Greater Threshold Changes Research Articles

Membrane property changes in most distal motor axons in chronic inflammatory demyelinating polyneuropathy.

Distal nerve terminals, where the blood-nerve barrier is anatomically deficient, are preferentially affected in immune-mediated neuropathies. Excitability alterations near the motor nerve terminals may be more prominent than the nerve trunk in typical chronic inflammatory demyelinating polyneuropathy (CIDP). In 20 patients with typical CIDP, motor nerve excitability testing was performed at the motor point and wrist of the ulnar nerve, and results were compared with those in 20 healthy persons. Chronic inflammatory demyelinating polyneuropathy patients showed greater threshold changes in hyperpolarizing threshold electrotonus at the motor point (P < .05) but not at the wrist. Strength-duration time constant did not show significant differences between CIDP and controls at both sites. Axonal property changes in CIDP are more prominent in distal portions of axons compared with the nerve trunk, presumably due to salient demyelination near the distal nerve terminals. Motor point excitability measurements could elucidate underlying pathophysiology in immune-mediated neuropathies.

Conduction block in immune-mediated neuropathy: paranodopathy versus axonopathy.

Conduction block is a pathognomonic feature of immune-mediated neuropathies. The aim of this study was to advance understanding of pathophysiology and conduction block in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). A multimodal approach was used, incorporating clinical phenotyping, neurophysiology, immunohistochemistry and structural assessments. Of 49 CIDP and 14 MMN patients, 25% and 79% had median nerve forearm block, respectively. Clinical scores were similar in CIDP patients with and without block. CIDP patients with median nerve block demonstrated markedly elevated thresholds and greater threshold changes in threshold electrotonus, whilst those without did not differ from healthy controls in electrotonus parameters. In contrast, MMN patients exhibited marked increases in superexcitability. Nerve size was similar in both CIDP groups at the site of axonal excitability. However, CIDP patients with block demonstrated more frequent paranodal serum binding to teased rat nerve fibres. In keeping with these findings, mathematical modelling of nerve excitability recordings in CIDP patients with block support the role of paranodal dysfunction and enhanced leakage of current between the node and internode. In contrast, changes in MMN probably resulted from a reduction in ion channel density along axons. The underlying pathologies in CIDP and MMN are distinct. Conduction block in CIDP is associated with paranodal dysfunction which may be antibody-mediated in a subset of patients. In contrast, MMN is characterized by channel dysfunction downstream from the site of block.

T38. Altered axonal excitability in spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease characterized with prominent fasciculations. Fasciculations suggest motor nerve hyperexcitability and potentially result in a burden to motor neuron. Axonal excitability and nerve conduction studies were performed in 31 patients with SBMA and 140 with amyotrophic lateral sclerosis (ALS). These results were compared with those of 16 healthy males (HM). In SBMA, correlations between neurophysiological studies and clinical profiles were examined. Patient backgrounds in SBMA were as follows; mean age; 58 years, mean disease duration; 152 months, mean ALS functional rating scale (ALSFRS-R); 41, mean CAG repeat expansion; 46, mean compound muscle action potential (CMAP) amplitude on abductor pollicis brevis muscle was 6.0 mV. Compared with HM, SBMA patients had longer strength-duration time constant (SDTC), greater threshold change in depolarizing threshold electrotonus (TEd) and greater supernormality (all p < 0.05). ALS patients had similar findings and smaller late subexcitability (all p < 0.05). In SBMA, TEd (90–100 ms) was related to ALSFRS-R (R = 0.42, p < 0.05), and CAG repeat was related to CMAP amplitude (R = −0.52, p < 0.05) and superexcitability (R = −0.46, p < 0.05). Patients were divided into two groups according to CMAP amplitude (over and under 5 mV). Compared with HM, SBMA patients with over 5 mV had greater TEd (10–20 ms) and greater superexcitability (all p < 0.05). SBMA patients with under 5 mV had longer SDTC, greater TEd and greater superexcitability (all p < 0.05). ALS patients with over 5 mV had greater TEd (90–100 ms) and greater superexcitability (all p < 0.05). ALS patients with under 5 mV had longer SDTC, greater TEd, greater superexcitability and smaller subexcitability (all p < 0.05). A previous study investigated axonal excitabilities in 7 patients with SBMA and revealed increased sodium currents. Our findings suggest that SBMA patients have increased sodium and decreased fast potassium currents. Similar findings and decreased slow potassium currents were found in ALS. This difference may suggest that ALS patients have more hyperexcitable motor nerve. Moreover, our findings suggest that decreased fast potassium currents are related to CAG repeat expansion in SBMA. It is already reported that SBMA patients have disruption of axonal transport. CAG repeat expansion may bring about axonal hyperexcitability and result in a burden to motor neuron.

