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Biomedical subjects

David Burke

Publications and source records attributed to David Burke.

34 records · Page 2Linked to original sources
PubMed2003

An EM algorithm for mapping binary disease loci: application to fibrosarcoma in a four-way cross mouse family.

Many diseases show dichotomous phenotypic variation but do not follow a simple Mendelian pattern of inheritance. Variances of these binary diseases are presumably controlled by multiple loci and environmental variants. A least-squares method has been developed for mapping such complex disease loci by treating the binary phenotypes (0 and 1) as if they were continuous. However, the least-squares method is not recommended because of its ad hoc nature. Maximum Likelihood (ML) and Bayesian methods have also been developed for binary disease mapping by incorporating the discrete nature of the phenotypic distribution. In the ML analysis, the likelihood function is usually maximized using some complicated maximization algorithms (e.g. the Newton-Raphson or the simplex algorithm). Under the threshold model of binary disease, we develop an Expectation Maximization (EM) algorithm to solve for the maximum likelihood estimates (MLEs). The new EM algorithm is developed by treating both the unobserved genotype and the disease liability as missing values. As a result, the EM iteration equations have the same form as the normal equation system in linear regression. The EM algorithm is further modified to take into account sexual dimorphism in the linkage maps. Applying the EM-implemented ML method to a four-way-cross mouse family, we detected two regions on the fourth chromosome that have evidence of QTLs controlling the segregation of fibrosarcoma, a form of connective tissue cancer. The two QTLs explain 50-60% of the variance in the disease liability. We also applied a Bayesian method previously developed (modified to take into account sex-specific maps) to this data set and detected one additional QTL on chromosome 13 that explains another 26% of the variance of the disease liability. All the QTLs detected primarily show dominance effects.

Algorithms↗
PubMed2003

Activity-dependent hyperpolarization and impulse conduction in motor axons in patients with carpal tunnel syndrome.

The differing contributions of axonal attenuation, ischaemia, demyelination and remyelination to the pathophysiology of carpal tunnel syndrome remain unresolved. Previous studies indicate that the hyperpolarization of motor axons produced by voluntary contractions may precipitate conduction block in chronic acquired demyelinating polyneuropathies. The present study investigated whether this axonal hyperpolarization can produce or accentuate conduction block in carpal tunnel syndrome, thereby implicating demyelination as a significant factor in its pathogenesis. Studies were performed in 12 patients with mild to moderate carpal tunnel syndrome and compared with 12 healthy control subjects. Using the technique of threshold tracking, the compound muscle action potential (CMAP) of abductor pollicis brevis (APB) was recorded in response to supramaximal stimuli to the median nerve at the wrist, alternating with measurements of axonal excitability. After a voluntary contraction of APB for 60 s, there was a lesser hyperpolarizing threshold increase in the patients (approximately 18%), than in controls (approximately 37%). The changes in strength-duration time constant and supernormality were appropriately smaller in the patients. The amplitude and area of the maximal CMAP was not significantly altered in either group. Activity-dependent conduction block was not precipitated in the carpal tunnel syndrome patients even though this degree of axonal hyperpolarization was sufficient to produce conduction block in chronic inflammatory demyelinating polyneuropathy. These studies support the view that demyelination may not be a critical factor in the slowing of impulse conduction in mild to moderate carpal tunnel syndrome.

Action Potentials↗
PubMed2002

Excitability of human muscle afferents studied using threshold tracking of the H reflex.

In human peripheral nerves, physiological evidence has been presented for a number of biophysical differences between cutaneous afferents and alpha motor axons. The differences in strength-duration properties for cutaneous afferents and motor axons in the median nerve have been attributed to greater expression of a persistent Na(+) conductance (I(Na,P)) on cutaneous afferents. However, it is unclear whether the biophysical properties of human group Ia afferents differ from those of cutaneous afferents. The present studies were undertaken to determine whether the properties of human group Ia afferents can be studied indirectly using 'threshold tracking' to measure the excitability changes in the H reflex, and to determine whether the excitability of group Ia afferents differs from that of cutaneous afferents. The strength-duration properties of the soleus H reflex and soleus motor axons were measured at rest and during sustained voluntary contractions. Similar experiments were performed on the median nerve at the wrist to study the strength-duration properties of cutaneous afferents, alpha motor axons and H reflex of the thenar muscles. In addition, the technique of 'latent addition' was used to determine whether there was a difference in a low-threshold conductance on soleus Ia afferent and motor axons. The present findings indicate that the strength-duration time constant (tau(SD)) for the H reflex is longer than that for alpha motor axons, but similar to that for cutaneous afferents. There were no differences in tau(SD) for the soleus H reflex at rest and during contractions, suggesting that tau(SD) for the H reflex is largely unaffected by changes in synaptic or motoneurone properties. Finally, the difference in latent addition suggests that the longer tau(SD) of the soleus H reflex may indeed be due to greater activity of a persistent Na(+) conductance on Ia afferents than on soleus alpha motor axons.

