GABA block

Pediatric Epilepsy Research Lab: Kevin J. Staley, MD

The Pediatric Epilepsy Research Lab studies how neuronal ion transport and synaptic plasticity alter the spread of epileptic activity in neural networks.

Overview

Research Description

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.

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. We have found evidence for reentrant or circular patterns of neural activity that resemble cardiac fibrillation and precede seizures. We are currently testing whether this reentrant activation of neural circuits is the earliest stage of a seizure, and the stage at which intervention is most effective. We are also testing whether long-term reductions in the strength of synaptic connections between neurons in epileptic networks can reduce the probability of seizures.

Group Members

Principal Investigator

Kevin J. Staley, MD

Kevin J. Staley, MD

  • Joseph P. and Rose F. Kennedy Professor of Child Neurology and Mental Retardation, Harvard Medical School
  • Chief, Pediatric Neurology, Massachusetts General Hospital

Research Interests: Epilepsy, synaptic physiology, neuronal ion transport, neural network activity.

Research Techniques: Single cell electrophysiology, in vivo radiotelemetry, ion-sensitive fluorescent imaging of ion transport and neural network activity, computer modeling.

Diseases Studied: Epilepsy


Staley Lab Members

Research Scientists

Trevor Balena, PhD, Research Staff

Volodymyr Dzhala, PhD, Instructor in Neurology

Joseph Glykys, MD, PhD, Assistant Professor

Sofia Karamintziou PhD, Research Fellow

Lauren Lau PhD, Research Fellow

Kyle Lillis, PhD, Instructor in Neurology

Kieran Normoyle MD, PhD, Research Fellow

Negah Rahmati PhD, Research Fellow

Research Assistants & Technicians

Tom Jasionowski, Research Assistant

Hannah Lynch, Research Assistant

Michelle Mail, Technologist, Lab Manager

Patti Staley, Staff Assistant

Affiliated Lab Members

Catherine Chu, MD, Assistant Professor in Neurology, MGH, K23 Grantee

M. Zelime Elibol, MD, Instructor in Neurology, MGH, K12 Grantee

Albert Misko MD, PhD, Instructor in Neurology, MGH, R25 Grantee

Patricia Musolino, MD, PhD, Assistant Professor of Neurology, MGH, K08 Grantee

Student Interns

Megan Audette, SUNY Upstate Medical Univ., Syracuse, NY

Nolan Wu, Trinity Univ., Houston, TX

Accepting applications for 2019

Staley Lab Members 2018

Trevor Balena, PhD
Trevor Balena, PhD
Volodymyr Dzhala, PhD
Volodymyr Dzhala, PhD
Joseph Glykys, MD, PhD
Joseph Glykys, MD, PhD
Tom Jasionowski
Tom Jasionowski
Sofia Karamintziou PhD, Research Fellow
Sofia Karamintziou, PhD
Lauren Lau PhD, Research Fellow
Lauren Lau, PhD
Kyle Lillis, PhD
Kyle Lillis, PhD
Hannah Lynch
Hannah Lynch
Michelle Mail
Michelle Mail
Kieran Normoyle MD PhD
Kieran Normoyle MD PhD
Negah Rahmati, PhD
Negah Rahmati, PhD

Alumni

Research Assistants & Technicians

Research Assistant/TechCurrentLocation
Samantha Kumarasena Medical Student Tufts University School of Medicine, Boston, MA
Kimberly Lu Medical Student Boston University School of Medicine, MA
Yero Saponjian Life Science Strategy Consultant Boston, MA
Brittany Van Nelson, MPH Biomedical Research Assistant Nemours Children’s Hospital, FL

