Optimal control methods for nonlinear parameter estimation in biophysical neuron models

Functional forms of biophysically-realistic neuron models are constrained by neurobiological and anatomical considerations, such as cell morphologies and the presence of known ion channels. Despite these constraints, neurons models still contain unknown static parameters which must be inferred from experiment. This inference task is most readily cast into the framework of state-space models, which systematically takes into account partial observability and measurement noise. Inferring only dynamical state variables such as membrane voltages is a well-studied problem, and has been approached with a wide range of techniques beginning with the well-known Kalman filter. Inferring both states and fixed parameters, on the other hand, is less straightforward. Here, we develop a method for joint parameter and state inference that combines traditional state space modeling with chaotic synchronization and optimal control. Our methods are tailored particularly to situations with considerable measurement noise, sparse observability, very nonlinear or chaotic dynamics, and highly uninformed priors. We illustrate our approach both in a canonical chaotic model and in a phenomenological neuron model, showing that many unknown parameters can be uncovered reliably and accurately from short and noisy observed time traces. Our method holds promise for estimation in larger-scale systems, given ongoing improvements in calcium reporters and genetically-encoded voltage indicators.

Distribution of spiking and bursting in Rulkov’s neuron model

Large-scale brain simulations require the investigation of large networks of realistic neuron models, usually represented by sets of differential equations. Here we report a detailed fine-scale study of the dynamical response over extended parameter ranges of a computationally inexpensive model, the two-dimensional Rulkov map, which reproduces well the spiking and spiking-bursting activity of real biological neurons. In addition, we provide evidence of the existence of nested arithmetic progressions among periodic pulsing and bursting phases of Rulkov’s neuron. We find that specific remarkably complex nested sequences of periodic neural oscillations can be expressed as simple linear combinations of pairs of certain basal periodicities. Moreover, such nested progressions are robust and can be observed abundantly in diverse control parameter planes which are described in detail. We believe such findings to add significantly to the knowledge of Rulkov neuron dynamics and to be potentially helpful in large-scale simulations of the brain and other complex neuron networks.

Prediction of Neural Diameter From Morphology to Enable Accurate Simulation

Accurate neuron morphologies are paramount for computational model simulations of realistic neural responses. Over the last decade, the online repository NeuroMorpho.Org has collected over 140,000 available neuron morphologies to understand brain function and promote interaction between experimental and computational research. Neuron morphologies describe spatial aspects of neural structure; however, many of the available morphologies do not contain accurate diameters that are essential for computational simulations of electrical activity. To best utilize available neuron morphologies, we present a set of equations that predict dendritic diameter from other morphological features. To derive the equations, we used a set of NeuroMorpho.org archives with realistic neuron diameters, representing hippocampal pyramidal, cerebellar Purkinje, and striatal spiny projection neurons. Each morphology is separated into initial, branching children, and continuing nodes. Our analysis reveals that the diameter of preceding nodes, Parent Diameter, is correlated to diameter of subsequent nodes for all cell types. Branching children and initial nodes each required additional morphological features to predict diameter, such as path length to soma, total dendritic length, and longest path to terminal end. Model simulations reveal that membrane potential response with predicted diameters is similar to the original response for several tested morphologies. We provide our open source software to extend the utility of available NeuroMorpho.org morphologies, and suggest predictive equations may supplement morphologies that lack dendritic diameter and improve model simulations with realistic dendritic diameter.

Numerical uncertainty can critically affect simulations of mechanistic models in neuroscience

Understanding neural computation on the mechanistic level requires biophysically realistic neuron models. To analyze such models one typically has to solve systems of coupled ordinary differential equations (ODEs), which describe the dynamics of the underlying neural system. These ODEs are solved numerically with deterministic ODE solvers that yield single solutions with either no or only a global scalar bound on precision. To overcome this problem, we propose to use recently developed probabilistic solvers instead, which are able to reveal and quantify numerical uncertainties, for example as posterior sample paths. Importantly, these solvers neither require detailed insights into the kinetics of the models nor are they difficult to implement. Using these probabilistic solvers, we show that numerical uncertainty strongly affects the outcome of typical neuroscience simulations, in particular due to the non-linearity associated with the generation of action potentials. We quantify this uncertainty in individual single Izhikevich neurons with different dynamics, a large population of coupled Izhikevich neurons, single Hodgkin-Huxley neuron and a small network of Hodgkin-Huxley-like neurons. For commonly used ODE solvers, we find that the numerical uncertainty in these models can be substantial, possibly jittering spikes by milliseconds or even adding or removing individual spikes from the simulation altogether.Author summaryComputational neuroscience is built around computational models of neurons that allow the simulation and analysis of signal processing in the central nervous system. These models come typically in the form of ordinary differential equations (ODEs). The solution of these ODEs is computed using solvers with finite accuracy and, therefore, the computed solutions deviate from the true solution. If this deviation is too large but goes unnoticed, this can potentially lead to wrong scientific conclusions.A field in machine learning called probabilistic numerics has recently developed a set of probabilistic solvers for ODEs, which not only produce a single solution of unknown accuracy, but instead yield a distribution over simulations. Therefore, these tools allow one to address the problem state above and quantitatively analyze the numerical uncertainty inherent in the simulation process.In this study, we demonstrate how such solvers can be used to quantify numerical uncertainty in common neuroscience models. We study both Hodgkin-Huxley and Izhikevich neuron models and show that the numerical uncertainty in these models can be substantial, possibly jittering spikes by milliseconds or even adding or removing individual spikes from the simulation altogether. We discuss the implications of this finding and discuss how our methods can be used to select simulation parameters to trade off accuracy and speed.

