were 21.4 ± 2.7 μ V, 16.0 ± 1.1 μ V and 13.5 ± 1.5 μ V respectively, with 85 of 86 individual values falling within our laboratory normative reference values for age. All lower limb tibial motor amplitudes and upper limb superficial radial amplitudes were also within normative reference values for age. No significant difference was seen in multiple median sensory nerve excitability parameters between colorectal patients ( n =60) and controls including refractoriness at 2.5ms (colorectal 22.84 ± 2.32%, controls 19.30 ± 2.53%, p =0.56), superexcitability (colorectal −16.54 ± 0.76%, controls −18.53 ± 1.30%, p =0.11) and hyperpolarising threshold electrotonus at 90–100ms (colorectal −129.57 ± 2.5%, controls −123.35 ± 4.13%, p =0.13). Clinical history and examination findings were obtained in a subset of 52 participants. 39/52 (75%) participants had no peripheral sensory or motor symptoms or examination abnormalities. 13/52 had distal symptoms and/or signs in 1–2 modalities (reduced ankle jerks, vibration and pinprick sensibilities in toes) which did not correlate with abnormalities on conventional nerve conduction studies. 11/13 patients were > 60years of age and these isolated changes can also be seen in older individuals in the normal population. Conclusion This study demonstrates that there is a low likelihood of significant distal symmetrical polyneuropathy in colorectal cancer patients, prior to chemotherapy initiation.

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.

Aging-associated changes in motor axon voltage-gated Na+ channel function in mice

Accumulating myelin abnormalities and conduction slowing occur in peripheral nerves during aging. In mice deficient of myelin protein P0, severe peripheral nervous system myelin damage is associated with ectopic expression of Nav1.8 voltage-gated Na+ channels on motor axons aggravating the functional impairment. The aim of the present study was to investigate the effect of regular aging on motor axon function with particular emphasis on Nav1.8. We compared tibial nerve conduction and excitability measures by threshold tracking in 12 months (mature) and 20 months (aged) wild-type (WT) mice. With aging, deviations during threshold electrotonus were attenuated and the resting current-threshold slope and early refractoriness were increased. Modeling indicated that, in addition to changes in passive membrane properties, motor fibers in aged WT mice were depolarized. An increased Nav1.8 isoform expression was found by immunohistochemistry. The depolarizing excitability features were absent in Nav1.8 null mice, and they were counteracted in WT mice by a Nav1.8 blocker. Our data suggest that alteration in voltage-gated Na+ channel isoform expression contributes to changes in motor axon function during aging.