Fast Axons Research Articles

Mechanisms and treatment strategies of demyelinating and dysmyelinating Charcot-Marie-Tooth disease.

Schwann cells, the myelinating glia of the peripheral nervous system, wrap axons multiple times to build their myelin sheath. Myelin is of paramount importance for axonal integrity and fast axon potential propagation. However, myelin is lacking or dysfunctional in several neuropathies including demyelinating and dysmyelinating Charcot-Marie-Tooth disease. Charcot-Marie-Tooth disease represents the most prevalent inherited neuropathy in humans and is classified either as axonal, demyelinating or dysmyelinating, or as intermediate. The demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease constitute the majority of the disease cases and are most frequently due to mutations in the three following myelin genes: peripheral myelin protein 22, myelin protein zero and gap junction beta 1 (coding for Connexin 32) causing Charcot-Marie-Tooth disease type 1A, Charcot-Marie-Tooth disease type 1B, and X-linked Charcot-Marie-Tooth disease type 1, respectively. The resulting perturbation of myelin structure and function leads to axonal demyelination or dysmyelination and causes severe disabilities in affected patients. No treatment to cure or slow down the disease progression is currently available on the market, however, scientific discoveries led to a better understanding of the pathomechanisms of the disease and to potential treatment strategies. In this review, we describe the features and molecular mechanisms of the three main demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease, the rodent models used in research, and the emerging therapeutic approaches to cure or counteract the progression of the disease.

The Cortical "Upper Motoneuron" in Health and Disease.

Upper motoneurons (UMNs) in motor areas of the cerebral cortex influence spinal and cranial motor mechanisms through the corticospinal tract (CST) and through projections to brainstem motor pathways. The primate corticospinal system has a diverse cortical origin and a wide spectrum of fibre diameters, including large diameter fibres which are unique to humans and other large primates. Direct cortico-motoneuronal (CM) projections from the motor cortex to arm and hand motoneurons are a late evolutionary feature only present in dexterous primates and best developed in humans. CM projections are derived from a more restricted cortical territory (‘new’ M1, area 3a) and arise not only from corticospinal neurons with large, fast axons but also from those with relatively slow-conducting axons. During movement, corticospinal neurons are organised and recruited quite differently from ‘lower’ motoneurons. Accumulating evidence strongly implicates the corticospinal system in the early stages of ALS, with particular involvement of CM projections to distal limb muscles, but also to other muscle groups influenced by the CM system. There are important species differences in the organisation and function of the corticospinal system, and appropriate animal models are needed to understand disorders involving the human corticospinal system.

Nerve excitability differences in slow and fast motor axons of the rat: more than just Ih.

The objective was to determine biophysical differences between fast and slow motor axons using threshold tracking and demonstrate confounds related to anesthetic. Nerve excitability of motor axons innervating the slow-twitch soleus (SOL) and fast-twitch tibialis anterior (TA) muscles was tested. The experiments were conducted with pentobarbital sodium (SP) anesthetic and compared with previous results that used ketamine-xylazine (KX). Nerve excitability indices measured with SP show definitive differences between TA and SOL motor axons that extend beyond previous reports. Nerve excitability indices sensitive to changes in Ih indicated an increase in SOL axons compared with TA axons [e.g., S3 t = 7.949 (df = 10), P < 0.001; hyperpolarizing threshold electrotonus (90-100 ms), t = 2.659 (df = 20); P = 0.01; hyperpolarizing I/V slope, t = 4.308 (df = 19); P < 0.001]. SOL axons also had a longer strength-duration time constant [t = 3.35 (df = 20); P = 0.003] and a longer and larger magnitude relative refractory period [RRP (ms) t = 3.53 (df = 12); P = 0.004; Refractoriness at 2 ms, t = 0.0055 (df = 9); P = 0.006]. Anesthetic choice affected many measures of peripheral nerve excitability with differences most apparent in tests of threshold electrotonus and recovery cycle. For example, recovery cycle with KX lacked a clear superexcitable and late subexcitable period. We conclude that KX had a confounding effect on nerve excitability results consistent with ischemic depolarization. Results using SP revealed the full extent of differences in nerve excitability measures between putative slow and fast motor axons of the rat. These results provide empirical evidence, beyond conduction velocity, that the biophysical properties of motor axons vary with the type of muscle fiber innervated. These differences suggest that fast axons may be predisposed to dysfunction during hyperpolarizing stresses, e.g., electrogenic sodium pumping following sustained impulse conduction.NEW & NOTEWORTHY Nerve excitability testing is a tool used to provide insight into the properties of ion channels in peripheral nerves. It is used clinically to assess pathophysiology of axons. Researchers customarily think of motor axons as homogeneous; however, we demonstrate there are clear differences between fast and slow axons in the rat. This is important for interpreting results with selective motor neuronopathy, like aging where fast axons are at high risk of degeneration.

