Strength-duration Time Constant Research Articles

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.

3. An effect of video-assisted motor imagery on F waves during motor imagery after volitional relaxation

s of the 41th Annual Meeting of Japanese Society of Clinical Neurophysiology, Shizuoka, Japan, November 10–12, 2011 Akio Kimura , Koichi Hirata b,⇑ Koishikawa Building 4F, 5-3-13 Otsuka, Bunkyo-ku, Tokyo 112-0012, Japan, Department of Neurology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan 1. Altered axonal excitability and ‘‘split hand’’ in amyotrophic lateral sclerosis—Kazumoto Shibuya, Kazuaki Kanai, Sonoko Misawa, Saiko Nasu, Yukari Sekiguchi, Satsuki Mitsuma, Minako Beppu, Yumi Fujimaki, Shigeki Ohmori, Satoshi Kuwabara (Department of Neurology, Chiba University, Chiba, Japan) In amyotrophic lateral sclerosis (ALS), muscle wasting preferentially affects abductor pollicis brevis (APB) compared with abductor digit minimi (ADM). This phenomenon is termed ‘split hand’ and considered to be specific to ALS. To elucidate the pathophysiology of ‘split hand’, we prospectively studied excitability properties at the wrist in the median-APB and ulnar-ADM motor axons in 19 ALS patients and 16 normal controls. In patients with ALS, there were longer strength duration time constant, larger threshold changes in depolarizing threshold electrotonus, greater supernormality, and greater late subnormality both in the median-APB and ulnar-ADM motor axons, compared with normal controls. The above findings suggest motor axonal hyperexcitability in ALS and the extent of excitability changes were more remarkable in the median-APB axons than in the ulnar-ADM axons. Differences in motor axonal excitability could lead to the different extent of glutamate excitotoxicity or metabolic demand spinal motoneurons. Excessive membrane excitability, which is prominent in the median-APB axons, could facilitate motor neuronal loss and this might correlate pathophysiology of ‘split hand’ in ALS. doi:10.1016/j.clinph.2012.02.002 2. Neuromagnetic evoked field measurements in the lumbar spine after tibial nerve stimulation at the popliteal fossa—Dai Ukegawa, Shigenori Kawabata, Shoji Tomizawa, Senichi Ishii, Kyohei Sakaki, Hiroyuki Inose, Toshitaka Yoshii, Tsuyoshi Kato, Atsushi Okawa (Tokyo Medical and Dental University, Tokyo, Japan) We previously reported successfully measuring neuromagnetic evoked fields in the lumbar spine (Cauda Equina Action Fields; CEAFs) of healthy subjects after tibial nerve stimulation at the ankle. The objective of this study was to measure larger CEAFs after tibial nerve stimulation at the level of the popliteal fossa in 3 healthy subjects. Neuromagnetic fields were measured over the surface of the lower back with a Superconducting Quantum Interference Device (SQUID) fluxmeter. A spatial filter method (UGMN) was applied to the magnetic field data obtained. Neuromagnetic fields propagating from the intervertebral foramina into the spinal canal were measured in each healthy subject by stimulation at each site. The magnetic fields were approximately 4 times larger after electrostimulation at the level of the popliteal fossa than at the ankle. The latencies of the magnetic fields corresponded to the physiological nerve conduction velocity. Isomagnetic field maps of the CEAFs showed a quadrupolar pattern propagating in a caudal to cranial direction along the lumbar spine in response to stimulation at both sites. We succeeded in measuring large CEAFs in healthy subjects by using the new stimulation method. Improving this method may allow diagnostic testing of spinal nerve function by a completely non-invasive technique. doi:10.1016/j.clinph.2012.02.003 3. An effect of video-assisted motor imagery on F waves during motor imagery after volitional relaxation—Shinichirou Taniguchi, Toshikazu Tani, Kenji Ishida, Takahiro Ushida, Tatsunori Ikemoto, Noritsuna Nakajima, Nobuaki Tadokoro, Takanori Saito, Jun Kimura (Kansai Medical University, Takii Hospital, Osaka, Japan) To investigate the effect of video-assisted motor imagery during volitional relaxation, we recorded 100 F waves from APB, during continuous motor imagery of thumb abduction, before and after the relaxation in 9 healthy volunteers. In experiment (1), the subjects were immobilized with bandage and instructed to relax for 3 h. In experiment (2) and (3), the subjects were repeated the same sequence but instructed to periodically image muscle contraction, without any aids in experiment (2) or with the aid of video in experiment (3), during the 3-h relaxation period. F-wave persistence and baseline-to-peak amplitude were statistically analyzed (ANOVA). Results: In experiment (1), both F-wave persistence and amplitude (mean) declined from the baseline value of (50.2% and 140.5 lV) to (38.7% and 92.5 lV) after volitional relaxation, showing a statistical difference (P < 0.05). The corresponding sequence consisted of ⇑ Corresponding author. Tel.: +81 282 87 2152; fax: +81 282 86 5884. E-mail address: hirata@dokkyomed.ac.jp (K. Hirata). Clinical Neurophysiology 123 (2012) e87–e100

