Dario J. Englot - US grants

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Absence epilepsy is a common seizure disorder in children, associated with 5-10 second episodes of unresponsiveness that can adversely affect a child's academic performance and psychosocial interactions. On EEG, absence seizures are characterized by rhythmic "spike-wave" discharges (SWD), likely generated by corticothalamic neuronal networks. Although absence seizures are classically considered generalized epileptic events, recent studies suggest that focal brain regions are involved while other areas are spared. Our central hypothesis is that specific cortical and subcortical networks are involved in SWD, with some regions displaying increased neuronal activity and others showing decreased activity compared to baseline. [unreadable] Functional neuroimaging has the potential to map regional activity changes during SWD noninvasively throughout the brain. Previous neuroimaging studies have established a strong relationship between fMRI signals and neuronal activity. However, neuroimaging has limited spatiotemporal resolution and is only indirectly related to neuronal activity. These limitations can be overcome by associating fMRI signals with localized energetics and then directly connecting energetics to neuronal activity. Therefore, to accurately characterize the brain regions involved in spike-wave seizures, we propose a multimodal study of SWD in a rat model, using techniques spanning a wide range of spatiotemporal domains. Our specific aims are: 1) To map the cortical and subcortical networks involved in SWD using fMRI, 2) To measure vascular responses and calculate neuroenergetics during SWD, relating imaging signals to neuronal activity, and 3) To directly measure electrophysiological changes during SWD within involved brain regions. This combination of neuroimaging and electrophysiological techniques will allow unambiguous description of changes in neuronal activity throughout the brain during SWD, allowing a comprehensive characterization of the networks involved in these seizures. We expect to find regional heterogeneity, with certain regions showing increases in neuronal activity during SWD, some showing decreases, and sparing of other areas. Knowledge of which cortical and subcortical networks are involved in SWD will guide future studies into the local pathophysiology of absence epilepsy and may lead to the development of targeted treatments. [unreadable] Public Health Relevance: Absence seizures affect 17% of children with epilepsy, and are associated with staring spells that negatively impact a child's school performance and social interactions. A better understanding of the mechanisms of absence seizures and knowledge of which brain regions are involved may lead to better treatments for absence epilepsy and other related seizure disorders. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Epilepsy is a devastating disorder affecting one percent of the population. Seizures cannot be controlled by medications in thirty percent of patients with epilepsy, causing significant morbidity and even mortality. In focal neocortical epilepsy (FNE), seizures typically originate from the lateral cortex of the brain. While epilepsy surgery can lead to complete seizure-freedom in patients with medically-intractable focal neocortical epilepsy with current approaches, nearly half of these cases fail to adequately control seizures. Failures in the surgical treatment of FNE stem in part from limited techniques for accurately mapping where seizures originate in the brain (termed the epileptogenic zone), and a limited understanding of epileptic brain networks. The goal of this study is to reach a better understanding of brain network dysfunction in FNE patients. Before undergoing surgical resection of a presumed epileptogenic zone, all epilepsy patients in this study will receive noninvasive magnetoencephalography (MEG) recordings. Invasive procedures will be performed strictly for clinical diagnosis and treatment, and data analysis for research purposes will not subject patients to any additional risk. Non-epileptic control subject volunteers will als undergo noninvasive MEG recordings for comparison. MEG data will be analyzed using customized software to measure resting-state functional connectivity (RSFC) throughout the brain. RSFC is statistical technique used to study coherence between signals from separate brain regions, and it allows examination of abnormal functional connections in the brain. We will also compare pre-operative RSFC maps in epilepsy patients with the resection area defined by post- operative magnetic resonance imaging (MRI), and relate these connectivity patterns to post-operative clinical outcomes. While RSFC studies have been performed in epilepsy patients in the past, most of these have utilized functional MRI techniques, and the results have been inconsistent. Compared to functional MRI, however, MEG allows more direct recordings of brain activity at a higher resolution, representing a novel and promising approach to the study of functional connectivity in epilepsy. Based on preliminary analyses, it is expected that this study will reveal widespread decreased connectivity in focal epilepsy patients compared to controls, but that within individual patients, the epileptogenic zone will represent the region of highest connectivity. Resection of tissue with highest connectivity will predict post- operative seizure freedom. This study will allow a better understanding of brain network dysfunction in epilepsy, and may ultimately lead to new targeted treatments for seizure disorders.

