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The parameterization method (PM) provides a broad theoretical and numerical foundation for computing invariant manifolds of dynamical systems. PM implements a change of variables in order to represent trajectories of a system of ordinary differential equations ``as simply as possible." In this paper we pursue a similar goal for stochastic oscillator systems. For planar nonlinear stochastic systems that are ``robustly oscillatory", we find a change of variables through which the dynamics are as simple as possible $\textit{in the mean}$. We prove existence and uniqueness of a deterministic vector field, the trajectories of which capture the local mean behavior of the stochastic oscillator. We illustrate the construction of such an ``effective vector field" for several examples, including a limit cycle oscillator perturbed by noise, an excitable system derived from a spiking neuron model, and a spiral sink with noise forcing (2D Ornstein-Uhlenbeck process). The latter examples comprise contingent oscillators that would not sustain rhythmic activity without noise forcing. Finally, we exploit the simplicity of the dynamics after the change of variables to obtain the effective diffusion constant of the resulting phase variable, and the stationary variance of the resulting amplitude (isostable) variable.

Although the raison d'etre of the brain is the survival of the body, there are relatively few theoretical studies of closed-loop rhythmic motor control systems. In this paper we provide a unified framework, based on variational analysis, for investigating the dual goals of performance and robustness in powerstroke-recovery systems. We augment two previously published closed-loop motor control models by equipping each model with a performance measure based on the rate of progress of the system relative to a spatially extended external substrate -- such as progress relative to the ground for a locomotor task. The sensitivity measure quantifies the ability of the system to maintain performance in response to external perturbations. Motivated by a search for optimal design principles for feedback control achieving the complementary requirements of efficiency and robustness, we discuss the performance-sensitivity patterns of the systems featuring different sensory feedback architectures. In a paradigmatic half-center oscillator (HCO)-motor system, we observe that the excitation-inhibition property of feedback mechanisms determines the sensitivity pattern while the activation-inactivation property determines the performance pattern. Moreover, we show that the nonlinearity of the sigmoid activation of feedback signals allows the existence of optimal combinations of performance and sensitivity. In a detailed hindlimb locomotor system, we find that a force-dependent feedback can simultaneously optimize both performance and robustness, while length-dependent feedback variations result in significant performance-versus-sensitivity tradeoffs. Thus, this work provides an analytical framework for studying feedback control of oscillations in nonlinear dynamical systems, leading to several insights that have the potential to inform the design of control or rehabilitation systems., Comment: 48 pages, 17 figures, 3 tables

Phase reduction is an important tool for studying coupled and driven oscillators. The question of how to generalize phase reduction to stochastic oscillators remains actively debated. In this work, we propose a method to derive a self-contained stochastic phase equation of the form $d\vartheta = a_\vartheta(\vartheta)dt + \sqrt{2D_\vartheta(\vartheta)}\,dW_\vartheta(t)$ that is valid not only for noise-perturbed limit cycles, but also for noise-induced oscillations. We show that our reduction captures the asymptotic statistics of qualitatively different stochastic oscillators, and use it to infer their phase-response properties., Comment: 12 pages, 7 figures

While our understanding of the way single neurons process chromatic stimuli in the early visual pathway has advanced significantly in recent years, we do not yet know how these cells interact to form stable representations of hue. Drawing on physiological studies, we offer a dynamical model of how the primary visual cortex tunes for color, hinged on intracortical interactions and emergent network effects. After detailing the evolution of network activity through analytical and numerical approaches, we discuss the effects of the model's cortical parameters on the selectivity of the tuning curves. In particular, we explore the role of the model's thresholding nonlinearity in enhancing hue selectivity by expanding the region of stability, allowing for the precise encoding of chromatic stimuli in early vision. Finally, in the absence of a stimulus, the model is capable of explaining hallucinatory color perception via a Turing-like mechanism of biological pattern formation., Comment: 21 pages, 15 figures

