Changes In Supernormality Research Articles

Velocity recovery cycles of human muscle action potentials in chronic renal failure

To test the hypothesis that muscle fibers are depolarized in patients with chronic renal failure, by measuring velocity recovery cycles of muscle action potentials as indicators of muscle membrane potential. Velocity recovery cycles were recorded from brachioradialis muscle by direct muscle stimulation in 13 patients, before, immediately after, and 1h after haemodialysis, and compared with those from 10 age-matched controls. In the patients, supernormality was reduced by 47%, and relative refractory period increased by 60.5% compared with controls (both P<0.001). Dialysis normalized the supernormality, but an hour later it was again reduced. These changes in supernormality were strongly correlated with the changes in serum potassium levels (P<0.0001). A late component of supernormality, attributed to potassium accumulation in the t-tubule system, was also reduced in the patients but remained abnormally low after dialysis. Muscle membranes in the patients were chronically depolarized by hyperkalemia. Whereas dialysis transiently normalized muscle membrane potential, it was not adequate to normalize t-tubule function. Chronic muscle membrane depolarization by hyperkalemia may account for some of the functional deficits in uremic myopathy. Consistent normalization of membrane potential by avoiding hyperkalemia may therefore reduce symptoms of 'uremic myopathy'.

Post‐spike excitability indicates changes in membrane potential of isolated C‐fibers

Recording of action potentials from single unmyelinated nerve fibers by microneurography is an important tool to investigate peripheral neural functions in human neuropathies. However, the interpretation of microneurography recordings can be difficult because axonal membrane potential is not revealed by this method. We tested the hypothesis that the recovery cycle of excitability after a single action potential is correlated with changes in the axonal membrane potential. To this end, we used the threshold tracking technique to study how different chemical mediators, with known effects on the membrane potential, influence the post-spike superexcitability of C-fiber compound action potentials in isolated rat sural and vagus nerves. We found that: (1) some chemical mediators (e.g., adenosine 5'-triphosphate) produce a reduction or loss of superexcitability together with increased axonal excitability, indicating membrane depolarization; (2) blockade of axonal hyperpolarization-activated (Ih) currents produces an enhancement of superexcitability together with a decreased excitability, indicating membrane hyperpolarization; and (3) application of calcium produces an increase in membrane threshold without an alteration in superexcitability, indicating a non-specific increase in surface charge and a change in the voltage-dependent activation of sodium channels. In addition, we demonstrated that membrane depolarization and hyperpolarization induce opposite post-spike latency shifts (changes in supernormality) in rat and human nerve segments. Thus, recordings of post-spike excitability and shifts in latency are sensitive techniques for detection of various types of neuromodulation, which are correlated with changes in membrane potential of unmyelinated peripheral axons and may help to understand observations obtained by microneurography in peripheral human neuropathies.

The effects of mexiletine on excitability properties of human median motor axons

Objective To investigate the effects of mexiletine, an analog of lidocaine, on excitability of human axons in vivo. Methods Threshold tracking was used to measure multiple excitability indices (strength-duration time constant, rheobase, refractoriness, supernormality, and threshold electrotonus) in median motor axons of 20 patients with neuropathic pain or muscle cramping, before and 3 months after treatment with oral 300 mg mexiletine per day. Results After treatment, there was a reduction in pain/muscle cramps, associated with decreased strength-duration time constants ( P=0.01), increased rheobasic currents ( P=0.06), and lower refractoriness ( P=0.02), all of which were consistent with reduced nodal Na + currents. Supernormality and threshold electrotonus did not change significantly. The changes in strength-duration properties suggest a decrease in persistent Na + conductance. The lowered refractoriness after treatment might result from reduced transient Na + currents, but the lack of change in supernormality and threshold electrotonus was not consistent with this hypothesis. Conclusions Oral mexiletine in a dosage of 300 mg daily suppresses persistent Na + currents in human motor axons. Significance Measurements of the excitability indices can be used for non-invasive assessment and monitoring of the effects of mexiletine in patients with neuropathic pain or muscle cramps.

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.

Ischaemic changes in refractoriness of human cutaneous afferents under threshold-clamp conditions.

1. A technique was developed to counteract the changes in threshold to electrical stimuli of large myelinated cutaneous afferents in the human median nerve induced by ischaemia for 13 min. Intermittent application of polarizing currents was used in five subjects, in whom refractoriness, supernormality and the strength-duration time constant (tauSD) were tracked to determine whether compensating for the ischaemia-induced changes in threshold also controlled the ischaemic changes in these excitability parameters. 2. The threshold compensation prevented the ischaemic changes in tauSD, an excitability parameter dependent on nodal Na+ channels. Threshold compensation did not prevent the changes in refractoriness and supernormality, whether the compensation began 10, 100 or 200 ms prior to the test stimuli. 3. In three subjects, continuous polarizing current was injected for 13 min to compensate for the ischaemic change in threshold, thus clamping threshold at the pre-ischaemic level. Again, tauSD was effectively controlled, but there were still ischaemic changes in refractoriness and supernormality. 4. The effective control of tauSD suggests that both the intermittent threshold compensation and the continuous threshold clamp effectively controlled membrane potential at the node of Ranvier. 5. The ischaemic increase in refractoriness when threshold was kept constant could be due to interference with the processes responsible for refractoriness by a metabolic product of ischaemia. The ischaemic change in supernormality during effective compensation probably results from the intrusion of refractoriness into the conditioning-test intervals normally associated with maximal supernormality. 6. The present results indicate that ischaemia has effects on axonal excitability that cannot be readily explained by changes in membrane potential. Specifically, it is suggested that ischaemic metabolites interfere with the recovery of Na+ channels from inactivation.

