Kilohertz waveforms optimized to produce closed-state Na+ channel inactivation eliminate onset response in nerve conduction block.
Ontology highlight
ABSTRACT:
SUBMITTER: Yi G
PROVIDER: S-EPMC7316353 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
Publications
Kilohertz waveforms optimized to produce closed-state Na+ channel inactivation eliminate onset response in nerve conduction block.
Yi Guosheng G Grill Warren M WM
PLoS computational biology 20200615 6
The delivery of kilohertz frequency alternating current (KHFAC) generates rapid, controlled, and reversible conduction block in motor, sensory, and autonomic nerves, but causes transient activation of action potentials at the onset of the blocking current. We implemented a novel engineering optimization approach to design blocking waveforms that eliminated the onset response by moving voltage-gated Na+ channels (VGSCs) to closed-state inactivation (CSI) without first opening. We used computation ...[more]
Similar Datasets
Project description:ObjectiveThere is growing interest in delivering kilohertz frequency (KHF) electrical signals to block conduction in peripheral nerves for treatment of various diseases. Previous studies used different KHF waveforms to achieve block, and it remains unclear how waveform affects nerve block parameters.ApproachWe quantified the effects of waveform on KHF block of the rat tibial nerve in vivo and in computational models. We compared block thresholds and onset responses across current-controlled sinusoids and charge-balanced rectangular waveforms with different asymmetries and duty cycles.Main resultsSine waves had higher block thresholds than square waves, but used less power at block threshold. Block threshold had an inverse relationship with duty cycle of rectangular waveforms irrespective of waveform asymmetry. Computational model results were consistent with relationships measured in vivo, although the models underestimated the effect of duty cycle on increasing thresholds. The axonal membrane substantially filtered waveforms, the filter transfer function was strikingly similar across waveforms, and filtering resulted in post-filtered rms block thresholds that were approximately constant across waveforms in silico and in vivo. Onset response was not consistently affected by waveform shape, but onset response was smaller at amplitudes well above block threshold. Therefore, waveforms with lower block thresholds (e.g. sine waves or square waves) could be more readily increased to higher amplitudes relative to block threshold to reduce onset response. We also observed a reduction in onset responses across consecutive trials after initial application of supra-block threshold amplitudes.SignificanceWaveform had substantial effects on block thresholds, and the amplitude relative to block threshold had substantial effects on onset response. These data inform choice of waveform in subsequent studies and clinical applications, enhance effective use of block in therapeutic applications, and facilitate the design of parameters that achieve block with minimal onset responses.
| S-EPMC7742218 | biostudies-literature
Project description:Background and purposeRosiglitazone is a widely used oral hypoglycaemic agent, which improves insulin resistance in type 2 diabetes. Chronic rosiglitazone treatment is associated with a number of adverse cardiac events. The present study was designed to characterize the effects of rosiglitazone on cloned K(v)4.3 potassium channels.Experimental approachThe interaction of rosiglitazone with cloned K(v)4.3 channels stably expressed in Chinese hamster ovary cells was investigated using whole-cell patch-clamp techniques.Key resultsRosiglitazone decreased the currents carried by K(v)4.3 channels and accelerated the current inactivation, concentration-dependently, with an IC(50) of 24.5 µM. The association and dissociation rate constants for rosiglitazone were 1.22 µM(-1)·s(-1) and 31.30 s(-1) respectively. Block by rosiglitazone was voltage-dependent, increasing in the voltage range for channel activation; however, no voltage dependence was found in the voltage range required for full activation. Rosiglitazone had no effect on either the deactivation kinetics or the steady-state activation of K(v)4.3 channels. Rosiglitazone shifted the steady-state inactivation curves in the hyperpolarizing direction, concentration-dependently. The K(i) for the interaction between rosiglitazone and the inactivated state of K(v)4.3 channels was 1.49 µM, from the concentration-dependent shift in the steady-state inactivation curves. Rosiglitazone also accelerated the kinetics of the closed-state inactivation of K(v)4.3 channels. Rosiglitazone did not affect either use dependence or recovery from inactivation of K(v)4.3 currents.Conclusion and implicationsOur results indicate that rosiglitazone potently inhibits currents carried by K(v)4.3 channels by interacting with these channels in the open state and by accelerating the closed-state inactivation of K(v)4.3 channels.
