Neuronal activity induces symmetry breaking in neurodegenerative disease spreading.

Dynamical systems on networks typically involve several dynamical processes evolving at different timescales. For instance, in Alzheimer's disease, the spread of toxic protein throughout the brain not only disrupts neuronal activity but is also influenced by neuronal activity itself, establishing a feedback loop between the fast neuronal activity and the slow protein spreading. Motivated by the case of Alzheimer's disease, we study the multiple-timescale dynamics of a heterodimer spreading process on an adaptive network of Kuramoto oscillators. Using a minimal two-node model, we establish that heterogeneous oscillatory activity facilitates toxic outbreaks and induces symmetry breaking in the spreading patterns. We then extend the model formulation to larger networks and perform numerical simulations of the slow-fast dynamics on common network motifs and on the brain connectome. The simulations corroborate the findings from the minimal model, underscoring the significance of multiple-timescale dynamics in the modeling of neurodegenerative diseases.

Mean-Field Approximations With Adaptive Coupling for Networks With Spike-Timing-Dependent Plasticity.

Understanding the effect of spike-timing-dependent plasticity (STDP) is key to elucidating how neural networks change over long timescales and to design interventions aimed at modulating such networks in neurological disorders. However, progress is restricted by the significant computational cost associated with simulating neural network models with STDP and by the lack of low-dimensional description that could provide analytical insights. Phase-difference-dependent plasticity (PDDP) rules approximate STDP in phase oscillator networks, which prescribe synaptic changes based on phase differences of neuron pairs rather than differences in spike timing. Here we construct mean-field approximations for phase oscillator networks with STDP to describe part of the phase space for this very high-dimensional system. We first show that single-harmonic PDDP rules can approximate a simple form of symmetric STDP, while multiharmonic rules are required to accurately approximate causal STDP. We then derive exact expressions for the evolution of the average PDDP coupling weight in terms of network synchrony. For adaptive networks of Kuramoto oscillators that form clusters, we formulate a family of low-dimensional descriptions based on the mean-field dynamics of each cluster and average coupling weights between and within clusters. Finally, we show that such a two-cluster mean-field model can be fitted to synthetic data to provide a low-dimensional approximation of a full adaptive network with symmetric STDP. Our framework represents a step toward a low-dimensional description of adaptive networks with STDP, and could for example inform the development of new therapies aimed at maximizing the long-lasting effects of brain stimulation.

A multi-scale model explains oscillatory slowing and neuronal hyperactivity in Alzheimer's disease.

Alzheimer's disease is the most common cause of dementia and is linked to the spreading of pathological amyloid-ß and tau proteins throughout the brain. Recent studies have highlighted stark differences in how amyloid-ß and tau affect neurons at the cellular scale. On a larger scale, Alzheimer's patients are observed to undergo a period of early-stage neuronal hyperactivation followed by neurodegeneration and frequency slowing of neuronal oscillations. Herein, we model the spreading of both amyloid-ß and tau across a human connectome and investigate how the neuronal dynamics are affected by disease progression. By including the effects of both amyloid-ß and tau pathology, we find that our model explains AD-related frequency slowing, early-stage hyperactivation and late-stage hypoactivation. By testing different hypotheses, we show that hyperactivation and frequency slowing are not due to the topological interactions between different regions but are mostly the result of local neurotoxicity induced by amyloid-ß and tau protein.

Symmetry breaking yields chimeras in two small populations of Kuramoto-type oscillators.

Despite their simplicity, networks of coupled phase oscillators can give rise to intriguing collective dynamical phenomena. However, the symmetries of globally and identically coupled identical units do not allow solutions where distinct oscillators are frequency-unlocked-a necessary condition for the emergence of chimeras. Thus, forced symmetry breaking is necessary to observe chimera-type solutions. Here, we consider the bifurcations that arise when full permutational symmetry is broken for the network to consist of coupled populations. We consider the smallest possible network composed of four phase oscillators and elucidate the phase space structure, (partial) integrability for some parameter values, and how the bifurcations away from full symmetry lead to frequency-unlocked weak chimera solutions. Since such solutions wind around a torus they must arise in a global bifurcation scenario. Moreover, periodic weak chimeras undergo a period-doubling cascade leading to chaos. The resulting chaotic dynamics with distinct frequencies do not rely on amplitude variation and arise in the smallest networks that support chaos.

