Nonlinear phase-amplitude reduction of delay-induced oscillations
Abstract
Spontaneous oscillations induced by time delays are observed in many real-world systems. Phase reduction theory for limit-cycle oscillators described by delay-differential equations (DDEs) has been developed to analyze their synchronization properties, but it is applicable only when the perturbation applied to the oscillator is sufficiently weak. In this study, we formulate a nonlinear phase-amplitude reduction theory for limit-cycle oscillators described by DDEs on the basis of the Floquet theorem, which is applicable when the oscillator is subjected to perturbations of moderate intensity. We propose a numerical method to evaluate the leading Floquet eigenvalues, eigenfunctions, and adjoint eigenfunctions necessary for the reduction and derive a set of low-dimensional nonlinear phase-amplitude equations approximately describing the oscillator dynamics. By analyzing an analytically tractable oscillator model with a cubic nonlinearity, we show that the asymptotic phase of the oscillator state in an infinite-dimensional state space can be approximately evaluated and non-trivial bistability of the oscillation amplitude caused by moderately strong periodic perturbations can be predicted on the basis of the derived phase-amplitude equations. We further analyze a model of gene-regulatory oscillator and illustrate that the reduced equations can elucidate the mechanism of its complex dynamics under non-weak perturbations, which may be relevant to real physiological phenomena such as circadian rhythm sleep disorders.
pacs:
05.45.Xt, 02.30.KsI Introduction
Time-delayed feedback can break continuous time-translational symmetry and lead to oscillatory behavior in many physical, biological, social, and engineered systems Glass+ ; Lewis+ ; Dfiremother ; Brent+ ; Peterka+ ; Soriano ; Kalmar+ ; Szydlowski+ . In biology, for example, ultradian oscillations in the hypothalamic-pituitary-adrenal (HPA) system are induced by time-delayed synthesis of hormones in the adrenal cortex Walker+ . Also, somite segmentation in zebrafish is regulated by oscillatory dynamics induced by time delays in the synthesis of proteins Ishimatsu , and mammalian circadian rhythm is generated by feedback regulations of clock genes in suprachiasmatic nucleus (SCN) Lema+ . Such oscillatory dynamics in systems with time delays can be described as stable limit-cycle orbits of delay-differential equations (DDEs).
In many of such systems, each oscillatory unit, or oscillator, is not isolated but perturbed by external forcing or by mutual coupling with other oscillators, and the state of each oscillator may deviate from the unperturbed limit cycle of an isolated oscillator when the perturbation is not sufficiently weak. Therefore, it is important to understand how perturbations of moderate intensity can modulate the period, amplitude, and other properties of delay-induced oscillations.
For example, in the case of zebrafish somite segmentation, it is known that strong couplings between cells are necessary for the spatio-temporal oscillatory dynamics of her1 (zebrafish hairy-related gene1) expression Ishimatsu . In the case of circadian clock genes, the oscillatory period in the free-running condition is known to be slightly different from 24 h, but they are entrained by the periodic external day-and-night lights through retinal ganglion cells SackI ; Berson . Strong light stimulation can further induce large modulation in the activities of the clock genes Ukai+ . Since irregular dynamics of circadian rhythms manifest themselves as diseases such as sleep disorders SackI ; Thorpy+ ; Jones ; Moldofsky , understanding of the dynamics of circadian clock genes under strong perturbations may facilitate therapies for sleep disorders.
The phase reduction theory is a standard mathematical framework for characterizing response properties of weakly perturbed limit-cycle oscillators and analyzing their synchronization dynamics via dimensionality reduction Winfree2 ; Kuramoto ; Pikovsky ; Ermentrout2 ; Nakao ; KuramotoPTRSA ; Ashwin . Recently, the phase reduction theory has been extended also to DDEs exhibiting stable limit-cycle oscillations, which requires non-trivial mathematical generalization because DDEs are infinite-dimensional dynamical systems Kotani ; Pyragas . However, the phase reduction has a strong limitation in that it is applicable only when the oscillator state remains sufficiently close to the unperturbed limit cycle. Specifically, when non-weak perturbations are applied or relaxation time of the system state to the limit cycle is not sufficiently small, the amplitude degrees of freedom may no longer be enslaved by the phase, leading to the breakdown of the lowest-order phase-only description. In such cases, the nonlinear interaction of the phase and amplitude may lead to non-trivial dynamics that cannot be captured by the phase reduction.
To overcome this difficulty, several mathematical frameworks have been proposed for oscillatory systems described by ordinary differential equations (ODEs), such as higher-order phase resetting curves Canavier+ , extended phase equations Rubin+ , and higher-order phase-amplitude equations Castejon+ . Still, for oscillatory dynamics of DDEs away from the limit cycle, much remains unknown because of their infinite-dimensional nature. Thus, a general framework for dimensionality reduction of limit-cycle oscillators described by DDEs that can analyze the effect of moderately strong perturbations is needed. Such a framework would shed light on oscillatory dynamical systems in which nonlinearity, time delay, and strong perturbations coexist.
