Mechanisms and Control of Thalamocortical Synchrony in Absence Epilepsy

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Project Summary The foundation of epilepsy diagnosis and patient-tailored treatment strategies relies on the detection of stereotyped patterns in EEG recordings. These patterns require synchronous brain activity because electrical signals are additive, and thus peaks and troughs cancel when misaligned. Despite this connection, the role of neuronal synchrony in epilepsy mechanisms is surprisingly unclear. I am seeking to test for the presence and origin of widespread neuronal synchronization in absence epilepsy and test if it has a causal role in absence seizure generation. Absence seizures have an abrupt onset of bilaterally synchronous spike wave discharge (SWD) EEG pattern across widespread areas of the brain. These seizures depend on both cortical and thalamic networks but we do not know to what degree widespread cortical and thalamic synchronous firing occurs, which brain structures are involved, or if there is any direct causal role of synchronization between cortex and thalamus in absence seizure generation or maintenance. A fundamental principle for understanding synchronization between network nodes is the following: the greater the similarity between the two nodes in oscillation frequencies, the more readily they synchronize. My central hypothesis is that coordinated changes in firing rates to a common frequency promotes corticothalamic synchronization, generating seizures. In aim 1 I seek to measure and perturb firing rates to test whether firing rate convergences to a common rate directly promote their synchronization. I will use multiple high density silicon probes to measure the population firing rates of various target brain areas in the cortex and thalamus in the times leading up to and during absence seizures. Subsequently, using chemogenetics, I will force a subset of neurons within a given target region to fire at an incompatible firing frequency, which I predict will preclude its recruitment into this otherwise globally synchronous firing during a seizure. In aim 2, I seek to test for a causal role of corticothalamic synchronization in absence seizures. I will initiate seizures optogenetically with halorhodopsin induced rebound firing in thalamocortical neurons as has been done previously, and then use closed loop activation of channelrhodopsin expressed in the corresponding corticothalamic input axons. This will provide cortical input to the thalamus at defined phases and frequencies relative to the SWDs, testing whether cortical synchronization and/or specific relative frequencies with thalamus regulates seizure induction or duration. This work will for the first time demonstrate both the widespread presence of synchronous neuronal firing and a causal role of corticothalamic synchronization in absence seizure generation. This project will be performed under the guidance of two mentors, Dr. Huguenard guiding training in experimental aspects and Dr. Ganguli guiding theoretical, computational, and analysis techniques. With this combined approach along with extensive institution and professional support at Stanford, I will develop a highly unique skillset with which to begin my own laboratory.