Circuits and mechanisms for TMS-induced corticospinal waves: Connecting sensitivity analysis to the network graph.

Transcranial magnetic stimulation (TMS) is a non-invasive, FDA-cleared treatment for neuropsychiatric disorders with broad potential for new applications, but the neural circuits that are engaged during TMS are still poorly understood. Recordings of neural activity from the corticospinal tract provide a direct readout of the response of motor cortex to TMS, and therefore a new opportunity to model neural circuit dynamics. The study goal was to use epidural recordings from the cervical spine of human subjects to develop a computational model of a motor cortical macrocolumn through which the mechanisms underlying the response to TMS, including direct and indirect waves, could be investigated.

Bridging Hierarchies in Multi-Scale Models of Neural Systems: Look-Up Tables Enable Computationally Efficient Simulations of Non-linear Synaptic Dynamics.

Synapses are critical actors of neuronal transmission as they form the basis of chemical communication between neurons. Accurate computational models of synaptic dynamics may prove important in elucidating emergent properties across hierarchical scales. Yet, in large-scale neuronal network simulations, synapses are often modeled as highly simplified linear exponential functions due to their small computational footprint.

Topographic Organization of Correlation Along the Longitudinal and Transverse Axes in Rat Hippocampal CA3 Due to Excitatory Afferents.

The topographic organization of afferents to the hippocampal CA3 subfield are well-studied, but their role in influencing the spatiotemporal dynamics of population activity is not understood. Using a large-scale, computational neuronal network model of the entorhinal-dentate-CA3 system, the effects of the perforant path, mossy fibers, and associational system on the propagation and transformation of network spiking patterns were investigated. A correlation map was constructed to characterize the spatial structure and temporal evolution of pairwise correlations which underlie the emergent patterns found in the population activity.

A Computational Model of the Cholinergic Modulation of CA1 Pyramidal Cell Activity.

Dysfunction in cholinergic modulation has been linked to a variety of cognitive disorders including Alzheimer's disease. The important role of this neurotransmitter has been explored in a variety of experiments, yet many questions remain unanswered about the contribution of cholinergic modulation to healthy hippocampal function. To address this question, we have developed a model of CA1 pyramidal neuron that takes into consideration muscarinic receptor activation in response to changes in extracellular concentration of acetylcholine and its effects on cellular excitability and downstream intracellular calcium dynamics.

Generation of Granule Cell Dendritic Morphologies by Estimating the Spatial Heterogeneity of Dendritic Branching.

Biological realism of dendritic morphologies is important for simulating electrical stimulation of brain tissue. By adding point process modeling and conditional sampling to existing generation strategies, we provide a novel means of reproducing the nuanced branching behavior that occurs in different layers of granule cell dendritic morphologies. In this study, a heterogeneous Poisson point process was used to simulate branching events.

Network Activity Due to Topographic Organization of Schaffer Collaterals in a Large-Scale Model of Rat CA1.

Connectivity between neural regions, particularly in the hippocampus, is seldom all-to-all or random, yet it is the predominant method by which connectivity is implemented in most models of neuronal networks. We have been developing a computational platform for simulating the trisynaptic circuit of rat hippocampus with which we have constructed a large-scale, biologically-realistic, spiking neuronal network model of the entorhinal-dentate-CA3 system. Using the model, we had demonstrated a non-trivial effect of topographic connectivity on network dynamics and function.

Axonal Anatomy Optimizes Spatial Encoding in the Rat Entorhinal-Dentate System: A Computational Study.

Objective: The network architecture connecting neural regions is defined by the organization and anatomical properties of the projecting axons, but its contributions to neural encoding and system function are difficult to study experimentally.

Methods: Using a large-scale, spiking neuronal network model of rat dentate gyrus, the role of the anatomy of the entorhinal-dentate axonal projection was evaluated in the context of spatial encoding by incorporating grid cell activity to provide physiological, spatially-correlated input. The dorso-ventral extents of the entorhinal axon terminal fields were varied to generate different feedforward architectures, and the resulting spatial representations and spatial information scores of the network were evaluated.

Decoding Position to Analyze Spatial Information Encoding in a Large-Scale Neuronal Network Model of Rat Dentate Gyrus.

Spatial information is encoded by the hippocampus, and the factors that contribute to the amount of information that can be encoded and the transformation of spatial information through the trisynaptic circuit remain an important issue. A large-scale neuronal network model of the rat entorhinal-dentate system was developed with multicompartmental representations of the neurons within the dentate gyrus. Spatial information was introduced to the network via grid cell activity, and the spatial information encoding capabilities of the network were assessed using a recursive decoding algorithm to estimate the position of a virtual rat using the dentate activity.