In this study, our interest lies in the situation where the phase and amplitude of DDEs interact significantly in a nonlinear manner. We develop a nonlinear phase-amplitude reduction theory for DDEs, which gives a general mathematical framework for reducing DDEs describing limit-cycle oscillators to low-dimensional ordinary differential equations on the basis of the Floquet theory Stokes ; Hale ; Simmendinger . We also propose a practical numerical method, which we call the extended adjoint method, to evaluate the Floquet eigenvalues, eigenfunctions, and their adjoint functions, which are necessary for the reduction. By using biorthogonality of the Floquet eigenfunctions and their adjoints, we project the oscillator state onto an eigenspace spanned by a few slowly-decaying Floquet eigenfunctions and derive a set of phase-amplitude equations which takes into account nonlinear interactions between the slowly-decaying Floquet eigenmodes. In contrast to the standard lowest-order phase reduction, the amplitude component associated with the second Floquet eigenfunction is included, which can play important roles when the relaxation of the system is slow or when the system is strongly perturbed.
We confirm the validity of the theory using an analytically-tractable DDE with a cubic nonlinearity by showing that the reduced phase-amplitude equations accurately predict the amplitude of the phase-locked oscillations under a periodic force, which exhibits non-trivial bistable response induced by the non-weak amplitude effects. We then apply the theory to a model of a gene-regulatory oscillator under moderately strong forcing and analyze its synchronization dynamics. We show that the reduced phase-amplitude equations can also predict nontrivial bistable dynamics of the system, which is analogous to a circadian disorder called advanced sleep-phase syndrome (ASPS) Thorpy+ ; Jones ; Moldofsky .
II Theory
In this section, we derive a set of reduced nonlinear phase-amplitude equations for limit-cycle oscillators described by DDEs on the basis of the Floquet theory and propose a practical numerical method to calculate the Floquet eigenvalues, eigenfunctions and their adjoints that are necessary for the reduction. We also derive approximate phase-amplitude equations for the oscillators subjected to periodic external forcing.
II.1 DDEs with a stable limit-cycle solution
We consider general delay-differential equations (DDEs) that have a stable limit-cycle solution. Mathematical analysis of such DDEs, for example, analyzing the synchronization properties when they are periodically perturbed, is not easy because they describe nonlinear infinite-dimensional dynamical systems on Banach spaces. Our aim is to derive simpler tractable equations by reducing them to low-dimensional ODEs while preserving their essential quantitative properties and to analyze synchronization dynamics of nonlinear oscillators described by such DDEs under moderately strong external perturbations. In previous studies Kotani ; Pyragas , phase reduction methods for stable limit-cycle solutions of DDEs have been developed, which are applicable when the perturbations given to the system is sufficiently weak. In this study, we develop a nonlinear phase-amplitude reduction theory for DDEs.
We consider a DDE for , represented as a column vector, with a maximum delay time . To construct a solution of the DDE, we have to take into account the history of from to . Thus, we introduce its history-function representation, Stokes ; Hale ; Simmendinger . Here, and is a Banach space of (column) vector-valued continuous functions mapping into , which is equipped with a norm , where is the usual Euclidean norm on . This history function represents the state of the dynamical system described by the DDE at time , where the state space of the system is given by the infinite-dimensional Banach space .
Using the above notation, a DDE can generally be written as
(4) |
Here, the vector-valued functional represents the system dynamics and denotes external perturbation applied to the system that depends on the system state . Both functionals are assumed to be sufficiently smooth. This DDE can describe not only systems with discrete delays but also systems with distributed delays Wischert ; see Ref. Palm for the relation between nonlinear functionals and their kernel representations, which are widely used for systems with distributed delays described by integro-differential equations.
We consider a situation in which the DDE (4) without the external perturbation () has a stable limit-cycle solution whose period is , i.e., , and represent it as a history function satisfying , where
(5) |
In what follows, we also denote the limit cycle as , where we use the phase () in place of the time to parametrize system state on the limit cycle. The phase increases from to , where the origin can be chosen as a specific system state on the limit cycle. When the system state evolves along the limit cycle without perturbation, the phase increases with a constant frequency , i.e., . Similarly, we also denote -periodic history functions, such as the Floquet eigenfunctions, using the phase instead of when necessary.
The definition of the phase can further be extended to the basin of attraction of the limit cycle by assigning the same phase value to the set of system states that asymptotically converge to the same system state as when the system evolves without perturbation Kotani ; Pyragas , i.e., , yielding the notion of asymptotic phase that maps a system state in the basin to a phase value. The asymptotic phase satisfies
(6) |
when the system state evolves in the basin of the limit cycle without perturbation. The isosurfaces of , called isochrons, are not simply hyperplanes in general. For ordinary differential equations, the asymptotic phase has been used as a canonical representation of rhythms of stable oscillatory dynamics Winfree2 ; Kuramoto ; Pikovsky ; Ermentrout2 ; Hale_ODE and provides in-depth insights into strongly-perturbed oscillatory dynamics Ashwin ; Canavier+ ; Rubin+ ; Castejon+ ; Rabinovitch+ . Recently, it has also been defined for DDEs and other non-conventional oscillatory systems Kotani ; Pyragas .
