Reversible Conduction Block Research Articles

High frequency stimulation can block axonal conduction

High frequency stimulation (HFS) is used to control abnormal neuronal activity associated with movement, seizure, and psychiatric disorders. Yet, the mechanisms of its therapeutic action are not known. Although experimental results have shown that HFS suppresses somatic activity, other data has suggested that HFS could generate excitation of axons. Moreover it is unclear what effect the stimulation has on tissue surrounding the stimulation electrode. Electrophysiological and computational modeling literature suggests that HFS can drive axons at the stimulus frequency. Therefore, we tested the hypothesis that unlike cell bodies, axons are driven by pulse train HFS. This hypothesis was tested in fibers of the hippocampus both in-vivo and in-vitro. Our results indicate that although electrical stimulation could activate and drive axons at low frequencies (0.5–25 Hz), as the stimulus frequency increased, electrical stimulation failed to continuously excite axonal activity. Fiber tracts were unable to follow extracellular pulse trains above 50 Hz in-vitro and above 125 Hz in-vivo. The number of cycles required for failure was frequency dependent but independent of stimulus amplitude. A novel in-vitro preparation was developed, in which, the alveus was isolated from the remainder of the hippocampus slice. The isolated fiber tract was unable to follow pulse trains above 75 Hz. Reversible conduction block occurred at much higher stimulus amplitudes, with pulse train HFS (> 150 Hz) preventing propagation through the site of stimulation. This study shows that pulse train HFS affects axonal activity by: (1) disrupting HFS evoked excitation leading to partial conduction block of activity through the site of HFS; and (2) generating complete conduction block of secondary evoked activity, as HFS amplitude is increased. These results are relevant for the interpretation of the effects of HFS for the control of abnormal neural activity such as epilepsy and Parkinson's disease.

Axonal Guillain‐Barré syndrome: carbohydrate mimicry and pathophysiology

Acute motor axonal neuropathy (AMAN), an axonal subtype of Guillain-Barré syndrome (GBS), is characterized by pure motor involvement, frequent antecedent infection by Campylobacter jejuni, association with anti-GM1 or anti-GD1a immunoglobulin G (IgG) antibodies, and the electrophysiological features of axonal degeneration and reversible conduction block. Molecular mimicry exists between GM1 and GD1a gangliosides and lipooligosaccharides (LOSs) of C. jejuni isolates from AMAN. Sensitization of rabbits with GM1 or C. jejuni LOS induces anti-GM1 IgG antibodies and subsequent flaccid paralysis. Pathological changes seen in rabbit model peripheral nerves are identical to those in human AMAN. Immunohistochemistry of AMAN rabbits shows disruption of nodal sodium channel clusters and detachment of paranodal myelin terminal loops, similar to paranodal demyelination, which would significantly reduce the safety factor for impulse transmission and might be responsible for the rapidly reversible conduction block frequently present in human AMAN. C. jejuni sialyltransferase (Cst-II), which functions in the biosynthesis of ganglioside-like LOSs, determines the transferase activity. Strains with cst-II (Thr51) express GM1 and GD1a epitopes, whereas GBS patients infected with cst-II (Thr51) strains have anti-GM1 or anti-GD1a IgG antibodies. The cst-II gene is responsible for the development of GBS. Immunological, pathological, electrophysiological, and bacteriological studies have provided strong evidence of carbohydrate mimicry being a cause of AMAN and clarified the mechanisms of nerve conduction failure in AMAN.

