Epilepsy Intractable

The purpose of the research is to better understand how the human brain accomplishes the basic cognitive tasks of learning new information, recalling stored information, making decisions or choices about presented information and self-control. These investigations are critical to better understand human cognition and to design treatments for disorders of learning, memory, decision making and cognitive control.

Epilepsy affects millions worldwide, with 40% of patients experiencing uncontrolled seizures despite medication. Comprehensive epilepsy centers recommend continuous video-electroencephalography monitoring to define seizure type and distinguish mimickers. This process, however, is resource-intensive, with lengthy hospital stays. The investigators' recent study identified a heightened association between arousals and epileptic activity in drug-resistant focal epilepsy patients. Building on these findings, the investigators aim to explore whether disrupting sleep with an alarm system triggers earlier occurrence of seizures, potentially offering insights to reduce hospital stay durations in epilepsy monitoring units.

Spatial navigation is a fundamental human behavior, and deficits in navigational functions are among the hallmark symptoms of severe neurological disorders such as Alzheimer's disease. Understanding how the human brain processes and encodes spatial information is thus of critical importance for the development of therapies for affected patients. Previous studies have shown that the brain forms neural representations of spatial information, via spatially-tuned activity of single neurons (e.g., place cells, grid cells, or head direction cells), and by the coordinated oscillatory activity of cell populations. The vast majority of these studies have focused on the encoding of self-related spatial information, such as one's own location, orientation, and movements. However, everyday tasks in social settings require the encoding of spatial information not only for oneself, but also for other people in the environment. At present, it is largely unknown how the human brain accomplishes this important function, and how aspects of human cognition may affect these spatial encoding mechanisms. This project therefore aims to elucidate the neural mechanisms that underlie the encoding of spatial information and awareness of others. Specifically, the proposed research plan will determine how human deep brain oscillations and single-neuron activity allow us to keep track of other individuals as they move through our environment. Next, the project will determine whether these spatial encoding mechanisms are specific to the encoding of another person, or whether they can be used more flexibly to support the encoding of moving inanimate objects and even more abstract cognitive functions such as imagined navigation. Finally, the project will determine how spatial information is encoded in more complex real-world scenarios, when multiple information sources (e.g., multiple people) are present. To address these questions, intracranial medial temporal lobe activity will be recorded from two rare participant groups: (1) Participants with permanently implanted depth electrodes for the treatment of focal epilepsy through responsive neurostimulation (RNS), who provide a unique opportunity to record deep brain oscillations during free movement and naturalistic behavior; and (2) hospitalized epilepsy patients with temporarily implanted intracranial electrodes in the epilepsy monitoring unit (EMU), from whom joint oscillatory and single-neuron activity can be recorded.

Epilepsy, a prevalent neurological disorder, affects 40% of patients with uncontrolled seizures despite medications. Sleep disturbance exacerbates epilepsy, and vice versa, but existing literature suffers from limitations. Studies conducted in hospital settings provide only brief observation periods and fail to capture the natural sleep environment. Wearable technology offers a promising solution, providing a nuanced understanding of the relationship between seizures and sleep. The Dreem headband, an EEG-based wearable, is well-suited for such studies, offering ease of use and validated accuracy. This technology enables extended observation periods under stable medication conditions, essential for assessing the complex interplay between sleep and epilepsy. By elucidating the impact of sleep on seizures, the researchers seek to identify patient populations where sleep significantly influences seizure susceptibility, ultimately informing personalized epilepsy treatments.

This study investigates the anatomical and physiological basis of spatial scene recognition memory in patients with temporal lobe epilepsy and temporal lobe lesions. Standard neuropsychological tests are insensitive to important memory deficits experienced by patients, particularly in spatial/scene memory, recollective experience, and familiarity processing. Using a validated virtual tour paradigm, the study examines how familiarity-based recognition and recall of spatial scenes relate to specific brain structures. In Aim I, a large cohort of patients with varied temporal lobe lesions at Emory University undergoes the virtual tour task with voxel-based lesion-symptom mapping to localize necessary brain regions. In Aim II, scalp event-related potentials and eye tracking in healthy participants at UC Davis characterize the temporal dynamics and lateralization of scene recognition. In Aim III, intracranial EEG recordings (including local field potentials and single-unit activity) in epilepsy surgery patients at UC Davis determine the precise network dynamics underlying spatial scene familiarity and recall. The long-term goal is to improve the prediction and prevention of cognitive morbidity from epilepsy surgery by providing a more complete model of spatial recognition memory circuits.

Upon successful completion of this study, the investigators expect the study's contribution to be the development of noninvasive imaging biomarkers to predict IEEG functional dynamics and epilepsy surgical outcomes. Findings from the present study may inform current and new therapies to map and alter seizure spread, and pave the way for less invasive, better- targeted, patient-specific interventions with improved surgical outcomes. This research is relevant to public health because over 20 million people worldwide suffer from focal drug-resistant epilepsy and are potential candidates for cure with epilepsy surgical interventions.

Overall, this observational cohort study aims to: 1. Improve our understanding of the genetic architecture of childhood focal epilepsies. 2. Develop a liquid biopsy of cerebrospinal fluid (CSF) and assess feasibility to detect cerebral mosaicism using cell-free DNA (cfDNA) analysis and evaluate its performance against brain tissue on the panel testing. 3. Develop a methodology to use trace tissue from Stereoelectroencephalography (SEEG) DNA and assess feasibility to detect cerebral mosaicism and evaluate its performance against brain tissue on the panel testing. 3\. Validate the use of the liquid biopsy and SEEG trace tissue for use in the English National Health Service clinical services and share with other Genomic Laboratory Hubs.