Adult↗
PubMed2002

Excitability changes in human peripheral nerve axons in a paradigm mimicking paired-pulse transcranial magnetic stimulation.

A peripheral nerve model was developed to determine whether changes in axonal excitability could affect the findings in studies of cortical processes using paired-pulse transcranial magnetic stimulation (TMS). The recovery of axonal excitability from a conditioning stimulus smaller than the test stimulus was qualitatively similar to that with suprathreshold conditioning stimuli. There was an initial decrease in excitability, equivalent to refractoriness at conditioning-test intervals < 4 ms, an increase in excitability, equivalent to supernormality, at intervals of 5-20 ms and a second phase of decreased excitability, equivalent to late subnormality at intervals > 30 ms. H reflex studies using conditioning stimuli below threshold for the H reflex established that these excitability changes could be faithfully translated across an excitatory synapse. Changing membrane potential by injecting polarising current altered axonal excitability in a predictable way, and produced results similar to those reported for many disease states using paired-pulse TMS. Specifically, axonal hyperpolarisation produced a smaller decrease in excitability followed by a greater increase in excitability. This study supports the view that changes in excitability of the stimulated axons should be considered before synaptic mechanisms are invoked in the interpretation of findings from paired-pulse TMS studies.

Adult↗
PubMed2002

Suppression of the H reflex in humans by disynaptic autogenetic inhibitory pathways activated by the test volley.

The present studies were designed to increase an existing limitation on the size of the H reflex by accentuating an inhibitory effect of group I afferents in the test volley. They were precipitated by the observation that, during strong voluntary contractions of quadriceps (Q), the late deep peroneal (DP) facilitation of the Q H reflex was suppressed but the facilitation of the ongoing EMG was not. The effects of conditioning stimuli to DP, superficial peroneal (SP) and articular afferents on the excitation of Q motoneurones (MNs) produced by femoral nerve (FN) stimulation were assessed in 11 healthy human subjects using the H reflex of vastus intermedius or the peak of group I excitation in post-stimulus time histograms (PSTHs) of single motor units (MUs) in vastus lateralis. The suppression of the late H reflex facilitation was observed during strong contractions after stimulation of DP and articular afferents, and at rest when DP and SP volleys were combined. In all single MUs tested, the FN-induced peak of excitation was suppressed by DP stimulation during strong Q contractions and by a combination of conditioning volleys (SP with DP or articular) during weak contractions. By themselves these conditioning volleys did not inhibit the background MU discharge even when delivered together. The suppression did not involve the initial bins of the peak; it began 0.7 ms later than the probable onset of monosynaptic Ia facilitation. It is argued that the suppression is not due to presynaptic inhibition of Ia terminals or to recurrent inhibition, but probably reflects convergence between the conditioning volleys and group I afferents in the test FN volley onto interneurones of the disynaptic non-reciprocal group I inhibition. It is concluded that the size of the H reflex is limited by disynaptic inhibition, and that changes in the excitability of this inhibitory pathway can produce prominent changes in the H reflex.

Adult↗
PubMed2002

Responses of human sensory and motor axons to the release of ischaemia and to hyperpolarizing currents.