P19-F Variability of Intraoperation monitoring parameters in patients with degenerative cervical myelopathy

Background motor cortex transcranial electric stimulation in Intraoperative monitoring (IOM) is used to assess the corticospinal functional state by measuring the fast axons conduction (registration of D-wave), motor evoked potentials (MEPs) threshold and amplitude. While D-wave is considered to be a stable parameter independent of anesthesia, the informativeness of MEPs amplitude is controversial due to its instability, especially when in cervical spine surgery. Material and methods 20 patients with cervical degenerative myelopathy underwent surgical decompression with anterior cervical discectomy. In Group 1 (10 patients) the TIVA anaestiological protocol was used and in Group 2 (10 patients) the Sevoflurane 0.6–0.8 MAC was added. In all patients before intubation MEPs threshold for m. abd. pollicis brevis, m.add. digiti minimi, m. tibialis anterior, m. add. hallucis were assessed in response to a train of 5 pulses with a duration of 0.5 ms and inter-pulse interval 2 ms. Results In the course of operation MEPs threshold increase and amplitude decrease were detected in all patients Group2. In 6 patients of Group 1 (4 – unilaterally, 2 – bilaterally) and 4 patients of Group 2 (2– unilaterally, 2 – bilaterally) during surgery MEPs responses were lost; though there were observed no signs of additional neurological deficit after surgery. Unilateral MEP changes in patients operated on cervical spine can be attributed to compression of the plexus related to the position and patient fixation; bilateral – because of traction manipulations and spinal cord ischemia. Conclusions for detection of intraoperational ischemia Multimodal IOM will be preferred.

The effect of retardation in the random networks of excitable nodes, embeddable in the Euclidean space

Some features of random networks with excitable nodes that are embeddable in the Euclidean space are not describable in terms of the conventional integrate and fire model alone, and some further details should be involved. In the present paper we consider the effect of the retardation, i.e. the time that is needed for a signal to traverse between two agents. This effect becomes important to discover the differences between, e.g. the neural networks with low and fast axon conduct times. We show that the inclusion of the retardation effects makes some important changes to the statistical properties of the system. It considerably diminishes the amplitude of the possible oscillations in the random network. Additionally, it causes the critical exponents in the critical regime to considerably change.

Slowly-Conducting Pyramidal Tract Neurons in Macaque and Rat.

Anatomical studies report a large proportion of fine myelinated fibers in the primate pyramidal tract (PT), while very few PT neurons (PTNs) with slow conduction velocities (CV) (<~10 m/s) are reported electrophysiologically. This discrepancy might reflect recording bias toward fast PTNs or prevention of antidromic invasion by recurrent inhibition (RI) of slow PTNs from faster axons. We investigated these factors in recordings made with a polyprobe (32 closely-spaced contacts) from motor cortex of anesthetized rats (n = 2) and macaques (n = 3), concentrating our search on PTNs with long antidromic latencies (ADLs). We identified 21 rat PTNs with ADLs >2.6 ms and estimated CV 3–8 m/s, and 67 macaque PTNs (>3.9 ms, CV 6–12 m/s). Spikes of most slow PTNs were small and present on only some recording contacts, while spikes from simultaneously recorded fast-conducting PTNs were large and appeared on all contacts. Antidromic thresholds were similar for fast and slow PTNS, while spike duration was considerably longer in slow PTNs. Most slow PTNs showed no signs of failure to respond antidromically. A number of tests, including intracortical microinjection of bicuculline (GABAA antagonist), failed to provide any evidence that RI prevented antidromic invasion of slow PTNs. Our results suggest that recording bias is the main reason why previous studies were dominated by fast PTNs.

FCNN-based axon segmentation for convection-enhanced delivery optimization.