Metastable oscillatory modes emerge from synchronization in the brain spacetime connectome.

A rich repertoire of oscillatory signals is detected from human brains with electro- and magnetoencephalography (EEG/MEG). However, the principles underwriting coherent oscillations and their link with neural activity remain under debate. Here, we revisit the mechanistic hypothesis that transient brain rhythms are a signature of metastable synchronization, occurring at reduced collective frequencies due to delays between brain areas. We consider a system of damped oscillators in the presence of background noise - approximating the short-lived gamma-frequency oscillations generated within neuronal circuits - coupled according to the diffusion weighted tractography between brain areas. Varying the global coupling strength and conduction speed, we identify a critical regime where spatially and spectrally resolved metastable oscillatory modes (MOMs) emerge at sub-gamma frequencies, approximating the MEG power spectra from 89 healthy individuals at rest. Further, we demonstrate that the frequency, duration, and scale of MOMs - as well as the frequency-specific envelope functional connectivity - can be controlled by global parameters, while the connectome structure remains unchanged. Grounded in the physics of delay-coupled oscillators, these numerical analyses demonstrate how interactions between locally generated fast oscillations in the connectome spacetime structure can lead to the emergence of collective brain rhythms organized in space and time.

Bifurcations of clusters and collective oscillations in networks of bistable units.

We investigate dynamics and bifurcations in a mathematical model that captures electrochemical experiments on arrays of microelectrodes. In isolation, each individual microelectrode is described by a one-dimensional unit with a bistable current-potential response. When an array of such electrodes is coupled by controlling the total electric current, the common electric potential of all electrodes oscillates in some interval of the current. These coupling-induced collective oscillations of bistable one-dimensional units are captured by the model. Moreover, any equilibrium is contained in a cluster subspace, where the electrodes take at most three distinct states. We systematically analyze the dynamics and bifurcations of the model equations: We consider the dynamics on cluster subspaces of successively increasing dimension and analyze the bifurcations occurring therein. Most importantly, the system exhibits an equivariant transcritical bifurcation of limit cycles. From this bifurcation, several limit cycles branch, one of which is stable for arbitrarily many bistable units.

Dead zones and phase reduction of coupled oscillators.

A dead zone in the interaction between two dynamical systems is a region of their joint phase space where one system is insensitive to the changes in the other. These can arise in a number of contexts, and their presence in phase interaction functions has interesting dynamical consequences for the emergent dynamics. In this paper, we consider dead zones in the interaction of general coupled dynamical systems. For weakly coupled limit cycle oscillators, we investigate criteria that give rise to dead zones in the phase interaction functions. We give applications to coupled multiscale oscillators where coupling on only one branch of a relaxation oscillation can lead to the appearance of dead zones in a phase description of their interaction.

Optimal closed-loop deep brain stimulation using multiple independently controlled contacts.

Deep brain stimulation (DBS) is a well-established treatment option for a variety of neurological disorders, including Parkinson's disease and essential tremor. The symptoms of these disorders are known to be associated with pathological synchronous neural activity in the basal ganglia and thalamus. It is hypothesised that DBS acts to desynchronise this activity, leading to an overall reduction in symptoms. Electrodes with multiple independently controllable contacts are a recent development in DBS technology which have the potential to target one or more pathological regions with greater precision, reducing side effects and potentially increasing both the efficacy and efficiency of the treatment. The increased complexity of these systems, however, motivates the need to understand the effects of DBS when applied to multiple regions or neural populations within the brain. On the basis of a theoretical model, our paper addresses the question of how to best apply DBS to multiple neural populations to maximally desynchronise brain activity. Central to this are analytical expressions, which we derive, that predict how the symptom severity should change when stimulation is applied. Using these expressions, we construct a closed-loop DBS strategy describing how stimulation should be delivered to individual contacts using the phases and amplitudes of feedback signals. We simulate our method and compare it against two others found in the literature: coordinated reset and phase-locked stimulation. We also investigate the conditions for which our strategy is expected to yield the most benefit.