Many systems in physics, chemistry and biology exhibit oscillations with a pronounced random component. Such stochastic oscillations can emerge via different mechanisms, for example linear dynamics of a stable focus with fluctuations, limit-cycle systems perturbed by noise, or excitable systems in which random inputs lead to a train of pulses. Despite their diverse origins, the phenomenology of random oscillations can be strikingly similar. Here we introduce a nonlinear transformation of stochastic oscillators to a new complex-valued function $Q^*_1(\textbf{x})$ that greatly simplifies and unifies the mathematical description of the oscillator's spontaneous activity, its response to an external time-dependent perturbation, and the correlation statistics of different oscillators that are weakly coupled. The function $Q^*_1(\textbf{x})$ is the eigenfunction of the Kolmogorov backward operator with the least negative (but non-vanishing) eigenvalue $\lambda_1=\mu_1+i\omega_1$. The resulting power spectrum of the complex-valued function is exactly given by a Lorentz spectrum with peak frequency $\omega_1$ and half-width $\mu_1$; its susceptibility with respect to a weak external forcing is given by a simple one-pole filter, centered around $\omega_1$; and the cross-spectrum between two coupled oscillators can be easily expressed by a combination of the spontaneous power spectra of the uncoupled systems and their susceptibilities. Our approach makes qualitatively different stochastic oscillators comparable, provides simple characteristics for the coherence of the random oscillation, and gives a framework for the description of weakly coupled oscillators.

Many natural and engineered systems can be modeled as discrete state Markov processes. Often, only a subset of states are directly observable. Inferring the conditional probability that a system occupies a particular hidden state, given the partial observation, is a problem with broad application. In this paper, we introduce a continuous-time formulation of the sum-product algorithm, which is a well-known discrete-time method for finding the hidden states' conditional probabilities, given a set of finite, discrete-time observations. From our new formulation, we can explicitly solve for the conditional probability of occupying any state, given the transition rates and observations within a finite time window. We apply our algorithm to a realistic model of the cystic fibrosis transmembrane conductance regulator (CFTR) protein for exact inference of the conditional occupancy probability, given a finite time series of partial observations., Comment: Accepted for publication in IEEE Transactions on Signal Processing

Similar activity patterns may arise from model neural networks with distinct coupling properties and individual unit dynamics. These similar patterns may, however, respond differently to parameter variations and, specifically, to tuning of inputs that represent control signals. In this work, we analyze the responses resulting from modulation of a localized input in each of three classes of model neural networks that have been recognized in the literature for their capacity to produce robust three-phase rhythms: coupled fast-slow oscillators, near-heteroclinic oscillators, and threshold-linear networks. Triphasic rhythms, in which each phase consists of a prolonged activation of a corresponding subgroup of neurons followed by a fast transition to another phase, represent a fundamental activity pattern observed across a range of central pattern generators underlying behaviors critical to survival, including respiration, locomotion, and feeding. To perform our analysis, we extend the recently developed local timing response curve (lTRC), which allows us to characterize the timing effects due to perturbations, and we complement our lTRC approach with model-specific dynamical systems analysis. Interestingly, we observe disparate effects of similar perturbations across distinct model classes. Thus, this work provides an analytical framework for studying control of oscillations in nonlinear dynamical systems, and may help guide model selection in future efforts to study systems exhibiting triphasic rhythmic activity., Comment: 49 pages, 21 figures, 8 tables

Motor systems show an overall robustness, but because they are highly nonlinear, understanding how they achieve robustness is difficult. In many rhythmic systems, robustness against perturbations involves response of both the shape and the timing of the trajectory. This makes the study of robustness even more challenging. To understand how a motor system produces robust behaviors in a variable environment, we consider a neuromechanical model of motor patterns in the feeding apparatus of the marine mollusk \textit{Aplysia californica} \citep{shaw2015,lyttle2017}. We established in \citep{WGCT2021} the tools for studying combined shape and timing responses of limit cycle systems under sustained perturbations and here apply them to study robustness of the neuromechanical model against increased mechanical load during swallowing. Interestingly, we discover that nonlinear biomechanical properties confer resilience by immediately increasing resistance to applied loads. In contrast, the effect of changed sensory feedback signal is significantly delayed by the firing rates' hard boundary properties. Our analysis suggests that sensory feedback contributes to robustness in swallowing primarily by shifting the timing of neural activation involved in the power stroke of the motor cycle (retraction). This effect enables the system to generate stronger retractor muscle forces to compensate for the increased load, and hence achieve strong robustness. The approaches that we are applying to understanding a neuromechanical model in \textit{Aplysia}, and the results that we have obtained, are likely to provide insights into the function of other motor systems that encounter changing mechanical loads and hard boundaries, both due to mechanical and neuronal firing properties., Comment: 26 pages, 13 figures