Glioblastoma multiforme treatment is a challenging task in clinical oncology. Convection- enhanced delivery (CED) is showing encouraging but still suboptimal results due to drug leakages. Numerical models can predict drug distribution within the brain, but require retrieving brain physical properties, such as the axon diameter distribution (ADD), through axon architecture analysis. The goal of this work was to provide an automatic, accurate and fast method for axon segmentation in electronic microscopy images based on fully convolutional neural network (FCNN) as to allow automatic ADD computation. The segmentation was performed using a residual FCNN inspired by U-Net and Resnet. The FCNN training was performed exploiting mini-batch gradient descent and the Adam optimizer. The Dice coefficient was chosen as loss function. The proposed segmentation method achieved results comparable with already existing methods for axon segmentation in terms of Information Theoretic Scoring ([Formula: see text]) with a faster training (5h on the deployed GPU) and without requiring heavy post-processing (testing time was 0.2s with a non-optimized code). The ADDs computed from the segmented and ground-truth images were statistically equivalent. The algorithm proposed in this work allowed fast and accurate axon segmentation and ADD computation, showing promising performance for brain microstructure analysis for CED delivery optimization.

Retinal ganglion cell function in recovered optic neuritis: Faster is not better

ObjectiveTo assess residual retinal ganglion cell (RGC) function in patients with recovered optic neuritis (ON) and multiple sclerosis (MS). MethodsAge-matched controls (C, n = 32) and MS patients (n = 17) with history of ON in one eye but normal visual acuity and color vision were tested with steady-state Pattern Electroretinogram (PERG). Light Emitting Diodes (LED)-generated bar gratings, robust signal averaging and Fourier analysis were used to assess response amplitude and latency. ResultsPERG amplitude was similar for C, ON and fellow eyes (FE) (P = 0.4), but PERG latency was shortened in ON by 3.2 ms (P = 0.002) and in FE by 2.0 ms (P = 0.02) and was correlated (P < 0.01) with both Retinal Nerve Fiber Layer (RNFL) and Ganglion Cell Inner Plexiform Layer (GCIPL) thicknesses. PERG latency shortening could be simulated in control subjects (n = 8) by dioptrically blurring the edges of gratings (high spatial frequencies), which reduced activity of parvocellular RGCs with smaller/slower axons. The blurred PERG latency was shorter than baseline by 2.9 ms (P = 0.01). ConclusionsPERG latency is shortened in both eyes of MS patients with recovered unilateral ON, suggesting relative dysfunction of RGCs with slower axons and sparing of RGCs with faster axons. SignificanceAssessment of PERG latency in MS and ON may help identifying and monitoring RGC dysfunction. PERG latency shortening in FE suggests primary retinopathy in MS.

Disease mechanisms in spinal muscular atrophy with respiratory distress type 1 (SMARD1): what about motoneurons?

Spinal muscular atrophy with respiratory distress type 1 (SMARD1), described as a fatal motoneuron disorder in children is characterized by α-motoneuron loss. Most of the SMARD1 patients suffer from diaphragmatic palsy leading to permanent ventilation at very early stages of disease. As muscular atrophy is the predominant clinical sign in SMARD1 patients, the question arises whether motoneuron degeneration occurs cell-autonomously. IGHMBP2, the disease causing gene in SMARD1, encodes for a helicase with still unknown function in motoneurons. Studies from a SMARD1 mouse model (Nmd2J mouse) revealed that degeneration of motor axons precedes muscle fiber atrophy in the gastrocnemius muscle aside from a pure myopathy of the diaphragm without affected motor nerve innervation. Nmd2J mice suffer from a reduced IGF1 level which can be compensated by external application of a polyethylene glycol (PEG)-coupled variant of IGF1 (PEG-IGF1). The beneficial effects in striated muscles corresponded to a marked activation of the IGF1 receptor (IGF1R), resulting in enhanced phosphorylation of Akt (protein kinase B) and the ribosomal protein S6 kinase. Unfortunately, no protective effects of PEG-IGF1 were observed at the level of motoneuron survival. Fast motor axon loss innervating the gastrocnemius muscle of Nmd2J mice does not correspond to morphological and functional alterations at the neuromuscular endplate as it is described in mouse models for proximal spinal muscular atrophy (SMA). However, the high capacity for axonal sprouting in Nmd2J mice indicates the functionality of the remaining motoneurons. These observations argue for additional non-cell-autonomous disease mechanisms which do not primarily affect the neuromuscular endplate and in general the functionality of Ighmbp2 deficient motoneurons.

Microglia activation mediated by toll-like receptor-4 impairs brain white matter tracts in rats.

