Leveraging deep learning to control neural oscillators.

Modulation of the firing times of neural oscillators has long been an important control objective, with applications including Parkinson's disease, Tourette's syndrome, epilepsy, and learning. One common goal for such modulation is desynchronization, wherein two or more oscillators are stimulated to transition from firing in phase with each other to firing out of phase. The optimization of such stimuli has been well studied, but this typically relies on either a reduction of the dimensionality of the system or complete knowledge of the parameters and state of the system. This limits the applicability of results to real problems in neural control. Here, we present a trained artificial neural network capable of accurately estimating the effects of square-wave stimuli on neurons using minimal output information from the neuron. We then apply the results of this network to solve several related control problems in desynchronization, including desynchronizing pairs of neurons and achieving clustered subpopulations of neurons in the presence of coupling and noise.

Analysis of neural clusters due to deep brain stimulation pulses.

Deep brain stimulation (DBS) is an established method for treating pathological conditions such as Parkinson's disease, dystonia, Tourette syndrome, and essential tremor. While the precise mechanisms which underly the effectiveness of DBS are not fully understood, several theoretical studies of populations of neural oscillators stimulated by periodic pulses have suggested that this may be related to clustering, in which subpopulations of the neurons are synchronized, but the subpopulations are desynchronized with respect to each other. The details of the clustering behavior depend on the frequency and amplitude of the stimulation in a complicated way. In the present study, we investigate how the number of clusters and their stability properties, bifurcations, and basins of attraction can be understood in terms of one-dimensional maps defined on the circle. Moreover, we generalize this analysis to stimuli that consist of pulses with alternating properties, which provide additional degrees of freedom in the design of DBS stimuli. Our results illustrate how the complicated properties of clustering behavior for periodically forced neural oscillator populations can be understood in terms of a much simpler dynamical system.

Optimal phase control of biological oscillators using augmented phase reduction.

We develop a novel optimal control algorithm to change the phase of an oscillator using a minimum energy input, which also minimizes the oscillator's transversal distance to the uncontrolled periodic orbit. Our algorithm uses a two-dimensional reduction technique based on both isochrons and isostables. We develop a novel method to eliminate cardiac alternans by connecting our control algorithm with the underlying physiological problem. We also describe how the devised algorithm can be used for spike timing control which can potentially help with motor symptoms of essential and parkinsonian tremor, and aid in treating jet lag. To demonstrate the advantages of this algorithm, we compare it with a previously proposed optimal control algorithm based on standard phase reduction for the Hopf bifurcation normal form, and models for cardiac pacemaker cells, thalamic neurons, and circadian gene regulation cycle in the suprachiasmatic nucleus. We show that our control algorithm is effective even when a large phase change is required or when the nontrivial Floquet multiplier is close to unity; in such cases, the previously proposed control algorithm fails.

Phase reduction and phase-based optimal control for biological systems: a tutorial.

A powerful technique for the analysis of nonlinear oscillators is the rigorous reduction to phase models, with a single variable describing the phase of the oscillation with respect to some reference state. An analog to phase reduction has recently been proposed for systems with a stable fixed point, and phase reduction for periodic orbits has recently been extended to take into account transverse directions and higher-order terms. This tutorial gives a unified treatment of such phase reduction techniques and illustrates their use through mathematical and biological examples. It also covers the use of phase reduction for designing control algorithms which optimally change properties of the system, such as the phase of the oscillation. The control techniques are illustrated for example neural and cardiac systems.

Phase model-based neuron stabilization into arbitrary clusters.

Deep brain stimulation (DBS) is a common method of combating pathological conditions associated with Parkinson's disease, Tourette syndrome, essential tremor, and other disorders, but whose mechanisms are not fully understood. One hypothesis, supported experimentally, is that some symptoms of these disorders are associated with pathological synchronization of neurons in the basal ganglia and thalamus. For this reason, there has been interest in recent years in finding efficient ways to desynchronize neurons that are both fast-acting and low-power. Recent results on coordinated reset and periodically forced oscillators suggest that forming distinct clusters of neurons may prove to be more effective than achieving complete desynchronization, in particular by promoting plasticity effects that might persist after stimulation is turned off. Current proposed methods for achieving clustering frequently require either multiple input sources or precomputing the control signal. We propose here a control strategy for clustering, based on an analysis of the reduced phase model for a set of identical neurons, that allows for real-time, single-input control of a population of neurons with low-amplitude, low total energy signals. After demonstrating its effectiveness on phase models, we apply it to full state models to demonstrate its validity. We also discuss the effects of coupling on the efficacy of the strategy proposed and demonstrate that the clustering can still be accomplished in the presence of weak to moderate electrotonic coupling.

Synchronization of heterogeneous oscillator populations in response to weak and strong coupling.