Long-term nerve excitability changes by persistent Na+ current blocker ranolazine

The persistent Na+ current (Nap) in peripheral axons plays 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 chronic behavior of selective Nap blockade, axonal excitability testing was performed in vivo in normal male mice exposed to ranolazine by recording the tail sensory nerve action potentials (SNAPs). Seven days after administering ranolazine i.p. (50mg/kg) daily for 1 week, nerve excitability testing showed decreased strength-duration time constant in the ranolazine group in comparison to the control (P<0.03). This change is explained by the long-term effects of ranolazine on Nap. Importantly, ranolazine showed no effect on other ion channels that influence axonal excitability. Further study is needed to assess the chronic Nap blockade as a useful therapy in peripheral nerve diseases associated with abnormal nerve excitability.

Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis

ObjectiveThe aim of this study was to investigate whether axonal excitability indices are associated with survival in patients with amyotrophic lateral sclerosis (ALS). Previous nerve excitability studies suggested increased persistent...

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.

Clarifying distal axonal properties of the median nerve

Although length-dependent axonal excitability changes have been reported in the median nerve, the mechanisms underlying these changes remain to be further clarified. Axonal excitability studies were performed on median nerve at the palm and wrist in 20 healthy controls, with responses recorded over the abductor pollicis brevis. The strength-duration time constant was significantly shorter (palm: 0.35 ± 0.01 ms; wrist: 0.48 ± 0.03 ms; P < 0.001), whereas rheobase was significantly increased (palm: 2.90 ± 1.12 mA; wrist: 2.09 ± 1.11 mA; P < 0.05) at the palm. In addition, there was a significant increase in depolarizing threshold electrotonus at 90-100 ms (P < 0.001) and a reduction in S2 accommodation (P < 0.001) and late subexcitability (P < 0.001) at the palm. The changes in excitability were independent of factors influencing median nerve cross-sectional area. The present study reveals significant length dependent changes in median nerve excitability which may reflect differences in intrinsic membrane properties.

Strength-Duration Time Constant in Peripheral Nerve: No Abnormality in Multiple Sclerosis

Objectives. To investigate the properties of the strength-duration time constant (SDTC) in multiple sclerosis (MS) patients. Methods. The SDTC and rheobase in 16 MS patients and 19 healthy controls were obtained following stimulation of the right median nerve at the wrist. Results. SDTC and rheobase values were 408.3 ± 60.0 μs and 4.0 ± 1.8 mA in MS patients, versus 408.0 ± 62.4 μs and 3.8 ± 2.1 mA in controls. The differences were not significant in SDTC or rheobase values between the patients and controls (P = 0.988 for SDTC and P = 0.722 for rheobase). Conclusion. Our study showed no abnormality in relapsing remitting MS patients in terms of SDTC, which gives some indirect information about peripheral Na+ channel function. This may indicate that alterations in the Na+ channel pattern in central nervous system (CNS) couldnot be shown in the peripheral nervous system (PNS) in the MS patients by SDTC. The opinion that MS can be a kind of channelopathy might be proven by performing other axonal excitability tests or SDTC in progressive forms of MS.

