Upregulation of inward rectifying currents and Fabry disease neuropathy

Peripheral neuropathy and neuropathic pain are common clinical manifestations of Fabry disease (FD). Although the mechanisms underlying the development of sensory neuropathy remain to be fully elucidated, a chronic ischemic process was proposed. Consequently, this study utilized axonal excitability techniques to gain further insights into the pathophysiological mechanisms underlying the development of FD neuropathy. Median motor and sensory axonal excitability studies were undertaken in 13 FD patients and results were compared to 19 healthy subjects. A “fanning‐in” of threshold electrotonus, suggestive of membrane depolarization, was evident only in motor axons in FD patients. In contrast, the sensory axons exhibited a lower threshold in FD (p < 0.05) and a significantly increased hyperpolarizing current/threshold (I/V) gradient (FD 0.48 ± 0.03; controls, 0.31 ± 0.02, p < 0.001), which correlated with clinical scores of disease severity (Rho = 0.65, p < 0.05), neuropathy (Rho = 0.54, p < 0.05) and neuropathic pain (Rho = 0.56, p < 0.05). These findings indicate that upregulation of I_h, rather than ischemia, may underlie the sensory symptoms and possibly development of neuropathy in FD. Modulation of sensory I_h may prove therapeutically useful in Fabry disease.     

Effects of experimental focal compression on excitability of human median motor axons

ObjectiveTo characterize the effect of focal compression by threshold tracking and other excitability measures of human median motor axons.MethodsWe conducted a sequence of excitability studies using a software written in BASIC (QTRAC version 4.0, ©Institute of Neurology, London, UK, with multiple excitability protocol TRONDXM 2) in 24 healthy subjects, stimulating the median nerve at the wrist and recording compound muscle action potentials from the abductor pollicis brevis. Constant, localized compression was applied at the wrist by mechanically lowering a probe attached to a disk electrode, which also served as the stimulating cathode.ResultsCompared with the pre-compression values, measurements during compression showed a shift of threshold electrotonus waveforms toward the baseline (fanning-in), steeper current–threshold relationships, increased strength-duration time constants, prolonged relative refractory periods and reduced levels of superexcitability, but no alteration in late subexcitability. These excitability changes indicating depolarization reversed to hyperpolarization immediately after release of compression. The nerve compression altered none of the excitability measures when recorded 2 cm distally from the pressure probe.ConclusionsMild nerve compression produces a very localized axonal depolarization at the compression site followed by hyperpolarization upon release of compression, as expected from focal ischemia.SignificanceThe current results imply that the sharply-localized conduction abnormalities demonstrated electrophysiologically in peripheral nerve entrapment syndromes and compression myelopathies may, in part, result from compression-induced focal nerve ischemia.     

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

Introduction: 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. Methods: Axonal excitability techniques were utilized to provide insights into pathophysiological mechanisms in 13 HNPP patients, stimulating median motor and sensory axons at the wrist. Results: 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. Conclusions: 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. Muscle Nerve 49 : 858–865, 2014     

Tibial nerve axonal excitability in type 1 diabetes mellitus

Introduction: The aim of this study was to determine alterations in axonal excitability in tibial nerve as compared with median nerve axonal excitability in patients with diabetic polyneuropathy. Methods: Six patients with diabetic polyneuropathy and 10 patients with diabetes mellitus without polyneuropathy were enrolled. Results: Compared with diabetic patients without polyneuropathy, the tibial nerve strength–duration time constant was significantly longer and supernormality was lower in those with polyneuropathy. Threshold electrotonus studies showed abnormalities in patients with diabetic polyneuropathy, in which smaller threshold changes from long-depolarizing and hyperpolarizing conditioning, termed “fanning-in,” were found. Discussion: This study confirms that axonal excitability is significantly altered in the tibial nerve of patients with diabetic polyneuropathy. Evaluating the axonal excitability of the median and tibial nerves may reveal the presence of length-dependent polyneuropathy at an early stage. Muscle Nerve 59 :76–81, 2019     

