Strong symmetry breaking rhythms created by folded nodes in a pair of symmetrically coupled, identical Koper oscillators.

The Koper model is a prototype system with two slow variables and one fast variable that possesses small-amplitude oscillations (SAOs), large-amplitude oscillations (LAOs), and mixed-mode oscillations (MMOs). In this article, we study a pair of identical Koper oscillators that are symmetrically coupled. Strong symmetry breaking rhythms are presented of the types SAO-LAO, SAO-MMO, LAO-MMO, and MMO-MMO, in which the oscillators simultaneously exhibit rhythms of different types. We identify the key folded nodes that serve as the primary mechanisms responsible for the strong nature of the symmetry breaking. The maximal canards of these folded nodes guide the orbits through the neighborhoods of these key points. For all of the strong symmetry breaking rhythms we present, the rhythms exhibited by the two oscillators are separated by maximal canards in the phase space of the oscillator.

Symmetry-breaking rhythms in coupled, identical fast-slow oscillators.

Symmetry-breaking in coupled, identical, fast-slow systems produces a rich, dramatic variety of dynamical behavior-such as amplitudes and frequencies differing by an order of magnitude or more and qualitatively different rhythms between oscillators, corresponding to different functional states. We present a novel method for analyzing these systems. It identifies the key geometric structures responsible for this new symmetry-breaking, and it shows that many different types of symmetry-breaking rhythms arise robustly. We find symmetry-breaking rhythms in which one oscillator exhibits small-amplitude oscillations, while the other exhibits phase-shifted small-amplitude oscillations, large-amplitude oscillations, mixed-mode oscillations, or even undergoes an explosion of limit cycle canards. Two prototypical fast-slow systems illustrate the method: the van der Pol equation that describes electrical circuits and the Lengyel-Epstein model of chemical oscillators.

Canard analysis reveals why a large Ca2+ window current promotes early afterdepolarizations in cardiac myocytes.

The pumping of blood through the heart is due to a wave of muscle contractions that are in turn due to a wave of electrical activity initiated at the sinoatrial node. At the cellular level, this wave of electrical activity corresponds to the sequential excitation of electrically coupled cardiac cells. Under some conditions, the normally-long action potentials of cardiac cells are extended even further by small oscillations called early afterdepolarizations (EADs) that can occur either during the plateau phase or repolarizing phase of the action potential. Hence, cellular EADs have been implicated as a driver of potentially lethal cardiac arrhythmias. One of the major determinants of cellular EAD production and repolarization failure is the size of the overlap region between Ca2+ channel activation and inactivation, called the window region. In this article, we interpret the role of the window region in terms of the fast-slow structure of a low-dimensional model for ventricular action potential generation. We demonstrate that the effects of manipulation of the size of the window region can be understood from the point of view of canard theory. We use canard theory to explain why enlarging the size of the window region elicits EADs and why shrinking the window region can eliminate them. We also use the canard mechanism to explain why some manipulations in the size of the window region have a stronger influence on cellular electrical behavior than others. This dynamical viewpoint gives predictive power that is beyond that of the biophysical explanation alone while also uncovering a common mechanism for phenomena observed in experiments on both atrial and ventricular cardiac cells.

A new class of chimeras in locally coupled oscillators with small-amplitude, high-frequency asynchrony and large-amplitude, low-frequency synchrony.

Chimeras are surprising yet important states in which domains of decoherent (asynchronous) and coherent (synchronous) oscillations co-exist. In this article, we report on the discovery of a new class of chimeras, called mixed-amplitude chimera states, in which the structures, amplitudes, and frequencies of the oscillations differ substantially in the decoherent and coherent regions. These mixed-amplitude chimeras exhibit domains of decoherent small-amplitude oscillations (phase waves) coexisting with domains of stable and coherent large-amplitude or mixed-mode oscillations (MMOs). They are observed in a prototypical bistable partial differential equation with oscillatory dynamics, spatially homogeneous kinetics, and purely local, isotropic diffusion. They are observed in parameter regimes immediately adjacent to regimes in which common large-amplitude solutions exist, such as trigger waves, spatially homogeneous MMOs, and sharp-interface solutions. Also, key singularities, folded nodes, and folded saddles arising commonly in multi-scale, bistable systems play important roles, and these have not previously been studied in systems with chimeras. The discovery of these mixed-amplitude chimeras is an important advance for understanding some processes in neuroscience, pattern formation, and physics, which involve both small-amplitude and large-amplitude oscillations. It may also be of use for understanding some aspects of electroencephalogram recordings from animals that exhibit unihemispheric slow-wave sleep.

