Estimating fractal dimensions: A comparative review and open source implementations.

The fractal dimension is a central quantity in nonlinear dynamics and can be estimated via several different numerical techniques. In this review paper, we present a self-contained and comprehensive introduction to the fractal dimension. We collect and present various numerical estimators and focus on the three most promising ones: generalized entropy, correlation sum, and extreme value theory. We then perform an extensive quantitative evaluation of these estimators, comparing their performance and precision using different datasets and comparing the impact of features like length, noise, embedding dimension, and falsify-ability, among many others. Our analysis shows that for synthetic noiseless data, the correlation sum is the best estimator with extreme value theory following closely. For real experimental data, we found the correlation sum to be more strongly affected by noise vs the entropy and extreme value theory. The recent extreme value theory estimator seems powerful as it has some of the advantages of both alternative methods. However, using four different ways for checking for significance, we found that the method yielded "significant" low-dimensional results for inappropriate data like stock market timeseries. This fact, combined with some ambiguities we found in the literature of the method applications, has implications for both previous and future real-world applications using the extreme value theory approach, as, for example, the argument for small effective dimensionality in the data cannot come from the method itself. All algorithms discussed are implemented as performant and easy to use open source code via the DynamicalSystems.jl library.

Optimising low-energy defibrillation in 2D cardiac tissue with a genetic algorithm.

Sequences of low-energy electrical pulses can effectively terminate ventricular fibrillation (VF) and avoid the side effects of conventional high-energy electrical defibrillation shocks, including tissue damage, traumatic pain, and worsening of prognosis. However, the systematic optimisation of sequences of low-energy pulses remains a major challenge. Using 2D simulations of homogeneous cardiac tissue and a genetic algorithm, we demonstrate the optimisation of sequences with non-uniform pulse energies and time intervals between consecutive pulses for efficient VF termination. We further identify model-dependent reductions of total pacing energy ranging from ∼4% to ∼80% compared to reference adaptive-deceleration pacing (ADP) protocols of equal success rate (100%).

Ordinal pattern-based complexity analysis of high-dimensional chaotic time series.

The ordinal pattern-based complexity-entropy plane is a popular tool in nonlinear dynamics for distinguishing stochastic signals (noise) from deterministic chaos. Its performance, however, has mainly been demonstrated for time series from low-dimensional discrete or continuous dynamical systems. In order to evaluate the usefulness and power of the complexity-entropy (CE) plane approach for data representing high-dimensional chaotic dynamics, we applied this method to time series generated by the Lorenz-96 system, the generalized Hénon map, the Mackey-Glass equation, the Kuramoto-Sivashinsky equation, and to phase-randomized surrogates of these data. We find that both the high-dimensional deterministic time series and the stochastic surrogate data may be located in the same region of the complexity-entropy plane, and their representations show very similar behavior with varying lag and pattern lengths. Therefore, the classification of these data by means of their position in the CE plane can be challenging or even misleading, while surrogate data tests based on (entropy, complexity) yield significant results in most cases.

Optical mapping of contracting hearts.

Optical mapping is a widely used tool to record and visualize the electrophysiological properties in a variety of myocardial preparations such as Langendorff-perfused isolated hearts, coronary-perfused wedge preparations, and cell culture monolayers. Motion artifact originating from the mechanical contraction of the myocardium creates a significant challenge to performing optical mapping of contracting hearts. Hence, to minimize the motion artifact, cardiac optical mapping studies are mostly performed on non-contracting hearts, where the mechanical contraction is removed using pharmacological excitation-contraction uncouplers. However, such experimental preparations eliminate the possibility of electromechanical interaction, and effects such as mechano-electric feedback cannot be studied. Recent developments in computer vision algorithms and ratiometric techniques have opened the possibility of performing optical mapping studies on isolated contracting hearts. In this review, we discuss the existing techniques and challenges of optical mapping of contracting hearts.

Non-monotonous dose response function of the termination of spiral wave chaos.

The conventional termination technique of life threatening cardiac arrhythmia like ventricular fibrillation is the application of a high-energy electrical defibrillation shock, coming along with severe side-effects. In order to improve the current treatment reducing these side-effects, the application of pulse sequences of lower energy instead of a single high-energy pulse are promising candidates. In this study, we show that in numerical simulations the dose-response function of pulse sequences applied to two-dimensional spiral wave chaos is not necessarily monotonously increasing, but exhibits a non-trivial frequency dependence. This insight into crucial phenomena appearing during termination attempts provides a deeper understanding of the governing termination mechanisms in general, and therefore may open up the path towards an efficient termination of cardiac arrhythmia in the future.

Control of escapes in two-degree-of-freedom open Hamiltonian systems.