Differences in excitability properties between medial gastrocnemius,tibialis anterior,and abductor pollicis brevis motor axons

Introduction: Excitability properties of motor nerves to different muscles are different, but the explanation is uncertain. We characterized motor axon excitability properties to the medial gastrocnemius (MG) in 27 adults, and made comparisons with the peroneal nerve to the tibialis anterior (TA) and median nerve to the abductor pollicis brevis (APB) in 10 subjects. Methods: Recordings of multiple excitability properties were made using threshold tracking, stimulating the nerves at the wrist or knee. Results: Threshold electrotonus and superexcitability differed between nerves (APB>MG>TA axons) that may reflect differences in fast K⁺ conductance. APB axons had larger S2 accommodation and undershoot than TA and MG axons, indicating greater slow K⁺ conductance. TA axons demonstrated greater accommodation during hyperpolarizing currents than MG and APB axons, suggestive of greater inwardly rectifying current. Discussion: Inherent differences in several conductances underlie nerve differences in excitability, presumably related to muscle or motoneuron properties. Muscle Nerve 57 : E60–E69, 2018     

Axonal excitability measured by tracking twitch contraction force

The present study addressed whether the excitability of motor axons could be documented by tracking a target submaximal contraction force rather than a target submaximal compound muscle action potential (CMAP). In 10 subjects, multiple excitability measures were recorded using the Trond protocol, tracking twitch contraction force and the CMAP in response to stimulation of the median nerve at the wrist and twitch force to stimulation at the motor point. With stimulation at the wrist, the findings were virtually identical with force tracking and CMAP tracking for indices dependent on unconditioned thresholds (stimulus-response curves; strength-duration properties) and when the conditioning stimulus was subthreshold (threshold electrotonus; current-threshold relationship). However, when the conditioning stimulus was supramaximal, as in recovery cycle studies, thresholds for the target force were lower in all subjects than for the target CMAP. There was variability between different subjects in the extent of this offset. However, force tracking can still be used to follow changes in refractoriness and supernormality when membrane potential changes during an experiment. The excitability indices differed with motor point stimulation, but it is argued that this could be due to the geographic dispersion of motor axons at the motor point in addition to or instead of differences in biophysical properties of the stimulated nodes. Thus, tracking twitch contraction force is a potentially valuable alternative to tracking the CMAP, but is more complicated and the results need to be interpreted with caution.     

Electrophysiological investigation of motor axonal excitability in a mouse model of nerve constriction injury

Peripheral nerve injuries caused by focal constriction are characterised by local nerve ischaemia, axonal degeneration, demyelination, and neuroinflammation. The aim of this study was to understand temporal changes in the excitability properties of injured motor axons in a mouse model of nerve constriction injury (NCI). The excitability of motor axons following unilateral sciatic NCI was studied in male C57BL/6J mice distal to the site of injury at the acute (6 hours‐1 week) and chronic (up to 20 weeks) phases of injury, using threshold tracking. Multiple measures of nerve excitability, including strength‐duration properties, threshold electrotonus, current‐threshold relationship, and recovery cycle were examined using the automated nerve excitability protocol (TRONDNF). Acutely, injured motor axons developed a pattern of excitability characteristic of ischemic depolarisation. In most cases, the sciatic nerve became transiently inexcitable. When a liminal compound muscle action potential could again be recorded, it had an increase in threshold and latency, compared to both pre‐injury baseline and sham‐injured groups. These axons showed a greater threshold change in response to hyperpolarising threshold electrotonus and a significant upward shift in the recovery cycle. Mathematical modelling suggested that the changes seen in chronically injured axons involve shortened internodes, reduced myelination, and exposed juxtaparanodal fast K⁺ conductances. The findings of this study demonstrate long‐term changes in motor excitability following NCI (involving alterations in axonal properties and ion channel activity) and are important for understanding the mechanisms of neurapraxic injuries and traumatic mononeuropathies.     