Propofol decreases the axonal excitability in rat primary sensory afferents

AimsThe aim of this present study was to investigate the changes of peripheral sensory nerve excitability produced by propofol. Main methodsIn a recently described in vitro model of rodent saphenous nerve we used the technique of threshold tracking (QTRAC®) to measure changes of axonal nerve excitability of Aβ-fibres caused by propofol. Concentrations of 10μMol, 100μMol and 1000μMol were tested. Latency, peak response, strength-duration time constant (τSD) and recovery cycle of the sensory neuronal action potential (SNAP) were recorded. Key findingsOur results have shown that propofol decreases nerve excitability of rat primary sensory afferents in vitro. Latency increased with increasing concentrations (0μMol: 0.96±0.07ms; 1000μMol 1.10±0.06ms, P<0.01). Also, propofol prolonged the relative refractory period (0μMol: 1.79±1.13ms; 100μMol: 2.53±1.38ms, P<0.01), and reduced superexcitability (0 μMol: −14.0±4.0%; 100μMol: −9.5±5.5%) and subexcitability (0μMol: 7.5±1.2%; 1000μMol: 3.6±1.2) significantly during the recovery cycle (P<0.01). SignificanceOur results have shown that propofol decreases nerve excitability of primary sensory afferents. The technique of threshold tracking revealed that axonal voltage-gated ion channels are significantly affected by propofol and therefore might be at least partially responsible for earlier described analgesic effects.

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.

Peripheral neuropathy in hereditary spastic paraplegia due to spastin (SPG4) mutation – A neurophysiological study using excitability techniques

ObjectiveTo identify peripheral nerve abnormalities in hereditary spastic paraplegia (HSP) due to mutations in the spastin gene (spastic paraplegia 4, SPG4) using standard nerve conduction (NCS) and novel tests of axonal excitability. MethodsEleven patients with known mutations in spastin were assessed with NCS for the upper and lower limbs, and axonal excitability testing on the median nerve. ResultsStandard nerve conduction studies revealed a sensorimotor neuropathy in two patients. Excitability studies on median motor axons showed an isolated abnormality (increased strength-duration time constant), but those on sensory axons were normal in nine patients with normal routine nerve conduction studies. ConclusionsPeripheral neuropathy occurs in HSP patients with SPG4 mutations, but axonal excitability studies provide limited additional evidence for subclinical peripheral nerve dysfunction, and add little further to standard nerve conduction studies. SignificanceThe features of HSP due to SPG4 mutations include sensorimotor polyneuropathy. The value of excitability studies is limited in individual patients.

Nerve excitability changes related to axonal degeneration in amyotrophic lateral sclerosis: Insights from the transgenic SOD1G127X mouse model

Motor nerve excitability studies by “threshold tracking” in amyotrophic lateral sclerosis (ALS) revealed heterogeneous abnormalities in motor axon membrane function possibly depending on disease stage. It remains unclear to which extent the excitability deviations reflect a pathogenic mechanism in ALS or are merely a consequence of axonal degeneration.We investigated motor axon excitability in presymptomatic and symptomatic SOD1G127X mutants, a mouse model of ALS with late clinical onset and rapid disease progression. After clinical onset, there was a rapid loss of functional motor units associated with an increase in rheobase and strength–duration time constant, an increase in refractoriness at the expense of the superexcitability, larger than normal threshold deviations during both depolarizing and hyperpolarizing threshold electrotonus with impaired accommodation and reduction of the input conductance. These abnormalities progressed rapidly over a few days and were associated with morphological evidence of ongoing axonal degeneration. Presymptomatic mice with unaltered motor performance at rotor-rod measurement also had an increase in refractoriness at the expense of the superexcitability during the recovery cycle. This was, however, associated with smaller than normal deviations during threshold electrotonus, and a steeper resting current–threshold slope indicating slight axonal depolarization in agreement with motoneuronal hyperexcitability indicated by enhanced F-waves. Our data suggest that SOD1G127X motor axons undergo a state of membrane depolarization; however, during rapid motoneuron loss disease-specific nerve excitability measures are confounded by excitability changes in degenerating but still conducting axons. These findings should be considered in the interpretation of disease-stage-related nerve excitability changes in ALS.