Epilepsy affects 1% of the population, leading to significant morbidity and mortality. In focal epilepsy, seizures originate from an epileptogenic zone (EZ), and surgical resection leads to seizure-freedom in many patients. However, deleterious effects of focal epilepsy extend beyond the anatomic EZ, including diffuse gray matter atrophy, neocortical hypometabolism, and impaired neurocognitive function. Previous interictal (between seizures) magnetoencephalography studies of functional connectivity in focal epilepsy patients have demonstrated decreased connectivity in association neocortex that is directly related to frequency of consciousness-impairing (but not consciousness-sparing) seizures. Furthermore, prior ictal (during seizures) electrocorticography (ECoG) studies have demonstrated depressed neocortical activity during consciousness-impairing (but not consciousness-sparing) seizures in focal epilepsy. The central hypothesis of the present proposal is that over time, recurrent seizures in focal epilepsy lead to aberrant connections between subcortical activating structures (e.g., thalamus, basal forebrain) and association cortex, resulting in depressed neocortical connectivity that may contribute to neurocognitive dysfunction. To address this hypothesis, the present studies will use functional magnetic resonance imaging (fMRI) to measure interictal functional connectivity between subcortical activating structures and association neocortex in pre-operative focal epilepsy patients vs. controls (Aim 1). Connectivity patterns will be related to seizure type/frequency and neurocognitive parameters. To determine if functional connectivity perturbations are reversible once patients achieve seizure freedom after surgery, fMRI analyses of subcortical-cortical connectivity and neuropsychological tests will be repeated in patients ? 1 year post-operatively (Aim 2). Finally, to determine whether abnormal neocortical rhythms during consciousness-impairing seizures (ictal) lead directly to long-term reductions in neocortical connectivity (interictal), dynamic changes in connectivity will be measured before, during, and after seizures using ECoG (Aim 3). It is anticipated that compared to non-epileptic controls, focal epilepsy patients will exhibit reduced subcortical-cortical connectivity on interictal fMRI, which will be related to frequency of consciousness-impairing seizures and neurocognitive dysfunction (Aim 1). However, it is expected that subcortical-cortical functional connectivity perturbations will improve in patients who become seizure free after epilepsy surgery (Aim 2). Finally, it is anticipated that ECoG studies of dynamic functional connectivity will demonstrate ictal reductions in neocortical connectivity during consciousness-impairing seizures compared to baseline, suggesting a direct link between seizure activity and altered neocortical connectivity (Aim 3). A detailed understanding of subcortical-cortical network dysfunction in focal epilepsy gained through these studies may lead to novel targets for neuromodulation-based treatment, improvements in surgical patient selection and outcome prediction, and better strategies to prevent neurocognitive sequelae in this devastating disorder.

PROJECT SUMMARY/ABSTRACT Temporal lobe epilepsy (TLE) is a devastating and common neurological disorder in which patients suffer from frequent consciousness-impairing seizures, broad neurocognitive deficits, and diminished quality of life. Given that seizures originate focally in the hippocampus or amygdala, why do TLE patients demonstrate cognitive deficits not associated with temporal lobe function ? such as decline in executive function, cognitive processing speed, and attention ? as well as diffuse decreases in neocortical metabolism and functional connectivity? Given prior observations of reduced vigilance levels in TLE, and that seizures may disrupt the activity and long- range connectivity of subcortical brain structures involved in vigilance regulation, we propose that subcortical activating networks underlying vigilance play a critical role in mediating the widespread neural and cognitive effects of focal TLE. Specifically, our central hypothesis is that recurrent consciousness-impairing seizures in TLE may lead to functional connectivity disturbances between subcortical vigilance centers and cortex, leading to impairments in vigilance state that may contribute to neurocognitive problems not explained by temporal lobe dysfunction. To address this hypothesis, we plan human neuroimaging studies that relate vigilance to brain connectivity (Aim 1), cognition to vigilance (Aim 2), and connectivity to cognition (Aim 3). In Aim 1, we will characterize vigilance-dependent functional connectivity in healthy controls using simultaneous fMRI-EEG, which will guide the selection of subcortical-cortical connections to probe in patients (Aim 3). In Aim 2, we will relate individual neurocognitive parameters to vigilance measures in patients and controls, using a full neuropsychological evaluation and assessments of psychomotor speed and excessive sleepiness, to determine which cognitive deficits in patients are related to impaired vigilance. In Aim 3, we will compare MRI measures of subcortical-cortical connectivity in patients vs. controls (focusing on areas uncovered in Aim 1) to examine how long-range connections from subcortical activating structures are perturbed in TLE, and we will relate these connectivity disturbances to neurocognitive deficits. Using this novel approach that integrates multi-modal imaging with in-depth neurocognitive assessments, we expect to identify vigilance center connectivity perturbations in TLE that influence vigilance state and may contribute to neurocognitive decline. This work may help uncover subcortical neuromodulation targets and suggest the need for earlier surgical intervention and behavioral therapies in this devastating disorder.