Noninvasive Biomarker Discovery

Benign epilepsy with centrotemporal spikes (BECTS) is the most common childhood epilepsy syndrome, accounting for 20% of all childhood epilepsy and characterized by a transient period of seizure susceptibility of uncertain duration in school-age children. Despite extensive clinical experience with this disease, it remains a challenge to determine who will benefit from antiepileptic drug (AED) treatment and when it is safe to discontinue. Current clinical practice requires a trial-and-fail method for AED initiation and discontinuation with wide variability and controversy in treatment strategies across practitioners. Although non-treatment or premature taper may result in seizures and injury, chronic AED exposure is also not benign and may cause attentional deficits, aggression, hostility, nervousness, and somnolence in 30-70% of exposed children. A biomarker to isolate which children are at risk for ongoing seizures is needed in order to avoid the unnecessary consequences of over- or under-medication during critical years of cognitive, psychosocial and behavioral maturation in this large cohort of children.  In this work, we leverage advanced, safe, non-invasive multimodal recording techniques from quantitative neurophysiology, structural, and functional neuroimaging and implement innovative approaches to integrate these technologies to develop objective measures of seizure risk and cognitive function in children with BECTS. By focusing on this unique, well-characterized, though poorly understood patient populations of the course of this transient disease, we also aim to identify candidate biomarkers of seizure risk which may have a broader relevance to other epilepsy syndromes.

We are also interested in evaluated biomarkers of cortical physiology in healthy development and other disorders of cortical physiology, such as autism, infantile spasms, coma, and disorders of consciousness.

Seizure Localization

Epilepsy is a common childhood neurological disorder, affecting over one percent of all children, and imposes an enormous toll on these children and their families. One third of children with epilepsy will have intractable seizures that cannot be controlled through medical management, and for these children surgical resection of the brain region responsible for generating the seizures (the seizure onset zone, SOZ) is the most effective option for cure. However, epilepsy surgery remains under-utilized and delayed in eligible children due to the unique challenges associated with accurate localization of SOZ in childhood epilepsy. Because early identification and surgical intervention leads to improved long-term outcomes in these children, better techniques to localize the SOZ in children are greatly needed.

Seizures result from brain regions with abnormal neuronal excitability and connectivity. These properties can now be estimated non-invasively using advanced electrical and neuroimaging techniques. We use advanced EEG and MRI techniques to evaluate several leading non-invasive measures of cortical excitability and connectivity to localize the SOZ in children with refractory focal epilepsy. This work exploits a readily available and novel technology to improve localization accuracy with the goal of improving surgical outcomes and minimizing the morbidities of epilepsy and poorly targeted surgical investigations. Continued investigations explore how to reliably identify abnormal cortical signals and which signals best correlate with surgical outcome.

Functional Brain Networks

The developing brain is an immensely complex system. During this critical period of cortical development, the neurological exam can be a poor assay of cortical function or long-term prognosis. However, scalp EEG recordings offer opportunities for improved measures of subtle cortical function and organization. The scalp EEG correlates with known stages of normal neurodevelopment, provides information on local circuitry, and reveals age-specific functional networks throughout childhood representing large-scale cortical organization. We have established robust methods for inference of functional networks from scalp EEG. Through this work, we have improved techniques to mitigate limitations of EEG analysis due to the reference effect, spatial blurring, skull thickness, head size, and muscle artifact. Using these techniques, we have shown that stable EEG networks can be extracted from short samples of scalp EEG, that EEG networks rapidly mature in a stereotyped fashion over normal development, and that they reflect underlying white matter anatomical connectivity. Continued investigations explore whether these techniques can provide improved measures cortical disease in a variety of neurological disorders in children and adults, including autism, epilepsy, and infantile spasms.

Neonatal Seizures and Early Onset Epilepsy

Neonates and young children experience a disproportionately high burden of epilepsy. However, the unique presentations, treatment efficacy, and other epidemiological characteristics of early onset epilepsy remain poorly characterized. For several years, we have participated in multi-institutional collaborations to characterize the natural history and contemporary clinical practices and observational outcomes in neonatal and early childhood epilepsies.