1. Axonal function in inflammatory neuropathy: The importance of conduction block

Introduction Conduction block (CB) is a pathognomonic feature of chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), but precise mechanisms remain elusive. The aim of this study was to determine whether median motor axonal excitability profiles differ in MMN vs CIDP associated with conduction block (CB). Methods Clinical assessments, nerve conduction studies, median motor axonal excitability studies and ultrasound testing was undertaken in 12 patients with MMN and 44 patients with CIDP with results compared with 29 age-matched healthy controls. Results Compared to healthy controls, MMN with median motor CB was associated with greater threshold changes in threshold electrotonus (TE) in both depolarising [TEd 90–100 ms: 53.1 ± 1.8% vs 44.7 ± 0.7%; p Conclusion Axonal excitability patterns differ in patients with MMN and CIDP with CB demonstrating differences in underlying pathophysiology. Differences in excitability patterns in patients with CIDP with and without block cannot be explained by structural differences.

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.

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.

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.

Altered axonal excitability properties and nerve edema in POEMS syndrome

ObjectivePOEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is a rare cause of demyelinating neuropathy with upregulation of vascular endothelial growth factor (VEGF). This study aimed to elucidate axonal excitability properties and their relation to VEGF levels and nerve edema in POEMS neuropathy. MethodsAxonal excitability measurement and nerve ultrasound were performed in the median nerve of 33 patients with POEMS syndrome. Serum VEGF levels were measured by ELISA. ResultsCompared with normal subjects (n=87), POEMS patients showed longer strength-duration time constant, fanning-out of threshold electrotonus curves, and greater threshold changes in a hyperpolarizing current–threshold relationship. Nerve ultrasound showed significant enlargement in POEMS patients. Serum VEGF levels and the extent of nerve edema partly correlated with nerve conduction slowing, as well as persistent sodium currents and inward rectification. ConclusionsIn POEMS syndrome, patterns of changes in excitability properties could suggest increased persistent sodium currents, and impaired potassium and inward rectifying channels. The findings were not consistent with depolarization due to nerve edema and compression ischemia. SignificanceIn addition to demyelination, nerve edema induced by upregulated VEGF, and upregulated inflammatory cytokines could modulate profiles of POEMS neuropathy.

Axonal dysfunction, dysmyelination, and conduction failure in hereditary neuropathy with liability to pressure palsies.

Patients with hereditary neuropathy with liability to pressure palsies (HNPP) manifest with episodes of focal paresis when exposed to mechanical stress, although the basis for vulnerability to conduction block remains relatively unexplained. Axonal excitability techniques were utilized to provide insights into pathophysiological mechanisms in 13 HNPP patients, stimulating median motor and sensory axons at the wrist. In HNPP, distal latencies were prolonged, and motor and sensory amplitudes were reduced. Threshold was increased. Depolarizing and hyperpolarizing electrotonus was greater, and resting current-threshold slope was reduced. There were greater threshold changes in superexcitability, and refractoriness was decreased. Taken together, excitability testing in patients with HNPP established axonal hyperpolarization in both motor and sensory axons that may be attributable to changes in nerve architecture. In turn, the hyperpolarized resting membrane potential in HNPP may be a major predisposing factor for development of conduction block with mechanical stresses.

