Barrow Neuroscience Research Center, Barrow Neurological Institute, Phoenix, Arizona
The Role of Research within the Barrow Hypothalamic Hamartoma Program
In addition to patient care, the Hypothalamic Hamartoma Program at the Barrow Neurological Institute seeks to contribute to new knowledge about hypothalamic hamartoma, and basic mechanisms of epilepsy, by conducting both clinical and basic science research.
Stated broadly, the mission of the Barrow Hypothalamic Hamartoma Research Program is to illuminate fundamental mechanisms of hypothalamic hamartoma pathophysiology, so that hypothalamic hamartoma and other catastrophic epilepsies of childhood can be more effectively treated or perhaps even prevented.
Barrow Neuroscience Research Center, Phoenix, Arizona
Fundamental Research Questions
Our research efforts are framed around three fundamental questions:
- What is the pathogenesis (cause) of the hypothalamic hamartoma lesion?
- Why are hypothalamic hamartoma lesions intrinsically epileptogenic (that is, what mechanisms cause seizures to arise directly from the hypothalamic hamartoma tissue)?
- Why does hypothalamic hamartoma pathology (or the seizures arising from them) result in such deleterious effects on the rest of the brain?
Informed Consent for Participation in Research
Entry of patient information into the Barrow Hypothalamic Hamartoma Research Database, and the research use of hypothalamic hamartoma tissue following surgical resection, is performed only after written Informed Consent has been obtained from the patient or the patient’s guardians.
The Institutional Review Board (IRB) for Human Research at the Barrow Neurological Institute of St. Joseph’s Hospital and Medical Center has approved the informed consent documents.
Questions?
Please direct questions about the research efforts of the Barrow Hypothalamic Hamartoma Research Program to:
Maggie Varland, RN
HH Program Coordinator
Phone: 602-406-7585
e-mail: mvarland@chw.edu
or
John F. Kerrigan, MD
Director, Barrow Hypothalamic Hamartoma Research Program
Tel: 602-406-3800
e-mail: jkerrigan@chw.edu
Participating Laboratories
Hypothalamic Hamartoma Tissue Research Laboratory
Team Members
John F. Kerrigan, M.D.
Principal Investigator
Kristina Fenoglio, Ph.D.
Post-Doctoral Fellow
Angela Strobel
Laboratory Technician
Laboratory Overview
Established in July 2006, the Barrow Hypothalamic Hamartoma Tissue Research Laboratory utilizes both new and traditional microanatomical techniques to determine the basic cellular mechanisms for intrinsic epileptogenesis of hypothalamic hamartoma tissue. This research is performed in close collaboration with the electrophysiological laboratory of Jie Wu, M.D., Ph.D., and the neuropathology laboratory of Steven Coons, M.D. The HH Tissue Research Laboratory is located on the fourth floor of the Neuroscience Research Center (4 NRC) at Barrow.
Hypothalamic Hamartoma Tissue
While it is known that hypothalamic hamartoma tissue (HH) is intrinsically epileptogenic (that is, the gelastic seizures that are characteristic of hypothalamic hamartoma arise directly from the hypothalamic hamartoma lesion), the basic cellular and molecular mechanisms are not known. Very simply, the primary question driving our research is why hypothalamic hamartoma tissue is capable of generating these seizures.
Our clinical hypothalamic hamartoma program is currently the busiest in the world for treating patients with this relatively rare disease. For those patients who undergo surgical treatment, the removal of the hypothalamic hamartoma gives us the opportunity to study and learn more about this disorder. Hypothalamic hamartoma tissue is available for research only if the patient (or the patient’s guardians) has agreed before surgery with written informed consent, and the type of surgery is based only upon the needs of the patient.
Unlike other human epileptic tissues, such as the hippocampus or the neocortex, hypothalamic hamartoma appears to be relatively simple, with two main neuron types. Small neurons are the most abundant type of nerve cell in hypothalamic hamartoma tissue, and appear to have an interneuron phenotype with spontaneous pacemaker-like activity. Large hypothalamic hamartoma neurons, which may be excitatory projection cells, appear to depolarize to GABA. We believe that these observations will prove to be key components of an experimental model for seizure genesis from hypothalamic hamartoma tissue.
