The Simulation of Repolarization Events of the Cardiac Purkinje Fiber Action Potential

A mathematical model based on the formalism of the Hodgkin-Huxley equations was implemented on a microcomputer system and used to simulate the membrane action potential of cardiac Purkinje fibers. The complete model is a modification of the representation used by McAllister et al. [1], mainly with respect to the outward current components during the late plateau, the repolarization phase, and the slow repolarization phase of the action potential. A new formulation of the potassium conductance was used, involving two distinct types of ionic channels corresponding, respectively, to the experimentally observed inward-going and outward-going rectification properties of the Purkinje fiber membrane. A unified representation of the Purkinje fiber current components was thus obtained which provides a more satisfactory interpretation of experimental results than was possible with the original model of McAllister et al. [1]. The membrane channel for the potassium pacemaker current is characterized by a set of first-order activation?inactivation variables and a constant fully activated conductance. The other channel carries the potassium current involved in the late plateau and repolarization phase of the action potential.     

Action Potential Collision in Heart Tissue-Computer Simulations and Tissue Expenrments

The electrical effects of action potential collision were studied using a computer simulation of one-dimensional action potential propagation and tissue experiments from isolated cardiac Purkinje strands and papillary muscles. The effects of collision, when compared to normal one-way propagation, included quantitative changes in all of the measured indexes of action potential upstroke and repolarization. These changes can be attributed to spatiotemporal changes in the net membrane current. Parameter sensitivity and analytic techniques identified five factors which determine the collision-induced decrease in action potential area: conduction velocity, action potential height, cable radius, specific intracellular resistivity, and the specific membrane resistance during action potential repolarization. The simulations demonstrated that collision effects were independent of inhomogeneity in action potential duration, the spatial extent of the collision effects was greater than the passive space constant, and certain simulated abnormal conditions (e. g., discontinuous propagation, ischemic tissue) increased the magnitude of the collision effects. The tissue experiments supported the simulations regarding the changes in action potential configuration directly at and on each side of the collision site. Elevated [K+]0 increased the changes in action potential duration in both tissue preparations. In papillary muscles, collision effects in the transverse direction were confined to a narrower region than collision effects in the longitudinal direction with no difference in the peak magnitude of the changes. Action potential collision is a common occurrence in the heart.     

Dual microcomputer analysis of cardiac transmembrane action potentials

A dual microcomputer system has been developed for automating the analysis of cardiac transmembrane action potentials. This system consists of two microcomputers and supporting function modules which digitize, detect, analyze, and plot the transmembrane action potentials from a cardiac cell impaled with a microelectrode. The action potentials are digitized at two sampling rates for computer processing; a sampling rate of 10 kHz is used to obtain the rapid initial upstroke, while a rate of 100 Hz is used to obtain the slower repolarization phase. The action potentials are characterized by graphic displays using the derived measurements. The system measures the resting potential, overshoot amplitude, dV/dtmax and time for 50, 70, and 95 percent repolarization of the action potential.     

A simultaneous multichannel monophasic action potential electrode array for in vivo epicardial repolarization mapping

While the recording of extracellular monophasic action potentials (MAPs) from single epicardial or endocardial sites has been performed for over a century, we are unaware of any previous successful attempt to record MAPs simultaneously from a large number of sites in vivo. We report here the design and validation of an array of MAP electrodes which records both depolarization and repolarization simultaneously at up to 16 epicardial sites in a square array on the heart in vivo. The array consists of 16 sintered Ag-AgCl electrodes mounted in a common housing with individual suspensions allowing each electrode to exert a controlled pressure on the epicardial surface. The electrodes are arranged in a square array, with each quadrant of four having an additional recessed sintered Ag-AgCl reference electrode at its center. A saline-soaked sponge establishes ionic contact between the reference electrodes and the tissue. The array was tested on six anesthetized open-chested pigs. Simultaneous diagnostic-quality MAP recordings were obtained from up to 13 out of 16 ventricular sites. Ventricular MAPs had amplitudes of 10-40 mV with uniform morphologies and stable baselines for up to 30 min. MAP duration at 90% repolarization was measured and shown to vary as expected with cycle length during sustained pacing. The relationship between MAP duration and effective refractory period was also confirmed. The ability of the array to detect local differences in repolarization was tested in two ways. Placement of the array straddling the atrioventricular (AV) junction yielded simultaneous atrial or ventricular recordings at corresponding sites during 1:1 and 2:1 AV conduction. Localized ischemia via constriction of a coronary artery branch resulted in shortening of the repolarization phase at the ischemic, but not the nonischemic, sites. In conclusion, these results indicate that the simultaneous multichannel MAP electrode array is a viable method for in vivo epicardial repolarization mapping. The array has the potential to be expanded to increase the number of sites and spatial resolution.     