Axonal excitability in X-linked dominant Charcot Marie Tooth disease

ObjectiveWe investigated peripheral nerve function in X-linked Charcot–Marie–Tooth disease type 1 (CMTX1), and considered the functional consequences of mutant connexin-32. MethodsTwelve subjects (9 female, 3 male) were assessed clinically, by nerve conduction and excitability studies. A model of myelinated axon was used to clarify the contributing changes. ResultsAll subjects had abnormal nerve conduction. Excitability studies on median nerve axons showed greater threshold changes to hyperpolarising currents, with “fanning out” in threshold electrotonus, and modest changes in the recovery cycle. Modelling suggested shortening of internodal length, increase in nodal fast potassium currents, shift of the voltage activation hyperpolarisation-activated cyclic-nucleotide-gated channels, and axonal hyperpolarisation. Plotting threshold versus extent of hyperpolarising threshold change in threshold electrotonus distinguished the CMTX1 patients from other chronic demyelinating neuropathies reported in the literature except hereditary neuropathy with pressure palsies (HNPP). ConclusionsSome measures of axonal excitability are similar in CMTX1 and HNPP (though not the recovery cycle), but they differ from those in other chronic demyelinating neuropathies. The findings in CMTX1 are consistent with known pathology, but are not correlated to neuropathy severity. SignificanceThe findings in CMTX1 could be largely the result of morphological alterations, rather than plasticity in channel expression or distribution.

Split hand syndrome in amyotrophic lateral sclerosis: different excitability changes in the thenar and hypothenar motor axons

BackgroundIn amyotrophic lateral sclerosis (ALS), muscle wasting preferentially affects the abductor pollicis brevis (APB) and first dorsal interosseous over the abductor digit minimi (ADM), and this is termed ‘split hand’....

Evolution of peripheral nerve function in humans: novel insights from motor nerve excitability.

While substantial alterations in myelination and axonal growth have been described during maturation, their interactions with the configuration and activity of axonal membrane ion channels to achieve impulse conduction have not been fully elucidated. The present study utilized axonal excitability techniques to compare the changes in nerve function across healthy infants, children, adolescents and adults. Multiple excitability indices (stimulus-response curve, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle) combined with conventional neurophysiological measures were investigated in 57 subjects (22 males, 35 females; age range 0.46-24 years), stimulating the median motor nerve at the wrist. Maturational changes in conduction velocity were paralleled by significant alterations in multiple excitability parameters, similarly reaching steady values in adolescence. Maturation was accompanied by reductions in threshold (P < 0.005) and rheobase (P = 0.001); depolarizing and hyperpolarizing electrotonus progressively reduced (P < 0.001), or 'fanned-in'; resting current-threshold slope increased (P < 0.0001); accommodation to depolarizing currents prolonged (P < 0.0001); while greater threshold changes in refractoriness (P = 0.001) and subexcitability (P < 0.01) emerged. Taken together, the present findings suggest that passive membrane conductances and the activity of K(+) conductances decrease with formation of the axo-glial junction and myelination. In turn, these functional alterations serve to enhance the efficiency and speed of impulse conduction concurrent with the acquisition of motor skills during childhood, and provide unique insight into the evolution of postnatal human peripheral nerve function. Significantly, these findings bring the dynamics of axonal development to the clinical domain and serve to further illuminate pathophysiological mechanisms that occur during development.

Changes of the peripheral nerve excitability in vivo induced by the persistent Na+ current blocker ranolazine

Persistent Na+ current (Nap) in the peripheral axons play an important functional role in controlling the axonal excitability. Abnormal Nap is believed to contribute to neurodegeneration and neuropathic pain, and thus it is an attractive therapeutic target. To assess the behavior of selective Nap blockade, axonal excitability testing was performed in vivo in 10 normal male mice exposed to ranolazine by recording the tail sensory nerve action potentials (SNAPs). Twenty minutes after administering ranolazine i.p. (50mg/kg), the following changes were observed: lower SNAP amplitudes and the need for greater stimulus currents; greater threshold changes induced by long hyperpolarizing currents; reduced accommodation to long depolarizing current along with reduced late subexcitability; and reduced strength-duration time constant. These changes are explained by the suppression of Nap leading to greater threshold currents, partial block of transient Na+ current, and suppression of slow K+ currents. The suppressed slow K+ currents appear to limit the modification of the membrane excitability by ranolazine. This study confirms the utility of axonal excitability testing as a useful treatment biomarker in neurological conditions in which Nap function is being modified.