We assume that the relaxation dynamics of the system state to the limit cycle can be decomposed into a few slow modes and remaining faster modes, which are well separated in time scale from each other. In this case, a rectangular coordinate frame moving along the periodic orbit, which was used in Refs. Hale_ODE ; Wedgwood ; Medvedev , is not useful for reducing the dynamics to low-dimensional ODEs, because fast and slow components interact already at the lowest order in this coordinate frame. It is also not easy to proceed with the asymptotic phase and associated amplitudes, because they are generally given by highly nonlinear functionals of the system state . We therefore use a coordinate frame defined by the Floquet eigenfunctions to decompose the system state as discussed in Ref. KuramotoPTRSA for ODEs. The space spanned by the Floquet eigenfunctions with non-vanishing relaxation rates is tangent to the isochron at each point on the limit cycle. For this purpose, we need to calculate the Floquet eigenvalues, eigenfunctions, and their adjoints of DDEs.
II.2 Floquet theory for DDEs
We first describe the Floquet theory for the DDE (4) without the perturbation term, i.e., . We denote small deviation of from as , and introduce its history-function representation with as
(7) |
The linearized variational equation for is given by
(8) |
where is a history representation of a linear functional defined by
(12) |
Here,
(13) |
is a functional differentiation of with respect to evaluated at the system state on the limit cycle. Note that Eq. (8) gives a periodically driven linear system because is -periodic. In what follows, we expand in a functional Taylor series in as
(14) |
where represents a linear functional of defined in Eq. (12) with and represents the remaining nonlinear functional of , respectively, and both of these functionals are evaluated at .
As an example, let us consider a simple DDE,
(15) |
which is equivalent to
(19) |
in the history-function representation. By using the chain rule for functional differentiation and representing the terms in as
(20) |
and
(21) |
using Dirac’s delta function , we obtain
(22) |
where is evaluated at . The linearized dynamics for the deviation can then be written as
(26) |
Let us introduce a time-periodic linear operator of period , which acts on a complexified Banach space (Diekmann, , Sec. III.7) as
(27) |
and rewrite Eq. (8) as . Because obeys a periodically driven linear system, by the Floquet theorem for linear DDEs Stokes ; Hale ; Simmendinger , the spectrum of is at most countable and
(28) |
is satisfied, where is the -th Floquet eigenvalue and is the corresponding -periodic Floquet eigenfunction (). Here, the largest eigenvalue, which is and simple by the Floquet theorem, is denoted as and the other eigenvalues are arranged in descending order of the real part.
We also introduce adjoint eigenfunctions with respect to a bilinear form appropriate for DDEs bilinear . Following Refs. Stokes ; Hale ; Simmendinger , we define a bilinear form of two functions, and , as
(29) |
Here, is the dual space of with respect to the bilinear form, consisting of (row) vector-valued functions that map the interval to , and denotes the Hermitian scalar product of and defined as where and are vector components of and , respectively. An adjoint operator of with respect to this bilinear form can then be derived as
(30) |
where
(34) |
Here, is a row vector of complex components and is its history-function representation.
The adjoint eigenfunction of , which is also -periodic, satisfies
(35) |
where is the complex conjugate of . If , is orthogonal to with respect to the bilinear form Eq. (29), and hence they can be normalized to satisfy the biorthogonal relation . The zero eigenfunction of the linear operator can be chosen as (), which can be confirmed by differentiating Eq. (4) with respect to at on the periodic orbit Kotani . Note that this definition specifies the normalization of . For the other eigenfunctions (), we normalize them such that . We use this convention for the normalization throughout this study. We note that the zero eigenfunction of the linear operator corresponds to the tangential component along the limit cycle, namely, the phase direction. Moreover, the zero eigenfunction of the adjoint operator gives the phase sensitivity function of the limit cycle, which characterizes linear response property of the oscillator phase to weak perturbations Kotani ; Pyragas . Similarly, the other eigenfunctions () characterize linear response properties of the amplitudes and called isostable response curves for the case of ODEs ErmentroutPTRSA .
The adjoint eigenfunctions can numerically be obtained by an extension of the adjoint method for DDEs, which was previously used to calculate the adjoint zero eigenfunction of Kotani ; Pyragas . That is, we numerically integrate the linearized and its adjoint equations while subtracting unnecessary functional components by using the biorthogonality between the eigenfunctions and adjoint eigenfunctions. The main difference from the adjoint method for developed in the previous studies is that we calculate the adjoint eigenfunctions also for . Therefore, during numerical integration, we need to remove unnecessary functional components in the directions of the lower-order eigenfunctions from -th to -th, which grow faster than the -th component in order to calculate the -th eigenfunction precisely. For , we also need to renormalize the solutions of the equations by a factor determined by the Floquet exponent in order to obtain the correct eigenfunctions.