Dysfunction of axonal membrane conductances in adolescents and young adults with spinal muscular atrophy

Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with onset in developing and maturing patients. Furthermore, the rate of degeneration appears to slow over time, at least in the milder forms. To investigate disease pathophysiology and potential adaptations, the present study utilized axonal excitability studies to provide insights into axonal biophysical properties and explored correlation with clinical severity. Multiple excitability indices (stimulus–response curve, strength–duration time constant, threshold electrotonus, current–threshold relationship and recovery cycle) were investigated in 25 genetically characterized adolescent and adult patients with spinal muscular atrophy, stimulating the median motor nerve at the wrist. Results were compared with 50 age-matched controls. The Medical Research Council sum score and Spinal Muscular Atrophy Functional Rating Scale were used to define the strength and motor functional status of patients with spinal muscular atrophy. In patients with spinal muscular atrophy, there were reductions in compound muscle action potential amplitude (P < 0.0005) associated with reduction in stimulus response slope (P < 0.0005), confirming significant axonal loss. In the patients with mild or ambulatory spinal muscular atrophy, there was reduction of peak amplitude without alteration in axonal excitability; in contrast, in the non-ambulatory or severe spinal muscular atrophy cohort prominent changes in axonal function were apparent. Specifically, there were steep changes in the early phase of hyperpolarization in threshold electrotonus (P < 0.0005) that correlated with clinical severity. Additionally, there were greater changes in depolarizing threshold electrotonus (P < 0.0005) and prolongation of the strength-duration time constant (P = 0.001). Mathematical modelling of the excitability changes obtained in patients with severe spinal muscular atrophy supported a mixed pathology comprising features of axonal degeneration and regeneration. The present study has provided novel insight into the pathophysiology of spinal muscular atrophy, with identification of functional abnormalities involving axonal K+ and Na+ conductances and alterations in passive membrane properties, the latter linked to the process of neurodegeneration.

Modulatory Effects on Axonal Function After Intravenous Immunoglobulin Therapy in Chronic Inflammatory Demyelinating Polyneuropathy

To investigate the immediate and longitudinal mechanisms of action of intravenous immunoglobulin (IVIg) on axonal function in chronic inflammatory demyelinating polyneuropathy (CIDP). Prospective single-center study. Hospitals and outpatient clinics. Clinical and functional assessment, nerve conduction studies, and 526 motor excitability studies were undertaken in 27 patients, matched before and immediately after infusion and followed up longitudinally. Axonal excitability variables were measured before and immediately after infusion and compared with matched studies and findings in healthy controls. Immediately after infusion, patients demonstrated decreased threshold, with significant reduction in strength-duration time constant (P=.003), reduction in accommodation to depolarization (P=.04), and reduced threshold change during hyperpolarization (P=.003), accompanied by significant decreases in superexcitability (P=.03) and subexcitability (P=.02). In contrast, changes were absent in disease controls, confirming a specific IVIg action in CIDP patients. Longitudinally, changes correlated with clinical improvement (mean [SE] increase in the Medical Research Council sum score, 2.7 [0.7]; P=.005). Increased compound muscle action potential amplitude was associated with reduction in terminal latency (correlation coefficient, -0.65; P=.02). In addition, these changes translated into improvement in functional assessment with the adjusted Inflammatory Neuropathy Cause and Treatment score, which demonstrated a significant correlation with nerve excitability variables longitudinally (P=.01). Findings from the present series establish a modulatory effect of IVIg on axonal function in CIDP patients, suggesting that IVIg stabilizes axonal membrane potential and promotes axonal recovery.

Axonal hyperpolarization in inclusion‐body myopathy, paget disease of the bone, and frontotemporal dementia (IBMPFD)

Inclusion-body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder due to mutations in the valosin-containing protein (VCP) gene. Patients with this disorder may have neuropathic or myopathic features. Peripheral nerve function and axonal excitability were studied in three members from two families with VCP mutations (p.Arg155Leu and p.Leu198Trp). Patients from the first family had neurogenic patterns on needle electromyography (EMG), whereas those in the second family had myopathic EMG changes. In threshold electrotonus for motor axons, the changes to depolarizing and hyperpolarizing conditioning currents were at or outside control limits in all three patients. Superexcitability was increased, and the relative refractory period was reduced. The strength-duration time constant was normal. In sensory axons of all three patients, there were similar changes in threshold electrotonus, but not in superexcitability. These features are best explained by axonal hyperpolarization. The findings provide insight into the pathophysiological mechanisms in these genotypes and, possibly, into all patients with IBMPFD.