We investigate the possibility of avoiding the escape of chaotic scattering trajectories in two-degree-of-freedom Hamiltonian systems. We develop a continuous control technique based on the introduction of coupling forces between the chaotic trajectories and some periodic orbits of the system. The main results are shown through numerical simulations, which confirm that all trajectories starting near the stable manifold of the chaotic saddle can be controlled. We also show that it is possible to jump between different unstable periodic orbits until reaching a stable periodic orbit belonging to a Kolmogorov-Arnold-Moser island.

The role of pulse timing in cardiac defibrillation.

Life-threatening cardiac arrhythmias require immediate defibrillation. For state-of-the-art shock treatments, a high field strength is required to achieve a sufficient success rate for terminating the complex spiral wave (rotor) dynamics underlying cardiac fibrillation. However, such high energy shocks have many adverse side effects due to the large electric currents applied. In this study, we show, using 2D simulations based on the Fenton-Karma model, that also pulses of relatively low energy may terminate the chaotic activity if applied at the right moment in time. In our simplified model for defibrillation, complex spiral waves are terminated by local perturbations corresponding to conductance heterogeneities acting as virtual electrodes in the presence of an external electric field. We demonstrate that time series of the success rate for low energy shocks exhibit pronounced peaks which correspond to short intervals in time during which perturbations aiming at terminating the chaotic fibrillation state are (much) more successful. Thus, the low energy shock regime, although yielding very low temporal average success rates, exhibits moments in time for which success rates are significantly higher than the average value shown in dose-response curves. This feature might be exploited in future defibrillation protocols for achieving high termination success rates with low or medium pulse energies.

Taming cardiac arrhythmias: Terminating spiral wave chaos by adaptive deceleration pacing.

Sequences of weak electrical pulses are considered a promising alternative for terminating ventricular and atrial fibrillations while avoiding strong defibrillation shocks with adverse side effects. In this study, using numerical simulations of four different 2D excitable media, we show that pulse trains with increasing temporal intervals between successive pulses (deceleration pacing) provide high success rates at low energies. Furthermore, we propose a simple and robust approach to calculate inter-pulse spacing directly from the frequency spectrum of the dynamics (for instance, computed based on the electrocardiogram), which can be practically used in experiments and clinical applications.

Some elements for a history of the dynamical systems theory.

Writing a history of a scientific theory is always difficult because it requires to focus on some key contributors and to "reconstruct" some supposed influences. In the 1970s, a new way of performing science under the name "chaos" emerged, combining the mathematics from the nonlinear dynamical systems theory and numerical simulations. To provide a direct testimony of how contributors can be influenced by other scientists or works, we here collected some writings about the early times of a few contributors to chaos theory. The purpose is to exhibit the diversity in the paths and to bring some elements-which were never published-illustrating the atmosphere of this period. Some peculiarities of chaos theory are also discussed.

Drift and termination of spiral waves in optogenetically modified cardiac tissue at sub-threshold illumination.

The development of new approaches to control cardiac arrhythmias requires a deep understanding of spiral wave dynamics. Optogenetics offers new possibilities for this. Preliminary experiments show that sub-threshold illumination affects electrical wave propagation in the mouse heart. However, a systematic exploration of these effects is technically challenging. Here, we use state-of-the-art computer models to study the dynamic control of spiral waves in a two-dimensional model of the adult mouse ventricle, using stationary and non-stationary patterns of sub-threshold illumination. Our results indicate a light-intensity-dependent increase in cellular resting membrane potentials, which together with diffusive cell-cell coupling leads to the development of spatial voltage gradients over differently illuminated areas. A spiral wave drifts along the positive gradient. These gradients can be strategically applied to ensure drift-induced termination of a spiral wave, both in optogenetics and in conventional methods of electrical defibrillation.

Susceptibility of transient chimera states.

Chaotic dynamics of a dynamical system is not necessarily persistent. If there is (without any active intervention from outside) a transition towards a (possibly nonchaotic) attractor, this phenomenon is called transient chaos, which can be observed in a variety of systems, e.g., in chemical reactions, population dynamics, neuronal activity, or cardiac dynamics. Also, chimera states, which show coherent and incoherent dynamics in spatially distinct regions of the system, are often chaotic transients. In many practical cases, the control of the chaotic dynamics (either the termination or the preservation of the chaotic dynamics) is desired. Although the self-termination typically occurs quite abruptly and can so far in general not be properly predicted, previous studies showed that in many systems a 'terminal transient phase" (TTP) prior to the self-termination existed, where the system was less susceptible against small but finite perturbations in different directions in state space. In this study, we show that, in the specific case of chimera states, these susceptible directions can be related to the structure of the chimera, which we divide into the coherent part, the incoherent part and the boundary in between. That means, in practice, if self-termination is close we can identify the direction of perturbation which is likely to maintain the chaotic dynamics (the chimera state). This finding improves the general understanding of the state space structure during the TTP, and could contribute also to practical applications like future control strategies of epileptic seizures which have been recently related to the collapse of chimera states.

