Changes In Nerve Excitability Research Articles

Revisiting distinct nerve excitability patterns in patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease, characterized by loss of central and peripheral motor neurons. Although the disease is clinically and genetically heterogeneous, axonal hyperexcitability is a commonly observed feature that has been suggested to reflect an early pathophysiological step linked to the neurodegenerative cascade. Therefore, it is important to clarify the mechanisms causing axonal hyperexcitability and how these relate to the clinical characteristics of patients. Measures derived directly from a nerve excitability recording are frequently used as study end points, although their biophysical basis is difficult to deduce. Mathematical models can aid in the interpretation but are reliable only when applied to group-averaged recordings. Consequently, model estimates of membrane properties cannot be compared with clinical characteristics or treatment effects in individual patients, posing a considerable limitation in heterogeneous diseases, such as amyotrophic lateral sclerosis. To address these challenges, we revisited nerve excitability using a new pattern analysis-based approach (principal component analysis). We evaluated disease-specific patterns of excitability changes and established their biophysical origins. Based on the observed patterns, we developed new compound measures of excitability that facilitate the implementation of this approach in clinical settings. We found that excitability changes in amyotrophic lateral sclerosis patients (n = 161, median disease duration = 11 months) were characterized by four unique patterns compared with controls (n = 50, age and sex matched). These four patterns were best explained by changes in resting membrane potential (modulated by Na+/K+ currents), slow potassium and sodium currents (modulated by their gating kinetics) and refractory properties of the nerve. Consequently, we were able to show that altered gating of slow potassium channels was associated with, and predictive of, the rate of progression of the disease on the amyotrophic lateral sclerosis functional rating scale. Based on these findings, we designed four composite measures that capture these properties to facilitate implementation outside this study. Our findings demonstrate that changes in nerve excitability in patients with amyotrophic lateral sclerosis are dominated by four distinct patterns, each with a distinct biophysical origin. Based on this new approach, we provide evidence that altered slow potassium-channel function might play a role in the rate of disease progression. The magnitudes of these patterns, quantified using a similar approach or our new composite measures, have potential as efficient measures to study membrane properties directly in amyotrophic lateral sclerosis patients, and thus aid prognostic stratification and trial design.

Therapeutic effects of p38 mitogen-activated protein kinase inhibition on hyperexcitability of capsaicin sensitive bladder afferent neurons in mice with spinal cord injury

AimsNerve growth factor (NGF) has been implicated as a key molecule of pathology-induced changes in C-fiber afferent nerve excitability, which contributes to the emergence of neurogenic detrusor overactivity due to spinal cord injury (SCI). It is also known that the second messenger signaling pathways activated by NGF utilize p38 Mitogen-Activated Protein Kinase (MAPK). We examined the roles of p38 MAPK on electrophysiological properties of capsaicin sensitive bladder afferent neurons with SCI mice. Main methodsWe used female C57BL/6 mice and transected their spinal cord at the Th8/9 level. Two weeks later, continuous administration of p38 MAPK inhibitor (0.51 μg/h, i.t. for two weeks) was started. Bladder afferent neurons were labelled with a fluorescent retrograde tracer, Fast-Blue (FB), injected into the bladder wall three weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurons were prepared and whole cell patch clamp recordings were performed in FB-labelled neurons. After recording action potentials or voltage-gated K+ currents, the sensitivity of each neuron to capsaicin was evaluated. Key findingsIn capsaicin-sensitive FB-labelled neurons, SCI significantly reduced the spike threshold and increased the number of action potentials during 800 ms membrane depolarization. Densities of slow-decaying A-type K+ (KA) and sustained delayed rectifier-type K+ (KDR) currents were significantly reduced by SCI. The reduction of KA, but not KDR, current density was reversed by the treatment with p38 MAPK inhibitor. SignificanceP38 MAPK plays an important role in hyperexcitability of capsaicin-sensitive bladder afferent neurons due to the reduction in KA channel activity in SCI mice.

