The properties of axons differ according to their function.
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Adaptation, Physiological↗
Biomedical subjects
David Burke
Publications and source records attributed to David Burke.
Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery.
Impressive progress in genome sequencing, protein expression and high-throughput crystallography and NMR has radically transformed the opportunities to use protein three-dimensional structures to accelerate drug discovery, but the quantity and complexity of the data have ensured a central place for informatics. Structural biology and bioinformatics have assisted in lead optimization and target identification where they have well established roles; they can now contribute to lead discovery, exploiting high-throughput methods of structure determination that provide powerful approaches to screening of fragment binding.
Computational Biology↗
Symptoms of thoracic outlet syndrome in women with carpal tunnel syndrome.
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Afferent Pathways↗
Augmentation of the contraction force of human thenar muscles by and during brief discharge trains.
We investigated the influence of the history of activity on the contractile properties of abductor pollicis brevis (APB) to define how the forces produced by individual stimuli change within a stimulus train, with a view to clarifying the optimal discharge frequency for force production in brief trains. Supramaximal electrical stimuli were delivered to the median nerve at the wrist singly or in trains of 2-5 at various interstimulus intervals (ISIs). The force and electromyographic (EMG) responses to trains of n stimuli were defined by online subtraction of the responses to n - 1 stimuli. The force attributable to the nth stimulus was normalized to that produced by a single stimulus. The contraction force produced by 2 stimuli exceeded the force expected with linear summation of 2 single twitches by 30-40% at ISIs of 2-100 ms. Increasing the number of stimuli resulted in less augmentation of the force produced by the last stimulus in the train for ISIs up to 20 ms, but greater augmentation for ISIs of 50-100 ms. At ISIs of less than 10 ms, the time to peak force produced by the last stimulus in a 5-pulse train was delayed by approximately 100 ms, the peak force produced by that stimulus was less than that produced by a single stimulus, and it occurred on the falling phase of the overall contraction. These properties are best explained by the catchlike property of muscle. This implies that the augmentation of contraction force due to this property can increase throughout a stimulus train, and is not restricted to the doublet discharges that have conventionally been studied. We conclude that, with brief discharge trains, maximal forces occur at ISIs of 56-75 ms, intervals that are longer than those conventionally associated with the catchlike property. Discharge rates of 15-20 HZ appear to be optimal for force generation by APB during steady contractions.
Adult↗
Frequency-dependent conduction block in carpal tunnel syndrome.
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Carpal Tunnel Syndrome↗
Riluzole therapy for motor neurone disease: an early Australian experience (1996-2002).
Riluzole is the only therapy proven in clinical trials to prolong survival in patients with motor neurone disease (MND). Prior to its listing by the Australian Pharmaceutical Benefits Advisory Scheme in June 2003, the aim of the present study was to provide Australian patients with MND early access to riluzole and to expand the safety profile data of this therapy. Patients with MND were referred to the programme by neurologists covering the Sydney metropolitan region. To be eligible to receive riluzole, patients had to be aged between 18 and 75 years and have probable or definite MND based on El Escorial criteria, with a disease duration of less than 5 years and a vital capacity greater than 60% before study entry. Patients were prescribed riluzole 50 mg twice daily. Safety data were collected through documentation of adverse events by clinical history in combination with regular laboratory screening. Full blood count, haematocrit, differential white cell counts and serum liver transaminase levels were obtained monthly for 3 months, and then at each 3-monthly visit for 1 year. In total, 25 patients with MND (17 male, 8 female; age range 40-74 years; mean age 59 years) were commenced on riluzole. Of these, 28% had definite MND and the remaining 72% were diagnosed as probable MND, with the majority (84%) having limb-onset MND. At 12 months, 68% of patients continued on riluzole, 16% had died from their disease and 16% ceased riluzole because of side-effects or other reasons, largely disenchantment owing to a perceived lack of efficacy. Haematological and biochemical assays showed no significant alteration during the initial 12-month period. Long-term survival data for patients in the present series suggest a greater benefit for patients who commenced riluzole early in the course of their illness. In conclusion, riluzole was generally tolerated well by Australian patients with MND. Of the few patients who experienced side-effects attributed to riluzole, all were reversible. Issues related to patient perceptions of efficacy highlight the need for patients and treating physicians to maintain realistic expectations of riluzole therapy.
Adult↗
Mutation in the Na+ channel subunit SCN1B produces paradoxical changes in peripheral nerve excitability.
