Recent developments in neural stimulation and recording technologies are providing scientists with the ability of recording and controlling the activity of individual neurons in vitro or in vivo, with very high spatial and temporal resolution. Tools such as optogenetics, for example, are having a significant impact in the neuroscience field by delivering optical firing control with the precision and spatiotemporal resolution required for investigating information processing and plasticity in biological brains. While a number of training algorithms have been developed to date for spiking neural network (SNN) models of biological neuronal circuits, exiting methods rely on learning rules that adjust the synaptic strengths (or weights) directly, in order to obtain the desired network-level (or functional-level) performance. As such, they are not applicable to modifying plasticity in biological neuronal circuits, in which synaptic strengths only change as a result of pre- and post-synaptic neuron firings or biological mechanisms beyond our control. This paper presents a weight-free training algorithm that relies solely on adjusting the spatiotemporal delivery of neuron firings in order to optimize the network performance. The proposed weight-free algorithm does not require any knowledge of the SNN model or its plasticity mechanisms. As a result, this training approach is potentially realizable in vitro or in vivo via neural stimulation and recording technologies, such as optogenetics and multielectrode arrays, and could be utilized to control plasticity at multiple scales of biological neuronal circuits. The approach is demonstrated by training SNNs with hundreds of units to control a virtual insect navigating in an unknown environment.

The incidence of cardiac arrhythmias is known to be associated with tissue heterogeneities including fibrosis. However, the impact of microscopic structural heterogeneities on conduction in excitable tissues remains poorly understood. In this study, we investigated how acellular microheterogeneities affect macroscopic conduction under conditions of normal and reduced excitability by utilizing a novel platform of paired in vitro and in silico studies to examine the mechanisms of conduction. Regular patterns of nonconductive micro-obstacles were created in confluent monolayers of the previously described engineered-excitable Ex293 cell line. Increasing the relative ratio of obstacle size to intra-obstacle strand width resulted in significant conduction slowing up to 23.6% and a significant increase in wavefront curvature anisotropy, a measure of spatial variation in wavefront shape. Changes in bulk electrical conductivity and in path tortuosity were insufficient to explain these observed macroscopic changes. Rather, microscale behaviors including local conduction slowing due to microscale branching, and conduction acceleration due to wavefront merging were shown to contribute to macroscopic phenomena. Conditions of reduced excitability led to further conduction slowing and a reversal of wavefront curvature anisotropy due to spatially non-uniform effects on microscopic slowing and acceleration. This unique experimental and computation platform provided critical mechanistic insights in the impact of microscopic heterogeneities on macroscopic conduction, pertinent to settings of fibrotic heart disease.

To understand how excitable tissues give rise to arrhythmias, it is crucially necessary to understand the electrical dynamics of cells in the context of their environment. Multicellular monolayer cultures have proven useful for investigating arrhythmias and other conduction anomalies, and because of their relatively simple structure, these constructs lend themselves to paired computational studies that often help elucidate mechanisms of the observed behavior. However, tissue cultures of cardiomyocyte monolayers currently require the use of neonatal cells with ionic properties that change rapidly during development and have thus been poorly characterized and modeled to date. Recently, Kirkton and Bursac demonstrated the ability to create biosynthetic excitable tissues from genetically engineered and immortalized HEK293 cells with well-characterized electrical properties and the ability to propagate action potentials. In this study, we developed and validated a computational model of these excitable HEK293 cells (called "Ex293" cells) using existing electrophysiological data and a genetic search algorithm. In order to reproduce not only the mean but also the variability of experimental observations, we examined what sources of variation were required in the computational model. Random cell-to-cell and inter-monolayer variation in both ionic conductances and tissue conductivity was necessary to explain the experimentally observed variability in action potential shape and macroscopic conduction, and the spatial organization of cell-to-cell conductance variation was found to not impact macroscopic behavior; the resulting model accurately reproduces both normal and drug-modified conduction behavior. The development of a computational Ex293 cell and tissue model provides a novel framework to perform paired computational-experimental studies to study normal and abnormal conduction in multidimensional excitable tissue, and the methodology of modeling variation can be applied to models of any excitable cell.

