In the new era of personalized medicine, the epilepsy field is at a tipping point to leverage emerging therapies that can being tailored to individual patient characteristics. Over 30% of children with epilepsy suffer from seizures that cannot be managed by mono- or poly-pharmacotherapies. Targeted neurostimulation and drug delivery are promising alternative therapies but, given the complexity and heterogeneity of the disorder, these therapies need to be precisely guided by the patient?s seizure dynamics. Despite decades of basic and clinical research, the latter remain elusive. In particular, seizure evolution from ictogenesis to ictal onset is poorly understood, in part due to a lack of fundamental understanding of how seizure precipitants impact the brain?s neurophysiological equilibrium, trigger ictogenesis and lead to cumulative changes that facilitate ictal onset. Although the underlying mechanisms of action of common precipitants such as stress and sleep loss are unclear, there is substantial evidence that they may modulate various hormones and neurotransmitters that impact the brain?s excitability and/or balance between excitation and inhibition. This project aims to systematically investigate the impact of large-scale hormonal fluctuations in pediatric epilepsy patients on brain dynamics, and quantify localized and distributed (network-level) electrophysiological changes during seizure evolution. Specifically, in a cohort of n = 40 patients with focal epilepsy who are undergoing continuous noninvasive neurophysiological monitoring as part of their presurgical evaluation, salivary cortisol and catecholamines will be measured 8 times daily, across all study days (Aim 1). Continuous scalp electroncephalograms (EEG) collected during this period will be analyzed in their entirety at the signal and network levels (Aim 2). Pathological high-frequency oscillations, a promising precursor of seizure activity in the epileptic brain will be estimated and classified across the entire period of recording. Multiscale brain networks and their topological properties will be quantified across all dominant frequencies of continuous EEG signals, and their time-dependent seizure sensitivity and specificity will be assessed. Statistical models will be developed to evaluate the relation between each patient-specific circadian hormone rhythms and corresponding temporal patterns of estimated electrophysiological measures, individually and combined into a seizure risk score (Aim 3). This is a first of its kind study that may significantly improve the field?s understanding of the direct and indirect (through hormonal modulations) impact of seizure precipitants, such as stress, on seizure dynamics from ictogenesis to ictal onset. This new knowledge may have a significant impact on the development of next-generation therapies that need to be guided by patient-specific seizure dynamics.
Through repeated hormone measurements and continuous electrophysiological (scalp EEG data), this project aims to systematically investigate the impact of (predominantly stress-related) hormonal fluctuations on the pediatric epileptic brain and their relationships to seizure evolution, from ictogenesis to ictal onset. The overarching goal of the study is to improve the field?s fundamental understanding of mechanisms underlying electrophysiological changes in the epileptic brain that favor seizure generation. In turn, this knowledge may have a transformative impact on promising next- generation individualized therapies for patients with medically refractory epilepsy.
