Phase resetting and bifurcation in the ventricular myocardium.

With the dynamic differential equations of Beeler, G. W., and H. Reuter (1977, J. Physiol. [Lond.]. 268:177-210), we have studied the oscillatory behavior of the ventricular muscle fiber stimulated by a depolarizing applied current I app. The dynamic solutions of BR equations revealed that as I app increases, a periodic repetitive spiking mode appears above the subthreshold I app, which transforms to a periodic spiking-bursting mode of oscillations, and finally to chaos near the suprathreshold I app (i.e., near the termination of the periodic state). Phase resetting and annihilation of repetitive firing in the ventricular myocardium were demonstrated by a brief current pulse of the proper magnitude applied at the proper phase. These phenomena were further examined by a bifurcation analysis. A bifurcation diagram constructed as a function of I app revealed the existence of a stable periodic solution for a certain range of current values. Two Hopf bifurcation points exist in the solution, one just above the lower periodic limit point and the other substantially below the upper periodic limit point. Between each periodic limit point and the Hopf bifurcation, the cell exhibited the coexistence of two different stable modes of operation; the oscillatory repetitive firing state and the time-independent steady state. As in the Hodgkin-Huxley case, there was a low amplitude unstable periodic state, which separates the domain of the stable periodic state from the stable steady state. Thus, in support of the dynamic perturbation methods, the bifurcation diagram of the BR equation predicts the region where instantaneous perturbations, such as brief current pulses, can send the stable repetitive rhythmic state into the stable steady state.     

Digital Computer Solutions for Excitation and Propagation of the Nerve Impulse

The Hodgkin-Huxley model of the nerve axon describes excitation and propagation of the nerve impulse by means of a nonlinear partial differential equation. This equation relates the conservation of the electric current along the cablelike structure of the axon to the active processes represented by a system of three rate equations for the transport of ions through the nerve membrane. These equations have been integrated numerically with respect to both distance and time for boundary conditions corresponding to a finite length of squid axon stimulated intracellularly at its midpoint. Computations were made for the threshold strength-duration curve and for the repetitive firing of propagated impulses in response to a maintained stimulus. These results are compared with previous solutions for the space-clamped axon. The effect of temperature on the threshold intensity for a short stimulus and for rheobase was determined for a series of values of temperature. Other computations show that a highly unstable subthreshold propagating wave is initiated in principle by a just threshold stimulus; that the stability of the subthreshold wave can be enhanced by reducing the excitability of the axon as with an anesthetic agent, perhaps to the point where it might be observed experimentally; but that with a somewhat greater degree of narcotization, the axon gives only decrementally propagated impulses.     

Derivation of cable parameters for a reduced model that retains asymmetric voltage attenuation of reconstructed spinal motor neuron dendrites

Spinal motor neurons have voltage gated ion channels localized in their dendrites that generate plateau potentials. The physical separation of ion channels for spiking from plateau generating channels can result in nonlinear bistable firing patterns. The physical separation and geometry of the dendrites results in asymmetric coupling between dendrites and soma that has not been addressed in reduced models of nonlinear phenomena in motor neurons. We measured voltage attenuation properties of six anatomically reconstructed and type-identified cat spinal motor neurons to characterize asymmetric coupling between the dendrites and soma. We showed that the voltage attenuation at any distance from the soma was direction-dependent and could be described as a function of the input resistance at the soma. An analytical solution for the lumped cable parameters in a two-compartment model was derived based on this finding. This is the first two-compartment modeling approach that directly derived lumped cable parameters from the geometrical and passive electrical properties of anatomically reconstructed neurons.     

Null space in the Hodgkin-Huxley Equations. A critical test.