New diagnostic measures of oxaliplatin-induced peripheral sensory neuropathy

ObjectiveOxaliplatin-induced peripheral neuropathy (OIPN) is an unwanted side effect of oxaliplatin chemotherapy treatment. OIPN manifests in an acute phase that lasts a few days after injection and a persistent phase that may become chronic. Currently, there is no consensus about a clinically applicable, quantitative, and objective measure of OIPN. MethodsSeventeen patients treated with oxaliplatin containing adjuvant chemotherapy for stage III colon cancer, but otherwise healthy, were tested with six quantitative sensory tests (QST) and five large fibre perception threshold tracking (PTT) measures (quantified by, e.g., rheobase and electrotonus threshold) one hour before each of the 12 chemotherapy cycles given at two weeks’ intervals. These measures were repeated at 3, 6, and 12-month follow-ups. The temporal development of OIPN assessed by the Common Terminology Criteria for Adverse Events (CTCAE) scale, QST, and PTT measures was calculated by linear regression. ResultsThe CTCAE score showed a tri-phasic increase during the treatment and remained increased during the follow-up. The vibration threshold (R = 0.25, p<0.001), the cold pain threshold (R = 0.17, p = 0.02), and the rheobase (R = 0.28, p < 0.001) increased during treatment, whereas the cold detection threshold (R=-0.16, p = 0.002) decreased. The cold pain threshold and the rheobase remained increased, and the cold detection and heat pain threshold remained decreased during follow-up. ConclusionsIncreased cold pain sensitivity and decreased large fibre sensitivity (increased rheobase) correlate to the persistent OIPN, whereas the CTCAE score assesses both acute and persistent OIPN. Furthermore, the novel PTT method assessed the nerve excitability changes caused by the oxaliplatin.

Nerve excitability study – a method to assess the pathophysiology of peripheral nervous system disorders

Nerve excitability study is an interesting extension of classical neurography. The principle of the test is to stimulate the nerve with a long-term depolarising or hyperpolarising stimulus, followed by a test stimulus that induces a complex motor or sensory potential of a given amplitude. The analysis of the intensity of the test stimulus used in chronic depolarisation or hyperpolarisation of the nerve fibre allows for the assessment of changes in nerve excitability. The median nerve is stimulated, and it is possible to assess the excitability of sensory or motor fibres. Nerve excitability study is the only method to evaluate the function of neuronal membrane ion channels in vivo. Test results are impacted by the following membrane-related factors: voltage-gated sodium and potassium ion channels, sodium and potassium ATPase, as well as the degree of fibre myelination and the levels of extracellular and intracellular electrolytes. Nerve excitability study yields a result in the form of a series of complex peripheral nerve excitability parameters, such as the relationship between the stimulus and the excitation threshold, rheobase, fibre chronaxie, threshold electrotonus, and reactivation after action potential. Nerve excitability study helps assess the pathophysiology of nerve fibre damage in various disorders of the peripheral nervous system, such as hereditary polyneuropathies, neurodegenerative or metabolic diseases. The test is highly sensitive, e.g. it shows pre-symptomatic excitability changes. It can also be used to monitor treatment outcomes in metabolic and drug-induced polyneuropathies and to search for peripheral markers of central nervous system channelopathies.

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.

Metabolic syndrome and anthropometric indices in CTS hands: an electrophysiological study.

This study aims to evaluate the effect of metabolic syndrome (MetS) and anthropometric indices on carpal tunnel syndrome (CTS). Forty-three healthy controls and 41 CTS patients were enrolled. Complaints of patients were assessed by Boston Questionnaire (BQ). MetS components were investigated. Wrist circumference, wrist depth, wrist width, palm width, and palm length were measured. Routine nerve conduction studies of median and ulnar nerves as well as the "sensitive" comparison tests were performed. Cutaneous silent period (CuSP) was studied by stimulating both second and fifth digital nerves while recording over thenar muscles. The vast majority of the participants were female and right-handed. CTS was bilateral in 61% of patients. Data of 109 hands were analyzed. MetS was more frequent in CTS patients. BQ scores were not related to MetS. Waist circumference, serum TG, and fasting glucose levels were higher in CTS patients. CTS hands with MetS had lower median CMAP amplitudes and increased sensory thresholds. Sensory thresholds were increased with both median and ulnar nerve stimulations suggesting a wider spread of peripheral nerve excitability changes in MetS presence. CuSPs were recorded from all 109 hands. CuSP latencies and durations were similar between controls and CTS patients. Wrist ratio was the only anthropometric index that was a statistically significant predictor for CTS development. MetS was more prevalent in CTS patients. Some clinical and electrophysiological features (mainly sensory thresholds) may worsen in presence of MetS, but not the wrist ratio.