Synchronous behavior of a population of chemical oscillators is analyzed in the presence of both weak and strong coupling. In each case, we derive upper bounds on the critical coupling strength which are valid for arbitrary populations of nonlinear, heterogeneous oscillators. For weak perturbations, infinitesimal phase response curves are used to characterize the response to coupling, and graph theoretical techniques are used to predict synchronization. In the strongly perturbed case, we observe a phase dependent perturbation threshold required to elicit an immediate spike and use this behavior for our analytical predictions. Resulting upper bounds on the critical coupling strength agree well with our experimental observations and numerical simulations. Furthermore, important system parameters which determine synchronization are different in the weak and strong coupling regimes. Our results point to new strategies by which limit cycle oscillators can be studied when the applied perturbations become strong enough to immediately reset the phase.

Phasic Burst Stimulation: A Closed-Loop Approach to Tuning Deep Brain Stimulation Parameters for Parkinson's Disease.

We propose a novel, closed-loop approach to tuning deep brain stimulation (DBS) for Parkinson's disease (PD). The approach, termed Phasic Burst Stimulation (PhaBS), applies a burst of stimulus pulses over a range of phases predicted to disrupt pathological oscillations seen in PD. Stimulation parameters are optimized based on phase response curves (PRCs), which would be measured from each patient. This approach is tested in a computational model of PD with an emergent population oscillation. We show that the stimulus phase can be optimized using the PRC, and that PhaBS is more effective at suppressing the pathological oscillation than a single phasic stimulus pulse. PhaBS provides a closed-loop approach to DBS that can be optimized for each patient.

Clustered Desynchronization from High-Frequency Deep Brain Stimulation.

While high-frequency deep brain stimulation is a well established treatment for Parkinson's disease, its underlying mechanisms remain elusive. Here, we show that two competing hypotheses, desynchronization and entrainment in a population of model neurons, may not be mutually exclusive. We find that in a noisy group of phase oscillators, high frequency perturbations can separate the population into multiple clusters, each with a nearly identical proportion of the overall population. This phenomenon can be understood by studying maps of the underlying deterministic system and is guaranteed to be observed for small noise strengths. When we apply this framework to populations of Type I and Type II neurons, we observe clustered desynchronization at many pulsing frequencies.

Dynamic analysis of a buckled asymmetric piezoelectric beam for energy harvesting.

A model of a buckled beam energy harvester is analyzed to determine the phenomena behind the transition between high and low power output levels. It is shown that the presence of a chaotic attractor is a sufficient condition to predict high power output, though there are relatively small areas where high output is achieved without a chaotic attractor. The chaotic attractor appears as a product of a period doubling cascade or a boundary crisis. Bifurcation diagrams provide insight into the development of the chaotic region as the input power level is varied, as well as the intermixed periodic windows.

Desynchronization of stochastically synchronized chemical oscillators.

Experimental and theoretical studies are presented on the design of perturbations that enhance desynchronization in populations of oscillators that are synchronized by periodic entrainment. A phase reduction approach is used to determine optimal perturbation timing based upon experimentally measured phase response curves. The effectiveness of the perturbation waveforms is tested experimentally in populations of periodically and stochastically synchronized chemical oscillators. The relevance of the approach to therapeutic methods for disrupting phase coherence in groups of stochastically synchronized neuronal oscillators is discussed.

An energy-optimal approach for entrainment of uncertain circadian oscillators.

We develop an approach to find an energy-optimal stimulus that entrains an ensemble of uncertain, uncoupled limit cycle oscillators. Furthermore, when entrainment occurs, the phase shift between oscillators is constrained to be less than a predetermined amount. This approach is illustrated for a model of Drosophila circadian activity, for which it performs better than a standard 24-h light-dark cycle. Because this method explicitly accounts for uncertainty in a given system and only requires information that is experimentally obtainable, it is well suited for experimental implementation and could ultimately represent what is believed to be a novel treatment for patients suffering from advanced/delayed sleep-phase syndrome.

Locally optimal extracellular stimulation for chaotic desynchronization of neural populations.

We use optimal control theory to design a methodology to find locally optimal stimuli for desynchronization of a model of neurons with extracellular stimulation. This methodology yields stimuli which lead to positive Lyapunov exponents, and hence desynchronizes a neural population. We analyze this methodology in the presence of interneuron coupling to make predictions about the strength of stimulation required to overcome synchronizing effects of coupling. This methodology suggests a powerful alternative to pulsatile stimuli for deep brain stimulation as it uses less energy than pulsatile stimuli, and could eliminate the time consuming tuning process.

A Hamilton-Jacobi-Bellman approach for termination of seizure-like bursting.

We use Hamilton-Jacobi-Bellman methods to find minimum-time and energy-optimal control strategies to terminate seizure-like bursting behavior in a conductance-based neural model. Averaging is used to eliminate fast variables from the model, and a target set is defined through bifurcation analysis of the slow variables of the model. This method is illustrated for a single neuron model and for a network model to illustrate its efficacy in terminating bursting once it begins. This work represents a numerical proof-of-concept that a new class of control strategies can be employed to mitigate bursting, and could ultimately be adapted to treat medically intractible epilepsy in patient-specific models.

