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Hugh Bostock

Publications and source records attributed to Hugh Bostock.

At least 19 recordsLinked to original sources
PubMed2006

Velocity recovery cycles of single C fibres innervating rat skin.

To improve knowledge about axonal membrane properties in nociceptive and non-nociceptive C fibres, we studied impulse-dependent velocity changes by in vivo microneurography in the rat sciatic nerve. Cutaneous C fibres were classified, based primarily on their activity-dependent slowing profile, as Type 1A (mechano-responsive nociceptors; CMR; n = 23), Type 1B (mechano-insensitive nociceptors; CMI; n = 24), Type 2 (cold units; n = 2), Type 3 units (unknown function; n = 4) or Type 4 (presumed sympathetics; n = 23) units. They were excited by single, double and triple electrical stimuli to the skin at mean rates of 0.25, 0.5, 1 and 2 Hz and with interstimulus intervals ranging from 2 to 1000 ms. All CMRs exhibited only postspike subnormality at 0.25 and 0.5 Hz. They gradually developed supernormality with higher stimulation rates, and 12/19 CMRs were supernormal at 1 Hz. The CMIs showed a greater tendency towards supernormality, with 10/21 already supernormal at 0.25 Hz, 17/24 at 0.5 Hz and all were supernormal at 1 Hz. In some CMIs but in none of the CMRs, the supernormal period was directly followed by a peak in late subnormality. Among non-nociceptive fibres, all Type 4 units exhibited long-lasting supernormality independent of the stimulation rate, whereas the cold units showed short-lived supernormality. In both, supernormality increased with higher stimulation rates. Regardless of fibre function or stimulation rate, a second conditioning stimulus always induced additional slowing, providing evidence for a passive origin of supernormality in all rat C fibre subtypes. However, the degree and time-course of extra slowing due to a preconditioning stimulus was highly dependent on fibre function and stimulation rate. These data indicate axonal membrane differences between different functional classes of C fibres, which resemble those previously described in human C fibres.

Animals↗
PubMed2006

Activity-dependent modulation of axonal excitability in unmyelinated peripheral rat nerve fibers by the 5-HT(3) serotonin receptor.

Activity-dependent fluctuations in axonal excitability and changes in interspike intervals modify the conduction of trains of action potentials in unmyelinated peripheral nerve fibers. During inflammation of a nerve trunk, long stretches of axons are exposed to inflammatory mediators such as 5-hydroxytryptamine [5-HT]. In the present study, we have tested the effects of m-chlorophenylbiguanide (mCPBG), an agonist at the 5-HT(3) serotonin receptor, on activity- and potential-dependent variations in membrane threshold and conduction velocity of unmyelinated C-fiber axons of isolated rat sural nerve segments. The increase in axonal excitability during application of mCPBG was much stronger at higher frequencies of action potentials and/or during axonal membrane hyperpolarization. The effects on the postspike recovery cycle also depended on the rate of stimulation. At an action potential frequency of 1 Hz or in hyperpolarized axons, mCPBG produced a loss of superexcitability. In contrast, at 0.33 Hz, a small increase in the postspike subexcitability was observed. Similar effects on excitability changes were found when latency instead of threshold was recorded, but only at higher action potential frequencies: at 1.8 Hz, mCPBG increased conduction velocity and reduced postspike supernormality. The latter effect would increase the interspike interval if pairs of action potentials were conducted along several cm in an inflamed nerve trunk. These data indicate that activation of axonal 5-HT(3) receptors not only enhances membrane excitability but also modulates action potential trains in unmyelinated, including nociceptive, nerve fibers at high impulse rates.

Animals↗
PubMed2006

Distal excitability changes in motor axons in amyotrophic lateral sclerosis.

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

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PubMed2006

Ischaemia induces paradoxical changes in axonal excitability in end-stage kidney disease.