This study compared directly the post-ischaemic behaviour of sensory and motor axons in the human median nerve, focusing on the excitability changes produced by ischaemia and its release and by continuous polarizing DC. The decrease in threshold during ischaemia for 13 min was greater, the post-ischaemic increase in threshold was more rapid, and the return to the pre-ischaemic excitability took longer in sensory axons. However, a transient depolarizing threshold shift developed in sensory axons a few minutes after release of ischaemia. This pattern could not be reproduced by polarizing currents designed to mimic the probable pump-induced changes in membrane potential, even though the applied currents produced greater changes in threshold. Hyperpolarizing currents of equivalent intensity produced a greater increase in threshold for motor axons than sensory axons and, in studies of threshold electrotonus using graded hyperpolarizing DC, accommodation was greater in sensory than motor axons. The post-ischaemic changes in threshold were not uniform for axons of different threshold, whether sensory or motor, the threshold increase was usually less prominent for low-threshold axons. A transient post-ischaemic depolarization could be produced in motor axons with ischaemia of 20 min duration. Greater ischaemic and post-ischaemic changes in threshold for sensory axons could reflect greater dependence on the electrogenic Na+-K+ pump to maintain resting membrane potential and/or greater extracellular K+ accumulation in ischaemic sensory axons. Inward K+ currents due to extracellular K+ accumulation would then be more likely to trigger a depolarizing shift in membrane potential, the degree of K+ accumulation and pump activity being dependent on the duration of ischaemia. In sensory axons the greater tendency to accommodate to hyperpolarizing stimuli presumably contributes to shaping their post-ischaemic behaviour but is probably insufficient to explain why their behaviour differs from that of motor axons.

Adolescent↗
PubMed2002

Sodium channel function and the excitability of human cutaneous afferents during ischaemia.

The changes in excitability of cutaneous afferents in the median nerve of healthy subjects were compared during 13 min of ischaemia and during 13 min continuous depolarizing DC. In addition, intermittent polarizing currents were used to compensate for or to accentuate the threshold change produced by ischaemia. Measurements were made alternately of the ischaemic (or current-induced) changes in threshold, refractoriness and, in some experiments, supernormality. The strength-duration time constant (tau(SD)) was calculated from the thresholds to test stimuli of different duration. During ischaemia for 13 min, the threshold decreased steadily by 34 % over the initial 8 min, reached a plateau and increased slightly over the final few minutes. However, with continuous depolarizing DC, the threshold decreased linearly with the applied current, by 55 % with strong current ramps. Intermittent injection of hyperpolarizing DC was used to compensate for the ischaemic threshold change, but the compensating current increased progressively and did not reach a plateau as had occurred with the ischaemic threshold change. During ischaemia, tau(SD) increased to a plateau, following the threshold more closely than the current required to compensate for threshold. Refractoriness, on the other hand, increased more steeply than the applied compensating current. There were similar discrepancies in the relationships of tau(SD) and refractoriness to supernormality. The smaller-than-expected threshold change during ischaemia could result from limitations on the change in excitability produced by ischaemic metabolites acting on the gating and/or permeability of Na(+) channels. Intermittent depolarizing DC was applied during the ischaemic depolarization to determine whether it would reduce or accentuate the discrepancies noted during ischaemia alone. The extent of the threshold change was greater than with ischaemia alone, and there was a greater change in tau(SD) and a proportionately smaller change in refractoriness. It is concluded that ischaemia produces factors that can block Na(+) channels and/or alter their gating. Without these processes, the ischaemic change in threshold would be much greater than that actually recorded, probably sufficient to produce prominent ectopic impulse activity.

Differential Threshold↗
PubMed2002

Differences in membrane properties of axonal and demyelinating Guillain-Barré syndromes.

Guillain-Barré syndrome is classified into acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinating polyneuropathy (AIDP) by electrodiagnostic and pathological criteria. In AMAN, the immune attack appears directed against the axolemma and nodes of Ranvier. Threshold tracking was used to measure indices of axonal excitability (refractoriness, supernormality, and threshold electrotonus) for median nerve axons at the wrist of patients with AMAN (n = 10) and AIDP (n = 8). Refractoriness (the increase in threshold current during the relative refractory period) was greatly increased in AMAN patients, but the abruptness of the threshold increases at short interstimulus intervals indicated conduction failure distal to the stimulation (ie, an increased refractory period of transmission). During the 4 week period from onset, the high refractoriness returned toward normal, and the amplitude of the compound muscle action potential increased, consistent with improvement in the safety margin for impulse transmission in the distal nerve. In contrast, refractoriness was normal in AIDP, even though there was marked prolongation of distal latencies. Supernormality and threshold electrotonus were normal in both groups of patients, suggesting that, at the wrist, membrane potential was normal and pathology was relatively minor. These results support the view that the predominantly distal targets of immune attack are different for AMAN and AIDP. Possible mechanisms for the reduced safety factor in AMAN are discussed.