Fast-slow analysis of a stochastic mechanism for electrical bursting.

Electrical bursting oscillations in neurons and endocrine cells are activity patterns that facilitate the secretion of neurotransmitters and hormones and have been the focus of study for several decades. Mathematical modeling has been an extremely useful tool in this effort, and the use of fast-slow analysis has made it possible to understand bursting from a dynamic perspective and to make testable predictions about changes in system parameters or the cellular environment. It is typically the case that the electrical impulses that occur during the active phase of a burst are due to stable limit cycles in the fast subsystem of equations or, in the case of so-called "pseudo-plateau bursting," canards that are induced by a folded node singularity. In this article, we show an entirely different mechanism for bursting that relies on stochastic opening and closing of a key ion channel. We demonstrate, using fast-slow analysis, how the short-lived stochastic channel openings can yield a much longer response in which single action potentials are converted into bursts of action potentials. Without this stochastic element, the system is incapable of bursting. This mechanism can describe stochastic bursting in pituitary corticotrophs, which are small cells that exhibit a great deal of noise as well as other pituitary cells, such as lactotrophs and somatotrophs that exhibit noisy bursts of electrical activity.

Phantom bursting may underlie electrical bursting in single pancreatic ß-cells.

Insulin is secreted by pancreatic ß-cellsthat are electrically coupled into micro-organs called islets of Langerhans. The secretion is due to the influx of Ca2+ions that accompany electrical impulses, which are clustered into bursts. So-called "medium bursting" occurs in many ß-cellsin intact islets, while in other islets the ß-cellsexhibit "slow bursting", with a much longer period. Each burst brings in Ca2+ that, through exocytosis, results in insulin secretion. When isolated from an islet, ß-cellsbehave very differently. The electrical activity is much noisier, and consists primarily of trains of irregularly-timed spikes, or fast or slow bursting. Medium bursting, so often seen in intact islets, is rarely if ever observed. In this study, we examine what the isolated cell behavior can tell us about the mechanism for bursting in intact islets. A previous mathematical study concluded that the slow bursting observed in isolated ß-cells, and therefore most likely in islets, must be due to intrinsic glycolytic oscillations, since this mechanism for bursting is robust to noise. It was demonstrated that an alternate mechanism, phantom bursting, was very sensitive to noise, and therefore could not account for the slow bursting in single cells. We re-examine these conclusions, motivated by recent experimental and mathematical modeling evidence that slow bursting in intact islets is, at least in many cases, driven by the phantom bursting mechanism and not endogenous glycolytic oscillations. We employ two phantom bursting models, one minimal and the other more biophysical, to determine the sensitivity of medium and slow bursting to electrical current noise. In the minimal model, both forms of bursting are highly sensitive to noise. In the biophysical model, while medium bursting is sensitive to noise, slow bursting is much less sensitive. This suggests that the slow bursting seen in isolated ß-cellsmay be due to a phantom bursting mechanism, and by extension, slow bursting in intact islets may also be driven by this mechanism.

Transitions between bursting modes in the integrated oscillator model for pancreatic ß-cells.

Insulin-secreting ß-cells of pancreatic islets of Langerhans produce bursts of electrical impulses, resulting in intracellular Ca2+ oscillations and pulsatile insulin secretion. The mechanism for this bursting activity has been the focus of mathematical modeling for more than three decades, and as new data are acquired old models are modified and new models are developed. Comprehensive models must now account for the various modes of bursting observed in islet ß-cells, which include fast bursting, slow bursting, and compound bursting. One such model is the Integrated Oscillator Model (IOM), in which ß-cell electrical activity, intracellular Ca2+, and glucose metabolism interact via numerous feedforward and feedback pathways. These interactions can produce metabolic oscillations with a sawtooth time course or a pulsatile time course, reflecting very different oscillation mechanisms. In this report, we determine conditions favorable to one form of oscillations or the other, and examine the transitions between modes of bursting and the relationship of the transitions to the patterns of metabolic oscillations. Importantly, this work clarifies what can be expected in experimental measurements of ß-cell oscillatory activity, and suggests pathways through which oscillations of one type can be converted to oscillations of another type.