To numerically calculate the -th eigenfunction , we integrate the linearized equation
(36) |
forward in time. During the calculation, we subtract the -th to -th eigencomponents from the numerical , which are unnecessary but arises due to numerical errors. The Floquet eigenvalue is numerically evaluated from the exponential decay rate of . Then the eigenfunction is obtained by compensating the exponential decay of as (). See Sec. III.C and Ref. footnotesec3c for further details. In a similar way, the -th adjoint eigenfunction is calculated by numerically integrating the adjoint linear equation
(37) |
backward in time while subtracting unnecessary eigencomponents and then compensating the numerical result by a factor . We call this procedure the extended adjoint method in this study.
II.3 Nonlinear phase-amplitude equations
Our aim is to derive a set of low-dimensional dynamical equations from the original DDE by projecting the system state onto a moving coordinate frame spanned by a small number of Floquet eigenfunctions. That is, we decompose the deviation of the system state from that on the limit cycle by using the eigenfunctions associated with the leading eigenvalues other than , which are assumed to be real and simple for the sake of simplicity lambda_complex , as
(38) |
where is a system state on the limit cycle parametrized by the phase , () is the Floquet eigenfunction associated with and denoted as a function of rather than , and are real expansion coefficients representing amplitudes of the Floquet eigenmodes. The symbol indicates that we approximate by its projection on the space spanned by the eigenfunctions . We here use the term “amplitude” in a generalized sense, allowing it to take both positive and negative values; it is the component of the system state along the Floquet eigenfunction corresponding to the direction transversal to the limit cycle and represents the deviation of the system state from the limit cycle. Here, the phase value for a given state is determined in such a way that the state difference does not have a tangential functional component along the limit cycle. Thus, we assume the following orthogonality condition:
(39) |
namely, the difference is on the hyperplane that is tangent to the isochron on the limit cycle at . Note that the phase defined in this way is different from the asymptotic phase.
Because we use a linear coordinate frame spanned by the Floquet eigenfunctions (), nonlinear interactions between different eigenmodes generally arise. Specifically, when the eigenvalue with the largest non-zero part is close to , the perturbed system state does not go back to the limit cycle quickly, and hence nonlinear interactions between the phase eigenmode and the slowest-decaying amplitude eigenmode should be taken into account for better description of the system.
For ordinary differential equations, such coupled nonlinear phase-amplitude equations have been derived by transforming the original equations around the limit cycle in several contexts Wedgwood ; Morita . Such transformation methods have also been developed for DDEs in Refs. Stokes2 ; Hale2 , though the treatments of oscillatory dynamics in these studies are rather abstract. Quantitative analysis of synchronization dynamics of DDEs using the coordinate transform proposed therein have not been very fruitful despite their potential advantages, mainly due to the lack of practical methods for numerically evaluating the Floquet eigenfunctions.
We hereafter restrict ourselves to the case in which takes a negative real value near zero and for simplicity. To derive the phase and amplitude equations, we retain only the slowest two modes associated with and and approximate as
(40) |
where is the amplitude of the eigenmode corresponding to . The symbol here indicates that we further approximate by its projection on a one-dimensional space spanned by . We substitute this expression into Eq. (4) and then project both sides of Eq. (4) onto the eigenfunctions and , respectively, by using biorthogonality of the eigenfunctions and derive the equations for the phase and the amplitude .
As explained in Appendix A, the phase equation can be derived as
(41) |
or, by rewriting the right-hand side,
(42) | ||||
(43) |
and the amplitude equation can similarly be derived as
(44) | ||||
(45) |
where the nonlinear functional in Eq. (14) is approximated by an ordinary function of and ,
(46) |
and the external perturbation is also approximated as
(47) |
In Eq. (43) and Eq. (45), both the second and third terms on the right-hand side depend on and . Note that includes only terms of or higher, because the constant terms and linear terms in have already been subtracted in Eq. (46).
Thus, by projecting the DDE onto the first two eigenfunctions, a set of two-dimensional coupled ordinary differential equations for the phase and amplitude is obtained. In order to consider the higher-order effects of the amplitude deviations, we have not expanded the third-order terms in Eq. (43) and Eq. (45) in a series of and hence the dynamics of and are nonlinearly coupled at the second and higher orders in . This nonlinearity can be a source of intriguing oscillatory dynamics Canavier+ ; Rubin+ ; Castejon+ ; Rabinovitch+ . We also note that the lowest-order phase-amplitude equations (see Refs. Castejon+ ; ErmentroutPTRSA ; KuramotoPTRSA for the case of ODEs)
(48) | ||||
(49) |
are obtained at the lowest-order approximation in , where is and does not appear at the lowest order.
Finally, before proceeding, we note that there are also other formulations of phase or phase-amplitude reduced equations for analyzing higher-order effects of perturbations on limit cycles described by ODEs, such as non-pairwise phase interactions KuramotoPTRSA , higher-order phase reduction Pazo , nonlinear phase coupling function RosenblumPTRSA , and higher-order approximations of coupling functions ErmentroutPTRSA , which can capture more detailed aspects of synchronization than the lowest-order phase equation.
II.4 Averaged phase-amplitude equations
When the perturbation applied to the oscillator is a periodic external force whose frequency is close to the natural frequency of the oscillator, we may further derive simpler, approximate phase-amplitude equations by averaging out the fast oscillatory component as follows.