MOTOR INNERVATION OF THE MUSCLE SPINDLE: THE CONTRIBUTION OF BERNHARD KATZ

![Graphic][1] Anthony Taylor discusses Bernhard Katz's 1949 paper entitled: The efferent regulation of the muscle spindle in the frog. A copy of the paper can be obtained from . In this article, we go back over 55 years to the paper by

Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is currently divided into the two major subtypes: acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). This review highlights relevant recent publications, particularly on the pathophysiology of AMAN. Molecular mimicry of the bacterial lipo-oligosaccharide by the human gangliosides is now considered an important cause of AMAN. Gangliosides GM1, GM1b, GD1a, and GalNAc-GD1a expressed on the motor axolemma are likely to be the epitopes for antibodies in AMAN. At the nodes or paranodes, deposition of antiganglioside antibodies initially cause reversible conduction block followed by axonal degeneration. Electrodiagnostic findings support this process. Disruption of glycolipids, which are important to maintain ion channel clustering at the nodes and paranode, may impair nerve conduction. Genetic polymorphisms of Campylobacter jejuni determine the expression of the gangliosides on the bacterial wall. In contrast, target molecules in AIDP have not yet been identified. Meta-analyses show efficacy of plasmapheresis and immunoglobulin therapy, but not corticosteroids, in hastening recovery.

Drastic Decrease in Isoflurane Minimum Alveolar Concentration and Limb Movement Forces after Thoracic Spinal Cooling and Chronic Spinal Transection in Rats

Individuals with spinal cord injury may undergo multiple surgical procedures; however, it is not clear how spinal cord injury affects anesthetic requirements and movement force under anesthesia during both acute and chronic stages of the injury. The authors determined the isoflurane minimum alveolar concentration (MAC) necessary to block movement in response to supramaximal noxious stimulation, as well as tail-flick and hind paw withdrawal latencies, before and up to 28 days after thoracic spinal transection. Tail-flick and hind paw withdrawal latencies were measured in the awake state to test for the presence of spinal shock or hyperreflexia. The authors measured limb forces elicited by noxious mechanical stimulation of a paw or the tail at 28 days after transection. Limb force experiments were also conducted in other animals that received a reversible spinal conduction block by cooling the spinal cord at the level of the eighth thoracic vertebra. A large decrease in MAC (to </= 40% of pretransection values) occurred after spinal transection, with partial recovery (to approximately 60% of control) at 14-28 days after transection. Awake tail-flick and hind paw withdrawal latencies were facilitated or unchanged, whereas reflex latencies under isoflurane were depressed or absent. However, at 80-90% of MAC, noxious stimulation of the hind paw elicited ipsilateral limb withdrawals in all animals. Hind limb forces were reduced (by >/= 90%) in both chronic and acute cold-block spinal animals. The immobilizing potency of isoflurane increases substantially after spinal transection, despite the absence of a baseline motor depression, or "spinal shock." Therefore, isoflurane MAC is determined by a spinal depressant action, possibly counteracted by a supraspinal facilitatory action. The partial recovery in MAC at later time points suggests that neuronal plasticity after spinal cord injury influences anesthetic requirements.

This Month in Anesthesiology

This Month in Anesthesiology

Nerve conduction block utilising high-frequency alternating current.

High-frequency alternating current (AC) waveforms have been shown to produce a quickly reversible nerve block in animal models, but the parameters and mechanism of this block are not well understood. A frog sciatic nerve/gastrocnemius muscle preparation was used to examine the parameters for nerve conduction block in vivo, and a computer simulation of the nerve membrane was used to identify the mechanism for block. The results indicated that a 100% block of motor activity can be accomplished with a variety of waveform parameters, including sinusoidal and rectangular waveforms at frequencies from 2 kHz to 20 kHz. A complete and reversible block was achieved in 34 out of 34 nerve preparations tested. The most efficient waveform for conduction block was a 3-5 kHz constant-current biphasic sinusoid, where block could be achieved with stimulus levels as low as 0.01 microCphase(-1). It was demonstrated that the block was not produced indirectly through fatigue. Computer simulation of high-frequency AC demonstrated a steady-state depolarisation of the nerve membrane, and it is hypothesised that the conduction block was due to this tonic depolarisation. The precise relationship between the steady-state depolarisation and the conduction block requires further analysis. The results of this study demonstrated that high-frequency AC can be used to produce a fast-acting, and quickly reversible nerve conduction block that may have multiple applications in the treatment of unwanted neural activity.

