Simulation of Brugada syndrome using cellular and three-dimensional whole-heart modeling approaches

Brugada syndrome (BS) is a genetic disease identified by an abnormal electrocardiogram ( ECG) ( mainly abnormal ECGs associated with right bundle branch block and ST-elevation in right precordial leads). BS can lead to increased risk of sudden cardiac death. Experimental studies on human ventricular myocardium with BS have been limited due to difficulties in obtaining data. Thus, the use of computer simulation is an important alternative. Most previous BS simulations were based on animal heart cell models. However, due to species differences, the use of human heart cell models, especially a model with three-dimensional whole-heart anatomical structure, is needed. In this study, we developed a model of the human ventricular action potential (AP) based on refining the ten Tusscher et al (2004 Am. J. Physiol. Heart Circ. Physiol. 286 H1573 - 89) model to incorporate newly available experimental data of some major ionic currents of human ventricular myocytes. These modified channels include the L-type calcium current (ICaL), fast sodium current (I-Na), transient outward potassium current (I-to), rapidly and slowly delayed rectifier potassium currents (I-Kr and I-Ks) and inward rectifier potassium current (I-Ki). Transmural heterogeneity of APs for epicardial, endocardial and mid-myocardial (M) cells was simulated by varying the maximum conductance of IKs and Ito. The modified AP models were then used to simulate the effects of BS on cellular AP and body surface potentials using a three-dimensional dynamic heart - torso model. Our main findings are as follows. (1) BS has little effect on the AP of endocardial or mid-myocardial cells, but has a large impact on the AP of epicardial cells. (2) A likely region of BS with abnormal cell AP is near the right ventricular outflow track, and the resulting ST-segment elevation is located in the median precordium area. These simulation results are consistent with experimental findings reported in the literature. The model can reproduce a variety of electrophysiological behaviors and provides a good basis for understanding the genesis of abnormal ECG under the condition of BS disease.

Opioids Inhibit Lateral Amygdala Pyramidal Neurons by Enhancing A Dendritic Potassium Current

Pyramidal neurons in the lateral amygdala discharge trains of action potentials that show marked spike frequency adaptation, which is primarily mediated by activation of a slow calcium-activated potassium current. We show here that these neurons also express an alpha-dendrotoxin- and tityustoxin-Kalpha-sensitive voltage-dependent potassium current that plays a key role in the control of spike discharge frequency. This current is selectively targeted to the primary apical dendrite of these neurons. Activation of mu-opioid receptors by application of morphine or D-Ala(2)-N-Me-Phe(4)-Glycol(5)-enkephalin (DAMGO) potentiates spike frequency adaptation by enhancing the alpha-dendrotoxin-sensitive potassium current. The effects of mu-opioid agonists on spike frequency adaptation were blocked by inhibiting G-proteins with N-ethylmaleimide (NEM) and by blocking phospholipase A(2). Application of arachidonic acid mimicked the actions of DAMGO or morphine. These results show that mu-opioid receptor activation enhances spike frequency adaptation in lateral amygdala neurons by modulating a voltage-dependent potassium channel containing Kv1.2 subunits, through activation of the phospholipase A(2)-arachidonic acid-lipoxygenases cascade.

Independent roles of calcium and voltage-dependent potassium currents in controlling spike frequency adaptation in lateral amygdala pyramidal neurons

The calcium-dependent afterhyperpolarization (AHP) that follows trains of action potentials is responsible for controlling action potential firing patterns in many neuronal cell types. We have previously shown that the slow AHP contributes to spike frequency adaptation in pyramidal neurons in the rat lateral amygdala. In addition, a dendritic voltage-gated potassium current mediated by Kv1.2-containing channels also suppresses action potential firing in these neurons. In this paper we show that this voltage-gated potassium current and the slow AHP act together to control spike frequency adaptation in lateral amygdala pyramidal neurons. The two currents have similar effects on action potential number when firing is evoked either by depolarizing current injections or by synaptic stimulation. However, they differ in their control of firing frequency, with the voltage-gated potassium current but not the slow AHP determining the initial frequency of action potential firing. This dual mechanism of controlling firing patterns is unique to lateral amygdala neurons and is likely to contribute to the very low levels of firing seen in lateral amygdala neurons in vivo.