Altered axonal excitability properties in facial palsy

Introduction: Axonal excitability measures give insight into the biophysical properties of peripheral nerve axons. In this study we applied these techniques to the study of facial palsy. Methods: Thirty patients with established facial palsy due to unresolved Bell's palsy or herpes zoster (>6 months duration), tumor invasion of the facial nerve, or traumatic facial nerve injury were assessed using facial nerve excitability techniques. Results: Full recordings were obtained in 23 patients (15 unrecovered Bell's palsy or herpes zoster, 5 trauma, 3 tumor‐related). Compared with normal controls, the facial palsy group demonstrated changes in stimulus response properties, threshold electrotonus, refractoriness, superexcitability, and I/V slope. Depolarizing threshold electrotonus distinguished between viral and non‐viral etiologies on subgroup analysis. Discussion: In this cross‐sectional study, established facial palsy demonstrated findings similar to those seen in studies of regenerated axons. The improved understanding of underlying axonal characteristics offered by the technique may guide future treatment. Muscle Nerve 57 : 268–272, 2018     

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 20weeks after the nerve crush. RESULTS: In patients, there were longer SDTC, greater threshold changes at 0.2ms 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 20weeks 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.     

Clarifying distal axonal properties of the median nerve

Introduction: Although length‐dependent axonal excitability changes have been reported in the median nerve, the mechanisms underlying these changes remain to be further clarified. Methods: 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. Results: 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. Conclusions: The present study reveals significant length dependent changes in median nerve excitability which may reflect differences in intrinsic membrane properties. Muscle Nerve, 2012     

Excitability properties of median and peroneal motor axons

Threshold tracking was used to compare excitability properties (stimulus-response curves, strength-duration properties, recovery cycle, and threshold electrotonus) of median motor axons at the wrist and peroneal motor axons at the ankle in 12 healthy subjects. Stimulus-response curves and strength-duration properties were similar, though higher stimulus intensities were required for peroneal axons. However, there were significant differences in the recovery cycle of excitability following a conditioning stimulus and in threshold electrotonus. In the recovery cycle, median axons had significantly greater supernormality and late subnormality. In threshold electrotonus, the initial slow threshold changes in response to subthreshold depolarizing and hyperpolarizing currents (S1) were significantly greater in median axons, and there was also greater accommodation to depolarizing currents (S2) and greater threshold undershoot after depolarization. Similar differences in supernormality and the S1 phase of threshold electrotonus were found between peroneal axons at ankle and knee, suggesting that these properties may be dependent on nerve length. When median motor axons at the wrist were compared with peroneal motor axons at the knee, there were no differences in refractoriness and supernormality and only small differences in S1, but the late subnormality and undershoot were significantly greater in the median axons. These findings suggest that, in addition to any length-dependent differences, peroneal axons have a less prominent slow K(+) conductance. We conclude that the properties of different motor axons are not identical and their responses to injury or disease may therefore differ.     

Identification and modelling of fast and slow Ih current components in vestibular ganglion neurons

Previous experimental data indicates the hyperpolarization‐activated cation (I_h) current, in the inner ear, consists of two components [different hyperpolarization‐activated cyclic nucleotide‐gated (HCN) subunits] which are impossible to pharmacologically isolate. To confirm the presence of these two components in vestibular ganglion neurons we have applied a parameter identification algorithm which is able to discriminate the parameters of the two components from experimental data. Using simulated data we have shown that this algorithm is able to identify the parameters of two populations of non‐inactivated ionic channels more accurately than a classical method. Moreover, the algorithm was demonstrated to be insensitive to the key parameter variations. We then applied this algorithm to I_h current recordings from mouse vestibular ganglion neurons. The algorithm revealed the presence of a high‐voltage‐activated slow component and a low‐voltage‐activated fast component. Finally, the electrophysiological significance of these two I_h components was tested individually in computational vestibular ganglion neuron models (sustained and transient), in the control case and in the presence of cAMP, an intracellular cyclic nucleotide that modulates HCN channel activity. The results suggest that, first, the fast and slow components modulate differently the action potential excitability and the excitatory postsynaptic potentials in both sustained and transient vestibular neurons and, second, the fast and slow components, in the control case, provide different information about characteristics of the stimulation and this information is significantly modified after modulation by cAMP.     