Minimum energy desynchronizing control for coupled neurons.

We employ optimal control theory to design an event-based, minimum energy, desynchronizing control stimulus for a network of pathologically synchronized, heterogeneously coupled neurons. This works by optimally driving the neurons to their phaseless sets, switching the control off, and letting the phases of the neurons randomize under intrinsic background noise. An event-based minimum energy input may be clinically desirable for deep brain stimulation treatment of neurological diseases, like Parkinson's disease. The event-based nature of the input results in its administration only when it is necessary, which, in general, amounts to fewer applications, and hence, less charge transfer to and from the tissue. The minimum energy nature of the input may also help prolong battery life for implanted stimulus generators. For the example considered, it is shown that the proposed control causes a considerable amount of randomization in the timing of each neuron's next spike, leading to desynchronization for the network.

Time optimal control of spiking neurons.

By injecting an electrical current control stimulus into a neuron, one can change its inter-spike intervals. In this paper, we investigate the time optimal control problem for periodically firing neurons, represented by different one-dimensional phase models, and find analytical expressions for the minimum and maximum values of inter-spike intervals achievable with small bounded control stimuli. We consider two cases: with a charge-balance constraint on the input, and without it. The analytical calculations are supported with numerical results for examples of qualitatively different neuron models.

Depolarization block in olfactory sensory neurons expands the dimensionality of odor encoding.

Upon strong and prolonged excitation, neurons can undergo a silent state called depolarization block that is often associated with disorders such as epileptic seizures. Here, we show that neurons in the peripheral olfactory system undergo depolarization block as part of their normal physiological function. Typically, olfactory sensory neurons enter depolarization block at odor concentrations three orders of magnitude above their detection threshold, thereby defining receptive fields over concentration bands. The silencing of high-affinity olfactory sensory neurons produces sparser peripheral odor representations at high-odor concentrations, which might facilitate perceptual discrimination. Using a conductance-based model of the olfactory transduction cascade paired with spike generation, we provide numerical and experimental evidence that depolarization block arises from the slow inactivation of sodium channels-a process that could affect a variety of sensory neurons. The existence of ethologically relevant depolarization block in olfactory sensory neurons creates an additional dimension that expands the peripheral encoding of odors.

Controlling Spike Timing and Synchrony in Oscillatory Neurons.

We describe an algorithm to control synchrony between two periodically firing neurons. The control scheme operates in real-time using a dynamic clamp platform. This algorithm is a low impact stimulation method that brings the neurons toward the desired level of synchrony over the course of several neuron firing periods. As a proof of principle, we demonstrate the versatility of the algorithm using real- time conductance models, and then show its performance with biological neurons of hippocampal region CA1 and entorhinal cortex.

Controlling spike timing and synchrony in oscillatory neurons.

We describe an algorithm to control synchrony between two periodically firing neurons. The control scheme operates in real-time using a dynamic clamp platform. This algorithm is a low-impact stimulation method that brings the neurons toward the desired level of synchrony over the course of several neuron firing periods. As a proof of principle, we demonstrate the versatility of the algorithm using real-time conductance models and then show its performance with biological neurons of hippocampal region CA1 and entorhinal cortex.

Event-based minimum-time control of oscillatory neuron models: phase randomization, maximal spike rate increase, and desynchronization.

We present an event-based feedback control method for randomizing the asymptotic phase of oscillatory neurons. Phase randomization is achieved by driving the neuron's state to its phaseless set, a point at which its phase is undefined and is extremely sensitive to background noise. We consider the biologically relevant case of a fixed magnitude constraint on the stimulus signal, and show how the control objective can be accomplished in minimum time. The control synthesis problem is addressed using the minimum-time-optimal Hamilton-Jacobi-Bellman framework, which is quite general and can be applied to any spiking neuron model in the conductance-based Hodgkin-Huxley formalism. We also use this methodology to compute a feedback control protocol for optimal spike rate increase. This framework provides a straightforward means of visualizing isochrons, without actually calculating them in the traditional way. Finally, we present an extension of the phase randomizing control scheme that is applied at the population level, to a network of globally coupled neurons that are firing in synchrony. The applied control signal desynchronizes the population in a demand-controlled way.

Partial phase synchronization of neural populations due to random Poisson inputs.

We show that populations of identical uncoupled neurons exhibit partial phase synchronization when stimulated with independent, random unidirectional current spikes with interspike time intervals drawn from a Poisson distribution. We characterize this partial synchronization using the phase distribution of the population, and consider analytical approximations and numerical simulations of phase-reduced models and the corresponding conductance-based models of typical Type I (Hindmarsh-Rose) and Type II (Hodgkin-Huxley) neurons, showing quantitatively how the extent of the partial phase synchronization depends on the magnitude and mean interspike frequency of the stimulus. Furthermore, we present several simple examples that disprove the notion that phase synchrony must be strongly related to spike synchrony. Instead, the importance of partial phase synchrony is shown to lie in its influence on the response of the population to stimulation, which we illustrate using first spike time histograms.