We assume that the perturbation is purely external (i.e. independent of the system state and periodic in with period (frequency ), i.e.,
(50) |
We also assume that the detuning between the natural frequency of the oscillator and the periodic force is small and denote it as .
We introduce a slow phase variable . The equations for and can be written as
(51) |
and
(52) | ||||
(53) | ||||
(54) |
We also expand the nonlinear term in Taylor series of up to as
(55) |
where () are expansion coefficients. Note that the series for starts from .
Considering that evolves only slowly while rapidly increases, we approximate the terms with in Eqs. (51) and (54) by their one-period average, for example, as
(56) |
and
(57) |
where is kept constant during the integration. Expanding up to and averaging the coefficients, we obtain approximate equations for and as
(58) |
and
(59) |
where the equations for the individual coefficients are given in Appendix B. We check the validity of the above averaging approximation numerically in the next section.
II.5 Evaluation of the phase and amplitude
Numerically, the values of the phase and amplitude can be evaluated from the system state by the following two-step procedure. First, we evaluate the phase of the state by choosing the phase value so that it satisfies the orthogonality condition Eq. (39). Numerically, we find the value that minimizes the mean squared error,
(60) |
There exists a neighborhood of the periodic orbit where the phase and amplitude components defined by using the Floquet eigenfunctions are uniquely determined (Hale2, , Lemma1). However, in general, there can exist multiple values of that satisfy Eq. (39) in the range . To choose the appropriate value from them, for each candidate of , we evaluate the corresponding component as
(61) |
and adopt the value of that has the smallest as the estimate of , and the smallest as the estimate of .
II.6 Approximate evaluation of the asymptotic phase
The phase defined by the Floquet eigenfunction, which we use in the present study for the phase-amplitude description, is different from the asymptotic phase ; the isosurface of is generally curved and tangent to the isophase plane of at each point on the limit cycle. Since the asymptotic phase provides useful information on the nonlinear dynamical properties of the oscillator, it is convenient if we can approximate using and . In this subsection, we propose a method to approximately evaluate the asymptotic phase of an unperturbed oscillator from and defined by the Floquet eigenfunctions, which is valid when is sufficiently small.
When the perturbation is absent (), Eq. (41) for can be written as
(62) |
where
(63) |
The asymptotic phase of the system state at time with phase and amplitude can approximately be obtained by integrating until the system state goes back sufficiently close to the limit cycle as
(64) |
When is sufficiently small, we may ignore the higher-order terms in in the equations for and and assume that increases constantly with frequency and decays exponentially with rate as
(65) |
at the lowest-order approximation. The asymptotic phase of the system state can then be approximately evaluated as
(66) |
In Sec. III E and Sec. IV, we use the above method to estimate the asymptotic phase of the oscillator and compare it with direct numerical results.
III Analytically tractable model
To demonstrate the validity of the proposed framework, we first consider a limit-cycle oscillator described by a scalar DDE with a cubic nonlinearity, for which approximate expressions of the Floquet eigenfunctions and their adjoints can be analytically derived, and analyze the effect of a periodic force on the dynamics.
III.1 Model
The model is represented as
(67) |
where , is a small constant, and the external periodic force is described by
(68) |
where is the intensity of the periodic force and is the ratio of the natural frequency of the limit cycle to that of the external force. It is assumed that is sufficiently close to .
When , this DDE has a limit cycle of period given by , or
(69) |
in the history-function representation, and its rate of attraction to the limit cycle is determined by . When is small, the relaxation time of the system state to the limit cycle is considerably large as compared to the oscillation period as shown in Figs. 1(a) and (b).
We denote the small deviation of the system state from the limit cycle as . The linear operator of this system is given by Eq. (12) with
(70) |
where is Dirac’s delta function. By retaining the first two leading eigenvalues, the nonlinear phase-amplitude equations can be derived as Eqs. (43) and (45).
III.2 Approximate analytical expressions of the eigenvalues and eigenfunctions
We first derive approximate Floquet eigenvalues, eigenfunctions, and adjoint eigenfunctions of the model Eq. (67) without the external force () analytically. In what follows, we consider the case in which the relaxation of the system state to the limit cycle is slow and assume that is small and . First, the zero eigenfunction of is given exactly as
(71) |
and the adjoint eigenfunction is
(72) |
To find the exponent with the second largest real part, we introduce an ansatz
(73) |
where is a constant and plug this into Eqs. (8) and (12). We then obtain the approximate eigenvalue and the associated eigenfunction up to as
(74) |
and
(75) |
respectively. Similarly, for the corresponding adjoint eigenfunction, we approximately obtain
(76) |
where the constant is determined from the normalization condition .
III.3 Numerical evaluation of the eigenvalues and eigenfunctions
To confirm the validity of the approximate analytical results for the Floquet eigenvalues, eigenfunctions, and adjoint eigenfunctions obtained in the previous subsection, we numerically evaluate these quantities by the extended adjoint method and compare with the approximate analytical results.