Action Potentials↗
PubMed2002

Effects of voluntary activity on the excitability of motor axons in the peroneal nerve.

To investigate whether there are inter-nerve differences in the extent and pattern of axonal excitability changes produced by voluntary contractions of tibialis anterior (TA) and abductor pollicis brevis (APB), threshold tracking was used to measure axonal excitability parameters [threshold, supernormality and strength-duration time constant (tauSD)] of peroneal and median motor axons in 11 healthy subjects. Maximal contractions for 1 min resulted in an increase in threshold, an increase in supernormality, a decrease in tauSD and an increase in latency, all of which indicate axonal hyperpolarization. The increase in threshold was less in peroneal axons (18 +/- 4%) than median axons (37 +/- 6%, mean +/- SEM, P < 0.001), and was accompanied by smaller absolute changes in latency, supernormality, and tauSD. Peroneal axons had less supernormality at rest but a greater change in supernormality for the change in threshold. There were major contraction-induced changes in the compound muscle action potential of TA but not that of APB. Voluntary contractions depress axonal excitability, but the changes are quantitatively different for motor axons innervating different muscles. There are three clinical implications. First, weakness and fatigue due to activity-dependent conduction block may vary for different muscles, independent of disease severity, and therapeutic strategies to overcome activity-dependent conduction block may not be equally effective for different muscles. Second, in motor control studies using the H reflex to document motoneuron excitability, a constant stimulus will not produce a constant neural volley if the stimulated axons have been activated by, for example, a voluntary contraction. Third, TA is probably not optimal for testing for activity-dependent conduction block.

Action Potentials↗
PubMed2002

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.

Action Potentials↗
PubMed2002

Abnormalities of axonal excitability are not generalized in early multifocal motor neuropathy.

The clinical and neurophysiological features of multifocal motor neuropathy (MMN) indicate selective involvement of motor axons, but pathological abnormalities in sensory axons suggest a more widespread disease process. The present study was undertaken to determine whether the focal abnormalities are associated with widespread subclinical abnormalities in motor axons. Threshold tracking was used to measure excitability properties (stimulus-response curves, strength-duration properties, recovery cycle, and threshold electrotonus) of the median nerve in five patients with MMN with lesions proximal to the site of testing. Patients were compared with 25 healthy controls. The changes in excitability indices were similar to those in controls, and in one patient there was no alteration after treatment with intravenous gammaglobulin. In this patient, indices of axonal excitability were also measured before, during, and after ischemia of the arm for 10 min. Again no differences were detected. This study provides no evidence for a generalized subclinical abnormality in MMN, at least when disease duration is less than 6 years.

Action Potentials↗
PubMed2002

Recent evidence for plateau potentials in human motoneurones.

Motoneurones in reduced animal preparations can exhibit plateau potentials that amplify their response to synaptic inputs and can persist for prolonged periods in the absence of synaptic drive. There is mounting evidence that a similar mechanism may be an integral part of the normal activation of motoneurones. Some of the work describing plateau potentials in reduced animal preparations is reviewed and then evidence that similar properties contribute to the normal activation of motoneurones in rats and humans is presented. Recent data have shown that during high-frequency electrical stimulation over human muscle, large contractions can develop which originate within the central nervous system and are present in addition to the contraction due to the direct activation of motor axons. These "extra" contractions may in part be due to plateau potentials in spinal motoneurones. It is becoming clear that intrinsic properties of human motoneurones may make a large contribution to muscle contractions during normal movements. The extent to which the nervous system uses this as a gain control mechanism to tailor motor output for a given task needs to be further explored.

Animals↗
PubMed2002

Effects of activity on axonal excitability: implications for motor control studies.