Epinephrine reduces the nerve conduction blockage induced by high-potassium in mammalian sciatic nerve

We investigated the effects of epinephrine on the reversible nerve conduction block induced by high [K +] o using electrophysiological extracellular recordings in the isolated rat sciatic nerve in vitro. Bath application of 400 μM epinephrine (EN) or norepinephrine (NE) reduced the high-potassium-induced compound action potentials (CAPs) blockage in both sensory and motor fibers. The β-adrenoreceptor agonist isoproterenol mimicked the EN effect while the α-adrenoreceptor agonists phenylephrine and guanfacine did not affect the CAPs reduction. Addition of EN to normal ACSF partially reversed the nerve conduction blockage induced by high frequency stimulation. These results suggest that EN and NE modulate the electrophysiological properties of both sensory and motor axons, and they improve the nerve conduction under high [K +] o by modulating nerve excitability.

Reversible conduction block in isolated frog sciatic nerve by high concentration of bupivacaine

We evaluated the effects of a high concentration of bupivacaine commonly used for spinal anaesthesia on the reversibility of conduction block and compound nerve action potential (CNAP) parameters in isolated frog sciatic nerve measured by extracellular recording technique. Isolated frog sciatic nerves were bathed in 1.3% bupivacaine solution for 20 min. In each nerve, action potentials were recorded before exposure to bupivacaine solution, which served as the control data. The extracellular action potentials were recorded after 20 min in the drug by using a BIOPAC MP 100 Acquisition System Version 3.5.7 (Santa Barbara, USA). The nerves were washed for 3 h continuously with Ringer’s solution and action potentials were recorded. The nerve was then soaked overnight in Ringer’s solution at room temperature and tested for impulse recovery. There were significant differences among the experiments regarding CNAP peak-to-peak amplitude, area and duration but conduction velocities among the experiments did not show any statistical difference. In the presence of bupivacaine the extracellular action potential amplitude decreased by 46.99±29.31% relative to the control amplitude ( P<0.05), recovered to 47.10±26.90% after 3 h of wash, and reached 123.20±39.70% after the overnight soak process. This study showed that exposing nerve to high concentration of bupivacaine causes reversible impulse blockade and that bupivacaine does not cause neurotoxic effect on isolated frog sciatic nerve.

Electrically active axons degenerate when exposed to nitric oxide

Axonal degeneration is a major cause of permanent deficit in inflammatory neurological diseases such as multiple sclerosis. Axons undergo degeneration specifically at the site of the inflammatory lesions, suggesting that locally produced inflammatory factors mediate the phenomenon. One such factor is nitric oxide (NO), which we have previously reported can cause reversible conduction block in axons. Here we confirm these observations and extend them to show that axons exhibit the early stages of wallerian degeneration if they are conducting impulses at physiological frequencies while they are exposed to the low micromolar concentrations of NO that are likely to occur at sites of inflammation. Rat dorsal roots were concurrently exposed in vivo to both NO and sustained impulse activity at 1, 50, or 100 Hz. Although our in vivo observations necessarily focused on the more acute responses, morphological examination of exposed roots at the end of the recording period revealed nodal and paranodal changes consistent with acute wallerian degeneration in roots stimulated at 50 or 100 Hz. This interpretation was confirmed in a few experiments that were prolonged to permit more obvious indicators of degeneration to develop. In these experiments the formation of myelin ovoids and frank axonolysis occurred in more than 95% of fibers. Roots stimulated at only 1 Hz appeared normal. We propose that the combination of normal impulse traffic and NO at sites of inflammation may cause axonal degeneration and that electrical activity may therefore be an important factor in causing permanent disability in patients with neuroinflammatory disorders.