Terminating transient chaos in spatially extended systems.

In many real-life systems, transient chaotic dynamics plays a major role. For instance, the chaotic spiral or scroll wave dynamics of electrical excitation waves during life-threatening cardiac arrhythmias can terminate by itself. Epileptic seizures have recently been related to the collapse of transient chimera states. Controlling chaotic transients, either by maintaining the chaotic dynamics or by terminating it as quickly as possible, is often desired and sometimes even vital (as in the case of cardiac arrhythmias). We discuss in this study that the difference of the underlying structures in state space between a chaotic attractor (persistent chaos) and a chaotic saddle (transient chaos) may have significant implications for efficient control strategies in real life systems. In particular, we demonstrate that in the latter case, chaotic dynamics in spatially extended systems can be terminated via a relatively low number of (spatially and temporally) localized perturbations. We demonstrate as a proof of principle that control and targeting of high-dimensional systems exhibiting transient chaos can be achieved with exceptionally small interactions with the system. This insight may impact future control strategies in real-life systems like cardiac arrhythmias.

High-Resolution Optical Measurement of Cardiac Restitution, Contraction, and Fibrillation Dynamics in Beating vs. Blebbistatin-Uncoupled Isolated Rabbit Hearts.

Optical mapping is a high-resolution fluorescence imaging technique, that uses voltage- or calcium-sensitive dyes to visualize electrical excitation waves on the heart surface. However, optical mapping is very susceptible to the motion of cardiac tissue, which results in so-called motion artifacts in the fluorescence signal. To avoid motion artifacts, contractions of the heart muscle are typically suppressed using pharmacological excitation-contraction uncoupling agents, such as Blebbistatin. The use of pharmacological agents, however, may influence cardiac electrophysiology. Recently, it has been shown that numerical motion tracking can significantly reduce motion-related artifacts in optical mapping, enabling the simultaneous optical measurement of cardiac electrophysiology and mechanics. Here, we combine ratiometric optical mapping with numerical motion tracking to further enhance the robustness and accuracy of these measurements. We evaluate the method's performance by imaging and comparing cardiac restitution and ventricular fibrillation (VF) dynamics in contracting, non-working vs. Blebbistatin-arrested Langendorff-perfused rabbit hearts (N = 10). We found action potential durations (APD) to be, on average, 25 ± 5% shorter in contracting hearts compared to hearts uncoupled with Blebbistatin. The relative shortening of the APD was found to be larger at higher frequencies. VF was found to be significantly accelerated in contracting hearts, i.e., 9 ± 2Hz with Blebbistatin and 15 ± 4Hz without Blebbistatin, and maintained a broader frequency spectrum. In contracting hearts, the average number of phase singularities was N PS = 11 ± 4 compared to N PS = 6 ± 3 with Blebbistatin during VF on the anterior ventricular surface. VF inducibility was reduced with Blebbistatin. We found the effect of Blebbistatin to be concentration-dependent and reversible by washout. Aside from the electrophysiological characterization, we also measured and analyzed cardiac motion. Our findings may have implications for the interpretation of optical mapping data, and highlight that physiological conditions, such as oxygenation and metabolic demand, must be carefully considered in ex vivo imaging experiments.

GPU accelerated study of a dual-frequency driven single bubble in a 6-dimensional parameter space: The active cavitation threshold.

The active cavitation threshold of a dual-frequency driven single spherical gas bubble is studied numerically. This threshold is defined as the minimum intensity required to generate a given relative expansion (Rmax-RE)/RE, where RE is the equilibrium size of the bubble and Rmax is the maximum bubble radius during its oscillation. The model employed is the Keller-Miksis equation that is a second order ordinary differential equation. The parameter space investigated is composed by the pressure amplitudes, excitation frequencies, phase shift between the two harmonic components and by the equilibrium bubble radius (bubble size). Due to the large 6-dimensional parameter space, the number of the parameter combinations investigated is approximately two billion. Therefore, the high performance of graphics processing units is exploited; our in-house code is written in C++ and CUDA C software environments. The results show that for (Rmax-RE)/RE=2, the best choice of the frequency pairs depends on the bubble size. For small bubbles, below 3µm, the best option is to use just a single frequency of a low value in the giant response region. For medium sized bubbles, between 3µm and 6µm, the optimal choice is the mixture of low frequency (giant response) and main resonance frequency. For large bubbles, above 6µm, the main resonance dominates the active cavitation threshold. Increasing the prescribed relative expansion value to (Rmax-RE)/RE=3, the optimal choice is always single frequency driving with the lowest value (20kHz here). Thus, in this case, the giant response always dominates the active cavitation threshold. The phase shift between the harmonic components of the dual-frequency driving (different frequency values) has no effect on the threshold.