Photolytic manipulation of [Ca2+](i) reveals slow kinetics of potassium channels underlying the afterhyperpolarization in hipppocampal pyramidal neurons

The identity of the potassium channel underlying the slow, apamin-insensitive component of the afterhyperpolarization current (sl(AHP)) remains unknown. We studied sl(AHP) in CA1 pyramidal neurons using simultaneous whole-cell recording, calcium fluorescence imaging, and flash photolysis of caged compounds. Intracellular calcium concentration ([Ca2+](i)) peaked earlier and decayed more rapidly than sl(AHP). Loading cells with low concentrations of the calcium chelator EGTA slowed the activation and decay of sl(AHP). In the presence of EGTA, intracellular calcium decayed with two time constants. When [Ca2+](i) was increased rapidly after photolysis of DM-Nitrophen, both apamin-sensitive and apamin-insensitive outward currents were activated. The apamin-sensitive current activated rapidly (<20 msec), whereas the apamin-insensitive current activated more slowly (180 msec). The apamin-insensitive current was reduced by application of serotonin and carbachol, confirming that it was caused by sl(AHP) channels. When [Ca2+](i) was decreased rapidly via photolysis of diazo-2, the decay of sl(AHP) was similar to control (1.7 sec). All results could be reproduced by a model potassium channel gated by calcium, suggesting that the channels underlying sl(AHP) have intrinsically slow kinetics because of their high affinity for calcium.

Synaptic activation of transient receptor potential channels by metabotropic glutamate receptors in the lateral amygdala

Classical mammalian transient receptor potential channels form non-selective cation channels that open in response to activation of phospholipase C-coupled metabotropic receptors, and are thought to play a key role in calcium homeostasis in non-excitable cells. Within the nervous system transient receptor potential channels are widely distributed but their physiological roles are not well understood. Here we show that in the rat lateral amygdala transient receptor potential channels mediate an excitatory synaptic response to glutamate. Activation of group l etabotropic glutamate receptors on pyramidal neurons in the lateral amygdala with either exogenous or synaptically released glutamate evokes an inward current at negative potentials with a current voltage relationship showing a region of negative slope and steep outward rectification. This current is blocked by inhibiting G protein function with GTP-beta-S, by inhibiting phospholipase C or by infusing transient receptor potential antibodies into lateral amygdala pyramidal neurons. Using RT-PCR and Western blotting we show that transient receptor potential 1, transient receptor potential 4 and transient receptor potential 5 are present in the lateral amygdala. Single cell PCR confirms the presence of transient receptor potential 1 and transient receptor potential 5 in pyramidal neurons and we show by co-immunoprecipitation that transient receptor potential 1 and transient receptor potential 5 co-assemble as a heteromultimers in the amygdala. These results show that in lateral amygdala pyramidal neurons synaptically released glutamate activates transient receptor potential channels, which we propose are likely to be heteromultimeric channels containing transient receptor potential 1 and transient receptor potential 5/transient receptor potential 4. (c) 2005 Published by Elsevier Ltd on behalf of IBRO.

Calcium-activated potassium currents in mammalian neurons

1. Influx of calcium via voltage-dependent calcium channels during the action potential lends to increases in cytosolic calcium that can initiate a number of physiological processes. One of these is the activation of potassium currents on the plasmalemma. These calcium-activated potassium currents contribute to action potential repolarization and are largely responsible for the phenomenon of spike frequency adaptation. This refers to the progressive slowing of the frequency of discharge of action potentials during sustained injection of depolarizing current. In some cell types, this adaptation is so marked that despite the presence of depolarizing current, only a single spike (or a few spikes) is initiated, Following cessation of current injection, slow deactivation of calcium-activated potassium currents is also responsible for the prolonged hyperpolarization that often follows, 2. A number of macroscopic calcium-activated potassium currents that can be separated on the basis of kinetic and pharmacological criteria have been described in mammalian neurons. At the single channel level, several types of calcium-activated potassium channels also have been characterized. While for some macroscopic currents the underlying:single channels have been unambiguously defined, for other currents the identity of the underlying channels is not clear. 3. In the present review we describe the properties of the known types of calcium-activated potassium currents in mammalian neurons and indicate the relationship between macroscopic currents and particular single channels.