Peripheral neuropathy is present in 65% of patients with end-stage kidney disease (ESKD). No cause is yet established: nerve excitability studies have shown that axons are chronically depolarized, primarily owing to hyperkalaemia, but in vitro studies have suggested a role for axonal Na+/K+ pump dysfunction. To investigate Na+/K+ pump activity in vivo, lower limb ischaemia was induced in five ESKD patients and six healthy controls by a sphygmomanometer cuff, inflated to 200 mm Hg and maintained for 13 min. The peroneal nerve was stimulated at the fibular neck and excitability parameters were recorded from tibialis anterior (TA) and extensor digitorum brevis (EDB) before, during and after the ischaemic period. Baseline excitability studies in ESKD patients demonstrated reductions in threshold electrotonus and superexcitability and increased refractoriness, consistent with membrane depolarization. During ischaemia, threshold increased in ESKD patients [by +23.6 +/- 5.0% (TA); +32.1 +/- 7.3% (EDB)] in contrast to the persistent threshold reduction observed in normal controls [-2.4 +/- 5.2% (TA); -13.0 +/- 8.2% (EDB); P < 0.01]. These changes were accompanied by increased refractoriness and reduced superexcitability in both ESKD and control groups, consistent with ischaemic depolarization. Conversely, there was reduction in strength-duration time constant towards the end of ischaemia. Following release of ischaemia, the marked increase in threshold observed in normal controls was not evident in ESKD patients, but the rapid return of threshold to baseline argues against significant Na+/K+ pump dysfunction. The abnormal pattern of response to ischaemia in the ESKD patients was not fully explained by the hyperkalaemic membrane depolarization and suggests that another dialysable factor affects nerve excitability in ESKD patients, most likely H(+) ions, but that this factor only becomes evident during ischaemia. Blockade of persistent Na+ conductances by H+ would also explain the reduction in strength-duration time constant observed during ischaemia.

Adolescent↗
PubMed2006

Neuropathy, axonal Na+/K+ pump function and activity-dependent excitability changes in end-stage kidney disease.

OBJECTIVE: To investigate the mechanisms underlying peripheral neuropathy and to provide insights into axonal Na(+)/K(+) pump function in patients with end-stage kidney disease (ESKD). METHODS: Nerve excitability was assessed in 10 ESKD patients before and after a single session of haemodialysis and in 29 age-matched control subjects. Changes in excitability were recorded at baseline and following maximal voluntary contraction (MVC) of abductor pollicis brevis (APB) for 60s. Serum concentrations of putative neurotoxins including potassium, urea, parathyroid hormone and beta-2-microglobulin were also measured. RESULTS: Baseline excitability values were consistent with axonal depolarisation prior to dialysis. Following maximal voluntary contraction (MVC), there was an increase in threshold, which was associated with reduced strength-duration time constant and increased superexcitability, consistent with axonal hyperpolarisation. These changes were quantitatively similar for patients and controls, arguing against any significant reduction in the axonal Na(+)/K(+) pump in ESKD. Following dialysis, activity-dependent changes were less in ESKD, which suggests greater Na(+)/K(+) pump activity prior to dialysis, the opposite of the changes expected with reduced Na(+)/K(+) pump function. The reduced post-contraction threshold change in post-dialysis recordings is likely to be secondary to relative hyperpolarisation of the axonal membrane following dialysis and reduction in K(+) concentration. CONCLUSIONS: Our findings suggest that Na(+)/K(+) pump function is not impaired in patients with ESKD. SIGNIFICANCE: Pre-dialysis excitability changes in ESKD patients may be explained on the basis of hyperkalaemia. Alteration in Na(+)/K(+) pump function does not appear to be a contributing factor to the development of neuropathy in ESKD patients.

Adolescent↗
PubMed2006

Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage.