First, as in the conventional adjoint method for DDEs Kotani ; Pyragas , we compute , which is simply , and then by backwardly integrating the adjoint linear equation. The adjoint eigenfunction is normalized such that . Next, we obtain the eigenfunction with the largest negative eigenvalue (, for ) lambda_complex . As an initial function, we take an arbitrary function at comment0 , subtract the component from this initial function as (), where the second term represents the projection of onto , and numerically integrate the linear equation (36) for from this initial condition to as explained before.
Similarly, in order to compute the eigenfunction , we initialize () appropriately and numerically integrate Eq. (37) backward in time, subtracting the component at every period, and compensate the exponential decay in the numerical solution. The adjoint eigenfunction is normalized so that .
Figure 1(c) shows the exponential decay of the peak heights of , from which we obtain the Floquet eigenvalue . Figure 1(d) shows the time course of that is used for numerical computation of eigenfunction . Figures 1(e) and (f) show the obtained pair of Floquet eigenfunctions, where and are plotted with respect to in Fig. 1(e), and and are plotted with respect to in Fig. 1(f). We can confirm a good agreement between the numerical results and approximate analytical results for the eigenfunctions. The numerical value of the largest negative exponent is approximately evaluated as , which is also close to the theoretical value .
III.4 Phase-amplitude equations
We now derive a set of nonlinear phase-amplitude equations from Eq. (67) with the periodic sinusoidal force. The nonlinear term in Eq. (46) is explicitly given by
(77) | |||||
and the reduced equations (43) and (45) for and can be derived using this equation.
Expanding the nonlinear term and applying the averaging procedure, the approximate equations for the phase difference and are given in the form of Eqs. (58) and (59) with
(78) |
and
(79) |
Using numerically evaluated eigenvalues and eigenfunctions, the coefficients in Eqs. (58) and (59) can be calculated as , ,, ; ,, ; and , , , and . From these coefficients, the equations for the phase difference and the amplitude are obtained as
(80) | ||||
(81) | ||||
(82) |
Thus, we have approximately reduced an infinite-dimensional dynamical system described by a DDE to a set of ODEs for the phase and amplitude.
III.5 Approximate evaluation of the asymptotic phase
In this subsection, we verify the validity of the approximate expression for the asymptotic phase derived in Sec. II F by evolving the present model from initial conditions far from the limit cycle. From the reduced phase-amplitude equations and Eq. (66), the asymptotic phase for the present model can be approximately evaluated from the phase and amplitude as
(83) |
up to . For a given system state , the phase and amplitude can be evaluated as explained in Sec. II E, and the approximate asymptotic phase can then be obtained by Eq. (83). We also directly evaluate the asymptotic phase for several initial conditions by numerically integrating the system and measuring the time necessary for the system state to converge sufficiently close to the limit cycle for comparison.
As the first example, we try to estimate when the initial function is on the - plane, that is, (). Figure 2 (a) shows for given initial values of and obtained by direct numerical integration of the DDE, and Fig. 2 (b) shows analytical results of obtained from Eq. (83). Figure 2 (c) shows the absolute difference between and its analytical estimation . We can confirm a good agreement between the approximate analytical curve and direct numerical results for the whole range of when is not too large.
As the second example, we consider initial functions that are not on the - plane. We set the initial functions as ) with varying values of comment1 , and evaluated their asymptotic phase by direct numerical integration of the DDE. Figure 2 (d) shows the phase , the asymptotic phase estimated by Eq. (83), and the asymptotic phase obtained by direct numerical integration. We can confirm that the approximate analytical estimate of the asymptotic phase given by Eq. (83) gives reasonable agreement with the direct numerical results even though the system state is considerably far from the - plane.
III.6 Effect of a periodic force on the amplitude
In this subsection, we consider the effect of a periodic external force of moderate intensity with small frequency detuning. In particular, we focus on the average effect of the periodic force on the amplitude in the phase-locked state, which cannot be analyzed without the amplitude equation.
Since in Eq. (78), the -nullcline on which is obtained from the averaged equation (58) as
(84) |
when the argument of is in the range . By substituting Eq. (84) into Eq. (59), we can obtain the fixed points of the averaged amplitude dynamics satisfying , where represents the right-hand side of Eq. (59). The effect of the intensity of the periodic force and the detuning on the stationary amplitude of the oscillation in the steady state can be evaluated from the partial derivatives of by the implicit function theorem.
Figure 3 shows the predicted amplitude of the oscillation. The dependence of the amplitude on at is plotted in Fig. 3(a), where the stationary amplitude obtained from the averaged phase-amplitude equations (58) and (59) are compared with the linear approximation of the stationary amplitude with a slope . Similarly, Fig. 3 (b) shows the dependence of the amplitude on at , where the result of the phase-amplitude equations are compared with linear approximation of the amplitude with a slope . We can confirm that the linear approximation appropriately predicts the changes in the stationary amplitude of the delay-induced oscillator subjected to a non-weak external periodic force when it is slightly modulated. Moreover, the nonlinear phase-amplitude equations can predict the amplitude more precisely than the linear approximation in the given parameter range.