Electrically active axons degenerate when exposed to nitric oxide

Axonal degeneration is a major cause of permanent deficit in inflammatory neurological diseases such as multiple sclerosis. Axons undergo degeneration specifically at the site of the inflammatory lesions, suggesting that locally produced inflammatory factors mediate the phenomenon. One such factor is nitric oxide (NO), which we have previously reported can cause reversible conduction block in axons. Here we confirm these observations and extend them to show that axons exhibit the early stages of wallerian degeneration if they are conducting impulses at physiological frequencies while they are exposed to the low micromolar concentrations of NO that are likely to occur at sites of inflammation. Rat dorsal roots were concurrently exposed in vivo to both NO and sustained impulse activity at 1, 50, or 100 Hz. Although our in vivo observations necessarily focused on the more acute responses, morphological examination of exposed roots at the end of the recording period revealed nodal and paranodal changes consistent with acute wallerian degeneration in roots stimulated at 50 or 100 Hz. This interpretation was confirmed in a few experiments that were prolonged to permit more obvious indicators of degeneration to develop. In these experiments the formation of myelin ovoids and frank axonolysis occurred in more than 95% of fibers. Roots stimulated at only 1 Hz appeared normal. We propose that the combination of normal impulse traffic and NO at sites of inflammation may cause axonal degeneration and that electrical activity may therefore be an important factor in causing permanent disability in patients with neuroinflammatory disorders. Ann Neurol 2001;49:470–476

Protective effect of glove on median nerve compression in the carpal tunnel

To determine the protective effect of gel padded glove on median nerve compression in the carpal tunnel. Median nerve conduction parameters, skin temperature, laser Doppler flowmetry and pain modifications were measured during and after a 30-min carpal tunnel external compression protocol performed with and without glove in a random order on six healthy volunteers. Compression induced a rapidly reversible increase in sensory and motor distal latencies, a decrease in sensory amplitude, finger laser Doppler flowmetry and hand skin temperature supporting the hypothesis of a reversible conduction block of ischemic origin. There was no statistical difference between the tests (with or without glove) except for pain that was significantly reduced by glove protection. Gel padded glove does not seem to have a protective effect on the carpal tunnel syndrome induced by compression but provides significant comfort.

The potential role of nitric oxide in multiple sclerosis.

Nitric oxide (.NO) and its reactive derivative peroxynitrite (ONOO-) have been implicated in the pathogenesis of multiple sclerosis (MS). They are cytotoxic to oligodendrocytes and neurones in culture by inhibiting the mitochondrial respiratory chain (complexes II/III and IV) and inhibiting certain key intracellular enzymes. Recently .NO has been implicated as a possible aetiological factor in reversible conduction block in demyelinated axons. Inducible nitric oxide synthase (iNOS) is upregulated in the central nervous system of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. In some EAE models inhibiting iNOS activity decreases disease severity whilst in other models disease activity is exacerbated. Raised levels of nitrate and nitrite, stable end-products of .NO/ONOO-, are found in the cerebrospinal fluid, serum and urine of patients with MS. CSF levels of nitrate and nitrite correlate with blood-brain-barrier dysfunction, which suggests that .NO may play a role in inflammatory blood-brain-barrier dysfunction. In a longitudinal study on 24 patients with relapsing remitting and secondary progressive MS, raised serum nitrate and nitrite levels correlated with a relapsing course and infrequent relapses. However, no correlation was found between raised serum levels of nitrate and nitrite and MRI activity, disease progression, or the development of cerebral atrophy. In autoimmune mediated CNS demyelinating disease .NO may be a double-edged sword, mediating tissue damage on the one hand and on the other hand modulating complex immunological functions which may be protective.

Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible.