| S-EPMC3101614 | biostudies-literature
Project description:Patients with PMP22 deficiency present with focal sensory and motor deficits when peripheral nerves are stressed by mechanical force. It has been hypothesized that these focal deficits are due to mechanically induced conduction block (CB). To test this hypothesis, we induced 60-70% CB (defined by electrophysiological criteria) by nerve compression in an authentic mouse model of hereditary neuropathy with liability to pressure palsies (HNPP) with an inactivation of one of the two pmp22 alleles (pmp22(+/-)). Induction time for the CB was significantly shorter in pmp22(+/-) mice than that in pmp22(+/+) mice. This shortened induction was also found in myelin-associated glycoprotein knock-out mice, but not in the mice with deficiency of myelin protein zero, a major structural protein of compact myelin. Pmp22(+/-) nerves showed intact tomacula with no segmental demyelination in both noncompressed and compressed conditions, normal molecular architecture, and normal concentration of voltage-gated sodium channels by [(3)H]-saxitoxin binding assay. However, focal constrictions were observed in the axonal segments enclosed by tomacula, a pathological hallmark of HNPP. The constricted axons increase axial resistance to action potential propagation, which may hasten the induction of CB in Pmp22 deficiency. Together, these results demonstrate that a function of Pmp22 is to protect the nerve from mechanical injury.
| S-EPMC3676309 | biostudies-literature
Project description:Efferent activation of the cervical vagus nerve (cVN) dampens systemic inflammatory processes, potentially modulating a wide-range of inflammatory pathological conditions. In contrast, afferent cVN activation amplifies systemic inflammatory processes, leading to activation of the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system through the greater splanchnic nerve (GSN), and elevation of pro-inflammatory cytokines. Ideally, to clinically implement anti-inflammatory therapy via cervical vagus nerve stimulation (cVNS) one should selectively activate the efferent pathway. Unfortunately, current implementations, in animal and clinical investigations, activate both afferent and efferent pathways. We paired cVNS with kilohertz electrical stimulation (KES) nerve block to preferentially activate efferent pathways while blocking afferent pathways. Selective efferent cVNS enhanced the anti-inflammatory effects of cVNS. Our results demonstrate that: (i) afferent, but not efferent, cVNS synchronously activates the GSN in a dose-dependent manner; (ii) efferent cVNS enabled by complete afferent KES nerve block enhances the anti-inflammatory benefits of cVNS; and (iii) incomplete afferent KES nerve block exacerbates systemic inflammation. Overall, these data demonstrate the utility of paired efferent cVNS and afferent KES nerve block for achieving selective efferent cVNS, specifically as it relates to neuromodulation of systemic inflammation.
| S-EPMC5215548 | biostudies-literature
Project description:BACKGROUND AND PURPOSE:Neurolymphomatosis is a rare manifestation of hematological malignancy and is characterized by direct infiltration of the peripheral nervous system. The objective of this study was to identify the clinical and electrophysiological features of neurolymphomatosis. METHODS:We retrospectively analyzed the medical records of 13 patients with neurolymphomatosis. Seven (54%) of the patients were men, and the median age at symptom onset was 60.0 years. RESULTS:The most common type of underlying malignancy was diffuse large B-cell lymphoma (69%). Twelve patients had painful asymmetric neuropathies. The median survival time after diagnosis was 7 months, and 12 patients died during the study period. Thirty-eight motor nerve conduction studies (NCSs) were performed in the affected nerves. Ten and 28 motor nerves were classified into the conduction-block and simple-axon-degeneration groups, respectively. The median time interval between symptom onset and the NCS was significantly shorter in the conduction-block group than in the simple-axon-degeneration group (p=0.032). However, no significant differences in the motor nerve conduction velocities, terminal latencies, and distal compound muscle action potential amplitudes were identified between the conduction-block and simple-axon-degeneration groups. The conduction-block group showed excessive temporal dispersion in only five of the ten NCSs (50%). Follow-up NCSs revealed that partial conduction blocks had changed into axonal degeneration patterns. CONCLUSIONS:This is the first study to analyze the electrophysiological features of patients with neurolymphomatosis. Our findings showed that a partial conduction block is not rare and is an early nerve conduction abnormality in neurolymphomatosis.
