Electrical stimulation of the human peripheral nervous system can be a powerful tool to treat various medical conditions and provide insight into nervous system processes. A critical challenge for many applications is to selectively activate neurons that have the desired effect while avoiding the activation of neurons that produce side effects. To stimulate peripheral fibers, the longitudinal intrafascicular electrode (LIFE) targets small groups of fibers inside the fascicle using low-amplitude pulses and is well-suited for chronic use. This work aims to understand better the ability to use intrafascicular stimulation with LIFEs to activate small groups of neurons within a fascicle selectively.A hybrid workflow was developed to simulate: 1) the production/propagation of the electric field induced by the stimulation pulse and 2) the effect of the electric field on fiber activation (recruitment). To create efficient and robust strategies for the selective recruitment of axons, recognizing the effect of each parameter on their recruitment and activation pattern is essential. Thus, using this hybrid workflow, the effects of various factors such as fascicular anatomy, electrode parameters, and stimulation pulse parameters on recruitment have been characterized, and the sensitivity of the recruitment patterns to these parameters has been explored. Results demonstrated the potential advantages of specific stimulation strategies and the sensitivity of recruitment patterns to electrode placement and tissue properties. For example, it is demonstrated: the significant effect of endoneurium conductivities on threshold levels; that a configuration with a LIFE as a local ground can be used to deselect its surrounding axons; the advantages of changing the delay between pulses in dual monopolar stimulation in targeting different axons clusters and increasing the activation frequency of some axons; how monopolar and bipolar configurations can be used to enhance spatial selectivity; the effect of longitudinal displacement of axons, electrode length and electrode movement on the recruitment and the activation pattern. In summary, this work forms the foundation for developing stimulation strategies to enhance the selectivity that can be achieved with intrafascicular stimulation.

It is increasingly common to see machine learning techniques applied in conjunction with computational modeling for data-driven research in neuroscience. Such applications include using machine learning for model development, particularly for optimization of parameters based on electrophysiological constraints. Alternatively, machine learning can be used to validate and enhance techniques for experimental data analysis or to analyze model simulation data in large-scale modeling studies, which is the approach I apply here. I use simulations of biophysically-realistic cortical neuron models to supplement a common feature-based technique for analysis of electrophysiological signals. I leverage these simulated electrophysiological signals to perform feature selection that provides an improved method for neuron-type classification. Additionally, I validate an unsupervised approach that extends this improved feature selection to discover signatures associated with neuron morphologies - performing in vivo histology in effect. The result is a simulation-based discovery of the underlying synaptic conditions responsible for patterns of extracellular signatures that can be applied to understand both simulation and experimental data. I also use unsupervised learning techniques to identify common channel mechanisms underlying electrophysiological behaviors of cortical neuron models. This work relies on an open-source database containing a large number of computational models for cortical neurons. I perform a quantitative data-driven analysis of these previously published ion channel and neuron models that uses information shared across models as opposed to information limited to individual models. The result is simulation-based discovery of model sub-types at two spatial scales which map functional relationships between activation/inactivation properties of channel family model sub-types to electrophysiological properties of cortical neuron model sub-types. Further, the combination of unsupervised learning techniques and parameter visualizations serve to integrate characterizations of model electrophysiological behavior across scales.

Neuron models that behave like their biological counterparts are essential for computational neuroscience.Reduced neuron models, which abstract away biological mechanisms in the interest of speed and interpretability, have received much attention due to their utility in large scale simulations of the brain, but little care has been taken to ensure that these models exhibit behaviors that closely resemble real neurons.
In order to improve the verisimilitude of these reduced neuron models, I developed an optimizer that uses genetic algorithms to align model behaviors with those observed in experiments.
I verified that this optimizer was able to recover model parameters given only observed physiological data; however, I also found that reduced models nonetheless had limited ability to reproduce all observed behaviors, and that this varied by cell type and desired behavior.
These challenges can partly be surmounted by carefully designing the set of physiological features that guide the optimization. In summary, we found evidence that reduced neuron model optimization had the potential to produce reduced neuron models for only a limited range of neuron types.