Density dependence is important in the ecology and evolution of microbial and cancer cells. Typically, we can only measure net growth rates, but the underlying density-dependent mechanisms that give rise to the observed dynamics can manifest in birth processes, death processes, or both. Therefore, we utilize the mean and variance of cell number fluctuations to separately identify birth and death rates from time series that follow stochastic birth-death processes with logistic growth. Our method provides a novel perspective on stochastic parameter identifiability, which we validate by analyzing the accuracy in terms of the discretization bin size. We apply our method to the scenario where a homogeneous cell population goes through three stages: (1) grows naturally to its carrying capacity, (2) is treated with a drug that reduces its carrying capacity, and (3) overcomes the drug effect to restore its original carrying capacity. In each stage, we disambiguate whether it happens through the birth process, death process, or some combination of the two, which contributes to understanding drug resistance mechanisms. In the case of limited data sets, we provide an alternative method based on maximum likelihood and solve a constrained nonlinear optimization problem to identify the most likely density dependence parameter for a given cell number time series. Our methods can be applied to other biological systems at different scales to disambiguate density-dependent mechanisms underlying the same net growth rate.

May and Leonard (SIAM J. Appl. Math 1975) introduced a three-species Lotka-Volterra type population model that exhibits heteroclinic cycling. Rather than producing a periodic limit cycle, the trajectory takes longer and longer to complete each "cycle", passing closer and closer to unstable fixed points in which one population dominates and the others approach zero. Aperiodic heteroclinic dynamics have subsequently been studied in ecological systems (side-blotched lizards; colicinogenic E. coli), in the immune system, in neural information processing models ("winnerless competition"), and in models of neural central pattern generators. Yet as May and Leonard observed "Biologically, the behavior (produced by the model) is nonsense. Once it is conceded that the variables represent animals, and therefore cannot fall below unity, it is clear that the system will, after a few cycles, converge on some single population, extinguishing the other two." Here, we explore different ways of introducing discrete stochastic dynamics based on May and Leonard's ODE model, with application to ecological population dynamics, and to a neuromotor central pattern generator system. We study examples of several quantitatively distinct asymptotic behaviors, including total extinction of all species, extinction to a single species, and persistent cyclic dominance with finite mean cycle length., Comment: 21 pages, 6 figures

One notion of phase for stochastic oscillators is based on the mean return-time (MRT): a set of points represents a certain phase if the mean time to return from any point in this set to this set after one rotation is equal to the mean rotation period of the oscillator (irrespective of the starting point). For this so far only algorithmically defined phase, we derive here analytical expressions for the important class of isotropic stochastic oscillators. This allows us to evaluate cases from the literature explicitly and to study the behavior of the MRT phase in the limits of strong noise. We also use the same formalism to show that lines of constant return time variance (instead of constant mean return time) can be defined, and that they in general differ from the MRT-isochrons., Comment: 5 pages, 4 figures

We derive a factor graph EM (FGEM) algorithm, a technique that permits combined parameter estimation and statistical inference, to determine hidden kinetic microstates from patch clamp measurements. Using the cystic fibrosis transmembrane conductance regulator (CFTR) and nicotinic acetylcholine receptor (nAChR) as examples, we perform {\em Monte Carlo} simulations to demonstrate the performance of the algorithm. We show that the performance, measured in terms of the probability of estimation error, approaches the theoretical performance limit of maximum {\em a posteriori} estimation. Moreover, the algorithm provides a reliability score for its estimates, and we demonstrate that the score can be used to further improve the performance of estimation. We use the algorithm to estimate hidden kinetic states in lab-obtained CFTR single channel patch clamp traces.

Thomas and Lindner (2014, Phys.Rev.Lett.) defined an asymptotic phase for stochastic oscillators as the angle in the complex plane made by the eigenfunction, having a complex eigenvalue with a least negative real part, of the backward Kolmogorov (or stochastic Koopman) operator. We complete the phase-amplitude description of noisy oscillators by defining the stochastic isostable coordinate as the eigenfunction with the least negative nontrivial real eigenvalue. Our results suggest a framework for stochastic limit cycle dynamics that encompasses noise-induced oscillations.