Altered sensory nerve excitability in fibromyalgia

To investigate nerve excitability changes in patients with fibromyalgia and the correlation with clinical severity. We enrolled 20 subjects with fibromyalgia and 22 sex and age-matched healthy subjects to receive nerve excitability test and nerve conduction study to evaluate the peripheral axonal function. In the fibromyalgia cohort, the sensory axonal excitability test revealed increased superexcitability (%) (P=0.029) compared to healthy control. Correlational study showed a negative correlation between increased subexcitability (%) (r=-0.534, P=0.022) with fibromyalgia impact questionnaire (FIQ) score. Computer modeling confirmed that the sensory axon excitability pattern we observed in fibromyalgia cohort was best explained by increased Barrett-Barrett conductance, which was thought to be attributed to paranodal fast K+ channel dysfunction. The present study revealed that paranodal sensory K+ conductance was altered in patients with fibromyalgia. The altered conductance indicated dysfunction of paranodal fast K+ channels, which is known to be associated with the generation of pain.

Changes in motor nerve excitability in acute phase Guillain-Barré syndrome.

BackgroundThe most common subtypes of Guillain‐Barré syndrome (GBS) are acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). In the first days after the onset of weakness, standard nerve conduction studies (NCS) may not distinguish GBS subtypes. Reduced nerve excitability may be an early symptom of nerve dysfunction, which can be determined with the compound muscle action potential (CMAP) scan. The aim of this study was to explore whether early changes in motor nerve excitability in GBS patients are related to various subtypes.MethodsProspective case–control study in 19 GBS patients from The Netherlands and 22 from Bangladesh. CMAP scans were performed within 2 days of hospital admission and NCS 7–14 days after onset of weakness. CMAP scans were also performed in age‐ and country‐matched controls.ResultsCMAP scan patterns of patients who were classified as AMAN were distinctly different compared to the CMAP scan patterns of the patients who were classified as AIDP. The most pronounced differences were found in the stimulus intensity parameters.ConclusionsCMAP scans made at hospital admission demonstrate several characteristics that can be used as an early indicator of GBS subtype.

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.

530-P: Longitudinal Characterization of Peripheral Neuropathy in a Cafeteria Diet and Low-Dose Streptozotocin Rat Model of Type 2 Diabetes

Diabetic peripheral neuropathy is a major complication of diabetes with complex and incompletely understood pathophysiology. We utilised a cafeteria-style diet (Caf) and low dose streptozotocin (STZ) to model varying degrees of hyperglycemia. Adult male Sprague-Dawley rats were divided into four groups: control (chow diet), prediabetic (Caf diet for 21 weeks), diet reversal (13 weeks Caf diet then 8 weeks chow; all n=12) and type 2 diabetic (T2D - Caf+STZ 25mg/kg i.p, n=24). STZ was administered after 5 weeks of diet; one week later, non-fasted blood glucose was 16.09 ± 1.19 [SEM] and 78% of T2D rats had glucose levels ≥10mmol/L. Metabolic phenotyping revealed significantly increased body weight, fat mass, fasting blood HDL cholesterol, plasma insulin and impaired glucose tolerance in both prediabetic and T2D rats compared to controls; fasting glucose and HbA1c were significantly elevated only in T2D. Neuropathy phenotyping included sensory behavioural testing (thermal and mechanical nociceptive sensibility) and electrophysiology (nerve conduction studies and nerve excitability) which were assessed at two timepoints, early (8-11 weeks of diet) and late (17-19 weeks of diet). Nerve excitability abnormalities were present in prediabetes and T2D groups at the early stage (superexcitability p&amp;lt;0.05) while changes in nerve conduction velocity and amplitude emerged later. Mechanical and thermal hypoalgesia was observed in prediabetic and T2D rats only at the late stage. Diet reversal improved body weight, fat mass, HDL, HbA1c, glucose clearance and mechanical nociception response, with no changes in nerve conduction and excitability. Together these data suggest that Caf diet combined with low dose STZ could be utilized to investigate the onset of neuropathological changes in T2D and assessment of subsequent peripheral neuropathy. Disclosure M. Hossain: None. M.D. Kendig: None. B.M. Wild: None. M.J. Morris: None. R. Arnold: None. Funding National Health and Medical Research Council of Australia (1126929, 1091006); Rebecca L. Cooper Foundation (RG160627)