Differences in behaviour of sensory and motor axons following release of ischaemia.

The changes in excitability and supernormality of sensory and motor axons of the median (or ulnar) nerve were tracked during and following ischaemia at the wrist for periods of 5-20 min in normal human volunteers. Supernormality was defined as the fractional increase in excitability produced by a maximal conditioning stimulus, 10 ms before the test stimulus. With relatively brief periods of ischaemia (< 10 min), sensory and motor axons behaved similarly, with an increase in excitability (producing a decrease in threshold) and a decrease in supernormality during ischaemia and a long-lasting decrease in excitability (and increase in supernormality) following release of ischaemia. Most subjects reported paraesthesiae during brief periods of ischaemia but not after its release. No one experienced fasciculation. The threshold changes were generally similar during longer periods of ischaemia, but in the post-ischaemic phase the behaviour of sensory and motor axons diverged. After a rapid post-ischaemic increase, the threshold of sensory axons decreased, approaching the pre-ischaemic level, before rising again and then slowly returning to the control level. Sensory axons of different threshold behaved in a qualitatively similar manner, with no evidence of a bimodal distribution of thresholds in the post-ischaemic phase (as occurs with motor axons when the ischaemia is sufficient to produce fasciculation; see Bostock et al. J. Physiol (Lond) 1991; 441: 537-57). The 'notch' on the threshold plot for sensory axons lasted 20-40 min and was accompanied by a relatively small but appropriate change in supernormality. No such 'notch' was seen with motor axons. The changes in latency were generally similar for sensory and motor axons, largely paralleling the supernormality plots, except at the time of the 'notch'. To test the hypothesis that the differences in behaviour of sensory and motor axons resulted from differences in inward rectification activated by hyperpolarization, the changes in threshold produced by long-lasting (300 ms) depolarizing and hyperpolarizing current pulses were compared for sensory and motor axons. In seven of eight subjects, there was evidence of more inward rectification in sensory axons. In the eighth subject, motor axons behaved similarly to sensory axons. It is concluded that a difference in inward rectification contributes to but is insufficient by itself to account for the differences in behaviour of sensory and motor axons and that the greater propensity of sensor y axons to discharge ectopically cannot be attributed to a single factor.

Changes in excitability of human cutaneous afferents following prolonged high-frequency stimulation.

Prolonged high-frequency stimulation of cutaneous nerves can result in paraesthesiae that begin 20 to 30 s after the end of the train and last for 5 to 10 min. In the present experiments the effects of such stimulation on the excitability of human cutaneous afferents and on their refractory and supernormal periods were measured to determine whether these changes could explain the postactivation paraesthesiae. Attention was focused on the axons of lowest threshold (1.0-1.5 T) in the compound sensory action potential evoked by stimulating the digital nerves of the index or middle fingers. Repetitive activation produced two opposing effects on the excitability of low-threshold cutaneous afferents. Following stimulus trains of short duration (1-5 min) the dominant effect was a long-lasting decrease in excitability, such that the amplitude of a test afferent volley was always less than before stimulation. With these trains, no subject experienced paraesthesiae. For 10 min after stimulus trains lasting longer than 7 to 12 min the dominant effect was an increase in excitability such that the amplitude of the test volley was greater than before stimulation. Within this interval, following such trains, subjects experienced paraesthesiae. The extent and duration of supernormality induced by a supramaximal conditioning stimulus were greatly increased by stimulation for 1 min. Following stimulation for 10 min, the degree of supernormality of the enhanced test volley was much the same as before stimulation, but was inappropriately high for the size of the test volley. The sum total of the excitability change and the change in supernormality resulted in a larger potential after stimulation, whether the train lasted 1 min or 10 min. It is concluded that the postactivation changes in axonal excitability could predispose the most excitable axons to generate ectopic impulses and, thereby, to produce paraesthesiae.

Suppressive effect of carotid sinus stimulation on premature ventricular beats in certain instances

Suppression of premature ventricular beats by carotid sinus stimulation was repeatedly induced in eight individuals. Slowing of the heart rate accompanied or followed this suppression in all instances. The majority of these cases showed no evidence of heart disease. The mechanism of suppression by the carotid sinus reflex is not made apparent by the present data, but several possibilities are proposed. These are divided into indirect effects, the chief of which is a change in supernormality of the ventricular muscle resulting from slowing of the heart rate, and direct effects, by way of the vagus and sympathetic nerves.