The contributions of independent noise sources to the variability of action potential timing has not previously been studied at the level of individual directed molecular transitions within a conductance-based model ion-state graph. The underlying connection provides an important example of how mathematics can be applied to study the effects of unobservable microscopic fluctuations to macroscopically observable quantities. We study a stochastic Langevin model and show how to resolve the individual contributions that each transition in the ion channel graph makes to the variance of the interspike interval (ISI). We extend the mean--return-time (MRT) phase reduction developed in (Cao et al. 2020, SIAM J. Appl. Math) to the second moment of the return time from an MRT isochron to itself. Because fixed-voltage spike-detection triggers do not correspond to MRT isochrons, the inter-phase interval (IPI) variance only approximates the ISI variance. We find the IPI variance and ISI variance agree to within a few percent when both can be computed. Moreover, we prove rigorously, and show numerically, that our expression for the IPI variance is accurate in the small noise (large system size) regime; our theory is exact in the limit of small noise. By selectively including the noise associated with only those few transitions responsible for most of the ISI variance, our analysis extends the stochastic shielding (SS) paradigm (Schmandt et al. 2012, Phys. Rev. Lett.) from the stationary voltage-clamp case to the current-clamp case. We show numerically that the SS approximation has a high degree of accuracy even for larger, physiologically relevant noise levels. We show that the ISI variance is not an unambiguously defined quantity, but depends on the choice of voltage level set as the spike-detection threshold, both in vitro and in silico., Comment: 51 pages, 14 Figures

Competitive tournaments appear in sports, politics, population ecology, and animal behavior. All of these fields have developed methods for rating competitors and ranking them accordingly. A tournament is intransitive if it is not consistent with any ranking. Intransitive tournaments contain rock-paper-scissor type cycles. The discrete Helmholtz-Hodge decomposition (HHD) is well adapted to describing intransitive tournaments. It separates a tournament into perfectly transitive and perfectly cyclic components, where the perfectly transitive component is associated with a set of ratings. The size of the cyclic component can be used as a measure of intransitivity. Here we show that the HHD arises naturally from two classes of tournaments with simple statistical interpretations. We then discuss six different sets of assumptions that define equivalent decompositions. This analysis motivates the choice to use the HHD among other existing methods. Success in competition is typically mediated by the traits of the competitors. A trait-performance model assumes that the probability that one competitor beats another can be expressed as a function of their traits. We show that, if the traits of each competitor are drawn independently and identically from a trait distribution then the expected degree of intransitivity in the network can be computed explicitly. Using this result we show that increasing the number of pairs of competitors who could compete promotes cyclic competition, and that increasing the correlation in the performance of $A$ against $B$ with the performance of $A$ against $C$ promotes transitive competition. The expected size of cyclic competition can thus be understood by analyzing this correlation. An illustrative example is provided., Comment: 26 pages, 8 figures

Animals exhibit remarkable feats of behavioral flexibility and multifunctional control that remain challenging for robotic systems. The neural and morphological basis of multifunctionality in animals can provide a source of bio-inspiration for robotic controllers. However, many existing approaches to modeling biological neural networks rely on computationally expensive models and tend to focus solely on the nervous system, often neglecting the biomechanics of the periphery. As a consequence, while these models are excellent tools for neuroscience, they fail to predict functional behavior in real time, which is a critical capability for robotic control. To meet the need for real-time multifunctional control, we have developed a hybrid Boolean model framework capable of modeling neural bursting activity and simple biomechanics at speeds faster than real time. Using this approach, we present a multifunctional model of Aplysia californica feeding that qualitatively reproduces three key feeding behaviors (biting, swallowing, and rejection), demonstrates behavioral switching in response to external sensory cues, and incorporates both known neural connectivity and a simple bioinspired mechanical model of the feeding apparatus. We demonstrate that the model can be used for formulating testable hypotheses and discuss the implications of this approach for robotic control and neuroscience., Comment: Revisions have been made to improve manuscript clarity and expand the introduction and discussion. The results are unchanged

