Researchers use wide range of tools to understand causes of epilepsy
September 9, 2019
Epilepsy is a common condition that affects one in 26 people at some point in their lives. While many children receive effective treatment, some still suffer from poorly controlled seizures that can affect their development. Timely treatment is crucial, but physicians and researchers still have a limited understanding of the precise causes of epilepsy.
Wim van Drongelen, PhD, technical and research director at the University of Chicago Medicine Comer Children’s Pediatric Epilepsy Center, has devoted his life’s work to understanding the root causes of seizures and how they spread throughout the brain.
“Working in this field is not just an academic exercise to see how epilepsy works,” he said. “Ultimately it has real implications for patients with epilepsy.”
Van Drongelen has assembled a diverse team in his lab to tackle these complex problems. He has a biology and physics background himself, and has several researchers working on computer and mathematical models of the patterns of electrical activity that take place in the brain both during seizures and normal states. Medical students in his lab study potential clinical applications to improve the detection and diagnosis of seizures, while Andrew Tryba, PhD, a research assistant professor of pediatrics, studies the neurobiology of how seizures propagate through networks of brain cells.
One of the primary challenges of diagnosing epilepsy is the gap between what physicians can detect in the clinic and the wide range of seizure types and their underlying causes. The primary way to monitor brain activity in a patient is by using electroencephalography, or EEG. Physicians attach electrodes to the scalp that can record patterns of electrical activity in between seizures.
While immensely useful for initial diagnosis in the clinic, van Drongelen points out that standard EEG is measuring brain activity at a global scale. Each electrode monitors about a centimeter of space, which contains millions of brain cells. The seizure may be caused by just a handful of cells misfiring within that space. What the EEG is actually recording is the effect of that activity propagating through the larger network of nearby brain cells.
“EEG is really useful because they can determine at the centimeter scale where things may be going wrong and a surgeon can intervene,” van Drongelen said. “What it doesn’t do is give you insight into what the mechanism is that generates this network malfunction in the brain.”
His lab has been collaborating with teams at Columbia University and the University of Twente in the Netherlands to reconcile these differences and improve diagnosis. In a 2017 study published in the Proceedings of the National Academy of Sciences (PNAS), they used microelectrode arrays placed inside the brain in combination with another type of brain activity monitoring called electrocorticography, or ECoG. This allowed them to see more precise patterns of activity by collecting nerve cell activity data directly from the brain surface of human study subjects.
That study showed how the activity of the relatively few brain cells that trigger a seizure relate to the broader signals captured by the ECoG readings from the surface. In another study from 2018 published in the International Journal of Neural Systems, they explored the relationships between the activity of those few troublesome neurons and what can be detected at a larger scale by clinical tools like EEG.
Using the data generated by studies like this, van Drongelen and his team are able to create software models of the brain that recreate the kinds of small scale, local activity patterns they see from the electrode arrays and track how they propagate through networks of brain cells to create the large-scale patterns they see in clinical EEG readings. This allows them to define biomarkers, or measurable patterns of activity in the brain, that can indicate if a patient has been having seizures.
Unlike other neurological disorders like Parkinson’s disease, where symptoms are always present, a patient with epilepsy can seem normal most of the time. Unless they are continuously monitored, it can be difficult to detect when they have a seizure, especially when many types of seizures are subtle and don’t present the classic, full-body seizing or loss of muscle control.
For instance, van Drongelen is working with Douglas Nordli Jr., MD, chief of pediatric neurology at UChicago Medicine Comer Children’s Hospital, Julia Henry, MD, assistant professor of pediatrics, and students in the Medical Scientist Training Program at the Pritzker School of Medicine on a project to help monitor premature infants in the neonatal intensive care unit and detect seizures. Naoum Issa, MD, PhD, assistant professor of neurology, Shasha Wu, MD, PhD, assistant professor of neurology, and Somin Lee, another student in van Drongelen’s lab, are also studying ways to use non-invasive monitoring on the scalp to detect seizures that originate from deep within the brain, which can help make an earlier diagnosis before they spread to rest of the brain.
These clinical applications complement Tryba’s basic research in the lab. He has been working with sections of brain tissue that have been removed from patients during epilepsy surgery to understand how seizures propagate through brain cells, and the mechanisms for slowing them down. The lab is also experimenting with brain organoids, small clusters of neurons grown from stem cells that can simulate living brain tissue.
“The advantage of using our interdisciplinary research, combining complementary techniques in neurobiology, mathematics, computer science with clinical data, is the wide range of tools that are available to test hypotheses,” van Drongelen said. “With this approach, we hope to further our insight into what makes brain circuits go awry during seizures and ultimately how to fix this.”