Microglia activation and white matter injury coexist after repeated episodes of mild brain trauma and ischemic stroke. Axon degeneration and demyelination can activate microglia; however, it is unclear whether early microglia activation can impair the function of white matter tracts and lead to injury. Rat corpus callosum (CC) slices were treated with lipopolysaccharide (LPS) or LPS + Rhodobacter sphaeroides (RS)-LPS that is a toll-like receptor 4 (TLR-4) antagonist. Functional changes reflected by the change of axon compound action potentials (CAPs) and the accumulation of β-amyloid precursor protein (β-APP) in CC nerve fibers. Microglia activation was monitored by ionized calcium binding adaptor-1 immunofluorescent stain, based on well-established morphological criteria and paralleled proportional area measurement. Input-output (I/O) curves of CAPs in response to increased stimuli were significantly downshifted in a dose-dependent manner in LPS (0.2, 0.5 and 1.0 μg/mL)-treated slices, implying that axons neurophysiological function was undermined. LPS caused significant β-APP accumulation in CC tissues, reflecting the deterioration of fast axon transport. LPS-induced I/O curve downshift and β-APP accumulation were significantly reversed by the pre-treatment or co-incubation with RS-LPS. RS-LPS alone did not change the I/O curve. The degree of malfunction was correlated with microglia activation, as was shown by the measurements of proportional areas. Function of CC nerve fibers was evidently impaired by microglia activation and reversed by a TLP-4 antagonist, suggesting that the TLP-4 pathway lead to microglia activation.

Axon diameter relates to synaptic bouton size: structural properties define computationally different types of cortical connections in primates.

Neural connections are implemented by axons of different diameters, whose spectrum increases depending on species and areas. Axon diameter determines conduction velocity and is proportional to the size of the cell body of origin. We describe that in motor, callosal connections of the monkey thick axons distribute larger boutons than thin axons, suggesting that faster axons also release more neurotransmitter at their termination, probably activating more powerfully their targets.

Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism

Oligodendrocytes make myelin and support axons metabolically with lactate. However, it is unknown how glucose utilization and glycolysis are adapted to the different axonal energy demands. Spiking axons release glutamate and oligodendrocytes express NMDA receptors of unknown function. Here we show that the stimulation of oligodendroglial NMDA receptors mobilizes glucose transporter GLUT1, leading to its incorporation into the myelin compartment invivo. When myelinated optic nerves from conditional NMDA receptor mutants are challenged with transient oxygen-glucose deprivation, they show a reduced functional recovery when returned to oxygen-glucose but are indistinguishable from wild-type when provided with oxygen-lactate. Moreover, the functional integrity of isolated optic nerves, which are electrically silent, is extended by preincubation with NMDA, mimicking axonal activity, and shortened by NMDA receptor blockers. This reveals a novel aspect of neuronal energy metabolism in which activity-dependent glutamate release enhances oligodendroglial glucose uptake and glycolytic support of fast spiking axons.

Ephrin-A3 promotes and maintains slow muscle fiber identity during postnatal development and reinnervation.

Each adult mammalian skeletal muscle has a unique complement of fast and slow myofibers, reflecting patterns established during development and reinforced via their innervation by fast and slow motor neurons. Existing data support a model of postnatal "matching" whereby predetermined myofiber type identity promotes pruning of inappropriate motor axons, but no molecular mechanism has yet been identified. We present evidence that fiber type-specific repulsive interactions inhibit innervation of slow myofibers by fast motor axons during both postnatal maturation of the neuromuscular junction and myofiber reinnervation after injury. The repulsive guidance ligand ephrin-A3 is expressed only on slow myofibers, whereas its candidate receptor, EphA8, localizes exclusively to fast motor endplates. Adult mice lacking ephrin-A3 have dramatically fewer slow myofibers in fast and mixed muscles, and misexpression of ephrin-A3 on fast myofibers followed by denervation/reinnervation promotes their respecification to a slow phenotype. We therefore conclude that Eph/ephrin interactions guide the fiber type specificity of neuromuscular interactions during development and adult life.

Dynamics of signal propagation and collision in axons.