Delayed loss of stability due to the slow passage through Hopf bifurcations in reaction-diffusion equations.

This article presents the delayed loss of stability due to slow passage through Hopf bifurcations in reaction-diffusion equations with slowly-varying parameters, generalizing a well-known result about delayed Hopf bifurcations in analytic ordinary differential equations to spatially-extended systems. We focus on the Hodgkin-Huxley partial differential equation (PDE), the cubic Complex Ginzburg-Landau PDE as an equation in its own right, the Brusselator PDE, and a spatially-extended model of a pituitary clonal cell line. Solutions which are attracted to quasi-stationary states (QSS) sufficiently before the Hopf bifurcations remain near the QSS for long times after the states have become repelling, resulting in a significant delay in the loss of stability and the onset of oscillations. Moreover, the oscillations have large amplitude at onset, and may be spatially homogeneous or inhomogeneous. Space-time boundaries are identified that act as buffer curves beyond which solutions cannot remain near the repelling QSS, and hence before which the delayed onset of oscillations must occur, irrespective of initial conditions. In addition, a method is developed to derive the asymptotic formulas for the buffer curves, and the asymptotics agree well with the numerically observed onset in the Complex Ginzburg-Landau (CGL) equation. We also find that the first-onset sites act as a novel pulse generation mechanism for spatio-temporal oscillations.

Amplitude-Modulated Bursting: A Novel Class of Bursting Rhythms.

We report on the discovery of a novel class of bursting rhythms, called amplitude-modulated bursting (AMB), in a model for intracellular calcium dynamics. We find that these rhythms are robust and exist on open parameter sets. We develop a new mathematical framework with broad applicability to detect, classify, and rigorously analyze AMB. Here we illustrate this framework in the context of AMB in a model of intracellular calcium dynamics. In the process, we discover a novel family of singularities, called toral folded singularities, which are the organizing centers for the amplitude modulation and exist generically in slow-fast systems with two or more slow variables.

A geometric understanding of how fast activating potassium channels promote bursting in pituitary cells.

The electrical activity of endocrine pituitary cells is mediated by a plethora of ionic currents and establishing the role of a single channel type is difficult. Experimental observations have shown however that fast-activating voltage- and calcium-dependent potassium (BK) current tends to promote bursting in pituitary cells. This burst promoting effect requires fast activation of the BK current, otherwise it is inhibitory to bursting. In this work, we analyze a pituitary cell model in order to answer the question of why the BK activation must be fast to promote bursting. We also examine how the interplay between the activation rate and conductance of the BK current shapes the bursting activity. We use the multiple timescale structure of the model to our advantage and employ geometric singular perturbation theory to demonstrate the origin of the bursting behaviour. In particular, we show that the bursting can arise from either canard dynamics or slow passage through a dynamic Hopf bifurcation. We then compare our theoretical predictions with experimental data using the dynamic clamp technique and find that the data is consistent with a burst mechanism due to a slow passage through a Hopf.

Unsteady dynamics of a classical particle-wave entity.

A droplet bouncing on the surface of a vertically vibrating liquid bath can walk horizontally, guided by the waves it generates on each impact. This results in a self-propelled classical particle-wave entity. By using a one-dimensional theoretical pilot-wave model with a generalized wave form, we investigate the dynamics of this particle-wave entity. We employ different spatial wave forms to understand the role played by both wave oscillations and spatial wave decay in the walking dynamics. We observe steady walking motion as well as unsteady motions such as oscillating walking, self-trapped oscillations, and irregular walking. We explore the dynamical and statistical aspects of irregular walking and show an equivalence between the droplet dynamics and the Lorenz system, as well as making connections with the Langevin equation and deterministic diffusion.

Mixed mode oscillations as a mechanism for pseudo-plateau bursting.