Diseases such as multiple sclerosis and Guillain-Barré syndrome are characterized not only by widespread loss of myelin from nerve fibres, but also by widespread inflammation in the central and peripheral nervous systems, respectively. While the demyelination alone is sufficient to block conduction and thereby cause symptoms, there is increasing evidence that the inflammation may also contribute significantly to the conduction block, although the mechanisms are not understood. Nitric oxide is an important inflammatory mediator which is elevated within the central nervous system in multiple sclerosis and which can be experimentally applied to tissues using nitric oxide donors. We report that such compounds cause reversible conduction block in both normal and demyelinated axons of the central and peripheral nervous systems. Notably, conduction in demyelinated and early remyelinated axons is particularly sensitive to block by nitric oxide, so that at lower concentrations, including those expected at sites of inflammation, demyelinated axons are selectively affected. We therefore propose that inflammation may directly cause symptoms via nitric oxide release, and that the inhibition of such release may open a new therapeutic avenue for demyelinating disease.

Low-temperature mapping predicts site of successful ablation while minimizing myocardial damage.

Temperatures near 50 degrees C can cause reversible loss of excitability in myocardial cells. Low-temperature, short-duration applications of radiofrequency energy were used to determine the adequacy of electrophysiological mapping of accessory pathway (AP) locations in 15 patients at 27 target sites using a closed-loop, temperature-controlled generator set to 50 degrees C. Energy was delivered until evidence of conduction block, or for a maximum of 10 seconds. If AP block occurred, a full 70 degrees C set point radiofrequency application was delivered to the same site. In the absence of AP block, tests with higher temperature settings (60 degrees C and 70 degrees C) were delivered to determine if inadequate temperature or catheter position led to failure of the initial 50 degrees C test. At 15 successful target sites where permanent AP block was achieved, the 50 degrees C test resulted in AP block in 14 (93%). Conduction returned in 13 of 14 APs after radiofrequency power was turned off. The time to block for the 70 degrees C applications was significantly shorter than for the 50 degrees C tests, and the peak temperature achieved was significantly higher. At unsuccessful sites where permanent AP block was not achieved, no block was induced with 11 of 12 tests at 50 degrees C, 6 of 6 tests at 60 degrees C, and 1 of 2 tests at 70 degrees C, suggesting that failure was due to incorrect catheter position. The sensitivity and positive predictive values of a 50 degrees C test identifying a successful site were > 90%. Low-temperature radiofrequency applications that cause transient AP block predict permanent success when a higher-temperature application is delivered at the same site. The time to achieve conduction block is a function of the temperature set point, and low-temperature tests produce reversible conduction block, suggesting minimal permanent injury.

Diabetes Increases Sciatic Nerve Susceptibility to Endothelin-Induced Ischemia

Endothelin-1 (ET) is a potent vasoconstrictor of vasa nervorum, the vascular supply of peripheral nerve trunks, that may, through elevated circulating levels, promote microangiopathy in human diabetes patients. In previous work, we observed that sciatic nerve trunks of rats exposed to epineurial ET developed transient dose-dependent endoneurial ischemia that might be associated with reversible motor conduction block. In the present study, we explored the possibility that ET ischemia might selectively damage axons of diabetic nerve trunks. We exposed the sciatic nerves of rats with streptozotocin-induced diabetes of 6-8 weeks duration and age-matched nondiabetic controls to supramaximal vasoconstrictive concentrations of epineurial ET and studied serial regional erythrocyte flux (laser Doppler flowmeter) and sciatic tibial motor conduction for up to 14 days. In diabetic rats, but not controls, ET ischemia damaged a large proportion of sciatic axons, predicted in each instance by focal motor conduction block across the site of ET application and eventual loss of distal motor nerve excitability. Histological studies confirmed the presence of severe axonal degeneration in diabetic sciatic nerves exposed to ET. Part of the susceptibility to ET in diabetes was accounted for by more intense and prolonged vasoconstriction. Diabetic nerves are selectively susceptible to ET-mediated ischemia.

Uhthoff and His Symptom

At the turn of the last century, Wilhelm Uhthoff was a renowned clinical neuro-ophthalmologist, and probably the first clinician whose entire career was devoted to this discipline. His achievements are among those that mark the commencement of contemporary neuro-ophthalmology. Uhthoff's symptom of visual loss with exercise is most frequently associated with optic neuritis. The symptom carries a major risk for recurrence of optic neuritis and development of multiple sclerosis. This study and its companion in the publication show that, independently, a metabolic byproduct of exercise or increases in body temperature cause a reversible conduction block in demyelinated optic nerves and result in temporary loss of vision [corrected].

