About the Lab

Major Contributions

Redefining drug-resistance in focal cortical dysplasia-related epilepsy

Despite being the most frequent cause of pediatric drug-resistant epilepsy (DRE), children often spend years waiting for potentially-curative epilepsy surgery. One main barrier to surgical evaluation is the time spent waiting to achieve the current definition of DRE; that is, the failure of two or more, adequately-dosed, appropriately-selected antiseizure medications. In this Neurology study of 143 children with FCD done at Children’s National Hospital, we showed that the majority of kids with FCD develop epilepsy that is drug-resistant. Importantly, we found that the failure of just one antiseizure medication is associated with tremendous risk of future pharmacoresistance. These data support a major shift in practice: we recommend the One-and-Done rule where for FCD-related epilepsy, one antiseizure medication is tried and if there is failure, to move quickly z an epilepsy surgical evaluation.

Functional connectivity signatures that can differentiate FCD-DRE

Resting-state functional MRI is a widely-available tool that can measure and map the cortical functional networks of the human brain. In this Annals of Neurology study, we used advanced connectivity analyses of resting-state fMRI to demonstrate that there are group-level mutual connectivity differences, or “signatures,” in children with FCD-DRE compared to healthy controls. These connectivity alterations occur in regions of the dorsal attention, default mode and frontoparietal control networks. The FCD lesion has diminished connectivity within its dominant functional network and in homotopic cortex. These “signatures” also varied by FCD pathological subtype and related to eventual surgical outcomes, implying specificity. A future goal is to expand this type of work to develop precision diagnostic tools.

Relating brain networks to real-world epilepsy comorbidity. Epilepsy is a chronic disease that causes numerous associated comorbidities

Executive dysfunction is very common across focal epilepsies but had remained relatively underexplored. In this Neurology study, we demonstrate that FCD lesion overlap with the frontoparietal control network is associated with parent-reported measures of executive function by the Behavior Rating Inventory of Executive Function (BRIEF). Specifically, we found that FCD co-localization to the frontoparietal control network is associated with high risk of executive dysfunction, and that the altered BRIEF subscales correspond to the functional domains subserved by the control network. These data further our understanding of epilepsy as a brain network disorder, and help to support a unified theory of focal epilepsy through lesion-network interactions.

Discovery of network mechanisms underlying epilepsy onset in FCD-related epilepsy

FCDs are highly epileptogenic lesions that can occur throughout the brain. Extensive prior investigations using clinical, pathological and structural radiological data failed to explain variations in the age of epilepsy onset. In a multicenter study of 380 FCD patients, we showed that FCD co-localization to distributed cortical functional networks in a way that may mirror ontogenesis. That is, FCDs in earlier-activating unimodal networks such as visual and somatomotor networks have earlier epilepsy onset, but those in higher-order, multimodal networks such as the limbic network have the latest epilepsy onset. These data may explain a biological basis for age-dependent epilepsy expression in FCD-related epilepsy.

Collaborating worldwide to develop advanced diagnostic tools

We are active members of the Multi-centre Epilepsy Lesion Detection Project (Site PI: Nathan T. Cohen, MD), which is an international consortium dedicated to development of advanced imaging tools in patients with DRE. This has led to development of one of the largest prediction models of postsurgical seizure freedom in FCD-related epilepsy in Epilepsia. We helped to develop machine-learning based tools to enhance detection of subtle FCDs published in Brain and JAMA Neurology, as well as for hippocampal sclerosis published in Annals of Neurology.

Funding

We are thankful for the support past and present of our research endeavors.

Present funding includes research support to NTC from the National Institutes of Health/National Institute of Neurological Disorders and Stroke K23NS131522, the Hess Foundation, and support from the Children’s National Intellectual and Developmental Disabilities Research Center. Collaborative efforts with Dr. Xie are currently supported through the American Epilepsy Society (Young Investigator Award).

Prior completed support includes funding to NTC from the American Academy of Neurology (Career Development Award), the Pediatric Epilepsy Research Foundation/Child Neurology Foundation (Shields Research Grant), and the Children’s National Research Institute (Chief Research Officer Award).