A54 DELTA OPIOID RECEPTOR SIGNALING MEDIATES OPIOID INDUCED TOLERANCE AND HYPERALGESIA IN COLONIC SENSORY NERVES

Abstract Background While opioid drugs are widely used for treating abdominal pain, prolonged exposure to opioids can induce tolerance and paradoxically increase pain. We previously showed in colonic afferent nerves that chronic morphine treatment causes tolerance and paradoxical hyperalgesia, however the mechanisms are unknown. Aims To evaluate the role of delta opioid receptor (DOR) signaling in opioid induced tolerance and hyperalgesia in colonic nerves during chronic morphine exposure. Methods C57BL/6 mice were injected (i.p.) twice daily for 7 days with escalating doses of morphine (10, 20, 30 mg/kg for the first 3 days, then 40mg/kg on 4th to 7th day); a subset of mice were also injected with 2.5 mg/kg naltrindole (NTI), a DOR antagonist. The analgesic response in vivo was monitored daily using the tail-flick test. To assess the effect of chronic morphine exposure, mice were euthanized on day 8, and the dorsal root ganglia (DRGs) and colons were harvested. Isolated DRG neurons were incubated with 1μM morphine (30 min) and neuronal excitability was determined by measuring the rheobase (amount of current required to elicit an action potential) using perforated patch clamp. To assess changes in colonic afferent nerve excitability, ex vivo afferent nerve recordings were obtained from flat-sheet colon preparations to determine the effects of 1μM morphine (10 min perfusion) on mechanosensitivity by probing with 1g von Frey hair. Results The tail flick test showed that the DOR antagonist NTI inhibited (30%) the maximal antinociceptive effect of morphine and reduced morphine tolerance. In patch clamp recordings, 1μM morphine paradoxically increased the excitability of small DRG neurons from morphine mice (rheobase decreased 28%; p&amp;lt;0.05, 2-way ANOVA), whereas this excitatory effect was absent on neurons from NTI+morphine mice. Acute application of 1μM morphine had no effect on afferent nerve responses to probing in morphine mice (14.9 vs 16.7 Hz; p=ns, paired t test, n=15) whereas it inhibited the afferent nerve response to probing in NTI+morphine mice (15.2 vs 9.9 Hz; p&amp;lt;0.001, paired t test, n=16). Furthermore, most single units from morphine mice had an increased response to probing following acute morphine application (7/15 vs 2/16 units excited), whereas most units form NTI-morphine mice were inhibited (14/16 vs. 3/15 units inhibited, P&amp;lt;0.001, Chi-square). Conclusions These findings suggest that DOR signaling plays a significant role in the development of opioid tolerance and hyperalgesia in colonic afferent nerves induced by chronic morphine treatment. Thus, antagonists of DOR may help to mitigate these side effects induced by opioids. Funding Agencies CCC