In many motor control studies, such as those involving H reflexes in human subjects, stimuli are delivered to nerves in which axons are or have recently been active. It is assumed that a constant stimulus intensity ensures that the same population of axons has been activated, particularly when there is little change in the M wave. However, the neurophysiological literature is replete with evidence that activity depresses axonal excitability. Indeed, some motor control studies have exploited this phenomenon to stimulate specific afferent populations selectively. This chapter will review studies performed in human subjects demonstrating that a voluntary contraction can have profound effects on the excitability of the active axons and on their ability to transmit impulses. These data need to be considered when interpreting human reflex studies.

Afferent Pathways↗
PubMed2002

Corticospinal volleys and compound muscle action potentials produced by repetitive transcranial stimulation during spinal surgery.

OBJECTIVES: To report our experience with neurophysiological monitoring of corticospinal function using compound muscle action potentials (CMAPs) produced by repetitive transcranial electrical stimulation in a large series of patients, after defining optimal stimulus parameters in a small group of patients. METHODS: In 100 patients undergoing spinal surgery, corticospinal volleys were recorded using epidural electrodes, or CMAPs were recorded from innervated muscles, or both techniques were used to monitor spinal cord function. In subsets of patients, stimulus parameters were varied to determine the optimal parameters for CMAP recordings, using the corticospinal volleys to guide the initial choice. RESULTS: Recordings of corticospinal volleys indicated that less energy was delivered to the cortex if the duration of each stimulus in the stimulus train was brief (e.g. 50 micros) and that there was attenuation of D and I waves in the corticospinal volley when the interstimulus interval in the train was <5 ms. An interstimulus interval of 5 ms proved significantly more effective than an interstimulus interval of 2 ms in evoking CMAPs, but resulted in a more complex, dispersed electromyographic (EMG) potential. The superiority of the 5 ms interval did not depend on stimulus intensity or the existence of pre-existing neurological deficit. Using trains of 5 pulses of duration 50 micros, interstimulus interval 5 ms and intensity 500 V, satisfactory CMAPs could be recorded in 55 of 82 patients, significantly less often in neurologically impaired patients than in neurologically normal subjects. Epidural recordings of the corticospinal volley were obtained in 61 of 69 patients, again more often in neurologically normal subjects. CONCLUSIONS: When epidural recordings can be made, direct recordings of corticospinal activity are probably more reliable than recordings of CMAPs. However, epidural recordings are not suitable under all circumstances, and the ability to record CMAPs reliably represents an advance in intraoperative monitoring. Under the anaesthetic conditions used in the present study, the optimal stimulus parameters consist of a train of 5 stimuli of 50 micros duration at an interstimulus interval of 5 ms and an intensity of 500 V.

Action Potentials↗
PubMed2002

Conduction block during and after ischaemia in chronic inflammatory demyelinating polyneuropathy.

A previous study suggested that axonal hyperpolariza tion produced by maximal voluntary contraction could accentuate conduction block in symptomatic patients with chronic inflammatory demyelinating polyneuropathy (CIDP). If this is so, conduction block should occur with hyperpolarization due to other causes such as the release of ischaemia. The effects of ischaemia on axonal excitability and on impulse conduction were therefore studied in 12 healthy control subjects and seven patients with symptomatic CIDP. The compound muscle action potential (CMAP) of abductor pollicis brevis was recorded in response to supramaximal stimuli to the median nerve at the wrist alternating with measurements of axonal excitability before, during and after ischaemia for 10 min produced by inflation of a sphygmomanometer cuff around the arm. During ischaemia, the amplitude/area of the maximal CMAP was reduced in the patients by 10% and, after release of ischaemia, it was attenuated by 19%. There were only slight changes in the CMAPs in the healthy controls. The attenuation of the CMAP during ischaemia presumably results from depolarization-induced inactivation of Na(+) channels in axons critically dependent on the number of functioning Na(+) channels for action potential generation. The attenuation of the CMAP after release of ischaemia paralleled the post-ischaemic hyperpolarization and was probably precipitated by it. This study provides suggestive evidence that axonal depolarization can produce conduction block in CIDP, in addition to providing confirmation that axonal hyperpolarization can also do so. In patients with chronic demyelinating disorders, conduction block can probably result from a wider range of physiological stresses than previously appreciated, such as natural activity, ischaemia or recovery from transient ischaemia--all of which could produce fluctuations in symptoms.

Action Potentials↗