Axonal excitability properties in amyotrophic lateral sclerosis.

OBJECTIVE: To investigate axolemmal ion channel function in patients diagnosed with sporadic amyotrophic lateral sclerosis (ALS). METHODS: A recently described threshold tracking protocol was implemented to measure multiple indices of axonal excitability in 26 ALS patients by stimulating the median motor nerve at the wrist. The excitability indices studied included: stimulus-response curve (SR); strength-duration time constant (tauSD); current/threshold relationship; threshold electrotonus to a 100 ms polarizing current; and recovery curves to a supramaximal stimulus. RESULTS: Compound muscle action potential (CMAP) amplitudes were significantly reduced in ALS patients (ALS, 2.84+/-1.17 mV; controls, 8.27+/-1.09 mV, P<0.0005) and the SR curves for both 0.2 and 1 ms pulse widths were shifted in a hyperpolarized direction. Threshold electrotonus revealed a greater threshold change to both depolarizing and hyperpolarizing conditioning stimuli, similar to the 'fanned out' appearance that occurs with membrane hyperpolarization. The tauSD was significantly increased in ALS patients (ALS, 0.50+/-0.03 ms; controls, 0.42+/-0.02 ms, P<0.05). The recovery cycle of excitability following a conditioning supramaximal stimulus revealed increased superexcitability in ALS patients (ALS, 29.63+/-1.25%; controls, 25.11+/-1.01%, P<0.01). CONCLUSIONS: Threshold tracking studies revealed changes indicative of widespread dysfunction in axonal ion channel conduction, including increased persistent Na+ channel conduction, and abnormalities of fast paranodal K+ and internodal slow K+ channel function, in ALS patients. SIGNIFICANCE: An increase in persistent Na+ conductances coupled with reduction in K+ currents would predispose axons of ALS patients to generation of fasciculations and cramps. Axonal excitability studies may provide insight into mechanisms responsible for motor neuron loss in ALS.     

Muscarinic control of the excitability of hindlimb motoneurons in chronic spinal‐transected salamanders

The excitability of spinal motoneurons (MNs) is regulated by acetylcholine via the activation of muscarinic receptors. The objective of the present study was to determine whether this cholinergic modulation of MN excitability is altered following a chronic spinal cord transection. Juvenile salamanders (Pleurodeles waltlii) were spinally transected at the mid‐trunk level, and patch‐clamp recordings from hindlimb MNs in spinal cord slices were performed 9–30 days after transection, with and without bath application of muscarine (20 μm ). Our results showed that the input–output relationship was larger in MNs recorded 2 weeks after spinal transection than in MNs recorded 3–4 weeks after spinal transection. They further revealed that muscarine increased both the gain of MNs and the proportion of MNs that could exhibit plateau potentials and afterdischarges, whereas it decreased the amplitude of the medium afterhypolarizing potential. Moreover, muscarine had no effect on the hyperpolarization‐activated cation current (I_h), whereas it increased the inward rectifying K⁺ current (I_Kir) in MNs recorded ≥ 2 weeks after spinal transection. We conclude that following chronic spinal cord injury, the muscarinic modulation of some intrinsic properties of MNs previously reported in acute spinal‐transected animals [ S. Chevallier et al. (2006) The Journal of Physiology, 570 , 525–540] was preserved, whereas that of other intrinsic properties of MNs was suppressed, either transiently (I_Kir) or definitively (I_h). These alterations in muscarinic modulation of MN excitability may contribute to the spontaneous recovery of locomotion displayed in long‐term chronic spinal‐transected salamanders.     