A Computational Model of Bidirectional Axonal Growth in Micro-Tissue Engineered Neuronal Networks (micro-TENNs)

Micro-Tissue Engineered Neural Networks (Micro-TENNs) are living three-dimensional constructs designed to replicate the neuroanatomy of white matter pathways in the brain, and are being developed as implantable microtissue for axon tract reconstruction or as anatomically-relevant in vitro experimental platforms. Micro-TENNs are composed of discrete neuronal aggregates connected by bundles of long-projecting axonal tracts within miniature tubular hydrogels. In order to help design and optimize micro-TENN performance, we have created a new computational model including geometric and functional properties. The model is built upon the three-dimensional diffusion equation and incorporates large-scale uni- and bi-directional growth that simulates realistic neuron morphologies. The model captures unique features of 3D axonal tract development that are not apparent in planar outgrowth, and may be insightful for how white matter pathways form during brain development. The processes of axonal outgrowth, branching, turning and aggregation/bundling from each neuron are described through functions built on concentration equations and growth time distributed across the growth segments. Once developed we conducted multiple parametric studies to explore the applicability of the method and conducted preliminary validation via comparisons to experimentally grown micro-TENNs for a range of growth conditions. Using this framework, this model can be applied to study micro-TENN growth processes and functional characteristics using spiking network or compartmental network modeling. This model may be applied to improve our understanding of axonal tract development and functionality, as well as to optimize the fabrication of implantable tissue engineered brain pathways for nervous system reconstruction and/or modulation.

Biophysically Realistic Neuron Models for Simulation of Cortical Stimulation

1.AbstractObjectiveWe implemented computational models of human and rat cortical neurons for simulating the neural response to cortical stimulation with electromagnetic fields.ApproachWe adapted model neurons from the library of Blue Brain models to reflect biophysical and geometric properties of both adult rat and human cortical neurons and coupled the model neurons to exogenous electric fields (E-fields). The models included 3D reconstructed axonal and dendritic arbors, experimentally-validated electrophysiological behaviors, and multiple, morphological variants within cell types. Using these models, we characterized the single-cell responses to intracortical microstimulation (ICMS) and uniform E-field with dc as well as pulsed currents.Main resultsThe strength-duration and current-distance characteristics of the model neurons to ICMS agreed with published experimental results, as did the subthreshold polarization of cell bodies and axon terminals by uniform dc E-fields. For all forms of stimulation, the lowest threshold elements were terminals of the axon collaterals, and the dependence of threshold and polarization on spatial and temporal stimulation parameters was strongly affected by morphological features of the axonal arbor, including myelination, diameter, and branching.SignificanceThese results provide key insights into the mechanisms of cortical stimulation. The presented models can be used to study various cortical stimulation modalities while incorporating detailed spatial and temporal features of the applied E-field.

Radiation Damage to Nervous System: Designing Optimal Models for Realistic Neuron Morphology in Hippocampus

The present study is focused on the development of optimal models of neuron morphology for Monte Carlo microdosimetry simulations of initial radiation-induced events of heavy charged particles in the specific types of cells of the hippocampus, which is the most radiation-sensitive structure of the central nervous system. The neuron geometry and particles track structures were simulated by the Geant4/Geant4-DNA Monte Carlo toolkits. The calculations were made for beams of protons and heavy ions with different energies and doses corresponding to real fluxes of galactic cosmic rays. A simple compartmental model and a complex model with realistic morphology extracted from experimental data were constructed and compared. We estimated the distribution of the energy deposition events and the production of reactive chemical species within the developed models of CA3/CA1 pyramidal neurons and DG granule cells of the rat hippocampus under exposure to different particles with the same dose. Similar distributions of the energy deposition events and concentration of some oxidative radical species were obtained in both the simplified and realistic neuron models.

Formation of multi-armed spiral waves in neuronal network induced by adjusting ion channel conductance

The Hodgkin–Huxley neuron model is used to describe the local dynamics of nodes in a two-dimensional regular network with nearest-neighbor connections. Multi-armed spiral waves emerge when a group of spiral waves rotate the same core synchronously. Here we have numerically investigated how multi-armed spiral waves are formed in such a system. Under the appropriate conditions, multi-armed spiral waves were able to develop as a result of adjusting the conductance of ion channels of particular neurons in the network. In a realistic neuron model, it can be practiced by blocking potassium of ion channels embedded in the membrane of neurons. For example, decreasing the potassium channel conductance in some neurons with a certain transient period can lead to the development of a group of double spirals in a localized area of the network. Furthermore, decreasing the excitability and the external forcing current to zero led to the growth of these double spirals and the formation of a stable multi-armed spiral wave that occupied the network under inhomogeneity.