Fasciculations are a characteristic feature of amyotrophic lateral sclerosis (ALS), and can arise proximally or distally in the motor neuron, indicating a widespread disturbance in membrane excitability. Previous studies of axonal excitability properties (i.e. threshold electrotonus, strength-duration time constant) have suggested respectively that change in potassium or sodium channels may be involved. To reinvestigate these changes and explore their correlation with disease stage, multiple axonal excitability properties (threshold electrotonus, strength-duration time constant, recovery cycle and current-threshold relationship) were measured for the median nerve at the wrist in 58 ALS patients, and compared with 25 age-matched controls. In ALS, there were greater changes in depolarizing threshold electrotonus (i.e. less accommodation) (P < 0.001) and greater supernormality in the recovery cycles (P < 0.001). These abnormalities were more prominent in patients with moderately reduced CMAP (1-5 mV). Modelling the excitability changes in this group supported the hypothesis that axonal potassium conductances are reduced, resulting in increased supernormality despite membrane depolarization. The tendency for strength-duration time constant to be prolonged in ALS was only significant for patients with normal CMAP amplitude (>5 mV). Patients with severely reduced CMAP (<1 mV) alone showed reduced threshold changes to hyperpolarizing current. These results suggest a changing pattern of abnormal membrane properties with disease progression. First, persistent Na+ conductance increases, possibly associated with collateral sprouting, and then K(+) conductances decline. Both changes cause axonal hyperexcitability, and may contribute to the generation of fasciculations. These serial changes in axonal properties could provide insights into the pathophysiology of ALS, and implications for future therapeutic options.

Adult↗
PubMed2005

Altered motor nerve excitability in end-stage kidney disease.

Although multiple toxins have been implicated in the development of uraemic neuropathy, no causative agent has been identified. In the present study, the excitability properties of lower limb motor nerves in patients with end-stage kidney disease treated with haemodialysis were measured before, during and after a standard 5 h haemodialysis session, in an attempt to explore the pathophysiology of uraemic neuropathy. Compound muscle action potentials were recorded from tibialis anterior and extensor digitorum brevis, following stimulation of the common peroneal nerve in 14 patients. Measures of excitability were assessed in relation to changes in serum levels of potential neurotoxins, including potassium, calcium, urea, uric acid, parathyroid hormone and beta-2-microglobulin. Before dialysis, measures of nerve excitability were significantly abnormal in the patient group for axons innervating tibialis anterior and extensor digitorum brevis, consistent with axonal depolarization: refractoriness was increased and superexcitability and depolarizing threshold electrotonus were reduced. Pre-dialysis excitability abnormalities were strongly correlated with serum K+. Correlation was also noted between the severity of symptoms and excitability abnormalities. Haemodialysis normalized the majority of nerve excitability parameters. In conclusion, lower limb motor axons in uraemic patients are depolarized before dialysis. The correlation between serum K+ and excitability measures indicates that hyperkalaemia is primarily responsible for uraemic depolarization, and a likely contributing factor to the development of neuropathy.

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PubMed2005

After-effects of near-threshold stimulation in single human motor axons.

Subthreshold electrical stimuli can generate a long-lasting increase in axonal excitability, superficially resembling the phase of superexcitability that follows a conditioning nerve impulse. This phenomenon of 'subthreshold superexcitability' has been investigated in single motor axons in six healthy human subjects, by tracking the excitability changes produced by conditioning stimuli of different amplitudes and waveforms. Near-threshold 1 ms stimuli caused a mean decrease in threshold at 5 ms of 22.1 +/- 6.0% (mean +/-s.d.) if excitation occurred, or 6.9 +/- 2.6% if excitation did not occur. The subthreshold superexcitability was maximal at an interval of about 5 ms, and fell to zero at 30 ms. It appeared to be made up of two components: a passive component linearly related to conditioning stimulus amplitude, and a non-linear active component. The active component appeared when conditioning stimuli exceeded 60% of threshold, and accounted for a maximal threshold decrease of 2.6 +/- 1.3%. The passive component was directly proportional to stimulus charge, when conditioning stimulus duration was varied between 0.2 and 2 ms, and could be eliminated by using triphasic stimuli with zero net charge. This change in stimulus waveform had little effect on the active component of subthreshold superexcitability or on the 'suprathreshold superexcitability' that followed excitation. It is concluded that subthreshold superexcitability in human motor axons is mainly due to the passive electrotonic effects of the stimulating current, but this is supplemented by an active component (about 12% of suprathreshold superexcitability), due to a local response of voltage-dependent sodium channels.

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PubMed2005

Acute tetrodotoxin-induced neurotoxicity after ingestion of puffer fish.