Voltage perturbation methods based upon topological concepts are used to elicit responses from the Hodgkin-Huxley (HH) nonlinear differential equations. These responses present a critical check upon the validity of the HH model for electrical activity across squid axon membrane. It is shown that when a constant current is applied such that a stable equilibrium and rhythmic firing are present, the following predictions are inherent in the HH system of equations: (a) Small instantaneous voltage perturbations to the axon given at points along its firing spike result in phase resetting curves (when new phase versus old phase is plotted) with an average slope of 1. (b) A larger voltage perturbation (from certain points along the firing spike) results in the permanent cessation of periodic firing, with membrane voltage rapidly approaching the equilibrium value. (c) A still larger perturbation yields phase resetting curves with an average slope equal to 0. These predictions, coupled with Tasaki's experimental demonstration that squid axons in excellent condition do give repetitive firing under constant current, provide a critical test of the validity of the HH model.     

The interspike interval of a cable model neuron with white noise input

The firing time of a cable model neuron in response to white noise current injection is investigated with various methods. The Fourier decomposition of the depolarization leads to partial differential equations for the moments of the firing time. These are solved by perturbation and numerical methods, and the results obtained are in excellent agreement with those obtained by Monte Carlo simulation. The convergence of the random Fourier series is found to be very slow for small times so that when the firing time is small it is more efficient to simulate the solution of the stochastic cable equation directly using the two different representations of the Green's function, one which converges rapidly for small times and the other which converges rapidly for large times. The shape of the interspike interval density is found to depend strongly on input position. The various shapes obtained for different input positions resemble those for real neurons. The coefficient of variation of the interspike interval decreases monotonically as the distance between the input and trigger zone increases. A diffusion approximation for a nerve cell receiving Poisson input is considered and input/output frequency relations obtained for different input sites. The cases of multiple trigger zones and multiple input sites are briefly discussed.     

A cable model for coupled neurons with somatic gap junctions

A cable model is presented for a pair of electrotonically coupled neurons to investigate the spatial effects of soma-somatic gap junctions. The model extends that of Poznanski et al.(1995) in which each neuron is represented by a tapered equivalent cable attached to an isopotential soma with the two somas being electrically coupled. The model is posed generally, so that both active and passive properties can be considered. In the active case a system of nonlinear integral equations is derived for the voltage, whilst in the passive case these have an exact solution that also holds for inputs modelled as synaptic reversal potentials. Analytical and numerical methods are used to examine the sensitivity of the soma potentials (in particular) to the coupling resistance.     

Phase locking,period doubling bifurcations and chaos in a mathematical model of a periodically driven oscillator: A theory for the entrainment of biological oscillators and the generation of cardiac dysrhythmias

A mathematical model for the perturbation of a biological oscillator by single and periodic impulses is analyzed. In response to a single stimulus the phase of the oscillator is changed. If the new phase following a stimulus is plotted against the old phase the resulting curve is called the phase transition curve or PTC (Pavlidis, 1973). There are two qualitatively different types of phase resetting. Using the terminology of Winfree (1977, 1980), large perturbations give a type 0 PTC (average slope of the PTC equals zero), whereas small perturbations give a type 1 PTC. The effects of periodic inputs can be analyzed by using the PTC to construct the Poincaré or phase advance map. Over a limited range of stimulation frequency and amplitude, the Poincaré map can be reduced to an interval map possessing a single maximum. Over this range there are period doubling bifurcations as well as chaotic dynamics. Numerical and analytical studies of the Poincaré map show that both phase locked and non-phase locked dynamics occur. We propose that cardiac dysrhythmias may arise from desynchronization of two or more spontaneously oscillating regions of the heart. This hypothesis serves to account for the various forms of atrioventricular (AV) block clinically observed. In particular 22 and 42 AV block can arise by period doubling bifurcations, and intermittent or variable AV block may be due to the complex irregular behavior associated with chaotic dynamics.     

Diffusion approximation and first passage time problem for a model neuron

A diffusion equation for the transition p.d.f. describing the time evolution of the membrane potential for a model neuron, subjected to a Poisson input, is obtained, without breaking up the continuity of the underlying random function. The transition p.d.f. is calculated in a closed form and the average firing interval is determined by using the steady-state limiting expression of the transition p.d.f. The Laplace transform of the first passage time p.d.f. is then obtained in terms of Parabolic Cylinder Functions as solution of a Weber equation, satisfying suitable boundary conditions. A continuous input model is finally investigated.     