To determine the effect of an established mutation of the beta1 subunit of Na(+) channels on nerve excitability, studies were undertaken in patients diagnosed with generalized epilepsy with febrile seizures plus (GEFS+). Multiple nerve excitability measurements were used to investigate the membrane properties of sensory and motor axons in five patients (aged 18-55 years) who were currently experiencing no seizures and were not on anticonvulsants. There was no history of paraesthesiae, fasciculation or cramps to suggest hyperexcitability of peripheral nerve axons. The median nerve was stimulated at the wrist, and compound muscle action potentials (CMAPs) were recorded from abductor pollicis brevis and the antidromic compound sensory nerve action potential (CSAPs) from digit 2. Stimulus-response behaviour, strength-duration time constant, threshold electrotonus, current-threshold relationship and the recovery of excitability following a supramaximal conditioning stimulus were recorded using threshold tracking. Compared with normal controls (n = 29), the axons of patients were of higher threshold. CMAPs and CSAPs were relatively small, although individual values remained within the normal ranges. Refractoriness and relative refractory period (markers of transient Na(+) channel function) were significantly reduced in GEFS+ patients with established mutations in SCN1B (P < 0.05), and strength-duration time constants (dependent on persistent Na(+) conductances) were reduced. It is suggested that, in peripheral nerve axons, the mutation underlying GEFS+ reduces the number of functioning Na(+) channels at the node of Ranvier and that this rather than any change in gating of individual channels dominates axonal excitability in these patients.
Action Potentials↗
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.
Action Potentials↗
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.
Action Potentials↗
Functional neuroimaging and cognitive rehabilitation for people with traumatic brain injury.
Cognitive deficits are a common consequence of traumatic brain injury. Although such deficits are amenable to rehabilitation, methods for individualizing cognitive interventions are still unrefined. Functional neuroimaging methods such as positron emission tomography and functional magnetic resonance imaging are emerging as possible technologies for measuring and monitoring the cerebral consequences of plasticity associated with brain injury and for evaluating the effectiveness of rehabilitation interventions. Functional neuroimaging may even enable more customized and efficient selection, design, or adaptation of individual cognitive rehabilitation programs. We review the current literature on functional neuroimaging after traumatic brain injury, relating these findings to cognitive rehabilitation. Overall, functional neuroimaging after traumatic brain injury has shown reliable differences in brain activity within several regions of frontal cortex, partly but not uniformly consistent with neuropsychological and structural findings in traumatic brain injury. We also outline a number of promising research opportunities for applying functional neuroimaging in traumatic brain injury settings, along with associated challenges.
Brain Injuries↗
Differences in activity-dependent hyperpolarization in human sensory and motor axons.
The present study was undertaken to determine whether activity-dependent changes in axonal excitability are greater in motor axons than cutaneous afferents for the same impulse load. In nine healthy subjects, supramaximal stimulation at 8 Hz was delivered to the median nerve at the wrist. Changes in the threshold current required to generate compound motor and sensory potentials approximately 50% of maximum and other indices of axonal excitability were tracked before and after repetitive stimulation for 10 min. The long-lasting stimulation produced a prolonged depression in the excitability of both cutaneous afferents and motor axons, with gradual recovery to control levels over 15-20 min. These changes in threshold were associated with a reduction in refractoriness, an increase in supernormality and a decrease in the strength-duration time constant, changes consistent with axonal hyperpolarization. Greater changes in threshold occurred in motor axons: threshold increased by 9.9% and 16.4% for test stimulus durations of 0.1 and 1 ms, respectively, for motor axons and by 5.4% and 8.3% for cutaneous afferents. With higher stimulus frequencies and thereby greater impulse loads, greater threshold changes could be induced in cutaneous afferents. It is argued that the hyperpolarization resulted from activity of the electrogenic Na(+)-K+ pump, that it requires > 125 ms to restore the resting state following an action potential, and that significant intracellular Na+ accumulation occurs during a steady 8-Hz train. These findings imply that physiological discharge rates will activate the pump and thereby produce axonal hyperpolarization, the extent of which will vary with impulse load. A plausible explanation is that greater activity-dependent hyperpolarization in motor axons is due to less inward rectification as a result of less activity of the hyperpolarization-activated cation conductance (IH) than in cutaneous afferents.
Action Potentials↗
Forces consistent with plateau-like behaviour of spinal neurons evoked in patients with spinal cord injuries.
Percutaneous electrical stimulation over tibialis anterior and triceps surae was performed in 14 patients with traumatic spinal cord injury (SCI) to look for evidence that 'extra contractions' can develop, beyond those due to activation of the motor axons beneath the stimulating electrodes. Criteria for the extra contractions included marked asymmetry of force with respect to stimulation, progressively rising force during stimulation of constant amplitude and frequency, and force remaining high after stimulation frequency had returned to the control level following a high-frequency burst. Twelve of the 14 patients showed evidence of such behaviour, more frequently in triceps surae than tibialis anterior. Force or electromyographic activity commonly outlasted the stimulation in these patients. There was no apparent correlation between the completeness or level of injury and the ability to induce the behaviour. Evidence of force potentiation and 'habituation' was also seen. Eleven of the 14 patients exhibited hyper-reflexia and reported spontaneous spasms, but there was no obvious association with the extra contractions. It is concluded that non-classical behaviour of neurons within the spinal cord can contribute to the extra contractions evoked by electrical stimulation over muscles in spinal cord-injured subjects. This central contribution is less easy to obtain than in intact healthy subjects, all of whom showed the phenomenon. These contractions are consistent with the activation of plateau potentials in spinal neurons and, if so, plateau potentials may contribute to a patient's clinical manifestations.