Fox and Lu introduced a Langevin framework for discrete-time stochastic models of randomly gated ion channels such as the Hodgkin-Huxley (HH) system. They derived a Fokker-Planck equation with state-dependent diffusion tensor $D$ and suggested a Langevin formulation with noise coefficient matrix $S$ such that $SS^\intercal=D$. Subsequently, several authors introduced a variety of Langevin equations for the HH system. In this paper, we present a natural 14-dimensional dynamics for the HH system in which each \emph{directed} edge in the ion channel state transition graph acts as an independent noise source, leading to a $14\times 28$ noise coefficient matrix $S$. We show that (i) the corresponding 14D system of ordinary differential \rev{equations} is consistent with the classical 4D representation of the HH system; (ii) the 14D representation leads to a noise coefficient matrix $S$ that can be obtained cheaply on each timestep, without requiring a matrix decomposition; (iii) sample trajectories of the 14D representation are pathwise equivalent to trajectories of Fox and Lu's system, as well as trajectories of several existing Langevin models; (iv) our 14D representation (and those equivalent to it) give the most accurate interspike-interval distribution, not only with respect to moments but under both the $L_1$ and $L_\infty$ metric-space norms; and (v) the 14D representation gives an approximation to exact Markov chain simulations that are as fast and as efficient as all equivalent models. Our approach goes beyond existing models, in that it supports a stochastic shielding decomposition that dramatically simplifies $S$ with minimal loss of accuracy under both voltage- and current-clamp conditions., Comment: 55 pages, 9 figures

Acoustic metamaterials constructed from conventional base materials can exhibit exotic phenomena such as negative refractive index, extraordinary transmission-absorption and sub-wavelength imaging. These are typically achieved by combining geometrical and resonance effects. Holey-structured acoustic metamaterials have already shown potential for sub-wavelength acoustic imaging in air, where it is relatively simple to achieve the required difference in acoustic impedance needed to create resonances within the holes. However, the use of polymers for metamaterial operation in water is difficult, due to the much lower difference in acoustic impedance between water and the many polymers used, for example, in additive manufacturing. Hence, metals are commonly used. Here we show that this can be overcome by trapping air layers so that they surround each water-filled channel, making sub-wavelength imaging in water possible. The operation of such a Trapped air design is confirmed at 200-300 kHz ultrasonic frequencies via both finite element modelling and experimental measurements in a water tank. It is also shown quantitatively that the trapped air design outperforms its metal counterpart. The results indicate a way forward for exploiting additive-manufacturing for realising acoustic metamaterials in water at ultrasonic frequencies., Comment: 29 pages, 14 figures

Biochemical signal transduction, a form of molecular communication, can be modeled using graphical Markov channels with input-modulated transition rates. Such channel models are strongly non-Gaussian. In this paper we use a linear noise approximation to construct a novel class of Gaussian additive white noise channels that capture essential features of fully- and partially-observed intensity-driven signal transduction. When channel state transitions that are sensitive to the input signal are directly observable, high-frequency information is transduced more efficiently than low-frequency information, and the mutual information rate per bandwidth (spectral efficiency) is significantly greater than when sensitive transitions and observable transitions are disjoint. When both observable and hidden transitions are input-sensitive, we observe a superadditive increase in spectral efficiency., Comment: Accepted for publication at the 2019 IEEE Global Communications Conference (GLOBECOM)

Stochastic oscillations are ubiquitous in many systems. For deterministic systems, the oscillator's phase has been widely used as an effective one-dimensional description of a higher dimensional dynamics, particularly for driven or coupled systems. Hence, efforts have been made to generalize the phase concept to the stochastic framework. One notion of phase due to Schwabedal and Pikovsky is based on the mean-return time (MRT) of the oscillator but has so far been described only in terms of a numerical algorithm. Here we develop the boundary condition by which the partial differential equation for the MRT has to be complemented in order to obtain the isochrons (lines of equal phase) of a two-dimensional stochastic oscillator, and rigorously establish the existence and uniqueness of the MRT isochron function (up to an additive constant). We illustrate the method with a number of examples: the stochastic heteroclinic oscillator (which would not oscillate in the absence of noise); the isotropic Stuart-Landau oscillator, the Newby-Schwemmer oscillator, and the Stuart-Landau oscillator with polarized noise. For selected isochrons we confirm by extensive stochastic simulations that the return time from an isochron to the same isochron (after one complete rotation) is always the mean first-passage time (irrespective of the initial position on the isochron). Put differently, we verify that Schwabedal and Pikovsky's criterion for an isochron is satisfied. In addition, we discuss how to extend the construction to arbitrary finite dimensions. Our results will enable development of analytical tools to study and compare different notions of phase for stochastic oscillators., Comment: 32 pages, 10 figures, includes supplementary materials