Long-range communication in the nervous system is usually carried out with the propagation of action potentials along the axon of nerve cells. While typically thought of as being unidirectional, it is not uncommon for axonal propagation of action potentials to happen in both directions. This is the case because action potentials can be initiated at multiple "ectopic" positions along the axon. Two ectopic action potentials generated at distinct sites, and traveling toward each other, will collide. As neuronal information is encoded in the frequency of action potentials, action potential collision and annihilation may affect the way in which neuronal information is received, processed, and transmitted. We investigate action potential propagation and collision using an axonal multicompartment model based on the Hodgkin-Huxley equations. We characterize propagation speed, refractory period, excitability, and action potential collision for slow (type I) and fast (type II) axons. In addition, our studies include experimental measurements of action potential propagation in axons of two biological systems. Both computational and experimental results unequivocally indicate that colliding action potentials do not pass each other; they are reciprocally annihilated.

IH activity is increased in populations of slow versus fast motor axons of the rat.

Much is known about the electrophysiological variation in motoneuron somata across different motor units. However, comparatively less is known about electrophysiological variation in motor axons and how this could impact function or electrodiagnosis in healthy or diseased states. We performed nerve excitability testing on two groups of motor axons in Sprague–Dawley rats that are known to differ significantly in their chronic daily activity patterns and in the relative proportion of motor unit types: one group innervating the soleus (“slow motor axons”) and the other group innervating the tibialis anterior (“fast motor axons”) muscles. We found that slow motor axons have significantly larger accommodation compared to fast motor axons upon application of a 100 ms hyperpolarizing conditioning stimulus that is 40% of axon threshold (Z = 3.24, p = 0.001) or 20% of axon threshold (Z = 2.67, p = 0.008). Slow motor axons had larger accommodation to hyperpolarizing currents in the current-threshold measurement (-80% Z = 3.07, p = 0.002; -90% Z = 2.98, p = 0.003). In addition, we found that slow motor axons have a significantly smaller rheobase than fast motor axons (Z = -1.99, p = 0.047) accompanied by a lower threshold in stimulus-response curves. The results provide evidence that slow motor axons have greater activity of the hyperpolarization-activated inwardly rectifying cation conductance (IH) than fast motor axons. It is possible that this difference between fast and slow axons is caused by an adaptation to their chronic differences in daily activity patterns, and that this adaptation might have a functional effect on the motor unit. Moreover, these findings indicate that slow and fast motor axons may react differently to pathological conditions.

A Slow Axon Antidromic Blockade Hypothesis for Tremor Reduction via Deep Brain Stimulation

Parkinsonian and essential tremor can often be effectively treated by deep brain stimulation. We propose a novel explanation for the mechanism by which this technique ameliorates tremor: a reduction of the delay in the relevant motor control loops via preferential antidromic blockade of slow axons. The antidromic blockade is preferential because the pulses more rapidly clear fast axons, and the distribution of axonal diameters, and therefore velocities, in the involved tracts, is sufficiently long-tailed to make this effect quite significant. The preferential blockade of slow axons, combined with gain adaptation, results in a reduction of the mean delay in the motor control loop, which serves to stabilize the feedback system, thus ameliorating tremor. This theory, without any tuning, accounts for several previously perplexing phenomena, and makes a variety of novel predictions.

Retrograde signaling in the optic nerve is necessary for electrical responsiveness of retinal ganglion cells.

We investigated the role of retrograde signaling in the optic nerve on retinal ganglion cell (RGC) electrical responsiveness in the mouse model. Electrical response of RGC was measured by pattern electroretinogram (PERG) in 43 C57BL/6J mice 4 to 6 months old under ketamine/xylazine anesthesia. PERGs were recorded before and at different times after blockade of axon transport with lidocaine at either the retrobulbar level (2 μL, 40 μg/μL) or at level of the superior colliculus (SC, 1 μL, 40 μg/μL). PERGs also were recorded before and at different times after optic nerve crush 1.5 mm behind the eye, followed by TUJ1-positive RGC counts of excised retinas. As controls, PERGs also were recorded after either saline injections or sham optic nerve surgery. The photopic flash electroretinogram (FERG) and visual evoked potential (FVEP) also were recorded before lidocaine and at relevant times afterwards. Lidocaine injection caused rapid (retrobulbar ~10 minutes, SC 1 hour), reversible reduction of PERG amplitude (≥50%). Optic nerve crush caused rapid (10-20 minutes), irreversible reduction of PERG amplitude (70-75%), increase of PERG latency (>25%), as well as RGC loss (88%) 1 month after crush. FVEP was unaltered by lidocaine. For all procedures, the FERG was unaltered. As experimental interventions were made at postretinal level(s), PERG changes were likely associated with altered supply of retrogradely-delivered material from the SC. This implies that retrograde transport of target-derived molecules is necessary for normal RGC electrical responsiveness. The time course of early PERG changes is consistent with the speed of fast retrograde axon transport.