Extracting Robust Biomarkers From Multichannel EEG Time Series Using Nonlinear Dimensionality Reduction Applied to Ordinal Pattern Statistics and Spectral Quantities.

In this study, ordinal pattern analysis and classical frequency-based EEG analysis methods are used to differentiate between EEGs of different age groups as well as individuals. As characteristic features, functional connectivity as well as single-channel measures in both the time and frequency domain are considered. We compare the separation power of each feature set after nonlinear dimensionality reduction using t-distributed stochastic neighbor embedding and demonstrate that ordinal pattern-based measures yield results comparable to frequency-based measures applied to preprocessed data, and outperform them if applied to raw data. Our analysis yields no significant differences in performance between single-channel features and functional connectivity features regarding the question of age group separation.

Synchronization of viscoelastically coupled excitable oscillators.

Viscoelastically coupled excitable oscillators are used to model individually beating spatially separated cardiomyocytes surrounded by an extracellular matrix (ECM). We investigate how mechanical coupling via the ECM can synchronize two such oscillators with excitation contraction coupling and electromechanical feedback and how this synchronization depends on the rheological properties of the ECM. Extending our study to a linear chain of coupled oscillators we find a transition to synchronization as the ECM becomes stiffer. In the case of purely elastic coupling we observe antiphase chimera states.

Multiscale Modeling of Dyadic Structure-Function Relation in Ventricular Cardiac Myocytes.

Cardiovascular disease is often related to defects of subcellular components in cardiac myocytes, specifically in the dyadic cleft, which include changes in cleft geometry and channel placement. Modeling of these pathological changes requires both spatially resolved cleft as well as whole cell level descriptions. We use a multiscale model to create dyadic structure-function relationships to explore the impact of molecular changes on whole cell electrophysiology and calcium cycling. This multiscale model incorporates stochastic simulation of individual L-type calcium channels and ryanodine receptor channels, spatially detailed concentration dynamics in dyadic clefts, rabbit membrane potential dynamics, and a system of partial differential equations for myoplasmic and lumenal free Ca2+ and Ca2+-binding molecules in the bulk of the cell. We found action potential duration, systolic, and diastolic [Ca2+] to respond most sensitively to changes in L-type calcium channel current. The ryanodine receptor channel cluster structure inside dyadic clefts was found to affect all biomarkers investigated. The shape of clusters observed in experiments by Jayasinghe et al. and channel density within the cluster (characterized by mean occupancy) showed the strongest correlation to the effects on biomarkers.

Spontaneous termination of chaotic spiral wave dynamics in human cardiac ion channel models.

Chaotic spiral or scroll wave dynamics can be found in diverse systems. In cardiac dynamics, spiral or scroll waves of electrical excitation determine the dynamics during life-threatening arrhythmias like ventricular fibrillation. In numerical studies it was found that chaotic episodes of spiral and scroll waves can be transient, thus they terminate spontaneously. We show in this study that this behavior can also be observed using models which describe the ion channel dynamics of human cardiomyocytes (Bueno-Orovio-Cherry-Fenton model and the Ten Tusscher-Noble-Noble-Panfilov model). For both models we find that the average lifetime of the chaotic transients grows exponentially with the system size. With this behavior, we classify the systems into the group of type-II supertransients. We observe a significant difference of the breakup behavior between the models, which results in a distinct dynamics during the final phase just before the termination. The observation of a (temporally) stable single-spiral state affects the prevailing description of the dynamics of type-II supertransients as being "quasi-stationary" and also the feasibility of predicting the spontaneous termination of the spiral wave dynamics. In the long term, the relation between the breakup behavior of spiral waves and properties of chaotic transients like predictability or average transient lifetime may contribute to an improved understanding and classification of cardiac arrhythmias.

Simultaneous unpinning of multiple vortices in two-dimensional excitable media.

There are many examples of excitable media, such as the heart, that can show complex dynamics and where control is a challenging task. Heavy means like a strong electric shock are nowadays still necessary to control and terminate ventricular fibrillation (VF). It is known that heterogeneities in an excitable medium can stabilize the activity, e.g., spiral waves can pin to such obstacles. This might also be a reason for the persistence of VF and the difficulty to control it. Previous studies investigated systems with a single pinned spiral wave and demonstrated how the spiral can be unpinned. In this article, we extend this case and investigate a generic excitable system with multiple pinned spiral waves. We describe a control technique that allows the simultaneous unpinning of pinned spiral waves. Apart from theoretical considerations, we provide numerical evidence that the proposed technique is superior to the underdrive pacing method that has reportedly high success rates when applied to a single pinned spiral.