This study documents the effects of puffer-fish poisoning on peripheral nerve. Excitability measurements investigated membrane properties of sensory and motor axons in four patients. The median nerve was stimulated at the wrist, with compound muscle potentials recorded from abductor pollicis brevis and compound sensory potentials from digit 2. Stimulus-responses, strength-duration time constant (tau(SD)), threshold electrotonus, and current-threshold relations were recorded. The urine of each patient tested positive for tetrodotoxin. Compared with controls, axons were of higher threshold, compound muscle action potentials and compound sensory nerve action potentials were reduced in amplitude, latency was prolonged, and tau(SD) was reduced. In recovery cycles, refractoriness, superexcitability, and late subexcitability were decreased. Threshold electrotonus of motor axons exhibited distinctive abnormalities with less threshold decline than normal on depolarization and greater threshold increase on hyperpolarization (p < 0.0005 for each patient). The changes in excitability were reproduced in a mathematical model by reducing sodium (Na(+)) permeabilities by a factor of two. This study confirms that the neurotoxic effects of puffer-fish poisoning can be explained by tetrodotoxin blockade of Na(+) channels. It demonstrates the ability of noninvasive nerve excitability studies to detect Na(+) channel blockade in vivo and also the utility of mathematical modeling to aid interpretation of altered excitability properties in disease.

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PubMed2005

Hyperexcitable polymodal and insensitive nociceptors in painful human neuropathy.

Six patients with chronic pain, mechanical and thermal hyperalgesia/allodynia, and cutaneous vasodilatation starting distally in their extremities, were evaluated using clinical and neurophysiological methods and microneurography. Evidence of small-fiber polyneuropathy was documented in all, but the etiology remained cryptogenic in several. Different forms of hyperexcitability were detected by microneurography in both common polymodal and mechanically insensitive C nociceptors, which explain all the somatosensory abnormalities. Signs of hyperexcitability included reduced receptor threshold (accounting for mechanical and heat allodynias), spontaneous C nociceptor discharge (explaining spontaneous "burning" pain and antidromic vasodilatation), and multiplied nociceptor responses to stimulation (accounting for hyperalgesia). The clinical and electrophysiological profiles of these patients resemble the experimental syndrome evoked by application of capsaicin to the skin. This similarity, and the striking heat dependence of the spontaneous pain, suggest that a common feature may be altered expression or modulation of vanilloid 1 receptor, provoking abnormal nociceptor discharges.

Adolescent↗
PubMed2005

Evidence for motor axon depolarization in Fabry disease.

To investigate the pathophysiology of neuropathy in Fabry disease, multiple nerve excitability properties of median motor axons in 20 patients with this disorder but without hyperkalemia were compared with 35 age-matched normal controls. In the patients, depolarizing threshold electrotonus was reduced (P < 0.0001) and superexcitability was reduced (P < 0.001), but late subexcitability was normal. These findings indicate that the axons were mildly depolarized, probably due to ischemia, and are consistent with the hypothesis that poor nerve perfusion in Fabry disease contributes to axonal damage.

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PubMed2004

Variations in excitability of single human motor axons, related to stochastic properties of nodal sodium channels.

Threshold variability of single human motor axons was studied by delivering 0.1 ms constant current stimuli of randomly varied intensity over the ulnar nerve at the elbow, and recording all-or-none potentials from flexor carpi ulnaris. In nine normal subjects, a single unit was tested with 8-11,000 stimuli at intervals of 0.5 s. After allowing for slow changes in excitability, the probability of excitation was in all cases well fitted by a cumulative Gaussian function. The relative spread (RS) of thresholds (S.D./mean) averaged 1.65 +/- 0.26% (mean +/- S.D., n = 9). When threshold was tested 20 ms after the start of a polarizing current, RS increased on depolarization and decreased on hyperpolarization. The product RS x mean threshold also increased on depolarization, especially when threshold was reduced by more than 50%. When the mean was reduced by 90%, RS increased above 50% and the axon sometimes fired spontaneously. Threshold variability was simulated by a computer model of a single node of Ranvier, in which the variability arose because of the stochastic behaviour of nodal sodium channels. The observed values of RS, and potential dependence of RS, were well modelled by a node with 60,000 sodium channels, of which about 1% were modelled as persistent sodium channels. Threshold variations in the model at resting potential were not primarily due to fluctuations in the state of the node before the stimulus was delivered, but rather to the variable activation of channels by the stimulus pulse. On depolarization, however, current through (mainly persistent) sodium channels caused appreciable fluctuations in membrane potential, which increased RS and the probability of spontaneous firing.