Fast motor axon loss in SMARD1 does not correspond to morphological and functional alterations of the NMJ

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a childhood motoneuron disease caused by mutations in the gene encoding for IGHMBP2, an ATPase/Helicase. Paralysis of the diaphragm is an early and prominent clinical sign resulting both from denervation and myopathy. In skeletal muscles, muscle atrophy mainly results from loss of motoneuron cell bodies and axonal degeneration. Although it is well known that loss of motoneurons at the lumbar spinal cord is an early event in the pathogenesis of the disease, it is not clear whether the corresponding proximal axons and NMJs are also early affected. In order to address this question, we have investigated the time course of the disease progression at the level of the motoneuron cell body, proximal axon (ventral root), distal axon (sciatic nerve), NMJ, and muscle fiber in Nmd2J mice, a mouse model for SMARD1. Our results show an early and apparently parallel loss of motoneurons, proximal axons, and NMJs. In affected muscles, however, denervated fibers coexist with NMJs with normal morphology and unaltered neurotransmission. Furthermore, unaffected axons are able to sprout and reinnervate muscle fibers, suggesting selective vulnerability of neurons to Ighmbp2 deficiency. The preservation of the NMJ morphology and neurotransmission in the Nmd2J mouse until motor axon loss takes place, differs from that observed in SMA mouse models in which NMJ impairment is an early and more general phenomenon in affected muscles.

Large Identified Pyramidal Cells in Macaque Motor and Premotor Cortex Exhibit “Thin Spikes”: Implications for Cell Type Classification

Recent studies have suggested that extracellular recordings of putative cortical interneurons have briefer spikes than those of pyramidal neurons, providing a means of identifying cortical cell types in recordings from awake monkeys. To test this, we investigated the spike duration of antidromically identified pyramidal tract neurons (PTNs) recorded from primary motor (M1) or ventral premotor cortex (area F5) in 4 awake macaque monkeys. M1 antidromic latencies (ADLs) were skewed toward short ADLs (151 PTNs; 0.5-5.5 ms, median 1.1 ms) and significantly different from that of F5 ADLs (54 PTNs; 1.0-6.9 ms, median 2.6 ms). The duration of PTN spikes, recorded with a high-pass filter of 300 Hz and measured from the negative trough to the positive peak of the spike waveform, ranged from 0.15 to 0.71 ms. Importantly, we found a positive linear correlation between ADL and spike duration in both M1 (R(2) = 0.40, p < 0.001) and F5 (R(2) = 0.57, p < 0.001). Thus PTNs with the shortest ADL (fastest axons) had the briefest spikes, and since PTN soma size is correlated with axon size and conduction velocity, it is likely that the largest pyramidal neurons (Betz cells in M1) have spikes with short durations (0.15-0.45 ms), which overlap heavily with those reported for putative interneurons in previous studies in non-primates. In summary, one class of physiologically identified cortical pyramidal neuron exhibits a wide variety of spike durations and the results suggest that spike duration alone may not be a reliable indicator of cell type.

Distal motor axonal dysfunction in amyotrophic lateral sclerosis

Nerve conduction slowing in amyotrophic lateral sclerosis (ALS) is usually caused by loss of fast motor axons. We studied the frequency, extent, and distribution of prominently prolonged distal motor latencies in ALS. We reviewed results of median, ulnar, and tibial nerve conduction studies in 91 patients with ALS, 24 with lower motor neuron disorders, and 36 with axonal neuropathy. Coincidental carpal tunnel syndrome was found for 4 (4.4%) of the ALS patients who were excluded from analyses. Markedly prolonged distal latencies (> 125% of the upper limit of normal) were found only in the median nerve of ALS patients (9%), and in none of the disease controls. Excitability studies suggested membrane depolarization in some ALS patients. Our results show that approximately 10% of ALS patients shows prominently prolonged median distal latency, which cannot be explained by axonal loss and carpal tunnel lesion. The distal nerve conduction slowing may partly be caused by membrane depolarization possibly due to motor neuronal degeneration in ALS. We suggest that recognition of the pattern of distal motor axonal dysfunction predominant in the median nerve is clinically important, and could provide additional insights into the pathophysiology of ALS.