Analytical solution of the cable equation with synaptic reversal potentials for passive neurons with tip-to-tip dendrodendritic coupling

A passive cable model is presented for a pair of electrotonically coupled neurons in order to investigate the effects of tip-to-tip dendrodendritic gap junctions on the interaction between excitation and either pre or postsynaptic inhibition. The model represents each dendritic tree by a tapered equivalent cylinder attached to an isopotential soma. Analytical solution of the cable equation with synaptic reversal potentials is considered for each neuron to yield a system of Volterra integral equations for the voltage. The solution to the system of linear integral equations (expressed as a Neumann series) is used to determine the current spread within the two coupled neurons, and to re-examine the sensitivity of the soma potentials (in particular) to the coupling resistance for various loci of synaptic inputs. The model is actually posed generally, so that active as well as passive properties could be considered. In the active case, a system of non-linear integral equations is derived for the voltage.     

Spatio-temporal patterns in a mechanical model for mesenchymal morphogenesis

We present an in-depth study of spatio-temporal patterns in a simplified version of a mechanical model for pattern formation in mesenchymal morphogenesis. We briefly motivate the derivation of the model and show how to choose realistic boundary conditions to make the system well-posed. We firstly consider one-dimensional patterns and carry out a nonlinear perturbation analysis for the case where the uniform steady state is linearly unstable to a single mode. In two-dimensions, we show that if the displacement field in the model is represented as a sum of orthogonal parts, then the model can be decomposed into two sub-models, only one of which is capable of generating pattern. We thus focus on this particular sub-model. We present a nonlinear analysis of spatio-temporal patterns exhibited by the sub-model on a square domain and discuss mode interaction. Our analysis shows that when a two-dimensional mode number admits two or more degenerate mode pairs, the solution of the full nonlinear system of partial differential equations is a mixed mode solution in which all the degenerate mode pairs are represented in a frequency locked oscillation.     

Study of Oscillations in a Particular Case of Yates-Pardee-Goodwin Metabolic Pathway with Coupling

The aim of this work is to study the effect of coupling on a metabolic pathway. Specifically we assume that metabolites can exchange matter with outside pools via passive diffusion. The existence of periodic solutions in such a system is considered and resolved using the dual input describing function method. In one particular case of coupling for all permissible parameter sets the minimum dimension is given so that it is possible to detect a periodic solution. The results obtained are compared with previously derived results for systems without coupling. It is concluded that coupling with exterior pools of metabolites can give rise to steady state instead of periodic solution.     

Interaction of peristaltic flow with pulsatile flow in a circular cylindrical tube

The effect of pulsatile flow on peristaltic transport in a circular cylindrical tube is analysed. The flow of a Newtonian viscous incompressible fluid in a flexible circular cylindrical tube on which an axisymmetric travelling sinusoidal wave is imposed, is considered. The initial flow in the tube is induced by an arbitrary periodic pressure gradient. A perturbation solution with amplitude ratio (wave amplitude/tube radius) as a parameter is obtained when the frequency of the travelling wave and that of the imposed pressure gradient are equal. The interaction effects of periodic wall induced flow and periodic pressure imposed flow are visualized through the presence of substantially different components of steady and higher harmonic oscillating flow in the first order flow solution. Numerical results show a strong variation of steady state velocity profiles with boundary wave number and Reynolds number and a strong phase shift behaviour of the flow in the radial direction.     

Random currents through nerve membranes

The linear cable equation with uniform Poisson or white noise input current is employed as a model for the voltage across the membrane of a onedimensional nerve cylinder, which may sometimes represent the dendritic tree of a nerve cell. From the Green's function representation of the solutions, the mean, variance and covariance of the voltage are found. At large times, the voltage becomes asymptotically wide-sense stationary and we find the spectral density functions for various cable lengths and boundary conditions. For large frequencies the voltage exhibits “1/f ^3/2 noise”. Using the Fourier series representation of the voltage we study the moments of the firing times for the diffusion model with numerical techniques, employing a simplified threshold criterion. We also simulate the solution of the stochastic cable equation by two different methods in order to estimate the moments and density of the firing time.     