Modeling Nonlinear Synaptic Dynamics: A Laguerre-Volterra Network Framework for Improved Computational Efficiency in Large Scale Simulations.

Synapses are key components in signal transmission in the brain, often exhibiting complex non-linear dynamics. Yet, they are often crudely modelled as linear exponential equations in large-scale neuron network simulations. Mechanistic models that use detailed channel receptor kinetics more closely replicate the nonlinear dynamics observed at synapses, but use of such models are generally restricted to small scale simulations due to their computational complexity.

Point Process Filtering Estimates of Branching Rate for Neural Dendritic Morphology Generation.

Current parametric approaches to dendritic morphology generation are limited in their ability to replicate realistic branching. A non-parametric approach applying a point process filter and the expectation-maximization algorithm offers a data-based solution that estimates the dendritic branching rate based on observations of bifurcation events in real neurons. Point processes can then be simulated using this branching rate estimate to indicate when a generated morphology should branch.

Model-Based Analysis of Electrode Placement and Pulse Amplitude for Hippocampal Stimulation.

Objective: The ideal form of a neural-interfacing device is highly dependent upon the anatomy of the region with which it is meant to interface. Multiple-electrode arrays provide a system that can be adapted to various neural geometries. Computational models of stimulating systems have proven useful for evaluating electrode placement and stimulation protocols, but have yet to be adequately adapted to the unique features of the hippocampus.

A large-scale detailed neuronal model of electrical stimulation of the dentate gyrus and perforant path as a platform for electrode design and optimization.

Owing to the dramatic rise in treatment of neurological disorders with electrical micro-stimulation it has become apparent that the major technological limitation in deploying effective devices lies in the process of designing efficient, safe, and outcome specific electrode arrays. The time-consuming and low-fidelity nature of gathering test data using experimental means and the immense control and flexibility of computational models, has prompted us and others to build models of electrical stimulation of neural networks that can be simulated in a computer. Because prior work has been focused on single cells, very small networks, or non-biological models of neural tissue, it was expedient that we take advantage of our, 4,040 processor, computing cluster to construct a large-scale 3-dimensional emulation of hippocampal tissue using detailed neuronal models with explicit and unique morphologies.

Place field detection using grid-based clustering in a large-scale computational model of the rat dentate gyrus.

Place cells are neurons in the hippocampus that are sensitive to location within an environment. Simulations of a large-scale, computational model of the rat dentate gyrus using grid cell input have been performed resulting in granule cells that express multiple place fields. The typical method of detecting place fields using a global threshold on this data is unreliable as the characteristics of the place fields from a single neuron can be highly variable.

A million-plus neuron model of the hippocampal dentate gyrus: Dependency of spatio-temporal network dynamics on topography.

This paper describes a million-plus granule cell compartmental model of the rat hippocampal dentate gyrus, including excitatory, perforant path input from the entorhinal cortex, and feedforward and feedback inhibitory input from dentate interneurons. The model includes experimentally determined morphological and biophysical properties of granule cells, together with glutamatergic AMPA-like EPSP and GABAergic GABAA-like IPSP synaptic excitatory and inhibitory inputs, respectively. Each granule cell was composed of approximately 200 compartments having passive and active conductances distributed throughout the somatic and dendritic regions.

Topography-dependent spatio-temporal correlations in the entorhinal-dentate-CA3 circuit in a large-scale computational model of the Rat Hippocampus.

The correlation due to different topographies was characterized in a large-scale, biologically-realistic, computational model of the rat hippocampus using a spatio-temporal correlation analysis. The effect of the topographical projection between the following subregions of the hippocampus was investigated: the entorhinal to dentate projection, the entorhinal to CA3 projection, and the mossy fiber to CA3 projection. Through this work, analysis was performed on the individual and combined effects of these projections on the activity of the principal neurons of the dentate gyrus and CA3.

Interactions between Inhibitory Interneurons and Excitatory Associational Circuitry in Determining Spatio-Temporal Dynamics of Hippocampal Dentate Granule Cells: A Large-Scale Computational Study.

This paper reports on findings from a million-cell granule cell model of the rat dentate gyrus that was used to explore the contributions of local interneuronal and associational circuits to network-level activity. The model contains experimentally derived morphological parameters for granule cells, which each contain approximately 200 compartments, and biophysical parameters for granule cells, basket cells, and mossy cells that were based both on electrophysiological data and previously published models. Synaptic input to cells in the model consisted of glutamatergic AMPA-like EPSPs and GABAergic-like IPSPs from excitatory and inhibitory neurons, respectively.

A Million-Plus Neuron Model of the Hippocampal Dentate Gyrus: Critical Role for Topography in Determining Spatiotemporal Network Dynamics.