The increasing availability of experimental data and computational power have resulted in increasingly detailed and sophisticated models of brain structures. Biophysically realistic models allow detailed investigations of the mechanisms that operate within those structures. In this work, published mouse experimental data were synthesized to develop an extensible, open-source platform for modeling the mouse main olfactory bulb and other brain regions. A “virtual slice” model of a main olfactory bulb glomerular column that includes detailed models of tufted, mitral, and granule cells was created to investigate the underlying mechanisms of a gamma frequency oscillation pattern (“gamma fingerprint”) often observed in rodent bulbar local field potential recordings. The gamma fingerprint was reproduced by the model and a mechanistic hypothesis to explain aspects of the fingerprint was developed. A series of computational experiments tested the hypothesis. The results demonstrate the importance of interactions between electrical synapses, principal cell synaptic input strength differences, and granule cell inhibition in the formation of the gamma fingerprint. The model, data, results, and reproduction materials are accessible at https://github.com/justasb/olfactorybulb. The discussion includes a detailed description of mechanisms underlying the gamma fingerprint and how the model predictions can be tested experimentally. In summary, the modeling platform can be extended to include other types of cells, mechanisms and brain regions and can be used to investigate a wide range of experimentally testable hypotheses.

While techniques for reading DNA in some capacity has been possible for decades,

the ability to accurately edit genomes at scale has remained elusive. Novel techniques

have been introduced recently to aid in the writing of DNA sequences. While writing

DNA is more accessible, it still remains expensive, justifying the increased interest in

in silico predictions of cell behavior. In order to accurately predict the behavior of

cells it is necessary to extensively model the cell environment, including gene-to-gene

interactions as completely as possible.

Significant algorithmic advances have been made for identifying these interactions,

but despite these improvements current techniques fail to infer some edges, and

fail to capture some complexities in the network. Much of this limitation is due to

heavily underdetermined problems, whereby tens of thousands of variables are to be

inferred using datasets with the power to resolve only a small fraction of the variables.

Additionally, failure to correctly resolve gene isoforms using short reads contributes

significantly to noise in gene quantification measures.

This dissertation introduces novel mathematical models, machine learning techniques,

and biological techniques to solve the problems described above. Mathematical

models are proposed for simulation of gene network motifs, and raw read simulation.

Machine learning techniques are shown for DNA sequence matching, and DNA

sequence correction.

Results provide novel insights into the low level functionality of gene networks. Also

shown is the ability to use normalization techniques to aggregate data for gene network

inference leading to larger data sets while minimizing increases in inter-experimental

noise. Results also demonstrate that high error rates experienced by third generation

sequencing are significantly different than previous error profiles, and that these errors can be modeled, simulated, and rectified. Finally, techniques are provided for amending this DNA error that preserve the benefits of third generation sequencing.

During attempted fixation, the eyes are not still but continue to produce so called "fixational eye movements", which include microsaccades, drift, and tremor. Microsaccades are thought to help prevent and restore vision loss during fixation, and to correct fixation errors, but how they contribute to these functions remains a matter of debate. This dissertation presents the results of four experiments conducted to address current controversies concerning the role of microsaccades in visibility and oculomotor control.

The first two experiments set out to correlate microsaccade production with the visibility of foveal and peripheral targets of varied spatial frequencies, during attempted fixation. The results indicate that microsaccades restore the visibility of both peripheral targets and targets presented entirely within the fovea, as a function of their spatial frequency characteristics.

The last two experiments set out to determine the role of microsaccades and drifts on the correction of gaze-position errors due to blinks in human and non-human primates, and to characterize microsaccades forming square-wave jerks (SWJs) in non-human primates. The results showed that microsaccades, but not drifts, correct gaze-position errors due to blinks, and that SWJ production and dynamic properties are equivalent in human and non-human primates.