A comparison of the excitability of motor axons innervating the APB and ADM muscles

Objective Threshold tracking allows the non-invasive assessment of axonal excitability. This study aimed to determine whether axonal excitability of the motor axons of the median nerve (to APB) and ulnar nerve (to ADM) to the small muscles of the hands is sufficiently similar to be interchangeable; confirm the feasibility and reproducibility of ulnar studies and obtain control data for a young population for this site of stimulation. Methods Twenty normal subjects between the ages of 23–43 were studied using the TRONDF protocol of QTRACS, (©Prof Hugh Bostock, London). The median and ulnar nerves were stimulated at the wrist and the compound muscle action potentials were recorded from abductor pollicis brevis and abductor digiti minimi, respectively. Repeat studies were performed in four subjects to confirm reproducibility of the recordings. Results Stimulus intensity was greater and strength duration time constant was longer for the median nerve. Threshold electrotonus showed there was a greater change in threshold in the hyperpolarising direction for the median nerve compared with the ulnar nerve. There was however little difference in the recovery cycle and current threshold relationship. Conclusions Although recovery cycles and the current thresholds are similar for APB and ADM, there are definite differences in stimulus threshold, SDTC and threshold electrotonus which question the interchangeability of studies for these two sites. Significance This study demonstrates reproducibility of motor axonal excitability studies of the ulnar nerve at the wrist, provides young control data for this site of stimulation and suggests that although certain excitability indices are similar for the median nerve to APB and ulnar nerve to ADM there are definite differences making the interchangeability of the data questionable.

Dose Effects of Oxaliplatin on Persistent and Transient Na+ Conductances and the Development of Neurotoxicity

BackgroundOxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity- acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na+ channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na+ channel dysfunction.Methodology/Principal FindingsSpecifically the function of transient and persistent Na+ currents were followed during treatment and were investigated in relation to oxaliplatin dose level. Eighteen patients were assessed before and after a single oxaliplatin infusion with motor and sensory axonal excitability studies performed on the median nerve at the wrist. While refractoriness (associated with Na+ channel inactivation) was significantly altered post-oxaliplatin infusion in both motor (Pre: 31.7±6.4%; Post: 68.8±14.5%; P≤.001) and sensory axons (Pre: 31.4±5.4%; Post: 21.4±5.5%; P<.05), strength-duration time constant (marker of persistent Na+ conductances) was not significantly altered post-infusion (Motor Pre: 0.395±0.01 ms; Post: 0.394±0.02 ms; NS; Sensory Pre:0.544±0.03 ms; Post: 0.535±0.05 ms; NS). However, changes in strength-duration time constant were significantly correlated with changes in refractoriness in motor and sensory axons (Motor correlation coefficient = −.65; P<.05; Sensory correlation coefficient = .67; P<.05).Conclusions/SignificanceIt is concluded that the predominant effect of acute oxaliplatin exposure in human motor and sensory axons is mediated through changes in transient rather than persistent Na+ conductances. These findings are likely to have implications for the design and trial of neuroprotective strategies.

THE MYELIN SHEATH AQUEOUS LAYERS IMPROVE THE MEMBRANE PROPERTIES OF SIMULATED CHRONIC DEMYELINATING NEUROPATHIES

Recently, patients with chronic demyelinating neuropathies have demonstrated significant abnormalities in their multiple nerve excitability properties measured by a non-invasive threshold tracking technique. In order to expand our studies on the possible mechanisms underlying these abnormalities, which are not yet well understood, we investigate the contributions of the aqueous layers within the myelin sheath on multiple membrane properties of simulated fibre demyelinations. Four degrees of systematic paranodal demyelinations (two mild demyelinations termed PSD1 and PSD2, without/with aqueous layers respectively, and two severe demyelinations termed PSD3 and PSD4, with/without aqueous layers, respectively) are simulated using our previous multi-layered model of human motor nerve fibre. We studied the following parameters of myelinated axonal function: potentials (intracellular action, electrotonic-reflecting the propagating and accommodative fibre processes, respectively) and strength-duration time constants, rheobases, recovery cycles (reflecting the adaptive fibre processes). The results show that each excitability parameter is markedly potentiated when the aqueous layers within their paranodally demyelinated sheaths are taken into account. The effect of the aqueous layers is significantly higher on the propagating processes than on the accommodative and adaptive processes in the fibres. The aqueous layers restore the action potential propagation, which is initially blocked when they are not taken into account. The study provides new and important information on the mechanisms of chronic demyelinating neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP).