Long‐term high‐intensity sound stimulation inhibits h current (Ih) in CA1 pyramidal neurons

Afferent neurotransmission to hippocampal pyramidal cells can lead to long‐term changes to their intrinsic membrane properties and affect many ion currents. One of the most plastic neuronal currents is the hyperpolarization‐activated cationic current (I_h), which changes in CA1 pyramidal cells in response to many types of physiological and pathological processes, including auditory stimulation. Recently, we demonstrated that long‐term potentiation (LTP) in rat hippocampal Schaffer‐CA1 synapses is depressed by high‐intensity sound stimulation. Here, we investigated whether a long‐term high‐intensity sound stimulation could affect intrinsic membrane properties of rat CA1 pyramidal neurons. Our results showed that I_h is depressed by long‐term high‐intensity sound exposure (1 min of 110 dB sound, applied two times per day for 10 days). This resulted in a decreased resting membrane potential, increased membrane input resistance and time constant, and decreased action potential threshold. In addition, CA1 pyramidal neurons from sound‐exposed animals fired more action potentials than neurons from control animals; however, this effect was not caused by a decreased I_h. On the other hand, a single episode (1 min) of 110 dB sound stimulation which also inhibits hippocampal LTP did not affect I_h and firing in pyramidal neurons, suggesting that effects on I_h are long‐term responses to high‐intensity sound exposure. Our results show that prolonged exposure to high‐intensity sound affects intrinsic membrane properties of hippocampal pyramidal neurons, mainly by decreasing the amplitude of I_h.     

Axonal hyperpolarization associated with acute hypokalemia: multiple excitability measurements as indicators of the membrane potential of human axons

Multiple nerve excitability measurements have been proposed for clinical testing of nerve function, and an important determinant of excitability is membrane potential. We report a patient with acquired hypokalemic paralysis in whom multiple excitability indices (stimulus-response curve, strength-duration properties, threshold electrotonus, recovery cycle) were measured during and after an acute hypokalemic attack (serum K(+) level, 2.1 mEq/L and 4.5 mEq/L, respectively). During hypokalemia, there was a shift of the stimulus-response curve to the right, a decrease in strength-duration time constant, a "fanning-out" of responses during threshold electrotonus, a reduction in relative refractory period, and an increase in superexcitability; all of these indicate axonal hyperpolarization, presumably due to the K(+) equilibrium potential being more negative. These indices returned to normal 20 h later, associated with normalization of the serum K(+) level. These results demonstrate that the changes associated with hypokalemic paralysis are not confined to muscle and that axons undergo hyperpolarization in vivo. Multiple excitability measurements can be used as a tool to identify changes in membrane potential of human axons.     

The hyperpolarization‐activated non‐specific cation current (Ih) adjusts the membrane properties,excitability, and activity pattern of the giant cells in the rat dorsal cochlear nucleus

Giant cells of the cochlear nucleus are thought to integrate multimodal sensory inputs and participate in monaural sound source localization. Our aim was to explore the significance of a hyperpolarization‐activated current in determining the activity of giant neurones in slices prepared from 10 to 14‐day‐old rats. When subjected to hyperpolarizing stimuli, giant cells produced a 4‐(N‐ethyl‐N‐phenylamino)‐1,2‐dimethyl‐6‐(methylamino) pyridinium chloride (ZD7288)‐sensitive inward current with a reversal potential and half‐activation voltage of –36 and –88 mV, respectively. Consequently, the current was identified as the hyperpolarization‐activated non‐specific cationic current (I_h). At the resting membrane potential, 3.5% of the maximum I_h conductance was available. Immunohistochemistry experiments suggested that hyperpolarization‐activated, cyclic nucleotide‐gated, cation non‐selective (HCN)1, HCN2, and HCN4 subunits contribute to the assembly of the functional channels. Inhibition of I_h hyperpolarized the membrane by 6 mV and impeded spontaneous firing. The frequencies of spontaneous inhibitory and excitatory postsynaptic currents reaching the giant cell bodies were reduced but no significant change was observed when evoked postsynaptic currents were recorded. Giant cells are affected by biphasic postsynaptic currents consisting of an excitatory and a subsequent inhibitory component. Inhibition of I_h reduced the frequency of these biphasic events by 65% and increased the decay time constants of the inhibitory component. We conclude that I_h adjusts the resting membrane potential, contributes to spontaneous action potential firing, and may participate in the dendritic integration of the synaptic inputs of the giant neurones. Because its amplitude was higher in young than in adult rats, I_h of the giant cells may be especially important during the postnatal maturation of the auditory system.     