These combined findings suggest that microsaccades, like saccades, serve multiple and non-exclusive functional roles in vision and oculomotor control, as opposed to having a single specialized function.

One explanation for membrane accommodation in response to a slowly rising current, and the phenomenon underlying the dynamics of elliptic bursting in nerves, is the mathematical problem of dynamic Hopf bifurcation. This problem has been studied extensively for linear (deterministic and stochastic) current ramps, nonlinear ramps, and elliptic bursting. These studies primarily investigated dynamic Hopf bifurcation in space-clamped excitable cells. In this study we introduce a new phenomenon associated with dynamic Hopf bifurcation. We show that for excitable spiny cables injected at one end with a slow current ramp, the generation of oscillations may occur an order one distance away from the current injection site. The phenomenon is significant since in the model the geometric and electrical parameters, as well as the ion channels, are uniformly distributed. In addition to demonstrating the phenomenon computationally, we analyze the problem using a singular perturbation method that provides a way to predict when and where the onset will occur in response to the input stimulus. We do not see this phenomenon for excitable cables in which the ion channels are embedded in the cable membrane itself, suggesting that it is essential for the channels to be isolated in the spines.

Dopamine (DA) is a neurotransmitter involved in attention, goal oriented behavior, movement, reward learning, and short term and working memory. For the past four decades, mathematical and computational modeling approaches have been useful in DA research, and although every modeling approach has limitations, a model is an efficient way to generate and explore hypotheses. This work develops a model of DA dynamics in a representative, single DA neuron by integrating previous experimental, theoretical and computational research. The model consists of three compartments: the cytosol, the vesicles, and the extracellular space and forms the basis of a new mathematical paradigm for examining the dynamics of DA synthesis, storage, release and reuptake. The model can be driven by action potentials generated by any model of excitable membrane potential or even from experimentally induced depolarization voltage recordings. Here the model is forced by a previously published model of the excitable membrane of a mesencephalic DA neuron in order to study the biochemical processes involved in extracellular DA production. After demonstrating that the model exhibits realistic dynamics resembling those observed experimentally, the model is used to examine the functional changes in presynaptic mechanisms due to application of cocaine. Sensitivity analysis and numerical studies that focus on various possible mechanisms for the inhibition of DAT by cocaine provide insight for the complex interactions involved in DA dynamics. In particular, comparing numerical results for a mixed inhibition mechanism to those for competitive, non-competitive and uncompetitive inhibition mechanisms reveals many behavioral similarities for these different types of inhibition that depend on inhibition parameters and levels of cocaine. Placing experimental results within this context of mixed inhibition provides a possible explanation for the conflicting views of uptake inhibition mechanisms found in experimental neuroscience literature.

In vertebrate outer retina, changes in the membrane potential of horizontal cells affect the calcium influx and glutamate release of cone photoreceptors via a negative feedback. This feedback has a number of important physiological consequences. One is called background-induced flicker enhancement (BIFE) in which the onset of dim background enhances the center flicker response of horizontal cells. The underlying mechanism for the feedback is still unclear but competing hypotheses have been proposed. One is the GABA hypothesis, which states that the feedback is mediated by gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter released from horizontal cells. Another is the ephaptic hypothesis, which contends that the feedback is non-GABAergic and is achieved through the modulation of electrical potential in the intersynaptic cleft between cones and horizontal cells. In this study, a continuum spine model of the cone-horizontal cell synaptic circuitry is formulated. This model, a partial differential equation system, incorporates both the GABA and ephaptic feedback mechanisms. Simulation results, in comparison with experiments, indicate that the ephaptic mechanism is necessary in order for the model to capture the major spatial and temporal dynamics of the BIFE effect. In addition, simulations indicate that the GABA mechanism may play some minor modulation role.