Threshold variability in fibers with field stimulation of excitablemembranes

The central focus of this report is the evolution of transmembrane potentials following initiation of a point-source field stimulus, particularly when the stimulus is short and the stimulating electrode is close to the fiber. The transmembrane voltage threshold in response to a point-source field stimulus was determined in a numerical model of a single unmyelinated fiber. Both nerve (Hodgkin-Huxley [1952]) and cardiac (Ebihara-Johnson [1980]) models of the fiber membrane were evaluated. A central question is whether it is possible to know in advance whether a stimulus of specific magnitude, duration, and location will result in a subsequent action potential. Such determination can be based on the membrane's “voltage threshold”. In contrast to the commonly held view, the voltage threshold was found to vary markedly depending on the duration and location of the field stimulus. Voltage thresholds ranged from about 8 mV above baseline to more than 100 mV above baseline, the higher thresholds occurring with shorter stimuli and electrode locations closer to the membrane. A related question is whether the passive membrane response can be used as a tool in determining whether a subsequent action potential is elicited. If the answer is affirmative, this finding can be very useful, since passive properties are linear and thereby much simpler to evaluate than active ones. The results show that the passive response tracks active responses long enough to be a good estimator of subsequent action potential development. Examples show that the evaluation of V_m at 0.2-0.5 msec after stimulus initiation, times chosen on the basis of membrane characteristics, was a better predictor of subsequent excitation than was either initial transmembrane current or V_m at the time when the stimulus ends. Most of the circumstances analyzed here with electric field stimulation also appear likely to be valid with magnetic field stimulation     

Late phase of repolarization is autoregenerative and scales linearly with action potential duration in mammals ventricular myocytes: a model study

Scaling of action potential (AP) duration (APD) in mammals of different size is a rather complex phenomenon, dominated by a regulatory type mechanism of ion channels expression. By means of simulations performed on six published mathematical models of cardiac ventricular APs of different mammals, it is shown that AP repolarization is autoregenerative in its later phase (ARRP) and that the duration of such phase scales linearly with APD. For each AP, a 3-D instantaneous time-voltage-current surface is constructed, which has been recently described in a more simplified model. This representation allows us to measure ARRP and to study the contribution to it for different ion currents. It has been found that the existence of an ARRP is not intrinsic to cardiac models formulation; one out of the six models does not show this phase. A linear correlation between ARRP duration and APD in the remaining models is also found. It is shown that ARRP neither simply depend on AP shape nor on APD. Though I(K1) current seems to be the main responsible for determining and modulating this phase, the mechanism by which ARRP scales linearly with APD remains unclear and raises further questions on the scaling strategies of cardiac repolarization in mammals.     

Electrolyte-gated organic synapse transistor interfaced with neurons

We demonstrate an electrolyte-gated hybrid nanoparticle/organic synapstor (synapse-transistor, termed EGOS) that exhibits short-term plasticity as biological synapses. The response of EGOS makes it suitable to be interfaced with neurons: short-term plasticity is observed at spike voltage as low as 50 mV (in a par with the amplitude of action potential in neurons) and with a typical response time in the range of tens milliseconds. Human neuroblastoma stem cells are adhered and differentiated into neurons on top of EGOS. We observe that the presence of the cells does not alter short-term plasticity of the device.     

A dynamic action potential model analysis of shock-inducedaftereffects in ventricular muscle by reversible breakdown of cellmembrane