Average beta burst duration profiles provide a signature of dynamical changes between the ON and OFF medication states in Parkinson's disease.

Parkinson's disease motor symptoms are associated with an increase in subthalamic nucleus beta band oscillatory power. However, these oscillations are phasic, and there is a growing body of evidence suggesting that beta burst duration may be of critical importance to motor symptoms. This makes insights into the dynamics of beta bursting generation valuable, in particular to refine closed-loop deep brain stimulation in Parkinson's disease. In this study, we ask the question "Can average burst duration reveal how dynamics change between the ON and OFF medication states?". Our analysis of local field potentials from the subthalamic nucleus demonstrates using linear surrogates that the system generating beta oscillations is more likely to act in a non-linear regime OFF medication and that the change in a non-linearity measure is correlated with motor impairment. In addition, we pinpoint the simplest dynamical changes that could be responsible for changes in the temporal patterning of beta oscillations between medication states by fitting to data biologically inspired models, and simpler beta envelope models. Finally, we show that the non-linearity can be directly extracted from average burst duration profiles under the assumption of constant noise in envelope models. This reveals that average burst duration profiles provide a window into burst dynamics, which may underlie the success of burst duration as a biomarker. In summary, we demonstrate a relationship between average burst duration profiles, dynamics of the system generating beta oscillations, and motor impairment, which puts us in a better position to understand the pathology and improve therapies such as deep brain stimulation.

A universal route to explosive phenomena.

Critical transitions are observed in many complex systems. This includes the onset of synchronization in a network of coupled oscillators or the emergence of an epidemic state within a population. "Explosive" first-order transitions have caught particular attention in a variety of systems when classical models are generalized by incorporating additional effects. Here, we give a mathematical argument that the emergence of these first-order transitions is not surprising but rather a universally expected effect: Varying a classical model along a generic two-parameter family must lead to a change of the criticality. To illustrate our framework, we give three explicit examples of the effect in distinct physical systems: a model of adaptive epidemic dynamics, for a generalization of the Kuramoto model, and for a percolation transition.

Optimizing deep brain stimulation based on isostable amplitude in essential tremor patient models.

OBJECTIVE: Deep brain stimulation is a treatment for medically refractory essential tremor. To improve the therapy, closed-loop approaches are designed to deliver stimulation according to the system's state, which is constantly monitored by recording a pathological signal associated with symptoms (e.g. brain signal or limb tremor). Since the space of possible closed-loop stimulation strategies is vast and cannot be fully explored experimentally, how to stimulate according to the state should be informed by modeling. A typical modeling goal is to design a stimulation strategy that aims to maximally reduce the Hilbert amplitude of the pathological signal in order to minimize symptoms. Isostables provide a notion of amplitude related to convergence time to the attractor, which can be beneficial in model-based control problems. However, how isostable and Hilbert amplitudes compare when optimizing the amplitude response to stimulation in models constrained by data is unknown. APPROACH: We formulate a simple closed-loop stimulation strategy based on models previously fitted to phase-locked deep brain stimulation data from essential tremor patients. We compare the performance of this strategy in suppressing oscillatory power when based on Hilbert amplitude and when based on isostable amplitude. We also compare performance to phase-locked stimulation and open-loop high-frequency stimulation. MAIN RESULTS: For our closed-loop phase space stimulation strategy, stimulation based on isostable amplitude is significantly more effective than stimulation based on Hilbert amplitude when amplitude field computation time is limited to minutes. Performance is similar when there are no constraints, however constraints on computation time are expected in clinical applications. Even when computation time is limited to minutes, closed-loop phase space stimulation based on isostable amplitude is advantageous compared to phase-locked stimulation, and is more efficient than high-frequency stimulation. SIGNIFICANCE: Our results suggest a potential benefit to using isostable amplitude more broadly for model-based optimization of stimulation in neurological disorders.

Neuronal Oscillations on Evolving Networks: Dynamics, Damage, Degradation, Decline, Dementia, and Death.