Differences in excitability between median and superficial radial sensory axons

ObjectiveThe aim of this study was to investigate differences in excitability properties of human median and superficial radial sensory axons (e.g., axons innervating the glabrous and hairy skin in the hand). Previous studies have shown that excitability properties differ between motor and sensory axons, and even among sensory axons between median and sural sensory axons. MethodsIn 21 healthy subjects, threshold tracking was used to examine excitability indices such as strength–duration time constant, threshold electrotonus, supernormality, and threshold change at the 0.2ms inter-stimulus interval in latent addition. In addition, threshold changes induced by ischemia for 10min were compared between median and superficial radial sensory axons. ResultsCompared with radial sensory axons, median axons showed shorter strength–duration time constant, greater threshold changes in threshold electrotonus (fanning-out), greater supernormality, and smaller threshold changes in latent addition. Threshold changes in both during and after ischemia were greater for median axons. ConclusionsThese findings suggest that membrane potential in human median sensory axons is more negative than in superficial radial axons, possibly due to greater activity of electrogenic Na+/K+ pump. These results may reflect adaptation to impulses load carried by median axons that would be far greater with a higher frequency. SignificanceBiophysical properties are not identical in different human sensory axons, and therefore their responses to disease may differ.

Differences in excitability properties of FDI and ADM motor axons

The first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles are innervated by the same ulnar nerve, but studies have shown that the former is much more severely affected in amyotrophic lateral sclerosis. In this study, threshold tracking was used to investigate whether membrane properties differ between FDI and ADM motor axons. In 12 normal subjects, compound muscle action potentials were recorded from FDI and ADM after ulnar nerve stimulation at the wrist. The strength-duration time constant was significantly longer in the FDI axons than in the ADM axons, and latent addition studies showed greater threshold changes at the conditioning-test stimulus of 0.2 ms in FDI than in ADM axons. These findings suggest that nodal persistent sodium conductances are more prominent in FDI axons than in ADM axons, and therefore excitability is physiologically higher in FDI axons. Even in the same nerve at the same sites, membrane properties of FDI and ADM motor axons differ significantly, and thus their axonal/neuronal responses to disease may also differ.

Changes in excitability properties associated with axonal regeneration in human neuropathy and mouse Wallerian degeneration

Objective The aim of this study was to investigate changes in excitability properties associated with axonal regeneration in human neuropathy and a mouse Wallerian degeneration model. Methods Threshold tracking was used to measure axonal excitability indices such as strength–duration time constant (SDTC), threshold electrotonus, supernormality in median motor axons at the wrist of 13 patients with vasculitic neuropathy in their recovery phase, and in tibial motor axons at the ankle of mice with sciatic nerve crush. In the mouse model, excitability testing was performed 4, 8, 12, and 20 weeks after the nerve crush. Results In patients, there were longer SDTC, greater threshold changes at 0.2 ms in latent addition, and greater threshold changes in depolarizing and hyperpolarizing threshold electrotonus, compared with controls. The pattern of changes in excitability indices was similar to those in experimental nerve crush, in which the indices remained abnormal for 20 weeks after the crush. These changes suggest an increase in nodal persistent sodium currents, whereas multiple factors may also contribute to changes in excitability properties, such as axonal hyperpolarization, increased internodal resistance, and altered potassium currents. Conclusions Excitability properties in regenerating axons are characterized by increased nodal persistent currents with variable combination of changes in passive properties, membrane potential, and potassium currents. Significance Increased persistent sodium currents are potential reasons for positive symptoms in patients with axonal neuropathy. Sodium channel blockers could be considered a treatment option.