To elucidate the subcellular mechanism underlying the aftereffects of high-intensity dc shocks, a small pore, which mimics reversible breakdown of the cell membrane (electroporation), was incorporated into the phase-2 Luo-Rudy (L-R) model of ventricular action potentials. The pore size was set to occupy 0.15%-4.25% of the total cell membrane during the 10-ms shock. The pore was assumed to decrease after the shock exponentially with a time constant of 100-1,400 ms to simulate resealing process. In normal myocytes, the pore formation results in a delay of repolarization of the shocked action potential, which is followed by prolonged depolarization and oscillation of membrane potential like early afterdepolarization (EAD). Time- and voltage-dependent changes in the delayed rectifier K+ currents (IKr, IKs) in combination with those of L-type Ca2+ current (ICa,(L)) and ion flux through the pore (I(pore)) are responsible for the potential changes. Spontaneous excitation from the oscillation depends on activation of ICa,(L). In myocytes overloaded with Na+ and Ca2+ secondary to 90% inhibition of Na+-K+ pump, the pore formation results in a delay of repolarization of the shocked action potential, which is followed by slower cyclic depolarization in response to spontaneous release of Ca2+ from the sarcoplasmic reticulum (SR). This delayed afterdepolarization-type oscillation is abolished by complete block of Ca2+ release from the SR. These findings suggest that high-intensity electric field application will cause arrhythmogenic responses through a transient rupture of sarcolemma with different subcellular events in ventricular cells under normal and pathological conditions.     

A model of the muscle-fiber intracellular action potentialwaveform, including the slow repolarization phase

Recent studies have shown that the slow repolarization phase or "negative afterpotential" of the intracellular muscle-fiber action potential (IAP) plays an important role in determining the shape of the extracellularly recorded motor-unit action potential (MUAP). This paper presents a model of the IAP waveform as the sum of a spike and an afterpotential, both represented by simple analytical expressions. The model parameters that specify the sizes of the spike and afterpotential are shown to be proportional to the quadrupole and dipole moments of the transmembrane current distribution associated with the spike of the wave of excitation. The model provides a computationally efficient method for simulating the MUAP, and it can be reliably inverted to estimate the model parameters from empirical IAP and MUAP waveforms.     

Voltage-dependent effects of Ca(2+)/calmodulin on Cl(-) channel in cardiac sarcoplasmic reticulum

A new kind of chloride channels in the cardiac sarcoplasmic reticulum, 116 pS Cl(-) channel (500 mM Cl(-) in the cis and 50 mM Cl(-) in the trans chamber solutions), which is activated by protein-kinase-A-dependent phosphorylation, has been determined to conduct adenine nucleotide as a transporter between cytosol and SR lumen. We investigated the voltage-dependent gating of this Cl(-) channel by recording single-channel activities using the planar lipid bilayer-vesicle fusion technique. The channel activities did not change at different membrane potentials (-100 mV to +50 mV) or different Ca(2+) concentrations (1 nM to 1 mM) in cis solution. In the presence of calmodulin (CaM) (0.1 microM /microg SR vesicles), however, Ca(2+) added to the cis solution at 0 mV inhibited channel openings in a Ca(2+) -concentration-dependent manner. These effects were prevented by the addition of CaM inhibitors. The blocking effects of CaM differed depending on the membrane potentials at negative potentials below -20 mV. With CaM and 3 microM Ca(2+), the values of opening probability were 0 at -80 mV, 0.2 at -40 mV, 0.3 at -20 mV, 0.71 at 0 mV and 0.92 at +20 mV. These results may indicate the membrane potential affects the action of Ca(2+) /CaM complex     

Computational modeling of medium spiny projection neurons innucleus accumbens: toward the cellular mechanisms of afferent streamintegration

The nucleus accumbens (Nacc) regulates the major feedback pathways linking prefrontal cortex, hippocampus, and amygdala. We describe simulations of a biophysical level model of a single medium spiny projection (MSP) neuron, the principle cell of the Nacc. The model suggests that the unusual bistable membrane potential of MSP cells arises from the interplay between two potassium currents, K_IR and K_A. We find that the transition from the membrane potential down state (~-85 mV) to the upstate (~-60 mV) requires a significant barrage of synchronized inputs, and that ongoing afferent stimulation is required to maintain the cell in the up state. The Nacc receives the densest dopominergic innervation in the brain, and the model demonstrates, in agreement with recent experimental evidence, that dopamine acts to increase the energy barrier to membrane potential state transitions. Through its action on K_IR and L-type Ca²⁺ channels, dopamine selectively lowers cell gain in the down state and increases it in the up state, a mechanism for context-dependent gain control. These findings suggest a mechanism of afferent pattern integration in the accumbens arising from transient synchronization among ensembles of MSP neurons. We attempt to relate these findings to possible origins of abnormalities of sensory gating in schizophrenia     

Modulation of conduction at points of axonal bifurcation by appliedelectric fields