Neurodegenerative diseases, such as Alzheimer's or Parkinson's disease, show characteristic degradation of structural brain networks. This degradation eventually leads to changes in the network dynamics and degradation of cognitive functions. Here, we model the progression in terms of coupled physical processes: The accumulation of toxic proteins, given by a nonlinear reaction-diffusion transport process, yields an evolving brain connectome characterized by weighted edges on which a neuronal-mass model evolves. The progression of the brain functions can be tested by simulating the resting-state activity on the evolving brain network. We show that while the evolution of edge weights plays a minor role in the overall progression of the disease, dynamic biomarkers predict a transition over a period of 10 years associated with strong cognitive decline.

Understanding the dynamics of biological and neural oscillator networks through exact mean-field reductions: a review.

Many biological and neural systems can be seen as networks of interacting periodic processes. Importantly, their functionality, i.e., whether these networks can perform their function or not, depends on the emerging collective dynamics of the network. Synchrony of oscillations is one of the most prominent examples of such collective behavior and has been associated both with function and dysfunction. Understanding how network structure and interactions, as well as the microscopic properties of individual units, shape the emerging collective dynamics is critical to find factors that lead to malfunction. However, many biological systems such as the brain consist of a large number of dynamical units. Hence, their analysis has either relied on simplified heuristic models on a coarse scale, or the analysis comes at a huge computational cost. Here we review recently introduced approaches, known as the Ott-Antonsen and Watanabe-Strogatz reductions, allowing one to simplify the analysis by bridging small and large scales. Thus, reduced model equations are obtained that exactly describe the collective dynamics for each subpopulation in the oscillator network via few collective variables only. The resulting equations are next-generation models: Rather than being heuristic, they exactly link microscopic and macroscopic descriptions and therefore accurately capture microscopic properties of the underlying system. At the same time, they are sufficiently simple to analyze without great computational effort. In the last decade, these reduction methods have become instrumental in understanding how network structure and interactions shape the collective dynamics and the emergence of synchrony. We review this progress based on concrete examples and outline possible limitations. Finally, we discuss how linking the reduced models with experimental data can guide the way towards the development of new treatment approaches, for example, for neurological disease.

Phase-dependence of response curves to deep brain stimulation and their relationship: from essential tremor patient data to a Wilson-Cowan model.

Essential tremor manifests predominantly as a tremor of the upper limbs. One therapy option is high-frequency deep brain stimulation, which continuously delivers electrical stimulation to the ventral intermediate nucleus of the thalamus at about 130 Hz. Constant stimulation can lead to side effects, it is therefore desirable to find ways to stimulate less while maintaining clinical efficacy. One strategy, phase-locked deep brain stimulation, consists of stimulating according to the phase of the tremor. To advance methods to optimise deep brain stimulation while providing insights into tremor circuits, we ask the question: can the effects of phase-locked stimulation be accounted for by a canonical Wilson-Cowan model? We first analyse patient data, and identify in half of the datasets significant dependence of the effects of stimulation on the phase at which stimulation is provided. The full nonlinear Wilson-Cowan model is fitted to datasets identified as statistically significant, and we show that in each case the model can fit to the dynamics of patient tremor as well as to the phase response curve. The vast majority of top fits are stable foci. The model provides satisfactory prediction of how patient tremor will react to phase-locked stimulation by predicting patient amplitude response curves although they were not explicitly fitted. We also approximate response curves of the significant datasets by providing analytical results for the linearisation of a stable focus model, a simplification of the Wilson-Cowan model in the stable focus regime. We report that the nonlinear Wilson-Cowan model is able to describe response to stimulation more precisely than the linearisation.

State-dependent effective interactions in oscillator networks through coupling functions with dead zones.