III.7 Bistable response of delay-induced oscillation to a periodic force
In this subsection, we demonstrate that the present model can exhibit a nontrivial bistable response to a periodic force by a bifurcation analysis of Eq. (58) and Eq. (59). Such a phenomenon results from higher-order amplitude effects and cannot be described by the phase-only equation nor the lowest-order phase-amplitude equations. Using XPP-AUTO XPP , we numerically find stationary solutions in the range where the inverse exists (note that ). Depending on the parameters and , we observe quantitatively different behaviors of the system state as shown in Fig. 4.
Figures 4 (a) and (b) show the stable and unstable fixed points on the (, )-plane at two different values of . The system is always monostable when , while a bistable region where can take two stable fixed points is found around when . Thus, it is expected that DDE (67) with shows bistable dynamics. Figure 4 (c) shows the nullclines and stable fixed points on the - plane at and . The two crosses show the stable fixed points at and , and the two black lines show the trajectories started from and . These predictions from the reduced phase-amplitude equations can be confirmed in Fig. 4 (d), which shows the results of direct numerical integration of DDE (67) with . We can clearly observe the bistable dynamics of the oscillator caused by moderately strong periodic forcing.
IV Gene-regulatory oscillator
In this section, as a more complex, biologically-motivated example of DDEs, we investigate a model of gene regulation Dfiremother under a periodic sinusoidal force given by
(85) |
where is the state variable representing protein concentration and , and the delay time are real parameters. The first term of the right-hand side represents protein synthesis with time delay for transcription and translation, while the second and the third terms represent degradation and dilution of the protein, respectively. Following the previous research Dfiremother , we set , , and . The external periodic force is with intensity and frequency mismatch . We set the rate constant of synthesis as , degradation as , and Michaelis constant of degradation as so that the system exhibits a slow convergence to a limit cycle orbit and the effect of the amplitude dynamics can be clearly observed.
This system has a stable limit cycle with a period , which can be obtained only numerically. Figures 5 shows the system state converging toward the limit-cycle attractor; Fig. 5(a) plots the time course of as a function of and Fig. 5(b) shows the system trajectory projected on the -plane. The time constant of the relaxation to the limit cycle is much larger than the period of the oscillation as can be seen from the figures.
For this model, the -periodic linear operator is given by Eq. (27) with
(86) |
Figures 5 (c) and 5(d) show the first two eigenfunctions and adjoint eigenfunctions of obtained by the extended adjoint method origin , respectively. The second largest Floquet exponent is in this case. From these eigenfunctions, the phase-amplitude equations (58) and (59) under the sinusoidal force can be obtained, where the coefficients are given by , , , , , , , , , and .
We first evaluate the validity of the approximate expression of the asymptotic phase in the absence of the external force (). We take the initial condition as a constant function, , and evaluate the asymptotic phase by Eq. (66) and by direct numerical integration of the DDE. Figure 6 (a) shows the phase , the asymptotic phase estimated by using Eq. (66), and the asymptotic phase evaluated by direct numerical integration of the DDE. It can be seen that the approximate analytical result reproduces the result of direct numerical measurement of the asymptotic phase.
We next consider how the gene-regulatory oscillator behaves when it is subjected to a periodic external force. We conduct bifurcation analysis for different values of and in the same way as that for Eq. (67) using XPP-AUTO. When the external periodic force is weak () and the frequency mismatch is small enough, the system is synchronized to the periodic force with a single stable amplitude as shown in Fig. 6(b), namely, the amplitude response is monostable. When we apply a stronger force, , the region of synchronization becomes wider. The amplitude of synchronized oscillations is positive when the frequency mismatch is small, whereas the amplitude is negative when the mismatch is large. Moreover, there exists a bistable region around as shown in Fig. 6(c), where can take either of two stable values, similar to the previous simpler model with a cubic nonlinearity described by Eq. (67).
Figure 6 (d) shows two time courses of DDE (85) with and with different initial conditions. In this case, a small-amplitude out-of-phase oscillation emerges in addition to the large-amplitude oscillation that exists in a wider range of . Both types of oscillations are stable. In the video in the Supplemental Material supp , the slow convergence of the system state to either of these two oscillatory states are visualized by projecting the system state onto the -plane. It is noteworthy that the frequency mismatch required for this bistable dynamics is very small (less than 1 %) in this model.
V Summary
In this study, we have developed a general mathematical framework for reducing delay-induced limit-cycle oscillators described by DDEs into a set of nonlinear phase-amplitude equations on the basis of the Floquet theory. By projecting the original equation onto the reduced phase space spanned by the first two Floquet eigenfunctions, we derived a set of nonlinear phase-amplitude equations. We proposed an extended adjoint method for DDEs to numerically calculate the Floquet eigenfunctions and their adjoint eigenfunctions. We also developed a method to estimate the asymptotic phase of the system states in a neighborhood of the limit cycle from the phase and amplitude defined by the Floquet eigenfunctions. The validity of the framework has been confirmed by analyzing two models of delay-induced oscillations. In the present framework, the derivation of the reduced equations requires only the calculation of the first two Floquet and adjoint eigenfunctions. Therefore, the reduction is practically manageable even though the dynamical system to be reduced is an infinite-dimensional DDE.