P68-S The effect of compression on peripheral nerves in ALS patients

Background Compression over a peripheral nerve leads to several changes in structural and physiological properties of that nerve. Paranodal myelin abnormalities and impaired axonal transport are some pathological incidents defined after acute compression. Materials and methods In sixteen ALS patients and 16 controls, CMAP Scan curves were recorded from first dorsal interosseus (FDI) muscle by stimulating ulnar nerve at elbow before compression, compression in 5 consecutive CMAP scanning cycles, and after compression. Stimulus intensities needed to elicit 10% and 90% of CMAP and step number and step% were calculated for each scan. As a further comparison, areas under CMAP scan curves were examined using natural values, percentages, and differences between compression (comp) cycles. Results For both patients and controls, conventional CMAP scan parameters were not significantly different in consecutive cycles. During compression, a tendency of reduction in area under CMAP scan curve of ALS patients (164.8 mVms, 156.3 mVms, 146.5 mVms, 142.1 mVms, 142.7 mVms, 137 mVms, and 174.9 mVms for pre-comp, 1st comp, 2nd comp, 3rd comp, 4th comp, 5th comp, and post- comp cycles, respectively) and a tendency of increase in CMAP scan curve area of healthy subjects (283.3 mVms, 315.6 mVms, 298.5 mVms, 319.7 mVms, 336.1 mVms, 361.4 and 308.1 mVms for pre-comp, 1st comp, 2nd comp, 3rd comp, 4th comp,5th comp, and post- comp cycles, respectively) were observed. Conclusions Probably due to incidental changes in nerve excitability, ALS patients mostly reacted differently to nerve compression when compared with healthy subjects.

P50-T Changes in peripheral nerve excitability by transcutaneous direct currents in healthy subjects – pilot study

Background Anodal stimulation results in subthreshold depolarisation, while cathodal stimulation hyperpolarises neuronal membranes. There have been few studies on the possible modulatory effect of long lasting transcutaneous direct current stimulation on the axonal membrane properties of peripheral nerves, especially on the possible modulatory effect of such currents. We aimed to assess the applicability, safety and effects on axonal membrane excitability of transcutaneous peripheral nerve stimulation with direct currents (pDCS). Material and methods We included 15 healthy subjects. pDCS was performed with the active electrode placed over the forearm and the reference electrode on the back of the hand using 5 × 5 cm rubber electrodes. The current applied was 2.5 mA during 15 min. Following a sham stimulation, two different settings were randomly used, cathodal and anodal current. Excitability measurements were performed using the TRONDNF nerve excitability protocol of the QTRAC program. Results The protocol was completed and well tolerated in all subjects. The TEd (90–100 ms) was significantly lower for anodal stimulation (p = 0.04). There were no other significant differences. These results were not replicated in a repeated trial, and in addition multiTRAC assessment failed to demonstrate significant after-effects on excitability. Conclusions TEd 90–100 ms reflects function of slow K+ channels, mainly located at the nodes. Initial findings suggested that slow K+-channel expression or conductance may be reduced after the application of anodal DC current, however repeated studies and real-time assessment of excitability measures argue against a consistent effect. Further research should be performed, using different intensities and stimulation time, as well as other excitability measurements.

P75-F Evaluation of deterioration in sensory nerve conduction studies in Amyotrophic Lateral Sclerosis

Background Many neurophysiological and pathological studies showed sensory abnormalities in ALS patients as a part of multisystem disease. In this study, we assessed progression of sensory changes in ALS patients, using nerve conduction studies (sNCS) in two consecutive visits. Material and methods sNCSs were evaluated based on amplitudes and velocities of bilateral dorsal sural (DS), medial plantar, superficial peroneal (SP), sural and left radial sensory nerves. In addition a global Total Sensory Score (TSens) was determined using the amplitudes of these nerves. Results Although, for both visits, TSens was smaller in patients (p = 0.04 and P = 0.01, for consecutive visits) then controls, there was no significant change between two visits of the patients (P = 0.19). ALS patients had significantly smaller amplitudes and slower velocities for bilateral DS, and left radial nerves for both visits. TSens was reduced in 7 (63.3%) but increased in 4 (36.6%) ALS patients. Conclusions Although, ALS patients showed considerable changes in NCS, sensory denervation is probably slowly progressive. The patients with improved sNCS were attributed to possible changes in sensory nerve excitability following corrective measures, e.g. administration of parenteral gastrostomy or high caloric diet.