Adolescent↗
Cytoplasmic body myopathy masquerading as motor neuron disease.
Cytoplasmic body myopathy (CBM) is characterized by proteinaceous inclusion bodies in muscle tissue. A 43-year-old woman presented with rapidly progressive weakness and dysphagia. Electromyography (EMG) elsewhere demonstrated lower-limb chronic partial denervation. Muscle biopsy showed fiber size variation without diagnostic features. A diagnosis of possible motor neuron disease was made and the patient was commenced on riluzole. Subsequently, the patient's condition stabilized, prompting reassessment. Repeat EMG demonstrated no features of denervation and was more suggestive of a myopathic process. Review of the original muscle biopsy showed cytoplasmic bodies. The case highlights a further diagnostic possibility in the assessment of patients with "possible" motor neuron disease. The clinical features of CBM are briefly reviewed.
Action Potentials↗
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.
Action Potentials↗
Conduction block in demyelinated axons precipitated by normally innocuous physiological processes.
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Action Potentials↗
Quantitative trait locus mapping for age-related cataract severity and synechia prevalence using four-way cross mice.
PURPOSE: The goal of this study was to map mouse quantitative trait loci (QTL) that influence the development of murine age-related cataract and synechia, by using a genetically heterogeneous mouse population bred by a four-way cross. METHODS: The test population consisted initially of 510 mice bred as the progeny of (BALB/cJ x C57BL/6J)F1 females and (C3H/HeJ x DBA/2J)F1 males. Each mouse was examined by slit lamp at 18 and 24 months of age and scored for degree of lens opacity on a 0 to 4+ scale, and the presence or absence of additional anterior chamber disease was noted. The presence of synechia was confirmed by histology. Each mouse was genotyped at 96 maternal and 92 paternal loci, and the significance of association between genotype and eye lesions was tested by permutation analysis. RESULTS: Significant QTL with effects on lens opacity at 24 months were detected on mouse chromosomes 4, 11, and 12. The effects were additive, and severe cataracts were seen in 80% of the mice with all three high-risk alleles, but in only 28% of the mice with all three low-risk alleles. The risk of synechia was associated with paternal chromosome 1 and on both the maternal and paternally inherited chromosome 4. Mice with all three high-risk alleles had a 68% risk of synechia, compared with a 0% incidence in mice with all three counteralleles. CONCLUSIONS: A four-way cross population of mice can be used to map polymorphic loci that influence cataract severity and synechia prevalence in late life. The results provide a first step toward identification of the individual genes involved and may help to guide the search for homologous human genes.
Aging↗
Motoneuron excitability and the F wave.
For three motoneuron pools that differ in excitability to Ia inputs [tibialis anterior (TA), abductor pollicis brevis (APB), and soleus], F-wave parameters were measured at rest, during voluntary contraction, and following prolonged vibration. There was an inverse relationship between F-wave chronodispersion and F-wave persistence at rest, and this appeared to be related to the ease of recording the H reflex for the motoneuron pool. During a steady voluntary contraction, overall F-wave activity increased in amplitude but decreased in duration for TA and APB. Following vibration of the test muscle at 50 HZ for 10 min there was a long-lasting depression of the H reflexes of TA and APB, but no significant change in F-wave measurements. These findings are consistent with the view that reflex discharges can prevent F waves in low-threshold motor units, and that chronodispersion is affected by the extent of reflex activity; that is, chronodispersion and related F-wave measurements do not measure motor properties exclusively. The findings also suggest that F waves provide a flawed measure of the excitability of the motoneuron pool.
Action Potentials↗
The refractory period of transmission is impaired in axonal Guillain-Barré syndrome.
Guillain-Barré syndrome (GBS) is classified as acute motor axonal neuropathy (AMAN) or acute inflammatory demyelinating polyneuropathy (AIDP). Motor nerve conduction block is frequently found in both subtypes of GBS. To compare patterns of conduction block and the safety factor for impulse transmission in AMAN and AIDP, pairs of supramaximal stimuli at intervals of 1-5 ms were delivered to stimulate the median nerve at the wrist. At the 2- and 3-ms intervals, compound muscle action potentials (CMAPs) to the second stimulus were significantly smaller in AMAN patients (n = 7) than in normal subjects (n = 10) and AIDP patients (n = 6). Over 4 weeks from onset, the amplitude of both conditioned and unconditioned CMAPs returned toward normal, consistent with improvement in the safety factor for impulse transmission. The refractory period of transmission is impaired in AMAN, and the site of transmission failure is likely to be the motor nerve terminals. In addition to axonal degeneration, the critically but reversibly reduced safety factor is important in the pathophysiology of AMAN, and consistent with the rapid resolution of distal conduction block often seen in AMAN patients.
Action Potentials↗