Chronaxie Time Research Articles

Selective neural stimulation by leveraging electrophysiological differentiation and using pre-pulsing and non-rectangular waveforms.

Efforts on selective neural stimulation have concentrated on segregating axons based on their size and geometry. Nonetheless, axons of the white matter or peripheral nerves may also differ in their electrophysiological properties. The primary objective of this study was to investigate the possibility of selective activation of axons by leveraging an assumed level of diversity in passive (Cm & Gleak) and active membrane properties (Ktemp & Gnamax). First, the stimulus waveforms with hyperpolarizing (HPP) and depolarizing pre-pulsing (DPP) were tested on selectivity in a local membrane model. The default value of membrane capacitance (Cm) was found to play a critical role in sensitivity of the chronaxie time (Chr) and rheobase (Rhe) to variations of all the four membrane parameters. Decreasing the default value of Cm, and thus the passive time constant of the membrane, amplified the sensitivity to the active parameters, Ktemp and GNamax, on Chr. The HPP waveform could selectively activate neurons even if they were diversified by membrane leakage (Gleak) only, and produced higher selectivity than DPP when parameters are varied in pairs. Selectivity measures were larger when the passive parameters (Cm & Gleak) were varied together, compared to the active parameters. Second, this novel mechanism of selectivity was investigated with non-rectangular waveforms for the stimulating phase (and HPP) in the same local membrane model. Simulation results suggest that Kt2 is the most selective waveform followed by Linear and Gaussian waveforms. Traditional rectangular pulse was among the least selective of all. Finally, a compartmental axon model confirmed the main findings of the local model that Kt2 is the most selective, but rank ordered the other waveforms differently. These results suggest a potentially novel mechanism of stimulation selectivity, leveraging electrophysiological variations in membrane properties, that can lead to various neural prosthetic applications.

P6547The energy cost of His bundle pacing can be curtailed

Abstract Introduction His bundle pacing (HBP) allows physiological ventricular activation and prevents the electrical and mechanical desynchronization generally induced by myocardial stimulation, which can increase the risk of atrial fibrillation and heart failure. On the other hand, reliable HBP capture often requires higher energy than conventional myocardial pacing. This reduces the expected life of the stimulator and might limit the diffusion of HBP in the clinical practice. Purpose Decreasing HBP current drain by careful management of stimulation safety margin and pulse duration. Methods In 28 patients undergoing DDD pacing with HBP, a third lead was implanted in RV apex to provide back-up pacing on demand. HBP and apical leads were connected, respectively, to the V1 and V2 channels of a 3-chamber stimulator. When HBP was effective, apical sensing occurred within the VV delay and prevented V2 stimulation. In contrast, in case of HBP failure, V2 sensing was missing and apical back-up pacing was promptly delivered at the end of the VV delay. The availability of a back-up pulse on demand allowed reducing the HBP safety margin with no risk. Furthermore, the individual HBP strength-duration curve was derived in the aim of optimizing the Hisian pulse parameters, which are the major determinants of the device current drain. Results Correct back-up inhibition by successful HBP and stimulation in the event of capture loss was achieved in all the patients. The latency from Hisian pacing to apical sensing averaged 96±14 ms. According to the pacemaker counters, no back-up pulse was delivered in daily life in 59% of patients. In the remaining, the prevalence of back-up stimulation never exceeded 15% of paced ventricular cycles. The high HBP threshold was essentially due to an increased rheobase (1.2±0.6 V), while the chronaxie ranged from 0.30 to 0.53 ms in 71% of patients (median 0.44 ms), exceeding 0.6 ms only in 29% of the cases. An average current saving of 5.4±3.0 μA was obtained at the expense of a mild reduction in HBP safety margin (from 1.6±0.2 to 1.4±0.1 times). HBP and apical back-up Conclusions Back-up stimulation on demand is a reliable option to decrease HBP current drain and prolong the stimulator service life with full safety. In most of the cases, significant saving can be achieved by pulse shortening, as the chronaxie time is in the same range as with myocardial stimulation and longer pulses are not required. A pulse duration exceeding 0.6 ms is indicated in less than 1/3 of the implants.