When dynamical systems that produce rhythmic behaviors operate within hard limits, they may exhibit limit cycles with sliding components, that is, closed isolated periodic orbits that make and break contact with a constraint surface. Examples include heel-ground interaction in locomotion, firing rate rectification in neural networks and stick-slip oscillators. In many rhythmic systems, robustness against external perturbations involves response of both the shape and the timing of the limit cycle trajectory. The existing methods of infinitesimal phase response curve (iPRC) and variational analysis are well established for quantifying changes in timing and shape for smooth systems. These tools have recently been extended to nonsmooth dynamics with transversal crossing boundaries. In this work, we further extend the iPRC method to nonsmooth systems with sliding components, which enables us to make predictions about the synchronization properties of weakly coupled stick-slip oscillators. We observe a new feature of the isochrons in a planar limit cycle with hard sliding boundaries. Moreover, the classical variational analysis neglects timing information and is restricted to instantaneous perturbations. By defining the "infinitesimal shape response curve" (iSRC), we incorporate timing sensitivity of an oscillator to describe the shape response of this oscillator to parametric perturbations. In order to extract timing information, we also develop a "local timing response curve" (lTRC) that measures the timing sensitivity of a limit cycle within any given region. We demonstrate in a specific example that taking into account local timing sensitivity in a nonsmooth system greatly improves the accuracy of the iSRC over global timing analysis given by the iPRC., Comment: 73 pages

Stochastic oscillators play a prominent role in different fields of science. Their simplified description in terms of a phase has been advocated by different authors using distinct phase definitions in the stochastic case. One notion of phase that we put forward previously, the \emph{asymptotic phase of a stochastic oscillator}, is based on the eigenfunction expansion of its probability density. More specifically, it is given by the complex argument of the eigenfunction of the backward operator corresponding to the least negative eigenvalue. Formally, besides the `backward' phase, one can also define the `forward' phase as the complex argument of the eigenfunction of the forward Kolomogorov operator corresponding to the least negative eigenvalue. Until now, the intuition about these phase descriptions has been limited. Here we study these definitions for a process that is analytically tractable, the two-dimensional Ornstein-Uhlenbeck process with complex eigenvalues. For this process, (i) we give explicit expressions for the two phases; (ii) we demonstrate that the isochrons are always the spokes of a wheel, but that (iii) the spacing of these isochrons (their angular density) is different for backward and forward phases; (iv) we show that the isochrons of the backward phase are completely determined by the deterministic part of the vector field, whereas the forward phase also depends on the noise matrix; and (v) we demonstrate that the mean progression of the backward phase in time is always uniform, whereas this is not true for the forward phase except in the rotationally symmetric case. We illustrate our analytical results for a number of qualitatively different cases.

Molecular signals are abundant in engineering and biological contexts, and undergo stochastic propagation in fluid dynamic channels. The received signal is sensitive to a variety of input and channel parameter variations. Currently we do not understand how uncertainty or noise in a variety of parameters affect the received signal concentration, and nor do we have an analytical framework to tackle this challenge. In this paper, we utilize Polynomial Chaos Expansion (PCE) to show to uncertainty in parameters propagates to uncertainty in the received signal. In demonstrating its applicability, we consider a Turbulent Diffusion Molecular Communication (TDMC) channel and highlight which parameters affect the received signals. This can pave the way for future information theoretic insights, as well as guide experimental design.

In this paper, we consider the energy cost of communicating using molecular communication. In a simplified scenario, we show that the energy bound in Landauer's principle can be achieved, implying that molecular communication can approach fundamental thermodynamic limits., Comment: Accepted for publication at the 2018 IEEE International Symposium on Information Theory, Vail, Colorado

Biological systems transduce signals from their surroundings through a myriad of pathways. In this paper, we describe signal transduction as a communication system: the signal transduction receptor acts as the receiver in this system, and can be modeled as a finite-state Markov chain with transition rates governed by the input signal. Using this general model, we give the mutual information under IID inputs in discrete time, and obtain the mutual information in the continuous-time limit. We show that the mutual information has a concise closed-form expression with clear physical significance. We also give a sufficient condition under which the Shannon capacity is achieved with IID inputs. We illustrate our results with three examples: the light-gated Channelrhodopsin-2 (ChR2) receptor; the ligand-gated nicotinic acetylcholine (ACh) receptor; and the ligand-gated Calmodulin (CaM) receptor. In particular, we show that the IID capacity of the ChR2 receptor is equal to its Shannon capacity. We finally discuss how the results change if only certain properties of each state can be observed, such as whether an ion channel is open or closed., Comment: Accepted for publication in IEEE Transactions on Molecular, Biological, and Multi-Scale Communications