Two distinct types of depolarizing afterpotentials are differentially expressed in stellate and pyramidal‐like neurons of entorhinal‐cortex layer II

Two types of principal neurons, stellate cells and pyramidal‐like cells, are found in medial entorhinal‐cortex (mEC) layer II, and are believed to represent two distinct channels of information processing and transmission in the entorhinal cortex–hippocampus network. In this study, we found that depolarizing afterpotentials (DAPs) that follow single action potentials (APs) evoked from various levels of holding membrane voltage (V_h) show distinct properties in the two cells types. In both, an evident DAP followed the AP at near‐threshold V_h levels, and was accompanied by an enhancement of excitability and spike‐timing precision. This DAP was sensitive to voltage‐gated Na⁺‐channel block with TTx, but not to partial removal of extracellular Ca²⁺. Application of 5‐μM anandamide, which inhibited the resurgent and persistent Na⁺‐current components in a relatively selective way, significantly reduced the amplitude of this particular DAP while exerting poor effects on the foregoing AP. In the presence of background hyperpolarization, DAPs showed an opposite behavior in the two cell types, as in stellate cells they became even more prominent, whereas in pyramidal‐like cells their amplitude was markedly reduced. The DAP observed in stellate cells under this condition was strongly inhibited by partial extracellular‐Ca²⁺ removal, and was sensitive to the low‐voltage‐activated Ca²⁺‐channel blocker, NNC55‐0396. This Ca²⁺ dependence was not observed in the residual DAP evoked in pyramidal‐like cells from likewise negative V_h levels. These results demonstrate that two distinct mechanism of DAP generation operate in mEC layer‐II neurons, one Na⁺‐dependent and active at near‐threshold V_h levels in both stellate and‐pyramidal‐like cells, the other Ca²⁺‐dependent and only expressed by stellate cells in the presence of background membrane hyperpolarization. © 2015 Wiley Periodicals, Inc.     

Nitric oxide as intracellular modulator: internal production of NO increases neuronal excitability via modulation of several ionic conductances

Nitric oxide (NO) has been shown to regulate neuronal excitability in the nervous system, but little is known as to whether NO, which is synthesized in certain neurons, also serves functional roles within NO‐producing neurons themselves. We investigated this possibility by using a nitric oxide synthase (NOS)‐expressing neuron, and studied the role of intrinsic NO production on neuronal firing properties in single‐cell culture. B5 neurons of the pond snail Helisoma trivolvis fire spontaneous action potentials (APs), but once the intrinsic activity of NOS was inhibited, neurons became hyperpolarized and were unable to fire evoked APs. These striking long‐term effects could be attributed to intrinsic NO acting on three types of conductances, a persistent sodium current (I_NaP), voltage‐gated Ca currents (I_Ca) and small‐conductance calcium‐activated potassium (SK) channels. We show that NOS inhibitors 7‐nitroindazole and S‐methyl‐l ‐thiocitrulline resulted in a decrease in I_NaP, and that their hyperpolarizing and inhibiting effects on spontaneous spiking were mimicked by the inhibitor of I_NaP, riluzole. Moreover, inhibition of NOS, soluble guanylate cyclase (sGC) or protein kinase G (PKG) attenuated I_Ca, and blocked spontaneous and depolarization‐induced spiking, suggesting that intrinsic NO controlled I_Ca via the sGC/PKG pathway. The SK channel inhibitor apamin partially prevented the hyperpolarization observed after inhibition of NOS, suggesting a downregulation of SK channels by intrinsic NO. Taken together, we describe a novel mechanism by which neurons utilize their self‐produced NO as an intrinsic modulator of neuronal excitability. In B5 neurons, intrinsic NO production is necessary to maintain spontaneous tonic and evoked spiking activity.     

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.