Field evoked potentials in the globus pallidus of non-human primates

Stimulation-induced field evoked potentials (fEPs) have been described in the basal ganglia output nuclei of patients with Parkinson’s disease and dystonia. The aim of this study was to ascertain whether fEPs were inducible in the external (GPe) and internal (GPi) segments of the globus pallidus in normal non-human primates (NHPs). Microelectrode recording and stimulation was performed in the GPe and GPi of 2 healthy NHPs. Stimulus response curves of the fEP response to changing pulse width and amplitude examined strength-duration relationships and allowed for calculation of fEP chronaxie in the GPe and GPi. Traditional localization techniques were also used, including comparison of neuronal firing rates, optic tract activation, and internal capsule activation. Notable differences were seen in the fEPs found in GPe compared to the fEPs found in GPi. The GPe fEP had a smaller chronaxie time and larger positive deflection amplitude compared to GPi. In addition, an earlier negative deflection was identified in both nuclei and a late negative deflection was observed in the GPe in contrast to reported fEPs in patients with movement disorders. fEPs proved valuable as an ancillary method in localizing the GPe and GPi in NHPs and may be useful in the operating room during human GPi deep brain stimulation or pallidotomy procedures.

Magnetostimulation Limits in Magnetic Particle Imaging

For magnetic particle imaging (MPI), specific absorption rate (SAR) and more critically magnetostimulation (i.e., dB/dt) safety limits will determine the optimal scan parameters, such as the drive field strength and frequency. These parameters will impact the scanning speed, field-of-view (FOV) and signal-to-noise ratio in MPI. Understanding the potential safety hazards of the drive field is critical for scaling MPI for human use. In this work, we demonstrate that magnetostimulation is the primary magnetic safety consideration in MPI, and we describe the first human-subject magnetostimulation threshold experiments for MPI using homogeneous coils. Our experiments, performed on the arm and leg, indicate that magnetostimulation thresholds monotonically decrease with increasing frequency. Additionally, we show for the first time that a strong inverse correlation exists between the threshold and the body part size. The chronaxie time, on the other hand, did not vary with body part size. We conclude with an estimation of the magnetostimulation thresholds for a full-body MPI scanner: a mean asymptotic threshold of 14.3 mT-pp (peak-to-peak) with a mean chronaxie time of 289 μs, which correspond to a magnetostimulation threshold of about 15 mT-pp for frequencies between 25 and 50 kHz. These findings will have a great impact on the optimization of MPI parameters, especially in determining the number of partial FOVs required to cover a region of interest.

Chronic Augmentation of the Parasympathetic Tone to the Atrioventricular Node: A Nonthoracotomy Neurostimulation Technique for Ventricular Rate Control During Atrial Fibrillation

The right inferior ganglionated plexus (RIGP) selectively innervates the atrioventricular node. Temporary electrical stimulation of this plexus reduces the ventricular rate during atrial fibrillation (AF). We sought to assess the feasibility of chronic parasympathetic stimulation for ventricular rate control during AF with a nonthoracotomy intracardiac neurostimulation approach. In 9 mongrel dogs, the small endocardial area inside the right atrium, which overlies the RIGP, was identified by 20 Hz stimulation over a guiding catheter with integrated electrodes. Once identified, an active-fixation lead was implanted. The lead was connected to a subcutaneous neurostimulator. An additional dual-chamber pacemaker was implanted for AF induction by rapid atrial pacing and ventricular rate monitoring. Continuous neurostimulation was delivered for 1-2 years to decrease the ventricular rate during AF to a range of 100-140 bpm. Implantation of a neurostimulation lead was achieved within 37 +/- 12 min. The latency of the negative dromotropic response after on/offset or modulation of neurostimulation was <1 s. Continuous neurostimulation was effective and well tolerated during a 1-2 year follow-up with a stimulation voltage <5 V. The neurostimulation effect displayed a chronaxie-rheobase behavior (chronaxie time of 0.07 +/- 0.02 ms for a 50% decrease of the ventricular rate during AF). Chronic parasympathetic stimulation can be achieved via a cardiac neurostimulator. The approach is safe, effective, and well tolerated in the long term. The atrioventricular nodal selectivity and the opportunity to adjust the negative dromotropic effect within seconds may represent an advantage over pharmacological rate control.

Super-selective electrical stimulation of the left ventricle via a miniaturized magnetized stimulation wire: proof of concept study

Cardiac resynchronization therapy provides a treatment option for patients with congestive heart failure. Electrodes are usually advanced via the cardiac venous system (CVS). Placement is often hampered by small vessel diameter or tortuosity. The aim of this study was to develop and test a magnetized stimulation wire (MSW) capable of being navigated into small and tortuous CVS branches. Therefore, a conventional guide wire with a permanent magnet and a single stimulation electrode at its tip was coated with iridium oxide at the distal end and insulated except for the very tip (coating thickness: 500 nm, active uncoated area: 10 mm(2)). The MSW was designed to allow for a remote magnetic steering using a magnetic navigation system (MN) (Stereotaxis™). After in vitro testing of the electrical properties, the MSW was tested in an animal model (n=6 sheep): the MSW was placed in a CVS side branch and navigation characteristics of the MSW were determined. The effective (unipolar) pacing threshold was 4.9±2.4 V (at 2 ms pulse width). The rheobase was 1.89±0.44 V and the chronaxie time was 0.75±0.7 ms. The MSW could be navigated into small CVS branches with reasonable MN properties. This could allow stimulation at CVS sites currently not accessible for conventional stimulation catheters or electrodes.