This study investigated how weak electric fields, on the order of 100 mV/cm, modulate action potential conduction through points of axonal bifurcation in leech touch sensory neurons. Axonal branch points in neurons are ubiquitous structures, and they are sites of low safety-factor for action potential propagation. In this study calibrated electric fields were applied around excised ganglia from the leech central nervous system. The electric fields were generated by 500 ms constant current square waves applied to the bath containing the tissue. Microelectrode penetration of the neurons was used to: 1) record transmembrane potential changes in the cell body of the neuron that resulted from the external field; 2) monitor conduction block when action potentials, evoked in the periphery, propagated into the ganglion; 3) inject current directly into the cell in an experimental analysis of the mechanism by which the externally applied field produced block. Conduction block was reliably induced by electric fields too weak to reach threshold for firing action potentials. In an experimental analysis where block was produced by the direct intracellular injection of negative current, a reversed polarity field relieved it. This indicates that when the external field induces block, it does so by membrane hyperpolarization at the branch point.     

A model of the muscle action potential for describing the leadingedge, terminal wave, and slow afterwave

The leading edge, terminal wave, and slow afterwave of the motor-unit action potential (MUAP) are produced by changes in the strength of electrical sources in the muscle fibers rather than by movement of sources. The latencies and shapes of these features are, therefore, determined primarily by the motor-unit (MU) architecture and the intracellular action potential (IAP), rather than by the volume-conduction characteristics of the limb. We present a simple model to explain these relationships. The MUAP is modeled as the convolution of a source function related to the IAP and a weighting function related to the MU architecture. The IAP waveform is modeled as the sum of a spike and a slow repolarization phase. The MU architecture is modeled by assuming that the individual fibers lie along a single equivalent axis but that their action potentials have dispersed initiation and termination times. The model is illustrated by simulating experimentally recorded MUAPs and compound muscle action potentials.     

Ferroelectric Response and Induced Biaxiality in the Nematic Phase of Bent‐Core Mesogens

The still undiscovered fluid ferroelectric nematic phase is expected to exhibit a much faster and easier response to an external electric field compared to conventional ferroelectric smectic liquid crystals; therefore, the discovery of such a phase could open new avenues in electro‐optic device technology. Here, experimental evidence of a ferroelectric response to a switching electric field in a low molar mass nematic liquid crystal is reported and connected with field‐induced biaxiality. The fluid is made of bent‐core polar molecules and is nematic over a range of 120 °C. Combining repolarization current measurements, electro‐optical characterizations, X‐ray diffraction and computer simulations, ferroelectric switching is demonstrated and it is concluded that the response is due to field‐induced reorganization of polar cybotactic groups within the nematic phase. This work represents significant progress toward the realization of ferroelectric fluids that can be aligned at command with a simple electric field.     

A model study of extracellular stimulation of cardiac cells

Point source extracellular stimulation of a myocyte model was used to study the efficacy of excitation of cardiac cells, taking into account the shape of the pulse stimulus and its time of application in the cardiac cycle. The myocyte was modeled as a small cylinder of membrane (diameter 10 μm, length 100 μm) capped at both ends and placed in an unbounded volume conductor. A Beeler-Reuter model modified for the Na⁺ dynamics served to simulate the membrane ionic current. The stimulus source was located on the cylinder axis, close to the myocyte (50 μm) in order to generate a nonlinear extracellular field (φ_e). The low membrane impedance associated with the high frequency component of the make and break of the rectangular current pulse leads to a current flow across the membrane and an abrupt change in intracellular potential (φ_i). Because the intracellular space is very small, φ_e is nearly uniform over the length of the myocyte and the membrane potential (V=φ_i -φ_e) is governed by the applied field φ_e . There is then a longitudinal gradient of membrane polarization which is the inverse of the gradient of extracellular potential. With an anodal (positive) pulse, for instance, the proximal portion of the myocyte is hyperpolarized and the distal portion is depolarized. Based on this principle acid considering the voltage-dependent activation/inactivation dynamics of the membrane, it is shown that a cathodal (negative) pulse is the most efficacious stimulus at diastolic potentials, an anodal current is preferable during the plateau phase of the action potential, and a biphasic pulse is optimal during the relative refractory phase. Thus a biphasic pulse would constitute the best choice for maximum efficacy at all phases of the action potential     