THE AQUEOUS LAYERS WITHIN THE MYELIN SHEATH MODULATE THE MEMBRANE PROPERTIES OF SIMULATED HEREDITARY DEMYELINATING NEUROPATHIES

To expand our studies on the mechanisms underlying the clinical decline of the nerve excitability properties in patients with hereditary demyelinating neuropathies, the contribution of myelin sheath aqueous layers on multiple membrane properties of simulated fiber demyelinations is investigated. Three progressively greater degrees of internodal systematic demyelinations (two mild and one severe termed as ISD1, ISD2 and ISD3, respectively) without/with aqueous layers are simulated using our previous multi-layered model of human motor nerve fiber. The calculated multiple membrane excitability properties are as follows: potentials (intracellular action, electrotonic), strength-duration time constants, rheobasic currents and recovery cycles. They reflect the propagating, accommodative and adaptive processes in the fibers. The results show that all membrane properties, except for the strength-duration time constants and refractoriness, worsen when the myelin lamellae and their corresponding aqueous layers are uniformly reduced along the fiber length. The effect of the aqueous layers is significantly higher on the accommodative and adaptive processes than on the propagating processes in the fibers. Our multi-layered model better approximated some of the functional deficits documented for axons of patients with Charcot-Marie-Tooth disease type 1A. The study provides new and important information on the mechanisms underlying the pathophysiology of hereditary demyelinating neuropathies.

Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis

Fasciculation is a characteristic feature of ALS. Nerve excitability studies have shown increased persistent sodium currents and reduced potassium currents in motor axons of ALS patients, both of which lead to axonal hyperexcitability and thereby generation of fasciculations. The present study was undertaken to investigate whether abnormal axonal excitability indices are correlated with survival in ALS patients. A total of 112 consecutive patients with sporadic ALS were followed-up until endpoint (death or tracheostomy). Univariate analyses revealed longer strength-duration time constant (SDTC) was associated with a shorter survival. In multivariate analyses using the Cox proportional hazard model, onset age>60 years and longer SDTC were strong predictors of shorter survival. Assuming that SDTC depends on nodal persistent sodium conductances, our results showed that an increased persistent sodium current is strong and independent predictor for short survival of ALS patients. These findings support the hypothesis that membrane hyperexcitability would contribute to motor neuronal death in ALS.

Peripheral Nerve Axon Involvement in Myotonic Dystrophy Type 1, Measured Using the Automated Nerve Excitability Test

Background and PurposePrimary involvement of the peripheral nerves in myotonic dystrophy type I (MyD1) is controversial. We investigated whether the involvement of peripheral nerves is a primary event of MyD1 or secondary to another complication such as diabetes mellitus (DM).MethodsThe subjects comprised 12 patients with MyD1, 12 with DM and no peripheral nerve involvement, and 25 healthy volunteers. We measured multiple excitability indices in the median motor axons. The strength-duration time constant was calculated from the duration-charge curve, the threshold electrotonus and current-threshold relationships were calculated from the sequential subthreshold current, and the recovery cycle was derived from double suprathreshold stimulation.ResultsThe depolarizing and hyperpolarizing threshold electrotonus were significantly reduced and exhibited increased refractoriness in the MyD1 group compared with the DM and control groups. The SDTC, superexcitability, and subexcitability were not significantly altered in the MyD1 group.ConclusionsThe MyD1 group exhibited a depolarized axonal membrane potential. The significant differences in peripheral nerve excitability between the MyD1 group and the DM and normal control groups suggest that peripheral neuropathy is a primary event in MyD1 rather than a secondary complication of DM.