Modelled temperature-dependent excitability behaviour of a single ranvier node for a human peripheral sensory nerve fibre

The objective of this study was to determine whether the Hodgkin-Huxley model for unmyelinated nerve fibres could be modified to predict excitability behaviour at Ranvier nodes. Only the model parameters were modified to those of human, with the equations left unaltered. A model of a single Ranvier node has been developed as part of a larger model to describe excitation behaviour in a generalised human peripheral sensory nerve fibre. Parameter values describing the ionic and leakage conductances, corresponding equilibrium potentials, resting membrane potential and membrane capacitance of the original Hodgkin-Huxley model were modified to reflect the corresponding parameter values for human. Parameter temperature dependence was included. The fast activating potassium current kinetics were slowed down to represent those of a slow activating and deactivating potassium current, which do not inactivate. All calculations were performed in MATLAB. Action potential shape and amplitude were satisfactorily predicted at 20, 25 and 37 degrees C, and were not influenced by activation or deactivation of the slow potassium current. The calculated chronaxie time constant was 65.5 micros at 37 degrees C. However, chronaxie times were overestimated at temperatures lower than body temperature.

Non-rectangular waveforms for neural stimulation with practical electrodes

Historically the rectangular pulse waveform has been the choice for neural stimulation. The strength–duration curve is thus defined for rectangular pulses. Not much attention has been paid to alternative waveforms to determine if the pulse shape has an effect on the strength–duration relation. Similarly the charge injection capacity of neural electrodes has also been measured with rectangular pulses. In this study we questioned if non-rectangular waveforms can generate a stronger stimulation effect, when applied through practical electrodes, by minimizing the neural activation threshold and maximizing the charge injection capacity of the electrode. First, the activation threshold parameters were studied with seven different pulse shapes using computer simulations of a local membrane model. These waveforms were rectangular, linear increase and decrease, exponential increase and decrease, Gaussian, and sinusoidal. The chronaxie time was found to be longer with all the non-rectangular pulses and some provided more energy efficient stimulation than the rectangular waveform. Second, the charge injection capacity of titanium nitride microelectrodes was measured experimentally for the same waveforms. Linearly decreasing ramp provided the best charge injection for all pulse widths tested from 0.02 to 0.5 ms. Finally, the most efficient waveform that maximized the charge injection capacity of the electrode while providing the lowest threshold charge for neural activation was searched. Linear and exponential decrease, and Gaussian waveforms were found to be the most efficient pulse shapes.

Determinants and Effects of Electrical Stimulation of the Inferior Interatrial Parasympathetic Plexus During Atrial Fibrillation

Catheter stimulation of the inferior interatrial ganglionated parasympathetic plexus decreases the ventricular rate during atrial fibrillation (AF) in humans. However, the relatively high stimulation voltages might prevent implementation of neurostimulation in chronic implantable devices. From myocardial electrostimulation it is known that the required impulse energy and charge is lowest at the chronaxie time. In order to lower energy requirements for cardiac neurostimulation, the present study evaluates the impulse-strength versus impulse-duration relationship for a neurostimulation lead that was implanted into the inferior interatrial ganglionated plexus. In nine dogs, permanent epicardial bipolar screw-in electrodes were fixed in the inferior interatrial ganglionated plexus. AF was maintained via rapid atrial pacing. During AF, neural stimulation was performed at various frequencies (1-100 Hz), impulse durations (0.05-2 msec), and voltages (0.02-11.5 V). There was a linear correlation between R-R interval lengthening and stimulus voltage (R = 0.99; P < 0.001) and a bell-shaped relationship between stimulation frequency and negative dromotropic effect with maximum rate slowing at 30-50 Hz. The rheobase for a 50% R-R interval prolongation during AF was 1.81 V and 2.72 V for high-grade AVB yielding a chronaxie time of 0.14 msec and 0.18 msec, respectively. The impulse energy (charge) at the chronaxie time was 4-6 microJ (6-8 microC). Cardiac neurostimulation follows a chronaxie/rheobase behavior. Energy, charge, and voltage values needed to achieve significant negative dromotropic effects are within the limits of conventional cardiac pacemaker outputs, which may allow implementation of neurostimulation capabilities in current pacemaker technology.

Simple linear formulation for magnetostimulation specific to MRI gradient coils.