Evaluating neurological injury in Hirayama disease using threshold tracking technology

Objective To investigate the efficacy of neurological injury in patients with Hirayama disease using threshold tracking technique. Methods This study included 17 patients with Hirayama disease who visited the Department of Orthopaedics of Huashan Hospital from June 2017 to October 2017 (patient group, 16 males and 1 female, the average age was 18.06±0.50 years, ranging from 16 to 22 years, the average course of disease was 27.2±18.81 months, ranging from 1 to 60 months. Meanwhile, a total of 20 healthy volunteers (control group, 19 males and 1 female, the average age is 20.05±1.30 years, ranging from 17 to 23 years) were also enrolled in this study. In patient group, the median motor nerve conduction examination, needle EMG examination, and threshold tracking examination were performed on the severe side; while in control group, the median motor nerve conduction examination and threshold tracking examination were performed on either side. We evaluate the changes in peripheral motor nerve conduction of Hirayama disease by comparing CMAP (compound muscle action potential) and median motor nerve conduction velocity evaluate the changes in motor nerve excitability by comparing the rheobase, SDTC (Strength-duration time constant), threshold electrotonus, current-threshold I/V slope, superexcitability, and subexcitability. The upper limb function was assessed by disabilities of arm, shoulder and hand (DASH) score. The differences in threshold tracking parameters between groups were compared by independent t test, and the correlation between SDTC and DASH score was tested by Pearson correlation analysis. Results In the peripheral motor nerve conduction examination, the median nerve CMAP in patients with Hirayama disease was 4.12±1.43 mV in average, which is lower than healthy controls 8.23±1.61 mV (t=-3.8, P<0.01). There was no significant difference in the peripheral motor nerve conduction velocity (t=-0.86, P=0.39). In the threshold tracking examination, SDTC in patients with Hirayama disease was 0.48±0.09 ms, which was prolonged than healthy controls 0.39±0.06 ms (t=3.75, P<0.01). The absolute values of TEh (10-20) and TEh (20-40) decreased significantly (P<0.01), hence, the hyperpolarized part of the threshold-electrotonus curve showed fanning-in pattern. The slope of the current-threshold (I/V) curve had a decreasing trend. The hyperpolarized I/V slope in patients with Hirayama disease was 0.27±0.09 in average, which was lower than the healthy controls which was 0.34±0.07 (t=-2.73, P=0.01). The DASH score of patients ranged from 0.86 to 19.44, with an average of 6.99±5.79. There was a correlation between SDTC and DASH score, R2=0.36, which met the F test (P=0.01). Conclusion Threshold tracking technique can be adapted in evaluating nerve injury in Hirayama disease to determine the degree of injury and potential pathogenesis. Key words: Cervical vertebrae; Spinal cord compression; Upper extremity; Muscular atrophy; Spinal fusion; Electromyography

Axonal excitability changes and acute symptoms of oxaliplatin treatment: In vivo evidence for slowed sodium channel inactivation

ObjectiveNeurotoxicity 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. MethodsQuestionnaires, 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). ResultsThe 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/m2 with a half-life of about 10d. ConclusionsOxaliplatin 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. SignificanceNerve excitability data provide an index of sodium channel dysfunction: an objective biomarker of acute oxaliplatin neurotoxicity.

Effects of hemodialysis on intraneural blood flow in end-stage kidney disease.

We quantified intraneural blood flow (INBF) in 18 patients with end-stage kidney disease (ESKD) and examined its relationship with nerve size, neuropathy severity, and nerve excitability parameters. Sonographic measurements of the median nerve were performed at the same site before and after hemodialysis. INBF was quantified by analyzing power Doppler sonograms to obtain the vessel score (VSc) and maximum perfusion intensity (MPI). Corresponding median motor nerve excitability studies were performed. Neuropathy severity was assessed using Total Neuropathy Score. A total of 39% of ESKD patients had detectable INBF compared with none in the control group (P < 0.0001). Patients with detectable INBF had larger nerves and more severe neuropathy (P < 0.01). INBF parameters were significantly reduced after a session of dialysis (VSc: P < 0.01; MPI: P < 0.01). A significant relationship was found between interdialytic change in INBF and changes in nerve excitability. Increased INBF is a potential marker for neuropathy severity in ESKD patients. Muscle Nerve 57: 287-293, 2018.