Experimental nerve thermal injury.

Thermal injury to rat sciatic nerve was produced by local heating (47 and 58 degrees C) and studied physiologically and morphologically. Unmyelinated nerve fibres showed a greater direct vulnerability to hyperthermia; first manifest as a reversible conduction block of C fibre action potentials and at higher temperatures by immediate and selective axonal degeneration. By contrast, lower grade nerve thermal injury resulted in delayed, selective loss of myelinated fibres. Evidence from this study suggests that this is secondary to a heat-induced angiopathy, immediately and diffusely manifest in the vasa nervorum and giving rise to a progressive and ultimately severe reduction in nerve blood flow. The relative sparing of unmyelinated fibres is likely to be a result of their greater resistance to ischaemia. The pathological vulnerability of unmyelinated fibres to thermal injury, coupled with the susceptibility of large myelinated nerve fibres to secondary ischaemia, largely resolves previous contradictions in the literature.

Neurotoxic effect of two root canal sealers with calcium hydroxide on rat phrenic nerve in vitro

Root canal sealers placed into contact with the inferior alveolar nerve can cause paraesthesia in the area innervated by this nerve. The paraesthesia is due to neurotoxic effects of the sealers. In this study we examined the effect on nerve conduction in vitro of two calcium hydroxide-containing root canal sealers, Sealapex and CRCS. An isolated rat phrenic nerve was placed between two suction electrodes in a bath containing Tyrode solution. The sealers were brought into contact with the nerve, and the evoked compound action potentials (cAP) were recorded before and after contact with the materials. Both Sealapex and CRCS induced a fast and complete inhibition of the cAP in this model. The degree of reversibility of the inhibition varied from experiment to experiment. Both materials exhibited reversible and irreversible block of the nerve conduction after 90s and 5 min exposure. However, after 30 min of contact, the conduction of the cAP was irreversibly blocked for both materials.

Reversible nerve conduction block in patients with polyneuropathy after ultrasound thermotherapy at therapeutic dosage.

This study investigated the effect of ultrasound on nerve conduction in patients with polyneuropathy. Eight able-bodied controls (Group C) and 16 patients with clinical and physiologic evidence of polyneuropathy were tested. Eight patients (Group NP) had no aching pain symptoms; eight patients (Group P) had severe aching pain, burning sensation, unpleasant tingling, and/or hyperesthesia in the lower extremities. For two minutes, therapeutic ultrasound in doses of 0.5, 1.0, and 1.5W/cm2 were applied over the anterior surface of the leg along the pathway of the deep peroneal nerve. Peroneal nerve conduction studies were performed before, during, and after ultrasound treatment. The compound muscle action potential (CMAP) was recorded from the extensor digitorum brevis muscle. Nerve conduction studies on all eight patients in Group P revealed a significant decrease (41.4% and 44% reduced for doses of 1.0W/cm2 and 1.5W/cm2, respectively; p less than .05) in amplitude of CMAP (from baseline to the first negative peak), and an increase (6.4% and 6.7% increased for doses of 1.0W/cm2 and 1.5W/cm2, respectively; p less than .05) in proximal latency one minute after ultrasound application with a dose of 1.0 or 1.5W/cm2, but not with a dose of 0.5W/cm2 (p greater than 0.1). Changes returned to pretreatment values within five minutes of cessation of ultrasound therapy. In Groups C and NP, there were no significant changes in amplitudes of CMAP or proximal latency before, during, or after ultrasound therapy at a dose of 0.5, 1.0, or 1.5W/cm2. It was concluded that ultrasonic therapy with therapeutic dosage may cause a reversible conduction block on patients with painful polyneuropathy.