Physiological role of calcium-activated potassium currents in the rat lateral amygdala

Principal neurons in the lateral nucleus of the amygdala (LA) exhibit a continuum of firing properties in response to prolonged current injections ranging from those that accommodate fully to those that fire repetitively. In most cells, trains of action potentials are followed by a slow after hyperpolarization (AHP) lasting several seconds. Reducing calcium influx either by lowering concentrations of extracellular calcium or by applying nickel abolished the AHP, confirming it is mediated by calcium influx. Blockade of large conductance calcium-activated potassium channel (BK) channels with paxilline, iberiotoxin, or TEA revealed that BK channels are involved in action potential repolarization but only make a small contribution to the fast AHP that follows action potentials. The fast AHP was, however, markedly reduced by low concentrations of 4-aminopyridine and alpha-dendrotoxin, indicating the involvement of voltage-gated potassium channels in the fast AHP. The medium AHP was blocked by apamin and UCL1848, indicating it was mediated by small conductance calcium-activated potassium channel (SK) channels. Blockade of these channels had no effect on instantaneous firing. However, enhancement of the SK-mediated current by 1-ethyl-2-benzimidazolinone or paxilline increased the early interspike interval, showing that under physiological conditions activation of SK channels is insufficient to control firing frequency. The slow AHP, mediated by non-SK BK channels, was apamin-insensitive but was modulated by carbachol and noradrenaline. Tetanic stimulation of cholinergic afferents to the LA depressed the slow AHP and led to an increase in firing. These results show that BK, SK, and non-BK SK-mediated calcium-activated potassium currents are present in principal LA neurons and play distinct physiological roles.

Calcium-activated potassium channels: Multiple contributions to neuronal function

Calcium-activated potassium channels are a large family of potassium channels that are found throughout the central nervous system and in many other cell types. These channels are activated by rises in cytosolic calcium largely in response to calcium influx via voltage-gated calcium channels that open during action potentials. Activation of these potassium channels is involved in the control of a number of physiological processes from the firing properties of neurons to the control of transmitter release. These channels form the target for modulation for a range of neurotransmitters and have been implicated in the pathogenesis of neurological and psychiatric disorders. Here the authors summarize the varieties of calcium-activated potassium channels present in central neurons and their defining molecular and biophysical properties.

Outcomes of transient evoked otoacoustic emission testing in 6-year-old school children: A comparison with pure tone screening and tympanometry

Objectives: (1) To establish test performance measures for Transient Evoked Otoacoustic Emission testing of 6-year-old children in a school setting; (2) To investigate whether Transient Evoked Otoacoustic Emission testing provides a more accurate and effective alternative to a pure tone screening plus tympanometry protocol. Methods: Pure tone screening, tympanometry and transient evoked otoacoustic emission data were collected from 940 subjects (1880 ears), with a mean age of 6.2 years. Subjects were tested in non-sound-treated rooms within 22 schools. Receiver operating characteristics curves along with specificity, sensitivity, accuracy and efficiency values were determined for a variety of transient evoked otoacoustic emission/pure tone screening/tympanometry comparisons. Results: The Transient Evoked Otoacoustic Emission failure rate for the group was 20.3%. The failure rate for pure tone screening was found to be 8.9%, whilst 18.6% of subjects failed a protocol consisting of combined pure tone screening and tympanometry results. In essence, findings from the comparison of overall Transient Evoked Otoacoustic Emission pass/fail with overall pure tone screening pass/fail suggested that use of a modified Rhode Island Hearing Assessment Project criterion would result in a very high probability that a child with a pass result has normal hearing (true negative). However, the hit rate was only moderate. Selection of a signal-to-noise ratio (SNR) criterion set at greater than or equal to 1 dB appeared to provide the best test performance measures for the range of SNR values investigated. Test performance measures generally declined when tympanometry results were included, with the exception of lower false alarm rates and higher positive predictive values. The exclusion of low frequency data from the Transient Evoked Otoacoustic Emission SNR versus pure tone screening analysis resulted in improved performance measures. Conclusions: The present study poses several implications for the clinical implementation of Transient Evoked Otoacoustic Emission screening for entry level school children. Transient Evoked Otoacoustic Emission pass/fail criteria will require revision. The findings of the current investigation offer support to the possible replacement of pure tone screening with Transient Evoked Otoacoustic Emission testing for 6-year-old children. However, they do not suggest the replacement of the pure tone screening plus tympanometry battery. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