The thalamus plays a critical role in the genesis of thalamocortical oscillations, yet the underlying mechanisms remain elusive. To understand whether the isolated thalamus can generate multiple distinct oscillations, we developed a biophysical thalamic model to test the hypothesis that generation of and transition between distinct thalamic oscillations can be explained as a function of neuromodulation by acetylcholine (ACh) and norepinephrine (NE) and afferent synaptic excitation. Indeed, the model exhibited four distinct thalamic rhythms (delta, sleep spindle, alpha and gamma oscillations) that span the physiological states corresponding to different arousal levels from deep sleep to focused attention. Our simulation results indicate that generation of these distinct thalamic oscillations is a result of both intrinsic oscillatory cellular properties and specific network connectivity patterns. We then systematically varied the ACh/NE and input levels to generate a complete map of the different oscillatory states and their transitions. Lastly, we applied periodic stimulation to the thalamic network and found that entrainment of thalamic oscillations is highly state-dependent. Our results support the hypothesis that ACh/NE modulation and afferent excitation define thalamic oscillatory states and their response to brain stimulation. Our model proposes a broader and more central role of the thalamus in the genesis of multiple distinct thalamo-cortical rhythms than previously assumed.

Spiking neural networks have been shown capable of simulating sigmoidal artificial neural networks providing promising evidence that they too are universal function approximators. Spiking neural networks offer several advantages over sigmoidal networks, because they can approximate the dynamics of biological neuronal networks, and can potentially reproduce the computational speed observed in biological brains by enabling temporal coding. On the other hand, the effectiveness of spiking neural network training algorithms is still far removed from that exhibited by backpropagating sigmoidal neural networks. This paper presents a novel algorithm based on reward-modulated spike-timing-dependent plasticity that is biologically plausible and capable of training a spiking neural network to learn the exclusive-or (XOR) computation, through rate-based coding. The results show that a spiking neural network model with twenty-three nodes is able to learn the XOR gate accurately, and performs the computation on time scales of milliseconds. Moreover, the algorithm can potentially be verified in light-sensitive neuronal networks grown in vitro by determining the spikes patterns that lead to the desired synaptic weights computed in silico when induced by blue light in vitro.

CardioWave is a modular system for simulating wavefront conduction in the heart. These simulations may be used to investigate the factors that generate and sustain life-threatening arrhythmias such as ventricular fibrillation. The user selects a set of modules which most closely reflects the simulation they are interested in and the simulator is built automatically. Thus, we do not present one monolithic simulator, but rather a simulator-generator which allows the researcher to make the trade-offs of complexity versus performance. The results presented here are from simulations run on an IBM SP parallel computer and a cluster of workstations. The performance numbers show excellent scalability up through 128 processors. With the larger memory of the parallel machines, we have been able to perform highly realistic simulations of the human atria. These simulations include realistic, 3-D geometries with inhomogeneity and anisotropy as we as highly complex membrane dynamics.

The merging of hypotheses and techniques from physics, mathematics, biomedical engineering, cardiology, and computer science is helping to form increasingly more realistic computer models of the heart. These models complement experimental and clinical studies that seek to elucidate the mechanisms of arrhythmogenesis and improve pharmacological and electrical therapies. This paper reviews the current state of the art of computer models for investigating normal and abnormal conduction in cardiac muscle. A brief introduction to the mathematical foundations of continuous (monodomain and bidomain) and discrete tissue structure models and to ionic current based and FitzHugh-Nagumo membrane models is presented. The paper summarizes some of the recent contributions in validating tissue structure models, modeling unidirectional block and reentry in a 1-D loop, and applying generic spiral wave theory to cardiac arrhythmias.