Control of multistability in ring circuits of oscillators

The essential dynamics of some biological central pattern generators (CPGs) can be captured by a model consisting of N neurons connected in a ring. These circuits, like many oscillatory nonlinear circuits of sufficient complexity, are capable of multistability, that is, of generating different firing patterns distinguished by the phasic relationships between the firing in each circuit element (neuron). Moreover, a shift in firing pattern can be induced by a transient perturbation. A systematic approach, based on phase-response curve (PRC) theory, was used to determine the optimum timing for perturbations that induce a shift in the firing pattern. The first step was to visualize the solution space of the ring circuit, including the attractive basins for each stable firing pattern; this was possible using the relative phase of N−1 oscillators, with respect to an arbitrarily selected reference oscillator, as coordinate axes. The trajectories in this phase space were determined using an iterative mapping based only on the PRCs of the uncoupled component oscillators; this algorithm was called a circuit emulator. For an accurate mapping of the attractive basin of each pattern exhibited by the ring circuit, the emulator had to take into account the effect of a perturbation or input on the timing of two bursts following the onset of the perturbation, rather than just one. The visualization of the attractive basins for rings of two, three, and four oscillators enabled the accurate prediction of the amounts of phase resetting applied to up to N−1 oscillators within a cycle that would induce a transition from any pattern to any another pattern. Finally, the timing and synaptic characterization of an input called the switch signal was adjusted to produce the desired amount of phase resetting. Received: 29 May 1998 / Accepted in revised form: 18 September 1998     

Viscous drag as the source of active site perturbation during protease translocation: insights into how inhibitory processes are controlled by serpin metastability

The native form of serine protease inhibitors (serpins) is kinetically trapped in a metastable state, which is thought to play a central role in the inhibitory mechanism. The initial binding complex between a serpin and a target protease undergoes a conformational change that forces the protease to translocate toward the opposite pole. Although structural determination of the final stable complex revealed a detailed mechanism of keeping the bound protease in an inactive conformation, it has remained unknown how the serpin exquisitely translocates a target protease with an acyl-linkage unhydrolyzed. We previously suggested that the acyl-linkage hydrolysis is strongly suppressed by active site perturbation during the protease translocation. Here, we address what induces the transient perturbation and how the serpin metastability contributes to the perturbation. Inhibitory activity of alpha1-antitrypsin (alpha1AT) toward elastase showed negative correlations with medium viscosity and Stokes radius of elastase moiety, indicating that viscous drag directly affects the protease translocation. Stopped-flow measurements revealed that the change in the inhibitory activity is primarily caused by the change in the translocation rate. The native stability of alpha1AT cavity mutants showed a negative correlation with the translocation rate but a positive correlation with the acyl-linkage hydrolysis rate, suggesting that the two kinetic steps are not independent but closely related. The degree of active site perturbation was probed by amino acid nucleophiles, supporting the view that the changes in the acyl-linkage hydrolysis rate are due to different perturbation states. These results suggest that the active site perturbation is caused by local imbalance between a pulling force driving protease translocation and a counteracting viscous drag force. The structural architecture of serpin metastability seems to be designed to ensure the active site perturbation by providing a sufficient pulling force, so the undesirable hydrolytic activity of protease is strongly suppressed during the translocation.     

Temporal oscillations in neuronal nets

Summary A model for the interactions of cortical neurons is derived and analyzed. It is shown that small amplitude spatially inhomogeneous standing oscillations can bifurcate from the rest state. In a periodic domain, traveling wave trains exist. Stability of these patterns is discussed in terms of biological parameters. Homoclinic and heteroclinic orbits are demonstrated for the space-clamped system.The research reported in this paper was supported in part by NIH GM2037     

