Simulation and Analysis of Stimulus Evoked and Seizure-like Activity in an Acute Rat Neocortical Brain Slice Preparation

Abstract

This thesis aims to provide tools for the simulation and analysis of acute brain slice experiments that have recorded spontaneous seizure-like activity and activity evoked using electric eld stimulation. The Virtual Electrode Recording Tool for Extracellular Potentials (VERTEX) (Tomsett et al., 2015) is a simulation framework that can act as a sca old for anatomical and physiological knowledge and can be used to test how interventions a ect the dynamics observed in the extracellular potentials. We extend VERTEX so that one can model a greater range of experimental setups, in particular those that involve electric eld stimulation. We also devise a software pipeline for the identi cation and analysis of epileptiform neuronal activity, which we apply to in vitro recordings from acute neocortical slices from a chronic model of epilepsy in rat. In Chapter 1 we look at the intersection of electric eld stimulation, synaptic plasticity and epilepsy. In Chapter 2 we look at the implementation of electric eld stimulation that we have added to the VERTEX simulator. We show that our simulation compares well with simulations using detailed neuron models, and with previously published in vitro data. We also describe our implementations of short term plasticity and spike-timing dependent plasticity. In Chapter 3 we describe some example simulations of focal electric eld stimulation in neocortex, investigating a single pulse of stimulation, a paired pulse of stimulation and the role of short term plasticity in the response. We also use theta burst stimulation to provoke a potentiation of the response when we apply spike-timing dependent plasticity to the synapses of the network. We then look to the experimental context of our framework. Chapter 4 describes an analysis tool for identifying and evaluating epileptiform activity recorded in vitro and outlines a method devised to measure the abruptness of seizure build up. Chapter 5 uses this analysis pipeline to analyse seizure-like events recorded in vitro from slices of motor cortex prepared from rats with chronic seizures induced by injection of tetanus toxin. In this chapter we also describe two VERTEX simulations; one that uses short term plasticity as the vehicle for the breakdown in inhibition and the build up of activity during a seizure-like event, and another of stimulus evoked activity in a seizure-prone neocortical slice. We compare the latter with stimulus evoked potential in an example in vitro multi-electrode array recording from the chronic epilepsy model. In Chapter 6 we discuss the future uses of VERTEX in modelling stimulus evoked activity and epileptiform activity.