A simple linear formulation for magnetostimulation thresholds specific to MRI gradient coils is derived based on established hyperbolic electrostimulation strength vs. duration relations. Thresholds are derived in terms of the gradient excursion required to cause stimulation, and it is demonstrated that the threshold curve is a linear function of the gradient switching time. A parameter beta is introduced as being fundamental in the evaluation of gradient coil stimulation. beta is a map of the induced electric field per unit gradient slew rate, and can be calculated directly from the gradient coil wire pattern. Consideration of beta alone is sufficient to compare stimulation thresholds between different gradient coil designs, as well as to evaluate the expected dependency of stimulation threshold on position within the gradient coil. The linear gradient threshold curve is characterized by two parameters: SR(min) and DeltaG(min). SR(min) is the slope of the threshold curve and represents the minimum slew rate required to cause stimulation in the limit of infinite gradient strength. DeltaG(min) is the vertical axis intercept of the curve and represents the minimum gradient excursion required to cause stimulation in the limit of infinite slew rate. Both SR(min) and DeltaG(min) are functions of both beta and the standard tissue parameters E(r) (rheobase) and tau(c) (chronaxie time). The ease with which both the gradient system performance and the stimulation thresholds can be plotted on the same axes is noted and is used to introduce the concept of a piece-wise linear operational limit curve for a gradient system.

Modelling the effects of electric fields on nerve fibres: Influence of the myelin sheath

The excitation and conduction properties of computer-based cable models of mammalian motor nerve fibres, incorporating three different myelin representations, are compared. The three myelin representations are a perfectly insulating single cable (model A), a finite impedance single cable (model B) and a finite impedance double cable (model C). Extracellular stimulation of the three models is used to study their strength-duration and current-distance (I-X) relationships, conduction velocity (CV) and action potential shape. All three models have a chronaxie time that is within the experimental range. Models B and C have increased threshold currents compared with model A, but each model has slope to the I-X relationship that matches experimental results. Model B has a CV that matches experimental data, whereas the CV of models A and C are above and below the experimental range, respectively. Model C is able to produce a depolarising afterpotential (DAP), whereas models A and B exhibit hyperpolarising afterpotentials. Models A and B are determined to be the preferred models when low-frequency stimulation (< approximately 25 Hz) is used, owing to their efficiency and accurate excitation and conduction properties. For high frequency stimulation (approximately 25 Hz and greater), model C, with its ability to produce a DAP, is necessary accurately to simulate excitation behaviour.

Sensitivity analysis of a model of mammalian neural membrane.

The sensitivity of the strength-duration (S-D) relationship to changes in the parameters describing the sodium channel of mammalian neuronal membrane was determined by computer simulation. A space-clamped patch of neuronal membrane was modeled by a parallel nonlinear sodium conductance, linear leakage conductance, and membrane capacitance. Each parameter that governs the activation (m) and inactivation (h) variables of the sodium channel was varied from -50% to +50% of its default value, and for each variation a S-D relationship was generated. Individual changes in six of the eleven parameters (alpha mA, alpha mD, alpha hA, beta mA, beta mB, and beta hB) generated substantial changes in the rheobase current and chronaxie time (Tch) of the model. Changing the parameter values individually did not correct for the model's failure to generate excitation after the release from a long duration hyperpolarization (anode break excitation). Scaling a combination of five parameters (alpha mA, alpha mB, alpha hA, beta mA, and beta hB) by an equal amount produced a model that generated anode break excitation and increased Tch, but also decreased the amplitude of the action potential. To reproduce the amplitude of the action potential, the maximum sodium conductance and sodium Nernst potential were increased. These modifications generated a model that had S-D properties closer to experimental results, could produce anode break excitation, and reproduced the action potential amplitude.

The Chronaxie Time and Its Practical Importance

Describing mathematically, the intensity duration curves of electrostimulation by hyperbolas, Lapicque introduced two terms which characterized the functional relationship: "Rheobase" was the lowest intensity with indefinite pulse duration which just stimulated muscles or nerves. "Chronaxie" was that pulse duration at which the threshold intensity was twice that of the rheobase. Up to now, both terms have never played an important role in cardiac pacing. However, it can be shown that the chronaxie, especially, is an important parameter--influenced by several factors such as electrode size, material, and stimulation mode--which may help match the generator to its electrode. Practical consequences may be derived from the concept of chronaxie: 1) A pulse duration longer than the chronaxie is not desirable because current consumption is increased without decreasing the threshold significantly. 2) Pacing with constant current needs twice that pulse duration of constant voltage stimulation. 3) Smaller electrodes are more favorable because the pulse duration they need may be reduced without losing safety. 4) Estimation of the safety margin with decreasing output of the generator or with programmable pulse duration is possible if the chronaxie of a specific electrode is known.

Note on the Correlation between Chronaxie and Reaction Time

Note on the Correlation between Chronaxie and Reaction Time