Distal excitability changes in motor axons in amyotrophic lateral sclerosis

ObjectivePrevious axonal excitability studies in amyotrophic lateral sclerosis (ALS) have suggested that impaired potassium channel function could be responsible for the generation of fasciculations, but the ectopic activity arises predominantly from the motor nerve terminals. This study tested the hypothesis that dysfunction of potassium channels is more pronounced in the more distal parts of axons. MethodsThreshold electrotonus was used to compare accommodation at the motor point of abductor pollicis brevis, and at the wrist portion of the median nerve, between 22 patients with ALS and 19 normal subjects. As target responses for motor point stimulation, movement-related potentials were recorded using an accelerometer. ResultsCompared to normal subjects, ALS patients showed greater threshold changes to depolarizing conditioning currents at both the motor point and wrist, suggesting less accommodation by potassium currents. Differences in the threshold electrotonus curves between the normal and ALS groups were much more prominent at the motor point than at the wrist. ConclusionsIn ALS, axonal potassium channels are impaired more prominently in distal portions of axons than at the nerve trunk, and this is consistent with evidence that fasciculations mostly arise from the nerve terminals. SignificanceExcitability testing at the motor point provides additional information about the pathophysiology of ALS.

Nodal persistent Na + currents in human diabetic nerves estimated by the technique of latent addition

Objective To investigate the effects of hyperglycemia on persistent Na + currents in human diabetic nerves, eliminating the factors of passive membrane properties as a factor. Previous studies show that strength–duration time constant of a nerve is shortened under hyperglycemia, suggesting reduced axonal persistent Na + currents. However, the time constant is also affected by changes in passive membrane properties. Latent addition using computerized threshold tracking is a new method that can separately evaluate Na + currents and passive membrane properties. Methods Latent addition was used to estimate nodal Na + currents in median motor axons of 83 diabetic patients. Brief hyperpolarizing conditioning current pulses were delivered, and threshold changes at the conditioning-test interval of 0.2 ms were measured as an indicator of nodal persistent Na + currents. Seventeen patients were examined before and after insulin treatment. Results There was an inverse linear relationship between hemoglobin A1c levels and threshold changes at 0.2 ms ( P=0.02); the higher hemoglobin A1c levels were associated with smaller threshold changes. After insulin treatment, there was a significant improvement in nerve conduction velocities associated with greater threshold changes at 0.2 ms ( P=0.03), suggesting an increase in persistent Na + currents. The fast component of latent addition, an indicator of passive membrane properties, was not affected by the state of glycemic control. Conclusions Hyperglycemia could suppress nodal persistent Na + currents, presumably because of reduced trans-axonal Na + gradient or impaired Na + channels, and this can be rapidly restored by glycemic control. Significance Reduced nodal Na + currents may partly contribute to the pathophysiology of human diabetic neuropathy.

NEURAL LIMITATIONS OF VISUAL EXCITABILITY. VII. NONHOMONYMOUS RETROCHIASMAL INTERACTION.

Visual excitability changes were obtained from two trained observers by measuring threshold with a brief test flash of light at varying temporal intervals from the onset of a longer, supraliminal conditioning flash. The test target was either a 1°20' or a 5°20' solid disc, and was exposed to the right eye at 6°40' along the horizontal meridian in the temporal half field. The conditioning target was a 6°40' disc containing central masks of various angular subtenses, and was so placed in the left eye that the resulting annuli surrounded the test target in the binocularly fused field of view. For all conditions, threshold rose when test preceded conditioning flash in time, reaching a maximum at about o-msec interval between onsets. As the test flash was progressively delayed in time, thresholds fell to an asymptote, returning to resting level after termination of the conditioning flash. The smaller the mask diameter in the center of the conditioning target, i.e., the tighter the fit around the binocularly fused test target, the greater the maximum rise in threshold in the other eye. With small test targets, greater threshold changes were produced by conditioning targets with small masks than by those without a mask (solid targets). Observations on a third observer indicate that similar findings obtain when conditioning stimuli are equated for total luminous flux. These data indicate that retrochiasmal interaction is greater at target borders, and are compatible with recent unit studies on the cortical receptor field.