| S-EPMC5765259 | biostudies-literature
Project description:Reversible block of nerve conduction using kilohertz frequency electrical signals has substantial potential for treatment of disease. However, the ability to block nerve fibers selectively is limited by poor understanding of the relationship between waveform parameters and the nerve fibers that are blocked. Previous in vivo studies reported non-monotonic relationships between block signal frequency and block threshold, suggesting the potential for fiber-selective block. However, the mechanisms of non-monotonic block thresholds were unclear, and these findings were not replicated in a subsequent in vivo study. We used high-fidelity computational models and in vivo experiments in anesthetized rats to show that non-monotonic threshold-frequency relationships do occur, that they result from amplitude- and frequency-dependent charge imbalances that cause a shift between kilohertz frequency and direct current block regimes, and that these relationships can differ across fiber diameters such that smaller fibers can be blocked at lower thresholds than larger fibers. These results reconcile previous contradictory studies, clarify the mechanisms of interaction between kilohertz frequency and direct current block, and demonstrate the potential for selective block of small fiber diameters.
| S-EPMC7930193 | biostudies-literature
Project description:ImportanceAlthough a high body mass index (BMI) has been found to be associated with increased risk of cardiac conduction block (CCB) in older adults, no further studies have investigated the association between obesity and CCB in the general population.ObjectiveTo investigate the association between obesity and CCB, including its subtypes.Design, setting, and participantsThis cohort study used data from participants in the Kailuan Study in China (2006-2018) who had completed a physical examination in 2006 (baseline) and had not experienced CCB before baseline. Data analysis was conducted from March to September 2023.ExposuresObesity status was defined by BMI in 3 groups: normal weight (18.5 to <24), overweight (24 to <28), and obesity (≥28).Main outcome and measuresThe primary outcome was CCB, which was diagnosed from standard 12-lead electrocardiography. The primary end point included high-grade atrioventricular block (HAVB), complete right bundle branch block, complete left bundle branch block, left anterior fascicular block (LAFB), and left posterior fascicular block. First-degree atrioventricular block (FAVB), second-degree type 1 AVB, HAVB, complete and incomplete right and left bundle branch block, LAFB, and left posterior fascicular block were considered separately as secondary end points.ResultsAmong 86 635 participants (mean [SD] age, 50.8 [11.9] years; 68 205 males [78.7%]), there were 33 259 individuals with normal weight (38.4%), 37 069 individuals with overweight (42.8%), and 16 307 individuals with obesity (18.8%). The mean (SD) follow-up was 10.6 (3.07) years. In the multivariable Cox proportional hazards regression analysis, obesity was associated with an increased risk of incident CCB (hazard ratio [HR], 1.21; 95% CI, 1.04-1.42) vs normal BMI. In secondary analysis, obesity was associated with an increased risk of FAVB (HR, 1.44; 95% CI, 1.21-1.73), HAVB (HR, 1.99; 95% CI, 1.03-3.82), and LAFB (HR, 1.29; 95% CI, 1.03-1.62) vs normal BMI. There was no association between obesity and other CCB subtypes. Obesity was associated with a greater increase in risk of CCB vs normal BMI in older (aged ≥65 years; HR, 1.44; 95% CI, 1.05-1.96) vs younger (aged <65 years; HR, 1.13; 95% CI, 0.96-1.34) participants (P for interaction < .001) and those with diabetes (HR, 2.16; 95% CI, 1.24-3.76) vs without diabetes (HR, 1.19; 95% CI, 1.02-1.39) (P for interaction = .02).Conclusions and relevanceThis study found that obesity was associated with an increased risk of CCB, with greater increases in risk for FAVB, HAVB, and LAFB. Individuals who were older and those who had diabetes had larger increases in risk.