Experimental Approach
- Single cell cytology and structure determined by confocal microscopy following cellular microelectrode injection (such as with biocytin) or cellular impregnation with the Golgi technique
- Immunohistochemistry for protein components of the tissue, revealing information on cell function, structure, or lineage
- Mapping the three-dimensional microstructure of hypothalamic hamartoma tissue with the use of advanced stereological techniques
- Physiological assessment of the network excitability and neuropharmacology of hypothalamic hamartoma tissue with field recordings from multielectrode arrays
- Development of an animal model for HH
Selected References
Coons SW, Rekate HL, Prenger EC, Wang N, Drees C, Ng Y-t, Chung SS, Kerrigan JF. The histopathology of hypothalamic hamartomas: study of 57 cases. J Neuropathol Exp Neurol 2007;66:131-141.
Fenoglio KA, Wu J, Kim DY, Simeone TA, Coons SW, Rekate H, Rho JM, Kerrigan JF. Hypothalamic hamartoma: basic mechanisms of intrinsic epileptogenesis. Semin Ped Neurol 2007;14:51-59.
Beggs J, Nakada S, Fenoglio K, Coons S, Kerrigan JF. Hypothalamic hamartoma associated with epilepsy: ultrastructural features. J Neuropath Exp Neurol 2008;67:657-668.
Fenoglio KA, Simeone TA, Kim DY, Kerrigan JF, Rho JM. Spontaneous network activity in human epileptic hypothalamic hamartoma tissue assessed using multi-electrode arrays. Submitted for publication.
Chan YM, Fenoglio KA, Paraschos S, Muhammad L, Coons SW, Kerrigan JF, Seminara SB. Precocious puberty associated with hypothalamic hamartomas correlates with hamartoma size but not with expression of GnRH, TGFα, or KISS1. Submitted for publication.
HH Neuropathology Laboratory
Steven Coons, M.D.
John Beggs, Ph.D.
Dr. Coons and co-workers have recently published their first manuscript on the neuropathology of HH (see reference below), describing the micro-architecture and maturational markers of HH tissue. This paper, which includes an evaluation of 57 cases, describes the results of neuropathological study of more HH tissue specimens than the combined results of all previously published papers on HH neuropathology.
Continuing work in the neuropathology laboratory will include immunohistochemical studies (in collaboration with the HH Tissue Research Laboratory) examining 1) markers of cellular lineage, 2) neuroendocrine phenotype markers, and 3) neurotransmitter receptors and other markers of neurochemical phenotype.
Electron microscopy, examining the ultrastructure of HH tissue, is investigated by John Beggs, Ph.D. He is currently utilizing EM, in conjunction with immunohistochemistry, to define the ultrastructural features of the different neuronal phenotypes present in HH tissue, and to further define their functional relationships.
For more information > Barrow Neuropathology Laboratory
References
Coons SW, Rekate HL, Prenger EC, Wang N, Drees C, Ng Y-t, Chung SS, Kerrigan JF. The histopathology of hypothalamic hamartomas: study of 57 cases. J Neuropathol Exp Neurol 2007;66:131-141
Beggs J, Nakada S, Fenoglio K, Coons S, Kerrigan JF. Hypothalamic hamartoma associated with epilepsy: ultrastructural features. J Neuropath Exp Neurol 2008;67:657-668.
HH Genotyping and Expression Profiling Laboratory
David Craig, Ph.D., TGen (Translational Genomics Research Institute)
Dietrich Stephan, Ph.D., TGen
Lucy Treiman, Ph.D.
This collaborative effort between Barrow and Translational Genomics Research Institute (TGen) examines the possible molecular or genetic causes of HH pathogenesis. This includes the use of genome-wide screens for possible somatic mutations (mutations that are present in the HH tissue, but not elsewhere in the body) utilizing microarray technology. Additionally, this search makes use of the candidate gene approach, in which there is a search for mutations in genes that are suspected as being important in the HH disease process (see references below).
Another area of active research using molecular techniques is cell-specific expression profiling. A process of single-cell laser microcapture collects specific types of cells from HH tissue. The messenger RNA (mRNA) of these cells can then be examined to determine which genes are activated (or deactivated), which can lead to an understanding of how each cell functions.