Information theory provides powerful tools for understanding communication systems. This analysis can be applied to intercellular signal transduction, which is a means of chemical communication among cells and microbes. We discuss how to apply information-theoretic analysis to ligand-receptor systems, which form the signal carrier and receiver in intercellular signal transduction channels. We also discuss the applications of these results to neuroscience., Comment: Accepted for publication in 2016 IEEE International Conference on Acoustics, Speech, and Signal Processing, Shanghai, China

In this letter, we give a concise, closed-form expression for the differential entropy of the sum of two independent, non-identically-distributed exponential random variables. The derivation is straightforward, but such a concise entropy has not been previously given in the literature. The usefulness of the expression is demonstrated with examples.

Cyclic adenosine monophosphate (cAMP) is considered a model system for signal transduction, the mechanism by which cells exchange chemical messages. Our previous work calculated the Shannon capacity of a single cAMP receptor; however, a typical cell may have thousands of receptors operating in parallel. In this paper, we calculate the capacity of a cAMP signal transduction system with an arbitrary number of independent, indistinguishable receptors. By leveraging prior results on feedback capacity for a single receptor, we show (somewhat unexpectedly) that the capacity is achieved by an IID input distribution, and that the capacity for n receptors is n times the capacity for a single receptor., Comment: Accepted for presentation at the 2016 IEEE International Symposium on Information Theory (ISIT)

The asymptotic phase $\theta$ of an initial point $x$ in the stable manifold of a limit cycle identifies the phase of the point on the limit cycle to which the flow $\phi_t(x)$ converges as $t\to\infty$. The infinitesimal phase response curve (iPRC) quantifies the change in timing due to a small perturbation of a limit cycle trajectory. For a stable limit cycle in a smooth dynamical system the iPRC is the gradient $\nabla_x(\theta)$ of the phase function, which can be obtained via the adjoint of the variational equation. For systems with discontinuous dynamics, the standard approach to obtaining the iPRC fails. We derive a formula for the infinitesimal phase response curves (iPRCs) of limit cycles occurring in piecewise smooth (Filipov) dynamical systems of arbitrary dimension, subject to a transverse flow condition. Discontinuous jumps in the iPRC can occur at the boundaries separating subdomains, and are captured by a linear matching condition. The matching matrix, $M$, can be derived from the saltation matrix arising in the associated variational problem. For the special case of linear dynamics away from switching boundaries, we obtain an explicit expression for the iPRC. We present examples from cell biology (Glass networks) and neuroscience (central pattern generator models). We apply the iPRCs obtained to study synchronization and phase-locking in piecewise smooth limit cycle systems in which synchronization arises solely due to the crossing of switching manifolds., Comment: 37 pages, 10 figures

In his Comment [arXiv:1501.02126 (2015)] on our recent paper [Phys. Rev. Lett., v. 113, 254101 (2014)], Pikovsky compares two methods for defining the "phase" of a stochastic oscillator. We reply to his Comment by showing that neither method can unambiguously identify a unique system of isochrons, when multiple oscillations coexist in the same system., Comment: 1.5 pages, 1 figure. Reply to arXiv:1501.02126v2

Oscillations and noise are ubiquitous in physical and biological systems. When oscillations arise from a deterministic limit cycle, entrainment and synchronization may be analyzed in terms of the asymptotic phase function. In the presence of noise, the asymptotic phase is no longer well defined. We introduce a new definition of asymptotic phase in terms of the slowest decaying modes of the Kolmogorov backward operator. Our stochastic asymptotic phase is well defined for noisy oscillators, even when the oscillations are noise dependent. It reduces to the classical asymptotic phase in the limit of vanishing noise. The phase can be obtained either by solving an eigenvalue problem, or by empirical observation of an oscillating density's approach to its steady state., Comment: 5 pages, 3 figures

We model biochemical signal transduction, based on a ligand-receptor binding mechanism, as a discrete-time finite-state Markov channel, which we call the BIND channel. We show how to obtain the capacity of this channel, for the case of binary output, binary channel state, and arbitrary finite input alphabets. We show that the capacity-achieving input distribution is IID. Further, we show that feedback does not increase the capacity of this channel. We show how the capacity of the discrete-time channel approaches the capacity of Kabanov's Poisson channel, in the limit of short time steps and rapid ligand release., Comment: Accepted for publication in IEEE Transactions on Information Theory