Research Fellows

Research FellowCurrent PositionLocation
Thomas Blauwblomme MD, PhD Physician-Scientist, Department of Pediatric Neurosurgery Hospital Necker, Paris, France
Yevgeny Berdichevsky PhD Associate Professor, Electrical & Computer Engineering Lehigh University, Bethlehem, PA
Jonas Dyhrfjeld-Johnsen PhD VP of Research & Translational Development, Sensorion Company Montpellier, France
Kiyoshi Egawa MD, PhD Clinical Fellow, Pediatric Department Hokkaido University School of Medicine, Japan
Chris French MPDS, FRACP, PhD Senior Neurologist & Epileptologist Royal Melbourne Hospital, Melbourne, Australia
Michael Gutnick DVM, PhD (Sabbatical) Koret School of Veterinarian Medicine, Jerusalem, Israel
Arash Hadipour-Niktarash MD Assistant Professor of Neurology University of Colorado, Denver
Jennifer Hellier PhD Assistant Professor in Family Medicine and Cell & Developmental Biology University of Colorado, Denver
Theju Jacob PhD Scientist, Bayer Corporation Research Triangle Park, NC
Sonya Kee Yun Jakawich PhD Strategy Consulting Blue Print Research Group, NY
Kristopher Kahle MD, PhD Assistant Professor of Neurosurgery & Pediatrics Yale School of Medicine, CT
Ji Lee MD, PhD Assistant Professor in Child Neurology & Neuro-immunology Columbia University, NY
Kyung-IL Park MD, PhD Assistant Professor in Neurology Seoul Paik Hospital, Inje University, South Korea
Jon Moussally MD Instructor in Emergency Medicine North Shore Medical Center, Salem, MA
Helen Consiglio PhD Assistant Professor & Program Director of Psychology Regis College, Weston, MA
Waldemar Swiercz PhD Research Scientist Amazon, Reading, MA
Zemin Wang MD, PhD Instructor in Neurology Brigham and Women’s Hospital, Boston, MA

Student Interns

Student InternSchoolCurrent Position
Larry Chen University of Illinois at Urbana-Champaign  
Julia Fong University of Sydney Medical School, Australia MD PhD, Medical Resident-1st year
Tom Jasionowski Tufts University, Boston, MA MGH Research Assistant
Kimberly Lu Boston Univ. School of Medicine, MA MD-2019
Humzah Mahmood Boston University, Boston, MA Research Associate, Cellaria, LLC
Camila Cabarello MIT, Cambridge, MA PhD Student, CANDlab, Yale University
Yun Xiang Chu Harvard Med. School, Boston, MA MD PhD Student, HMS-5th year
Elon Gaffin-Cahn Union College, Schenectady, NY PhD Student, Psychology, NYU
Hillary Mullan Oberlin College, Oberlin, OH UMass Medical School-3rd year
William Neylon Dublin Institute of Technology, IRE University Hospital, Limerick, IRE
Rory Tinker University of Manchester Medical School, UK MD-2022

Research Projects

Illustration of study of Glykys et al. 2009

This cover of the journal Neuron illustrates the study of Glykys et al. 2009.

Cortical Seizures in Newborn Infants

Seizure activity in the cerebral cortex of the brain (represented by the white electrographic discharges in the illustration) is transmitted through subcortical brain regions to the muscles of the body, causing convulsions. However, cortical seizures in newborns are frequently observed on electrographic recordings without accompanying convulsions, a dissociation that is exacerbated by anticonvulsant treatment. Most newborn convulsions are treated with anticonvulsant drugs that enhance the activity of GABA, a neurotransmitter that inhibits neuronal activity and seizures by increasing the flow of chloride ions into neurons.

DClamp - Free data acquisition and analysis software for epilepsy animal research.

The main goal of this project is to provide free, open-source data acquisition and analysis software to the epilepsy research community. Our goal is to establish a common platform to facilitate data exchange and cooperation between research centers.DClamp is designed for unsupervised detection of ictal-like and inter-ictal-like events in very large EEG datasets, for example from days to months of continuous recordings. It includes algorithms for automatic detection, quantification, and analysis of seizures (White et al. J Neurosci Methods, 15;152:255-66, 2006) and interictal spikes (Dyhrfjeld-Johnsen et al. J Clin Neurophysiol 27:418-24, 2010; White et al. Epilepsia 51:371-83, 2010).

Currently DClamp can also be used for acquisition of in-vivo and in-vitro signals from as many as 64 separate channels or animals. Examples include chronic EEG data, ECoG data, extracellular field potentials, intracellular potentials, intracellular currents (using low cost acquisition cards). We plan to expand compatible hardware. Future expansions will include synchronization of signal recordings with surveillance videos. Project will be distributed as open source allowing users to modify the code.

Chloride Concentrations and GABA Signaling in Nonconvulsive Seizures

Using a genetically expressed chloride sensor and multiphoton microscopy, we show in this paper that cortical neurons in the developing mammalian brain have much higher chloride concentrations than do subcortical neurons (in the illustration, hotter colors represent higher chloride concentrations). These differences in chloride concentration lead to oppositely directed chloride flow, GABA signaling, and anticonvulsant effects in these two regions. The response of cortical neurons to GABA could be made to match the subcortical response by blocking the transporter that accumulates chloride in cortical neurons. Under these conditions, cortical seizure activity could be controlled as readily as subcortical seizure activity.

