Pediatric Epilepsy Research Lab: Kevin J. Staley, MD

Overview

Our long-term research goal is the development of new approaches to the treatment of epilepsy based on a clearer understanding of the necessary steps in seizure initiation and propagation.

The two major themes in the lab are neuronal ion transport and the spread of activity in neural networks. Neuronal ion transport underlies signaling at all fast synapses. The importance of neuronal ion transport was underscored by our recent discovery that reversed ion transport in the immature brain was blocking the effects of the anticonvulsants most commonly used to treat neonatal seizures, and that a safe and well-characterized diuretic could ameliorate this condition.  This work has recently gone from bench to bedside with the completion and publication of the successful phase I-II trial of bumetanide as adjunctive therapy for neonatal seizures.

Our work on the spread of excitation in neural networks combines fluorescent imaging of network activity with computerized analysis and modeling to understand how normal and abnormal signaling progresses through neural networks. In collaboration with Kyle Lillis, we have developed techniques to study the onset of spontaneous seizures in brain explants that are maintained for many weeks.  This provides a unique opportunity to study seizure onset in a preparation in which all cells can be studies, and all inputs are known.  Using this preparation we found evidence for reentrant or circular patterns of neural activity that resemble cardiac fibrillation and precede seizures.  These patterns do not originate from a particular group of “grandfather” neurons.  Rather the activity can begin in many different neurons and then spread to distant regions of the network.

Research Projects

Seizures and cerebral edema after brain injury

Seizures triggered by acute brain injury are poorly responsive to current therapies.  Understanding how injury shifts ions and water in the brain can advance the treatment of acute seizures and cerebral edema.  These two conditions lead to a great deal of morbidity, but without a clear understanding of the pathophysiology, more effective treatments cannot be developed.  We have developed preparations and imaging technologies to help visualize the movement of ions after acute brain injury, leading the way to studies to identify effective therapeutic strategies.   In one of these projects, Volodymyr Dzhala is seeking ways to increase the efficacy of bumetanide for the treatment of neonatal seizures.

Understanding interictal to ictal transitions

One of the most debilitating aspects of epilepsy is the unpredictable onset of seizure activity.  If we understood how seizures start, or ictogenesis, we might be able to predict and prevent seizures more effectively.  In long-term microscopic studies of in vitro and in vivo preparations, Kyle Lillis is tracking the activity of individual neurons to better understand how they come to participate in seizure activity.  Many of the findings run counter to canonical ideas regarding the onset of seizures.

Neuronal death after brain injury

After brain injury, the normal mechanisms of neuronal death and removal are overwhelmed by the large numbers of neurons that have been fatally injured.  Understanding how these mechanisms are altered provides a powerful and unique opportunity to improve the translation of studies of neuroprotection and neurotoxicity to clinical care.

Research Positions

Please contact Dr. Kevin Staley at Staley.Kevin@mgh.harvard.edu if you are interested in working in the lab.

Read about and apply for residency, fellowship and observership programs in neurology.

We are now accepting applications for 2022 student interns, pending COVID status.

Publications

Visit PubMed for a complete list of publications. Below is a selection of recent materials:

In vitro ictogenesis is stochastic at the single neuron level. Lau LA, Staley KJ, Lillis KP. Brain. 2021 Aug 25:awab312. doi: 10.1093/brain/awab312.

Featured as a Top Ten article, Journal of Neuroscience 2021 Spotlight: Unique Actions of GABA Arising from Cytoplasmic Chloride Microdomains. Rahmati N, Normoyle KP, Glykys J, Dzhala VI, Lillis KP, Kahle KT, Raiyyani R, Jacob T, Staley KJ. J Neurosci. 2021 Jun 9;41(23):4957-4975. doi: 10.1523/JNEUROSCI.3175-20.2021.

KCC2 Chloride Transport Contributes to the Termination of Ictal Epileptiform Activity. Dzhala VI, Staley KJ. eNeuro. 2021 Mar 9;8(2):ENEURO.0208-20.2020. doi: 10.1523/ENEURO.0208-20.2020.

A perfect storm: The distribution of tissue damage depends on seizure duration, hemorrhage, and developmental stage in a gyrencephalic, multi-factorial, severe traumatic brain injury model. Costine-Bartell B, Price G, Shen J, McGuone D, Staley K, Duhaime AC.  Neurobiol Dis. 2021 Jul;154:105334. doi: 10.1016/j.nbd.2021.105334.

Boston Bumetanide Trial Group. A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures. Soul JS, Bergin AM, Stopp C, Hayes B, Singh A, Fortuno CR, O'Reilly D, Krishnamoorthy K, Jensen FE, Rofeberg V, Dong M, Vinks AA, Wypij D, Staley KJ; Ann Neurol. 2021 Feb;89(2):327-340. doi: 10.1002/ana.25959.

A Proposed Mechanism for Spontaneous Transitions between Interictal and Ictal Activity. Jacob T, Lillis KP, Wang Z, Swiercz W, Rahmati N, Staley KJ.J Neurosci. 2019 Jan 16;39(3):557-575. doi: 10.1523/JNEUROSCI.0719-17.2018.

Research Scientists

• Trevor Balena, PhD, Research Staff
• Volodymyr Dzhala, PhD, Assistant Professor
• Lauren Lau PhD, Research Fellow
• Kyle Lillis, PhD, Assistant Professor
• Melanie McNally MD, Instructor in Neurology
• Kieran Normoyle MD, PhD, Research Fellow

Research Assistants & Technicians

• Michelle Mail, Technologist II
• Rehan Raiyyani, Research Tech II
• Patti Staley, Staff Assistant II

Affiliated Lab Members

• Beth Bartell PhD, Assistant Professor, Neurosurgery, Mass General Hospital
• Christopher McGraw MD PhD, Instructor in Neurology, Mass General, K08 Grantee

Student Interns