| S-EPMC10644217 | biostudies-literature
Project description:Shock waves are used clinically for breaking kidney stones and treating musculoskeletal indications. The mechanisms by which shock waves interact with tissue are still not well understood. Here, ultra-high-speed imaging was used to visualize the deformation of individual cells embedded in a tissue-mimicking phantom when subject to shock-wave exposure from a clinical source. Three kidney epithelial cell lines were considered to represent normal healthy (human renal epithelial), cancer (CAKI-2), and virus-transformed (HK-2) cells. The experimental results showed that during the compressive phase of the shock waves, there was a small (<2%) decrease in the projected cell area, but during the tensile phase, there was a relatively large (∼10%) increase in the projected cell area. The experimental observations were captured by a numerical model with a constitutive material framework consisting of an equation of state for the volumetric response and hyper-viscoelasticity for the deviatoric response. To model the volumetric cell response, it was necessary to change from a higher bulk modulus during the compression to a lower bulk modulus during the tensile shock loading. It was discovered that cancer cells showed a smaller deformation but faster response to the shock-wave tensile phase compared to their noncancerous counterparts. Cell viability experiments, however, showed that cancer cells suffered more damage than other cell types. These data suggest that the cell response to shock waves is specific to the type of cell and waveforms that could be tailored to an application. For example, the model predicts that a shock wave with a tensile stress of 4.59 MPa would increase cell membrane permeability for cancer cells with minimal impact on normal cells.
| S-EPMC5883951 | biostudies-literature
Project description:BackgroundMethods for the electrical inhibition of cardiac excitation have long been sought to control excitability and conduction, but to date remain largely impractical. High-amplitude alternating current (AC) stimulation has been known to extend cardiac action potentials (APs), and has been recently exploited to terminate reentrant arrhythmias by producing reversible conduction blocks. Yet, low-amplitude currents at similar frequencies have been shown to entrain cardiac tissues by generation of repetitive APs, leading in some cases to ventricular fibrillation and hemodynamic collapse in vivo. Therefore, an inhibition method that does not lead to entrainment - irrespective of the stimulation amplitude (bound to fluctuate in an in vivo setting) - is highly desirable.Methodology/principal findingsWe investigated the effects of broader amplitude and frequency ranges on the inhibitory effects of extracellular AC stimulation on HL-1 cardiomyocytes cultured on microelectrode arrays, using both sinusoidal and square waveforms. Our results indicate that, at sufficiently high frequencies, cardiac tissue exhibits a binary response to stimulus amplitude with either prolonged APs or no effect, thereby effectively avoiding the risks of entrainment by repetitive firing observed at lower frequencies. We further demonstrate the ability to precisely define reversible local conduction blocks in beating cultures without influencing the propagation activity in non-blocked areas. The conduction blocks were spatiotemporally controlled by electrode geometry and stimuli duration, respectively, and sustainable for long durations (300 s).Conclusion/significanceInhibition of cardiac excitation induced by high-frequency AC stimulation exhibits a binary response to amplitude above a threshold frequency, enabling the generation of reversible conduction blocks without the risks of entrainment. This inhibition method could yield novel approaches for arrhythmia modeling in vitro, as well as safer and more efficacious tools for in vivo cardiac mapping and radio-frequency ablation guidance applications.
| S-EPMC3340354 | biostudies-literature
Project description:Introduction: Motor nerve conduction blocks (CBs) could be detected in both acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). We aimed to identify the correlation between CBs and functional outcome in the two subtypes of GBS. Methods: Motor nerve conduction studies were performed in 17 patients with AIDP and 23 with AMAN. All patients were treated with intravenous immunoglobulin, and their disabilities were evaluated with Hughes functional grading scale before treatment, 1 month and 6 months after onset. Results: AMAN with CBs had higher reduction of Hughes grade (indicating more improved outcomes) at 1 month (1.71 ± 0.83 vs. 1 ± 0.67, p = 0.034) than AIDP with CBs. AMAN with CBs had higher reduction of Hughes grade at 1 month (1.71 ± 0.83 vs. 0.56 ± 0.73, p = 0.002) than AMAN without CBs. The reduction of Hughes grade at 1 month showed no significant difference between AIDP with and without CBs. Discussion: Motor nerve CBs in AMAN indicated better prognosis than in AIDP.
| S-EPMC5992574 | biostudies-literature