These differences provide the first candidate explanation for the puzzling dissociation of convulsions and electrographic seizure activity in newborns, the exacerbation of the dissociation by anticonvulsants, and the potential utility of blocking chloride transporters to improve control of nonconvulsive seizures in newborns.

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 at http://www.massgeneral.org/neurology/education/.

Publications

  1. Optogenetic dissection of ictogenesis: in search of a targeted anti-epileptic therapy. Lillis KP, Staley KJ. J Neural Eng. 2018 Mar 14. doi: 10.1088/1741-2552/aab66a. [Epub ahead of print] PMID:29536948
  2. Epileptiform activity in traumatic brain injury predicts post-traumatic epilepsy. Kim JA, Boyle E, Wu AC, Cole AJ, Staley KJ, Zafar S, Cash SS, Westover MB. Ann Neurol. 2018 Mar 14. doi: 10.1002/ana.25211. [Epub ahead of print] PMID:29537656
  3. Glykys J, Dzhala V, Egawa K, Kahle KT, Delpire E, Staley K. Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential. Trends Neurosci. 2017 May; 40(5):276-294. PMID: 28431741.
  4. Liu J, Saponjian Y, Mahoney MM, Staley KJ, Berdichevsky Y. Epileptogenesis in organotypic hippocampal cultures has limited dependence on culture medium composition.PLoS One. 2017 Feb 22;12(2):e0172677
  5. Berdichevsky Y, Saponjian Y, Park KI, Roach B, Pouliot W, Lu K, Swiercz W, Dudek FE, Staley KJ. Staged anticonvulsant screening for chronic epilepsy. Ann Clin Transl Neurol. 2016 Oct 18;3(12):908-923.
  6. Glykys J, Staley KJ. Developmental Decrease of Neuronal Chloride Concentration Is Independent of Trauma in Thalamocortical Brain Slices. PLoS One. 2016 Jun 23;11(6):e0158012. doi: 10.1371/journal.pone.0158012.
  7. Trevelyan AJ, Muldoon SF, Merricks EM, Racca C, Staley KJ. J Clin Neurophysiol. The role of inhibition in epileptic networks. T2015 Jun;32(3):227-34.
  8. Glykys, J, Staley, KJ. Diazepam effect during early neonatal development correlates with neuronal CL. Annals of Clinical Neurology, September 16, 2015, doi: 10.10002/acn7.259
  9. Shapiro, KA, McGuone, D, Deshpande, V, Sadow, PM, Stemmer‐Rachamimov, A, Staley, KJ. Failure to detect human papillomavirus in focal cortical dysplasia type II, Annals of Neurology, Volume 78, Number 1, 1 July 2015, pp. 63-67(5
  10. Dzhala V, Staley KJ. Acute and Chronic Efficacy of Bumetanide in an in vitro Model of Posttraumatic Epileptogenesis. CNS Neurosci Ther. 2015 Feb; 21(2):173-80.
  11. Lillis KP, Wang Z, Berdichevsky Y, Mail M, Zhao G, Bacskai B, Staley KJ, Evolution of network synchronization during early epileptogenesis parallels synaptic circuit alterations. J Neurosci., 2015 Jul 8; 35(27):9920-34
  12. Kyung-Il Park, Volodymyr Dzhala, Yero Saponjian, Kevin J. Staley, what elements of the inflammatory system are necessary for epileptogenesis In Vitro. eNeuro. Mar 2015, 2 (2) DOI: 10.1523/ENEURO.0027-14.2015
  13. Lillis KP, Dulla C, Maheshwari A, Coulter D, Mody I, Heinemann U, Armbruster M, Žiburkus J.,WONOEP appraisal: Molecular and cellular imaging in epilepsy. Epilepsia 56:505–513. 2015
  14. Kevin Staley, Molecular Mechanisms of Epilepsy. Nature Neuroscience. 18, 367-372, doi:10.1038/nn 3947, 2015
  15. Delpire E., Staley K.J. Novel Determinants of the Neuronal Cl- Concentration. J Physiol 592(Pt 19):4099-4114, 2014 
  16. Glykys J., Dzhala V., Egawa K., Balena T., Saponjian Y., Kuchibhotla K. V., Bacskai B. J., KahleK. T., Zeuthen T., Staley K.J. Local Impermeant Anions Establish the Neuronal Chloride Concentration. Science 343:670-675, 2014.