Pulse coupled oscillators and the phase resetting curve

Limit cycle oscillators that are coupled in a pulsatile manner are referred to as pulse coupled oscillators. In these oscillators, the interactions take the form of brief pulses such that the effect of one input dies out before the next is received. A phase resetting curve (PRC) keeps track of how much an input advances or delays the next spike in an oscillatory neuron depending upon where in the cycle the input is applied. PRCs can be used to predict phase locking in networks of pulse coupled oscillators. In some studies of pulse coupled oscillators, a specific form is assumed for the interactions between oscillators, but a more general approach is to formulate the problem assuming a PRC that is generated using a perturbation that approximates the input received in the real biological network. In general, this approach requires that circuit architecture and a specific firing pattern be assumed. This allows the construction of discrete maps from one event to the next. The fixed points of these maps correspond to periodic firing modes and are easier to locate and analyze for stability compared to locating and analyzing periodic modes in the original network directly. Alternatively, maps based on the PRC have been constructed that do not presuppose a firing order. Specific circuits that have been analyzed under the assumption of pulsatile coupling include one to one lockings in a periodically forced oscillator or an oscillator forced at a fixed delay after a threshold event, two bidirectionally coupled oscillators with and without delays, a unidirectional N-ring of oscillators, and N all-to-all networks.     

The pause in firing of a primary muscle spindle at the transition between dynamic and static stretch: A mathematical model

A mathematical model to offer an explanation of the pause in firing of a primary muscle spindle at the transition between dynamic and static stretch is suggested. It is proposed that the firing frequency is proportional to a generator current at the site of the transduction (presumably the five terminal endings) and that the receptor potential is a version of this current filtered by the passive cable properties of the nerve between site of transduction and site of measurement.A mathematical expression is derived for the receptor potential from data in the literature. From this and an equivalent circuit of the nerve, an expression for the generator current is derived.This work was partially supported by National Institutes of Health Training Grant, Presbyterian-St. Luke's Hospital grant-in-aid and National Science Foundation. It was done in partial fulfillment of the requirements for the degree of Doctor of Philosophy (HBN) at the University of Illinois at the Medical Center.     

Asymmetric electrotonic coupling between the soma and dendrites alters the bistable firing behaviour of reduced models

The goal of the study was to investigate the influence of asymmetric coupling, between the soma and dendrites, on the nonlinear dynamic behaviour of a two-compartment model. We used a recently published method for generating reduced two-compartment models that retain the asymmetric coupling of anatomically reconstructed motor neurons. The passive input-output relationship of the asymmetrically coupled model was analytically compared to the symmetrically coupled case. Predictions based on the analytic comparison were tested using numerical simulations. The simulations evaluated the nonlinear dynamics of the models as a function of coupling parameters. Analytical results showed that the input resistance at the dendrite of the asymmetric model was directly related to the degree of coupling asymmetry. In contrast, a comparable symmetric model had identical input resistances at both the soma and dendrite regardless of coupling strength. These findings lead to predictions that variations in dendritic excitability, subsequent to changes in input resistance, might change the current threshold and onset timing of the plateau potential generated in the dendrite. Since the plateau potential underlies bistable firing, these results further predicted that asymmetric coupling might alter nonlinear (i.e. bistable) firing patterns. The numerical simulations supported analytical predictions, showing that the fully bistable firing pattern of the asymmetric model depended on the degree of coupling asymmetry and its correlated dendritic excitability. The physiological property of asymmetric coupling plays an important role in generating and stabilizing the bistability of motor neurons by interacting with the excitability of dendritic branches.     

Anti-control of periodic firing in HR model in the aspects of position,amplitude and frequency

This paper proposes a novel controller to control position, amplitude and frequency of periodic firing activity in Hindmarsh–Rose model based on Hopf bifurcation theory which is composed of linear control gain and nonlinear control gain. First, we select the activation of the fast ion channel as control parameter. Based on explicit criterion of Hopf bifurcation, a series of conditions are obtained to derive the linear gains of controller responsible for control of the location where the periodic firing activity occurs. Then, based on the control parameter, a series of conditions are obtained to derive the nonlinear gains of controller responsible for controlling the amplitude and frequency of periodic firing activity by using center manifold and normal form. Finally, the numerical experiments show that our controller can make the periodic firing activity occur at designed value and control the amplitude and frequency of periodic firing activity by adjusting nonlinear control gain of controller.