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Excitable media are ubiquitous in nature, and in such systems the local excitation tends to self-organize in traveling waves, or in rotating spiral-shaped patterns in two or three spatial dimensions. Examples include waves during a pandemic or electrical scroll waves in the heart. Here we show that such phenomena can be extended to a space of four or more dimensions and propose that connections of excitable elements in a network setting can be regarded as additional spatial dimensions. Numerical simulations are performed in four dimensions using the FitzHugh-Nagumo model, showing that the vortices rotate around a two-dimensional surface which we define as the superfilament. Evolution equations are derived for general superfilaments of co-dimension two in an N -dimensional space and their equilibrium configurations are proven to be minimal surfaces. We suggest that biological excitable systems, such as the heart or brain which have non-local connections can be regarded, at least partially, as multidimensional excitable media and discuss further possible studies in this direction.

Many physical, chemical and biological processes rely on intrinsic oscillations to employ resonance responses to external stimuli of certain frequency. Such resonance phenomena in biological systems are typically explained by one of two mechanisms: either a classical linear resonance of harmonic oscillator, or entrainment and phase locking of nonlinear limit cycle oscillators subjected to periodic forcing. Here, we discover a nonlinear mechanism, which does not require intrinsic oscillations. Instead, the resonant frequency dependence arises from coupling between an excitable and a monostable region of the medium. This composite system is endowed with emergent bistability between a stable steady state and stable spatiotemporal oscillations. The resonant transition from stable state to oscillatory state is induced by waves of particular frequency travelling through the medium. This transition to the spatiotemporal oscillatory state requires accumulation of multiple waves, resulting in the exclusion of lower frequencies. The cutting off of high frequencies is realized by damping of wave amplitude in the monostable zone and then by activating amplitude sensitive dynamics in the monostable units. We demonstrate this new resonance mechanism in a simplistic reaction-diffusion model. Also, we reveal this collective resonance mechanism in in-vitro experiments and detailed biophysical simulations representing a major type of arrhythmia. We further demonstrate, both experimentally and theoretically, that the ongoing spatiotemporal oscillations, such as ectopic activity in cardiac tissue, can be stopped by travelling waves of high frequency. Overall, we claim the universality of this resonance mechanism in a broad class of nonlinear biophysical systems. Specifically, we hypothesize that such phenomena could be found in neuronal systems as an alternative to traditional resonant processes.

Uncertainty quantification (UQ) is a vital step in using mathematical models and simulations to take decisions. The field of cardiac simulation has begun to explore and adopt UQ methods to characterise uncertainty in model inputs and how that propagates through to outputs or predictions. In this perspective piece we draw attention to an important and under-addressed source of uncertainty in our predictions -- that of uncertainty in the model structure or the equations themselves. The difference between imperfect models and reality is termed model discrepancy, and we are often uncertain as to the size and consequences of this discrepancy. Here we provide two examples of the consequences of discrepancy when calibrating models at the ion channel and action potential scales. Furthermore, we attempt to account for this discrepancy when calibrating and validating an ion channel model using different methods, based on modelling the discrepancy using Gaussian processes (GPs) and autoregressive-moving-average (ARMA) models, then highlight the advantages and shortcomings of each approach. Finally, suggestions and lines of enquiry for future work are provided., Comment: This version is published in Philosophical Transactions of the Royal Society A; Updated in response to reviewer comments, including: added details to the introduction, fixed mathematical notations for clarity, and moved the original Table 3 to the supplement to avoid confusion

In many oscillatory or excitable systems, dynamical patterns emerge which are stationary or periodic up in a moving frame of reference. Examples include traveling waves or spiral waves in chemical systems or cardiac tissue. We present a unified theoretical framework for the drift of such patterns under small external perturbations, in terms of overlap integrals between the perturbation and the adjoint critical eigenfunctions of the linearised operator (i.e. `response functions'). For spiral waves, the finite radius of the spiral tip trajectory as well as spiral wave meander are taken into account. Different coordinates systems can be chosen, depending on whether one wants to predict the motion of the spiral wave tip, the time-averaged tip path, or the center of the meander flower. The framework is applied to analyse the drift of a meandering spiral wave in a constant external field in different regimes.