  17. Berdichevsky Y, Dryer A, Saponjian Y, Mahoney M, Pimentel C, Lucini C, Usenovic M, and Staley KJ. PI3K‐Akt signaling activates mTOR-mediated epileptogenesis in organotypic hippocampal culture model of posttraumatic epilepsy.  J Neurosci  33:9056-67, 2013
  18. Lillis KP, Kramer MA, Mertz J, Staley KJ, White JA. Pyramidal cells accumulate chloride at seizure onset.  Neurobiol Dis. 2012 Sep;47(3):358-66.
  19. Sabolek HR, Swiercz WB, Lillis K, Cash SS, Huberfeld G, Zhao G, Ste. Marie L, Clemenceau  S, Barsh G, Miles R, Staley KJ: A candidate mechanism underlying the variance of interictal spike propagation.  J Neurosci. 32:3009-3021, 2012.
  20. Dzhala V, Valeeva G, Glykys J, Khazipov R, and Staley KJ.  Traumatic alterations in GABA signaling disrupt hippocampal network activity in the developing brain, J Neurosci. 32:4017-31, 2012
  21. Yevgeny Berdichevsky; Volodymyr Dzhala; Michelle Mail; Corresponding Author: Dr. Kevin Staley. Interictal spikes, seizures and ictal cell death are not necessary for post-traumatic epileptogenesis in vitro. Neurobiology of Disease. 45:774-85, 2012.
  22. Dzhala V, Kuchibhotla KV, Glykys J, Kahle KT, Swiercz W, Feng G, Kuner T, Augustine G, Bacskai BJ, Staley KJ  Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures J Neurosci 30:11745-61, 2010.
  23. Dyhrfjeld-Johnsen J. Berdichevsky Y, Swiercz W, Sabolek H, Staley KJ.  Interictal spikes precede ictal discharges in an organotypic hippocampal slice culture model of epileptogenesis.  J Clin Neurophysiol 27:418-24, 2010.
  24. Glykys J, Kuchibhotla KV, Feng G, Kuner T, Augustine G, Bacskai BJ, Staley KJ.  Differences in cortical vs. subcortical GABAergic signaling: a candidate mechanism of electroclinical uncoupling of neonatal seizures.  Neuron 63:657-72, 2009.
  25. White A, Williams PA, Hellier J, Clark S, Dudek FE and Staley KJ. EEG spike activity precedes epilepsy after kainate-induce status epilepticus. Epilepsia in press 2009.
  26. Brumback A and Staley KJ, Thermodynamic regulation of NKCC1-mediated Cl- cotransport underlies plasticity of GABAA signaling in neonatal neurons, J Neurosci 28:1301-12, 2008.
  27. Dzhala V Brumback A and Staley KJ. Bumetanide enhances phenobarbital efficacy in a neonatal seizure model.   Ann Neurol 63:222-235, 2008.
  28. Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA, Delpire EJ, Jensen FE, and Staley KJ. NKCC1 transporter facilitates seizures in the developing brain. Nature Medicine, 11:1205-13, 2005.

NCBI PubMed Publications

Contact

Contact Us

Pediatric Epilepsy Research Lab: Kevin J. Staley, MD

Building 114, Charlestown Navy Yard

114 16th Street, Room 2600Massachusetts General Hospital, Neurology Research Boston, MA 02129
  • Near Public Transit
  • Accessible
  • Phone: 617-643-0363
  • Fax: 617-643-0141

E-mail Address

Kevin J. Staley, MD
staley.kevin@mgh.harvard.edu

Patricia Staley
staley.patricia@mgh.harvard.edu

 

 

Mailing Address

Kevin J. Staley, MD
Mailcode: CNY 114-2-2600
Massachusetts General Hospital, Neurology Research
114 16th Street, Room 2600
Charlestown, MA 02129

Patient Appointments & Clinical Office

General Child Neurology Clinic
Phone: 617-726-3402

Epilepsy Service at Mass General Hospital for Children
Phone: 617-726-6540

Clinical Mailing Address

Kevin J. Staley, MD
Mailcode: WACC 7-708D
Department of Neurology
Massachusetts General Hospital
55 Fruit Street
Boston, MA 02114

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