Nerve excitability changes related to muscle weakness in chronic progressive external ophthalmoplegia.

To explore potential spreading to peripheral nerves of the mitochondrial dysfunction in chronic progressive external ophthalmoplegia (CPEO) by assessing axonal excitability. CPEO patients (n=13) with large size deletion of mitochondrial DNA and matching healthy controls (n=22) were included in a case-control study. Muscle strength was quantified using MRC sum-score and used to define two groups of patients: CPEO-weak and CPEO-normal (normal strength). Nerve excitability properties of median motor axons were assessed with the TROND protocol and changes interpreted with the aid of a model. Alterations of nerve excitability strongly correlated with scores of muscle strength. CPEO-weak displayed abnormal nerve excitability compared to CPEO-normal and healthy controls, with increased superexcitability and responses to hyperpolarizing current. Modeling indicated that the CPEO-weak recordings were best explained by an increase in the 'Barrett-Barrett' conductance across the myelin sheath. CPEO patients with skeletal weakness presented sub-clinical nerve excitability changes, which were not consistent with axonal membrane depolarization, but suggested Schwann cell involvement. This study provides new insights into the spreading of large size deletion of mitochondrial DNA to Schwann cells in CPEO patients.

Impairments in Motor Neurons, Interneurons and Astrocytes Contribute to Hyperexcitability in ALS: Underlying Mechanisms and Paths to Therapy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of motor neurons leading to progressive paralysis and death. Using transcranial magnetic stimulation (TMS) and nerve excitability tests, several clinical studies have identified that cortical and peripheral hyperexcitability are among the earliest pathologies observed in ALS patients. The changes in the electrophysiological properties of motor neurons have been identified in both sporadic and familial ALS patients, despite the diverse etiology of the disease. The mechanisms behind the change in neuronal signalling are not well understood, though current findings implicate intrinsic changes in motor neurons and dysfunction of cells critical in regulating motor neuronal excitability, such as astrocytes and interneurons. Alterations in ion channel expression and/or function in motor neurons has been associated with changes in cortical and peripheral nerve excitability. In addition to these intrinsic changes in motor neurons, inhibitory signalling through GABAergic interneurons is also impaired in ALS, likely contributing to increased neuronal excitability. Astrocytes have also recently been implicated in increasing neuronal excitability in ALS by failing to adequately regulate glutamate levels and extracellular K+ concentration at the synaptic cleft. As hyperexcitability is a common and early feature of ALS, it offers a therapeutic and diagnostic target. Thus, understanding the underlying pathways and mechanisms leading to hyperexcitability in ALS offers crucial insight for future development of ALS treatments.

Nerve excitability and structural changes in myelinated axons from diabetic mice.

The mechanisms associated with nerve dysfunction and axonal loss in diabetes has not been fully clarified. Excitability and pathological aspects in nerves from diabetic mice were studied in order to explore the pathophysiology of diabetic neuropathy. Myelinated nerve fibres from the sciatic nerve of BKS.Cg-m (+/+) Lepr (db) /J mice were studied by registering the CMAP controlled by an automated threshold tracking method. The sciatic nerve was also studied pathologically. Diabetic mice displayed longer latencies, higher thresholds and lower amplitudes compared to controls and had a rightward shift in the stimulus response curves. Strength-duration time constant was lower in diabetic mice but not reaching statistical significance (p=0.09). Diabetics displayed an increase in accommodation, with a smaller change in excitability in threshold electrotonus. Refractoriness, mean superexcitability and late subexcitability were reduced in diabetic mice. Diabetic mice had a larger number of myelinated fibres compared to controls (p<0.05), but larger than 9 μm were virtually absent, accounting for near 7% in control animals. Db/db mice develop electrophysiological changes suggestive of membrane depolarization as the result of Na(+)/K(+) pump impairment. Loss of large myelinated fibres might also contribute to the nerve excitability profiles in this model.