Ca2+-activated K+(BK) channel inactivation contributes to spike broadening during repetitive firing in the rat lateral amygdala

In many neurons, trains of action potentials show frequency-dependent broadening. This broadening results from the voltage-dependent inactivation of K+ currents that contribute to action potential repolarisation. In different neuronal cell types these K+ currents have been shown to be either slowly inactivating delayed rectifier type currents or rapidly inactivating A-type voltage-gated K+ currents. Recent findings show that inactivation of a Ca2+-dependent K+ current, mediated by large conductance BK-type channels, also contributes to spike broadening. Here, using whole-cell recordings in acute slices, we examine spike broadening in lateral amygdala projection neurons. Spike broadening is frequency dependent and is reversed by brief hyperpolarisations. This broadening is reduced by blockade of voltage-gated Ca2+ channels and BK channels. In contrast, broadening is not blocked by high concentrations of 4-aminopyridine (4-AP) or alpha-dendrotoxin. We conclude that while inactivation of BK-type Ca2+-activated K+ channels contributes to spike broadening in lateral amygdala neurons, inactivation of another as yet unidentified outward current also plays a role.

Transient prenatal vitamin D deficiency is associated with hyperlocomotion in adult rats

Rat experiments have shown that prenatal Vitamin D deficiency leads to altered neonatal brain morphology, cell density and neurotrophin expression. In the current study we examined the hypothesis that Vitamin D deficiency during early development alters adult behaviour even when there is an intervening period in which the animal receives normal Vitamin D in later development. Rats were conceived and born to Vitamin D deficient dams (Birth); conceived, born and weaned from Vitamin D deficient dams (Weaning); or deficient in Vitamin D from conception to 10 weeks of age (Life). Litters were standardized to three males and three females per litter. All rat offspring were rendered normocalcaemic with calcium supplemented water (2 mM) after weaning. Control animals were born to mothers fed a normal diet but subject to similar litter size and calcium supplementation. At 10 weeks all animals were tested on the holeboard test, elevated plus maze test, social interaction observation, acoustic startle response test, prepulse inhibition of the acoustic startle response and a forced swim test. Early Vitamin D deficiency (Birth group) enhanced locomotion in the holeboard test and increased activity in the elevated plus maze. Thus, transient prenatal Vitamin D deficiency induces hyperlocomotion in adulthood, without severe motor abnormalities. (C) 2004 Elsevier B.V. All rights reserved.

Effect of body position on transient evoked accoustic emissions: The clinical perspective

The present study investigated body position effects on transient evoked otoacoustic emission (TEOAE) recordings of clinical significance. Sixty adults (30 males, 30 females) were assessed using the Otodynamics ILO88 Analyzer in three positions (sitting, supine, and side-lying). Results indicated significant positional effects on the TEOAE parameters of A-B difference, noise, whole wave reproducibility, and response levels. These differences included higher noise levels in supine and side-lying positions in comparison to the upright sitting position. Lower whole wave reproducibility measurements, and higher response amplitudes, in the side-lying position compared with supine and seated positions were also observed. No significant effects were evident for signal-to-noise ratio or band reproducibility. Given the lack of significant body position effects on these latter parameters and the infrequent clinical use of the other parameters in isolation, there was no evidence to suggest the future need for major review of current pass/fail criteria or of the standard test protocol.