Adult↗
PubMed2004

Two types of C nociceptors in human skin and their behavior in areas of capsaicin-induced secondary hyperalgesia.

Peripheral nociceptor sensitization is accepted as an important mechanism of cutaneous primary hyperalgesia, but secondary hyperalgesia has been attributed to central mechanisms since evidence for sensitization of primary afferents has been lacking. In this study, microneurography was used to test for changes in sensitivity of C nociceptors in the area of secondary hyperalgesia caused by intradermal injection of capsaicin in humans. Multiple C units were recruited by electrical stimulation of the skin at 0.25 Hz and were identified as discrete series of dots in raster plots of spike latencies. Nociceptors slowed progressively during repetitive stimulation at 2 Hz for 3 min. According to their response to mechanical stimulation, nociceptors could be classified as either mechano-sensitive (CM) or mechano-insensitive (CM(i)). These two nociceptor subtypes had different axonal properties: CM(i) units slowed by 2% or more when stimulated at 0.25 Hz after a 3-min pause, whereas CM units slowed by <1%. This stimulation protocol was used before capsaicin injection to identify nociceptor subtype without repeated probing, thus avoiding possible mechanical sensitization. Capsaicin, injected 10-50 mm away from the site of electrical stimulation, had no effect on any of 29 CM units, but induced bursts of activity in 11 of 15 CM(i) units, after delays ranging from 0.5 to 18 min. The capsaicin injections also sensitized a majority of the CM(i) units, so that 11 of 17 developed immediate or delayed responsiveness to mechanical stimuli. This sensitization may contribute a peripheral C fiber component to secondary hyperalgesia.

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PubMed2004

Threshold electrotonus in chronic inflammatory demyelinating polyneuropathy: correlation with clinical profiles.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterized by multifocal demyelination along the course of the nerves, and involvement of the intermediate segments may correlate with more severe demyelination associated with breakdown of the blood-nerve barrier. Threshold electrotonus was used to study whether altered membrane properties of the median nerve at the wrist (intermediate segment) are associated with clinical profiles in 21 CIDP patients. In response to hyperpolarizing conditioning stimuli, the threshold changes were significantly greater for CIDP patients than for normal controls (n = 49). The pattern was similar to that of 11 patients with Charcot-Marie-Tooth disease type 1a, who exhibited abnormally high thresholds to hyperpolarizing currents. The abnormal threshold electrotonus was present in 48% of the CIDP patients and was associated with longer disease duration, more severe disability, poorer response to immune treatments, and slower nerve conduction velocities. Threshold electrotonus can be used to detect demyelination at the tested sites and may provide new information about pathophysiology and distribution patterns of demyelination in CIDP.

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PubMed2004

Excitability properties of human median axons measured at the motor point.

Threshold tracking was used to measure excitability indices (strength-duration properties, threshold electrotonus, and the current-threshold relationship) at the motor point of the abductor pollicis brevis, and the results were compared with those of the median nerve at the wrist. Using an accelerometer placed at the thumb tip, movement-related potentials were recorded as target responses. When stimulating at the same site, excitability measurements were no different, and their variability no greater, when the target responses were movements rather than muscle action potentials. Motor point stimulation resulted in significantly shorter strength-duration time-constant and higher rheobase than wrist stimulation. In addition, the technique of latent addition showed that a slow component was much smaller at the motor point than at the wrist. In threshold electrotonus, threshold changes in response to depolarizing and hyperpolarizing conditioning currents were significantly smaller at the motor point than at the wrist. The differences in strength-duration time-constant and latent addition suggest that persistent Na(+) current at the resting potential is smaller at the motor point. The differences in threshold electrotonus may depend in part on altered fiber geometry but suggest that inward and possibly outward rectification are increased distally. Motor point excitability testing may provide new insights into the pathophysiology of the nerve terminals in a variety of peripheral neuropathies and motor neuron disorders.

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