Despite the simplicity, the resulting reduced equations convey richer information than simply linearizing the system state around the periodic orbit. To illustrate this, we first studied an analytically tractable DDE with a cubic nonlinearity. We derived an approximate expression of the nonlinear asymptotic phase in terms of the phase and amplitude and verified its validity using direct numerical integration of the original system. Moreover, we revealed nontrivial bistable synchronization of the system with a periodic external forcing, where the amplitude can take two different stable values depending on the initial condition, which cannot be analyzed within the conventional phase-only or the lowest-order phase-amplitude equations. We also analyzed a model of gene-regulatory oscillator and showed that the reduced phase-amplitude equations also enabled us to capture the nontrivial bistable synchronization with a non-weak periodic force.
The result for the gene-regulatory oscillator provides analytical insights into how the weak attraction of the limit cycle and nonlinear interactions between the phase and amplitude can alter the synchronization dynamics of gene regulatory systems for circadian oscillations. For example, it is known that, in the case of ASPS, out-of-phase (phase-advanced) synchronized oscillation with the day-and-night lights is stabilized in a similar manner to that is shown in Fig. 6(d) of the second model. It has also been reported that the free-running period of circadian oscillation in ASPS patients is shorter than 24 h Jones , and the temporal therapy (phase advance chronotherapy) can alter the out-of-phase synchronization into in-phase synchronization Moldofsky . Our theoretical results imply that weak attraction of the limit cycle and nonlinear interactions between the phase and amplitude could induce small-amplitude oscillations and bistability of the out-of phase and in-phase synchronized states. If this is the case, the rate of attraction of the system state to the limit cycle, the Floquet exponent in our study, could be used as another effective index to understand circadian rhythm disorders in addition to conventional indices like the free-running periods and amplitudes of oscillation Lema+ ; Thorpy+ ; Jones ; Ukai+ . Thus, the phase-amplitude analysis of delay-induced oscillations developed in this study can shed new light on the complex biological rhythms.
There are many other examples of natural and artificial systems that exhibit complex oscillations due to the effect of time delay Glass+ ; Lewis+ ; Dfiremother ; Brent+ ; Peterka+ ; Soriano ; Kalmar+ ; Szydlowski+ . For example, breathing of chronic heart failure patients is a typical example of such natural systems Glass+ . The present study would provide further insights into nontrivial breathing dynamics. An example of artificial systems is the Mackey-Glass electrical circuit MGC that can be modeled by a DDE, for which the present theory is readily applicable to analyze the synchronization dynamics. The present framework for reducing such time-delayed systems to a set of nonlinear phase-amplitude equations can be useful as a general analytical method to elucidate the origin of complex synchronization properties under the effect of non-weak perturbations or fluctuations. Further investigation on the nonlinear phase-amplitude equations would provide us with more insight into the synchronization dynamics in time-delayed systems.
VI Acknowledgments
We thank Yuki Shimono for helpful advice on computation of the eigenfunctions and G. Bard Ermentrout for fruitful discussion. This study is supported in part by JSPS KAKENHI (18H04122), The Asahi Glass Foundation, and JST PRESTO (JPMJPR14E2) to KK, and JSPS KAKENHI (JP16K13847, JP17H03279, 18K03471, and JP18H03287) and JST CREST (JPMJCR1913) to HN.
Appendix A Derivation of the nonlinear phase-amplitude equations
In this section, details of the derivation of the phase-amplitude equations are presented. We first define a phase along the unperturbed limit cycle of Eq. (4), and represent the -periodic eigenfunctions as functions of the phase as , where . Because we assume that the functional components associated with the eigenvalues decay quickly, we approximate the system state as (), where is the system state with phase on the limit cycle and is the amplitude of the eigencomponent corresponding to . Substitution of this approximation into the functional differential equation (4) yields
(87) | |||
(88) |
where
(89) |
To derive the phase equation, we project both sides of Eq. (88) onto the eigenfunction . Using the relations
(90) |
(91) |
and
(92) |
which follows from the definition , we obtain
(93) | |||||
The phase equation is thus given by
(94) | |||||
Appendix B Coefficients of the phase-amplitude equations
The expressions for the individual expansion coefficients in the phase and amplitude equations (58) and (59) are as follows.
(98) |
(99) |
(100) |
(101) |
(102) |
(103) |
(104) |
and
(105) |
Appendix C Supplementary video
This supplementary video shows how the oscillators converge to either of the two stable oscillatory states. We numerically integrated the DDE (85) of gene-regulatory oscillators subjected to a common sinusoidal external periodic force from several initial conditions from to . The parameters of the external force are and . The initial amplitude and phase of each oscillator is and .
In panel (a) of the video, the states of the oscillators projected onto the -plane are plotted. In panel (b) of the video, the time courses from two representative initial conditions are shown, where the magenta line is for and the blue one is for .






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