Rotors are functional reentry sources identified in clinically relevant cardiac arrhythmias, such as ventricular and atrial fibrillation. Ablation targeting rotor sites has resulted in arrhythmia termination. Recent clinical, experimental and modelling studies demonstrate that rotors are often anchored around fibrotic scars or regions with increased fibrosis. However the mechanisms leading to abundance of rotors at these locations are not clear. The current study explores the hypothesis whether fibrotic scars just serve as anchoring sites for the rotors or whether there are other active processes which drive the rotors to these fibrotic regions. Rotors were induced at different distances from fibrotic scars of various sizes and degree of fibrosis. Simulations were performed in a 2D model of human ventricular tissue and in a patient-specific model of the left ventricle of a patient with remote myocardial infarction. In both the 2D and the patient-specific model we found that without fibrotic scars, the rotors were stable at the site of their initiation. However, in the presence of a scar, rotors were eventually dynamically anchored from large distances by the fibrotic scar via a process of dynamical reorganization of the excitation pattern. This process coalesces with a change from polymorphic to monomorphic ventricular tachycardia., Comment: 16 pages, 7 figures

Here I introduce basic methods of qualitative analysis of differential equations used in mathematical biology for people with minimal mathematical background.

Disorganized electrical activity in the heart leads to sudden cardiac death. To what extent can this electrical turbulence be viewed as classical fluid turbulence,which is an important central problem in modern physics? We investigate,for the first time,via extensive DNSs,the statistical properties of spiral-and scroll-wave turbulence in two- and three-dimensional excitable media by using approaches employed in studies of classical turbulence. We use the Panfilov and the Aliev-Panfilov mathematical models for cardiac tissue. We show that once electrical-wave turbulence has been initiated,there is a forward cascade,in which spirals or scrolls form,interact,and break to yield a turbulent state that is statistically steady and,far away from boundaries,is statistically homogeneous and isotropic. For the transmembrane potential $V$ and the slow recovery variable $g$,which define our models,we define $E_V(k)$ and $E_g(k)$,the electrical-wave analogs of the fluid energy spectrum $E(k)$ in fluid turbulence. We show that $E_V(k)$ and $E_g(k)$ are spread out over several decades in $k$. Thus spiral- and scroll-wave turbulence involves a wide range of spatial scales. $E_V(k)$ and $E_g(k)$ show approximate power laws,in some range of $k$, however,their exponents cannot be determined as accurately as their fluid-turbulence counterparts. The dimensionless ratio $L/\lambda$ is a convenient control parameter like the Reynolds number for fluid turbulence,where $L$ is the linear size of the domain and $\lambda$ the wavelength of a plane wave in the medium. By comparing several other statistical properties for spiral- and scroll-wave turbulence with their fluid-turbulence counterparts,we show that,although spiral- and scroll-wave turbulence have some statistical properties like those of fluid turbulence,overall these types of turbulence are special and differ in important ways from fluid turbulence., Comment: 16 pages, 24 figures, One table

Rotating scroll waves are self-organising patterns which are found in many oscillating or excitable systems. Here we show that quasi-periodic (meandering) scroll waves, which include the rotors that organise cardiac arrhythmias, exhibit filament tension when averaged over the meander cycle. With strong filament curvature or medium thickness gradients, however, scroll wave dynamics are governed by phase-locked drift instead of filament tension. Our results are validated in computational models of cycloidal meander and a cardiac tissue model with linear core., Comment: accepted for publication in Physical Review Letters (December 2017)

Chirality is one of the most fundamental properties of many physical, chemical and biological systems. However, the mechanisms underlying the onset and control of chiral symmetry are largely understudied. We investigate possibility of chirality control in a chemical excitable system (the BZ reaction) by application of a chiral (rotating) electric field using the Oregonator model. We find that unlike previous findings, we can achieve the chirality control not only in the field rotation direction, but also opposite to it, depending on the field rotation frequency. To unravel the mechanism, we further develop a comprehensive theory of frequency synchronization based on the response function approach. We find that this problem can be described by the Adler equation and show phase-locking phenomena, known as the Arnold tongue. Our theoretical predictions are in good quantitative agreement with the numerical simulations and provide a solid basis for chirality control in excitable media., Comment: 21 pages with 9 figures; update references; to appear in J. Chem. Phys

We study the drift of spiral waves in a simple model of heterogeneous excitable medium, having gradients in local excitability or cellular coupling. For the first time, we report the anomalous drift of spiral waves towards regions having higher excitability, in contrast to all earlier observations in reaction-diffusion models of excitable media. Such anomalous drift can promote the onset of complex spatio-temporal patterns, e.g., those responsible for life-threatening arrhythmias in the heart., Comment: 4 pages, 4 figures