Goal: This paper describes a million-plus granule cell compartmental model of the rat hippocampal dentate gyrus, including excitatory, perforant path input from the entorhinal cortex, and feedforward and feedback inhibitory input from dentate interneurons.

Methods: The model includes experimentally determined morphological and biophysical properties of granule cells, together with glutamatergic AMPA-like EPSP and GABAergic GABAA-like IPSP synaptic excitatory and inhibitory inputs, respectively. Each granule cell was composed of approximately 200 compartments having passive and active conductances distributed throughout the somatic and dendritic regions.

Implementation of the excitatory entorhinal-dentate-CA3 topography in a large-scale computational model of the rat hippocampus.

The topography, or the anatomical connectivity, of the excitatory entorhinal-dentate-CA3 circuit of the rat hippocampus has been implemented for a large-scale, biologically realistic, computational model of the rat hippocampus. The implementation thus far covers only the excitatory synapses for the principal neurons in the hippocampal subregions. Starting from layer II of the entorhinal cortex, the projection of their perforant path axons has been mapped across the full extent of the dentate gyrus as well as to the CA3.

The contribution of relative activation levels between populations of cells to network activity in a large-scale biologically realistic model of the hippocampus.

In previously published work, we showed the progress we've made towards creating a large-scale, biologically realistic model of the rat hippocampus, starting with the projection from entorhinal cortex (EC) to the dentate gyrus (DG). We created the model to help us study how the common components of neurobiological systems in mammals - large numbers of neurons with intricate, branching morphologies; active, non-linear membrane properties; nonuniform distributions throughout membrane surface of these non-linear conductances; non-uniform and topographic connectivity between pre- and post-synaptic neurons; and activity-dependent changes in synaptic function - combine and contribute to give a particular brain region its "neural processing" properties. In this work, we report on the results of a series of simulations we ran to test the role of feed-forward and feedback inhibition in the dentate gyrus.

The role of topography in the transformation of spatiotemporal patterns by a large-scale, biologically realistic model of the rat dentate gyrus.

A large-scale, biologically realistic, computational model of the rat hippocampus is being constructed to study the input-output transformation that the hippocampus performs. In the initial implementation, the layer II entorhinal cortex neurons, which provide the major input to the hippocampus, and the granule cells of the dentate gyrus, which receive the majority of the input, are modeled. In a previous work, the topography, or the wiring diagram, connecting these two populations had been derived and implemented.

Towards a large-scale biologically realistic model of the hippocampus.

Real neurobiological systems in the mammalian brain have a complicated and detailed structure, being composed of 1) large numbers of neurons with intricate, branching morphologies--complex morphology brings with it complex passive membrane properties; 2) active membrane properties--nonlinear sodium, potassium, calcium, etc. conductances; 3) non-uniform distributions throughout the dendritic and somal membrane surface of these non-linear conductances; 4) non-uniform and topographic connectivity between pre- and post-synaptic neurons; and 5) activity-dependent changes in synaptic function. One of the essential, and as yet unanswered questions in neuroscience is the role of these fundamental structural and functional features in determining "neural processing" properties of a given brain system.

Implementation of activity-dependent synaptic plasticity rules for a large-scale biologically realistic model of the hippocampus.

A large-scale computational model of the hippocampus should consider plasticity at different time scales in order to capture the non-stationary information processing behavior of the hippocampus more accurately. This paper presents a computational model that describes hippocampal long-term potentiation/depression (LTP/LTD) and short-term plasticity implemented in the NEURON simulation environment. The LTP/LTD component is based on spike-timing-dependent plasticity (STDP).

Implementation of topographically constrained connectivity for a large-scale biologically realistic model of the hippocampus.

In order to understand how memory works in the brain, the hippocampus is highly studied because of its role in the encoding of long-term memories. We have identified four characteristics that would contribute to the encoding process: the morphology of the neurons, their biophysics, synaptic plasticity, and the topography connecting the input to and the neurons within the hippocampus. To investigate how long-term memory is encoded, we are constructing a large-scale biologically realistic model of the rat hippocampus.

Islet preconditioning via multimodal microfluidic modulation of intermittent hypoxia.

Simultaneous stimulation of ex vivo pancreatic islets with dynamic oxygen and glucose is a critical technique for studying how hypoxia alters glucose-stimulated response, especially in transplant environments. Standard techniques using a hypoxic chamber cannot provide both oxygen and glucose modulations, while monitoring stimulus-secretion coupling factors in real-time. Using novel microfluidic device with integrated glucose and oxygen modulations, we quantified hypoxic impairment of islet response by calcium influx, mitochondrial potentials, and insulin secretion.