We combine bifurcation analysis with the theory of canard-induced mixed mode oscillations to investigate the dynamics of a novel form of bursting. This bursting oscillation, which arises from a model of the electrical activity of a pituitary cell, is characterized by small impulses or spikes riding on top of an elevated voltage plateau. Oscillations with these characteristics have been called "pseudo-plateau bursting". Unlike standard bursting, the subsystem of fast variables does not possess a stable branch of periodic spiking solutions, and in the case studied here the standard fast/slow analysis provides little information about the underlying dynamics. We demonstrate that the bursting is actually a canard-induced mixed mode oscillation, and use canard theory to characterize the dynamics of the oscillation. We also use bifurcation analysis of the full system of equations to extend the results of the singular analysis to the physiological regime. This demonstrates that the combination of these two analysis techniques can be a powerful tool for understanding the pseudo-plateau bursting oscillations that arise in electrically excitable pituitary cells and isolated pancreatic beta-cells.

Why pacing frequency affects the production of early afterdepolarizations in cardiomyocytes: An explanation revealed by slow-fast analysis of a minimal model.

Early afterdepolarizations (EADs) are pathological voltage oscillations in cardiomyocytes that have been observed in response to a number of pharmacological agents and disease conditions. Phase-2 EADs consist of small voltage fluctuations during the plateau of an action potential, typically under conditions in which the action potential is elongated. Although a single-cell behavior, EADs can lead to tissue-level arrhythmias. Much is currently known about the biophysical mechanisms (i.e., the roles of ion channels and intracellular Ca^{2+} stores) for the various forms of EADs, due partially to the development and analysis of mathematical models. This includes the application of slow-fast analysis, which takes advantage of timescale separation inherent in the system to simplify its analysis. We take this further, using a minimal three-dimensional model to demonstrate that phase-2 EADs are canards formed in the neighborhood of a folded node singularity. This allows us to predict the number of EADs that can be produced for a given parameter set, and provides guidance on parameter changes that facilitate or inhibit EAD production. With this approach, we demonstrate why periodic stimulation, as occurs in intact heart, preferentially facilitates EAD production when applied at low frequencies. We also explain the origin of complex alternan dynamics that can occur with intermediate-frequency stimulation, in which varying numbers of EADs are produced with each pulse. These revelations fall out naturally from an understanding of folded node singularities, but are difficult to glean from knowledge of the biophysical mechanism for EADs alone. Therefore, understanding the canard mechanism is a useful complement to understanding of the biophysical mechanism that has been developed over years of experimental and computational investigations.

M-Current Expands the Range of Gamma Frequency Inputs to Which a Neuronal Target Entrains.

Theta (4-8 Hz) and gamma (30-80 Hz) rhythms in the brain are commonly associated with memory and learning (Kahana in J Neurosci 26:1669-1672, 2006; Quilichini et al. in J Neurosci 30:11128-11142, 2010). The precision of co-firing between neurons and incoming inputs is critical in these cognitive functions. We consider an inhibitory neuron model with M-current under forcing from gamma pulses and a sinusoidal current of theta frequency. The M-current has a long time constant (∼90 ms) and it has been shown to generate resonance at theta frequencies (Hutcheon and Yarom in Trends Neurosci 23:216-222, 2000; Hu et al. in J Physiol 545:783-805, 2002). We have found that this slow M-current contributes to the precise co-firing between the network and fast gamma pulses in the presence of a slow sinusoidal forcing. The M-current expands the phase-locking frequency range of the network, counteracts the slow theta forcing, and admits bistability in some parameter range. The effects of the M-current balancing the theta forcing are reduced if the sinusoidal current is faster than the theta frequency band. We characterize the dynamical mechanisms underlying the role of the M-current in enabling a network to be entrained to gamma frequency inputs using averaging methods, geometric singular perturbation theory, and bifurcation analysis.

The dynamics underlying pseudo-plateau bursting in a pituitary cell model.

Pituitary cells of the anterior pituitary gland secrete hormones in response to patterns of electrical activity. Several types of pituitary cells produce short bursts of electrical activity which are more effective than single spikes in evoking hormone release. These bursts, called pseudo-plateau bursts, are unlike bursts studied mathematically in neurons (plateau bursting) and the standard fast-slow analysis used for plateau bursting is of limited use. Using an alternative fast-slow analysis, with one fast and two slow variables, we show that pseudo-plateau bursting is a canard-induced mixed mode oscillation. Using this technique, it is possible to determine the region of parameter space where bursting occurs as well as salient properties of the burst such as the number of spikes in the burst. The information gained from this one-fast/two-slow decomposition complements the information obtained from a two-fast/one-slow decomposition.