The dynamics of networks of interacting dynamical systems depend on the nature of the coupling between individual units. We explore networks of oscillatory units with coupling functions that have 'dead zones', that is the coupling functions are zero on sets with interior. For such networks, it is convenient to look at the effective interactions between units rather than the (fixed) structural connectivity to understand the network dynamics. For example, oscillators may effectively decouple in particular phase configurations. Along trajectories, the effective interactions are not necessarily static, but the effective coupling may evolve in time. Here, we formalize the concepts of dead zones and effective interactions. We elucidate how the coupling function shapes the possible effective interaction schemes and how they evolve in time. This article is part of the theme issue 'Coupling functions: dynamical interaction mechanisms in the physical, biological and social sciences'.

Predicting the effects of deep brain stimulation using a reduced coupled oscillator model.

Deep brain stimulation (DBS) is known to be an effective treatment for a variety of neurological disorders, including Parkinson's disease and essential tremor (ET). At present, it involves administering a train of pulses with constant frequency via electrodes implanted into the brain. New 'closed-loop' approaches involve delivering stimulation according to the ongoing symptoms or brain activity and have the potential to provide improvements in terms of efficiency, efficacy and reduction of side effects. The success of closed-loop DBS depends on being able to devise a stimulation strategy that minimizes oscillations in neural activity associated with symptoms of motor disorders. A useful stepping stone towards this is to construct a mathematical model, which can describe how the brain oscillations should change when stimulation is applied at a particular state of the system. Our work focuses on the use of coupled oscillators to represent neurons in areas generating pathological oscillations. Using a reduced form of the Kuramoto model, we analyse how a patient should respond to stimulation when neural oscillations have a given phase and amplitude, provided a number of conditions are satisfied. For such patients, we predict that the best stimulation strategy should be phase specific but also that stimulation should have a greater effect if applied when the amplitude of brain oscillations is lower. We compare this surprising prediction with data obtained from ET patients. In light of our predictions, we also propose a new hybrid strategy which effectively combines two of the closed-loop strategies found in the literature, namely phase-locked and adaptive DBS.

Chaos in Kuramoto oscillator networks.

Kuramoto oscillators are widely used to explain collective phenomena in networks of coupled oscillatory units. We show that simple networks of two populations with a generic coupling scheme, where both coupling strengths and phase lags between and within populations are distinct, can exhibit chaotic dynamics as conjectured by Ott and Antonsen [Chaos 18, 037113 (2008)]. These chaotic mean-field dynamics arise universally across network size, from the continuum limit of infinitely many oscillators down to very small networks with just two oscillators per population. Hence, complicated dynamics are expected even in the simplest description of oscillator networks.

Heteroclinic switching between chimeras.

Functional oscillator networks, such as neuronal networks in the brain, exhibit switching between metastable states involving many oscillators. We give exact results how such global dynamics can arise in paradigmatic phase oscillator networks: Higher-order network interactions give rise to metastable chimeras-localized frequency synchrony patterns-which are joined by heteroclinic connections. Moreover, we illuminate the mechanisms that underly the switching dynamics in these experimentally accessible networks.

Robust Weak Chimeras in Oscillator Networks with Delayed Linear and Quadratic Interactions.

We present an approach to generate chimera dynamics (localized frequency synchrony) in oscillator networks with two populations of (at least) two elements using a general method based on a delayed interaction with linear and quadratic terms. The coupling design yields robust chimeras through a phase-model-based design of the delay and the ratio of linear and quadratic components of the interactions. We demonstrate the method in the Brusselator model and experiments with electrochemical oscillators. The technique opens the way to directly bridge chimera dynamics in phase models and real-world oscillator networks.

Isotropy of Angular Frequencies and Weak Chimeras with Broken Symmetry.

The notion of a weak chimeras provides a tractable definition for chimera states in networks of finitely many phase oscillators. Here, we generalize the definition of a weak chimera to a more general class of equivariant dynamical systems by characterizing solutions in terms of the isotropy of their angular frequency vector-for coupled phase oscillators the angular frequency vector is given by the average of the vector field along a trajectory. Symmetries of solutions automatically imply angular frequency synchronization. We show that the presence of such symmetries is not necessary by giving a result for the existence of weak chimeras without instantaneous or setwise symmetries for coupled phase oscillators. Moreover, we construct a coupling function that gives rise to chaotic weak chimeras without symmetry in weakly coupled populations of phase oscillators with generalized coupling.