Block of voltage-gated potassium channels by Pacific ciguatoxin-1 contributes to increased neuronal excitability in rat sensory neurons

The present study investigated the actions of the polyether marine toxin Pacific ciguatoxin-1 (P-CTX-1) on neuronal excitability in rat dorsal root ganglion (DRG) neurons using patch-clamp recording techniques. Under current-clamp conditions, bath application of 2-20 nM P-CTX-1 caused a rapid, concentration-dependent depolarization of the resting membrane potential in neurons expressing tetrodotoxin (TTX)-sensitive voltage-gated sodium (Na-v,.) channels. This action was completely suppressed by the addition of 200 nM TTX to the external solution, indicating that this effect was mediated through TTX-sensitive Na-v channels. In addition, P-CTX-1 also prolonged action potential and afterhyperpolarization (AHP) duration. In a subpopulation of neurons, P-CTX-1 also produced tonic action potential firing, an effect that was not accompanied by significant oscillation of the resting membrane potential. Conversely, in neurons expressing TTX-resistant Na-v currents, P-CTX-1 failed to alter any parameter of neuronal excitability examined in this study. Under voltage-clamp conditions in rat DRG neurons, P-CTX-1 inhibited both delayed-rectifier and 'A-type' potassium currents in a dose-dependent manner, actions that Occurred in the absence of alterations to the voltage dependence of activation. These actions appear to underlie the prolongation of the action potential and AHP. and contribute to repetitive firing. These data indicate that a block of potassium channels contributes to the increase in neuronal excitability, associated with a modulation of Na-v. channel gating, observed clinically in response to ciguatera poisoning. (c) 2004 Elsevier Inc. All rights reserved.

Analysis of transient eddy currents in MRI using a cylindrical FDTD method

Most magnetic resonance imaging (MRI) spatial encoding techniques employ low-frequency pulsed magnetic field gradients that undesirably induce multiexponentially decaying eddy currents in nearby conducting structures of the MRI system. The eddy currents degrade the switching performance of the gradient system, distort the MRI image, and introduce thermal loads in the cryostat vessel and superconducting MRI components. Heating of superconducting magnets due to induced eddy currents is particularly problematic as it offsets the superconducting operating point, which can cause a system quench. A numerical characterization of transient eddy current effects is vital for their compensation/control and further advancement of the MRI technology as a whole. However, transient eddy current calculations are particularly computationally intensive. In large-scale problems, such as gradient switching in MRI, conventional finite-element method (FEM)-based routines impose very large computational loads during generation/solving of the system equations. Therefore, other computational alternatives need to be explored. This paper outlines a three-dimensional finite-difference time-domain (FDTD) method in cylindrical coordinates for the modeling of low-frequency transient eddy currents in MRI, as an extension to the recently proposed time-harmonic scheme. The weakly coupled Maxwell's equations are adapted to the low-frequency regime by downscaling the speed of light constant, which permits the use of larger FDTD time steps while maintaining the validity of the Courant-Friedrich-Levy stability condition. The principal hypothesis of this work is that the modified FDTD routine can be employed to analyze pulsed-gradient-induced, transient eddy currents in superconducting MRI system models. The hypothesis is supported through a verification of the numerical scheme on a canonical problem and by analyzing undesired temporal eddy current effects such as the B-0-shift caused by actively shielded symmetric/asymmetric transverse x-gradient head and unshielded z-gradient whole-body coils operating in proximity to a superconducting MRI magnet.

Optimum switching point assessment of parallel braking resistor and serial current limiter for power system stability enhancement

A new control algorithm using parallel braking resistor (BR) and serial fault current limiter (FCL) for power system transient stability enhancement is presented in this paper. The proposed control algorithm can prevent transient instability during first swing by immediately taking away the transient energy gained in faulted period. It can also reduce generator oscillation time and efficiently make system back to the post-fault equilibrium. The algorithm is based on a new system energy function based method to choose optimal switching point. The parallel BR and serial FCL resistor can be switched at the calculated optimal point to get the best control result. This method allows optimum dissipation of the transient energy caused by disturbance so to make system back to equilibrium in minimum time. Case studies are given to verify the efficiency and effectiveness of this new control algorithm.