弱激光对神经细胞膜延迟整流钾通道电流特性的影响

利用波长650 nm,功率5 mW的半导体激光器照射急性分离的大鼠海马CA3区锥体神经细胞,应用全细胞膜片钳技术研究其延迟整流钾通道的电流特性。实验发现,弱激光对延迟整流钾电流IK有抑制作用,且抑制呈时间依赖性,5min激光抑制作用达到稳定,抑制百分比为34.54%±3.22%(统计样本数n=15);弱激光对IK的抑制作用还具有电压依赖性和可逆性,对照组、照射组和恢复组最大激活电流密度分别为429.78±41.40 pA/pF,283.26±39.62 pA/pF(n=10,t检验中P<0.01)和397.22±36.81 pA/pF(n=10,P>0.05);激光作用可显著地影响IK的激活过程,对照组和照射组半数激活电压分别为5.74±1.56 mV和20.98±8.85 mV(n=10,P<0.01),斜率因子分别为16.51±6.67 mV和17.44±5.19 mV(n=10,P>0.05)。结果表明,弱激光作用海马神经细胞可以改变其延迟整流钾通道特性,从而影响动作电位复极化过程,调节神经细胞的生理功能,有利于受损神经元的恢复和再生。     

对称迟后-超前校正的一体化设计方法

本文首先分析了一类迟后-超前校正环节的频率特性,严格证明了在半对数坐标系下,其幅频特性是轴对称的,其相频特性是中心对称的,进而将此类校正环节称为对称迟后-超前校正环节。在校正环节的参数满足一定条件下,本文指出：对称迟后-超前校正环节在超前环节作用的频段内,能提供正的相角和负的幅值。进一步,给出了该校正环节所能提供的近似最大相角和所对应频率,并给出了在该频率点该校正环节的近似幅值。基于这些结论,给出了利用对称迟后-超前环节进行校正的两种一体化设计方法。     

The action potential clamp as a test of space-clamp effectiveness--the Lettvin analog axon

For a Lettvin analog axon, in which spurious currents due to inadequate space clamp are absent, the action potential clamp technique accurately reproduces the original stimulating current. The action potential generated for the first phase of the experiment is stored digitally. When this action potential waveform is used for the voltage clamp phase of the experiment, digital noise in the resultant current record is a factor of ten smaller than that of the reproduced current record. The requirement of rapid transition between the two experimental components for such experiments with squid giant axon is examined.     

Attojoule MOSFET logic devices using low voltage swings and low temperature

Previous estimates of the performance limits of MOSFET logic devices, including the possibility of low temperature operation, have used the conventional static electrical behavior as a starting point. Typically, such studies conclude that the minimum voltage swing is ～ 200 mV, leading to practical limits on power dissipation and switching speed that prohibit the combination of very low-power dissipation and very high speed achieved in Josephson junction logic. At such low voltages, the device behavior becomes very sensitive to fabrication, making high yields difficult. Here we consider the conditions which must be met to achieve high speed and low power VLSI logic devices through voltage swings ～ 25 mV. Dynamic logic through bulk conduction devices operating at T ? 30K represents the major requirements. At such low temperatures, nonequilibrium processes provide a new basis for device action, and a novel relaxation mode MOSFET operating under carrier freezeout conditions is suggested as a possible low-voltage swing logic switch with power-delay products in the attojoule range.     

A dual-mechanism solid-state carbon-monoxide and hydrogen sensor utilizing an ultrathin layer of palladium

Pd-gate MOS sensors were fabricated on p-type silicon wafers. The gate films were 25 and 40 Å thick with an oxide thickness of 100 Å. Contacts were made to allow measurement of the MOS capacitance and of the impedance across the gate film. Voltage shifts in the MOS C-V curves and shifts in the Pd film impedance were measured as functions of 1) the concentration of CO and H2; 2) time as the gas ambient was varied. The devices showed sensitivity to H2at room temperature and to CO and H2at elevated temperatures. When the 25-Å device was exposed to 300 ppm H2in air at room temperature, the C-V curve shifted by -430 mV and the impedance decreased by 20 ω or 5 percent. When the 25-Å device was exposed to 5000 ppm CO in air at 150°C, the C-V curve shifted - 200 mV and the impedance decreased by 140 ω (10 percent). When exposed to 0.1-percent H2in argon, the resistance of the 40-Å device increased by about 2 percent. When measured as a function of time, the changes in MOS capacitance tend to track the changes in impedance. An effect similar to hydrogen-induced drift (HID) was observed for CO at elevated temperature.