For more information > Barrow Laboratory of Dr. Lucy Treiman
For more information > TGen (Translational Genomics Research Institute)
(The website link is provided for your convenience only. Barrow Neurological Institute does not necessarily endorse the views expressed or the facts presented on the site, nor is responsible for the content on the site in any way.)
References
Kerrigan JF, Kruer MC, Corneveaux J, Panganiban CB, Itty A, Reiman D, Ng Y-t, Stephan DA, Craig DW. Chromosomal abnormality at 6p25.1-25.3 identifies a susceptibility locus for hypothalamic hamartoma associated with epilepsy. Epilepsy Res 2007;55:70-73.
Craig DW, Itty A, Panganiban C, Szelinger S, Kruer M, Reiman D, Narayanan V, Stephan DA, Kerrigan JF. Identification of somatic chromosomal abnormalities in hypothalamic hamartoma tissue at the GLI3 locus. Am J Hum Genet 2008;82:366-374.
HH Cellular Neurophysiology Laboratory
Jie Wu, M.D., Ph.D.
Dr. Wu published his initial observations on HH neuron electrophysiology, describing the highly novel finding of intrinsic pacemaker-like activity in individual small HH neurons, in Annals of Neurology in 2005. He is continuing his work, examining the molecular mechanisms of this intrinsic pacemaker activity, and also examining GABAA receptor function in HH neurons. GABA is the major inhibitory neurotransmitter in mammalian brain, and abnormalities of the GABA system of inhibition result in epileptic seizures in animal models and in some forms of human epilepsy. Recent findings in Dr. Wu’s laboratory, and by DoYoung Kim, Ph.D., D.V.M. in the laboratory of Dr. Jong Rho at Barrow, suggests that large HH neurons depolarize (are excited) by GABA agonists, which are usually expected to act in a hyperpolarizing (or inhibitory) manner (see references below).
Dr. Wu has been awarded a National Institutes of Health (NIH) R21 grant, funding his continuing work on HH tissue for the next two years.
For more information > Barrow Laboratory of Dr. Jie Wu
References
Wu J, Xu L, Kim DY, Rho JM, St. John PA, Lue L-F, Coons S, Ellsworth K, Nowak L, Johnson E, Rekate H, Kerrigan JF. Electrophysiological properties of human hypothalamic hamartomas. Ann Neurol 2005;58:371-382
Wu J, Chang Y, Li G, Xue F, DeChon J, Ellsworth K, Liu Q, Yang K, Bahadroani N, Zheng C, Zhang J, Rekate H, Rho JM, Kerrigan JF. Electrophysiological properties and subunit composition of GABAA receptors in patients with gelastic seizures and hypothalamic hamartoma. J Neurophysiol 2007;98:5-15.
Wu J, DeChon J, Xue F, Li G, Ellsworth K, Gao M, Liu Q, Yang K, Zheng C, He P, Tu J, Kim DY, Rho J, Rekate H, , Kerrigan JF, Chang Y. GABAA receptor-mediated excitation in dissociated neurons from human hypothalamic hamartomas. Exp Neurol 2008, in press.
In situ HH Tissue Cellular Electrophysiology Laboratory
Peter Steinmetz, M.D., Ph.D.
Harold Rekate, M.D.
Scott Wait, M.D.
Peter Steinmetz, M.D., Ph.D. is Associate Professor of Bioengineering at Arizona State University, and is collaborating with Dr. Rekate and the HH team in the operating room to study the physiological properties of HH neurons in situ (prior to surgical resection).
For selected patients, following agreement to participate through the informed consent process, recording electrodes will be placed through the surgical endoscope and into the HH lesion under direct visualization, which positions multiple micro-wire electrodes into HH tissue. The activity of the HH tissue will be recorded for approximately 15 minutes, prior to HH resection. Subsequently, off-line computational methods on the stored data allows for identification of single cell activity, and can then possibly characterize the presence or absence of functional linkage (network synchrony) between HH neurons. These studies complement the neurophysiological recordings of acutely dissociated single HH neurons, and HH tissue slice preparations.
Reference
Lekovic GP, Kerrigan JF, Wait S, Rekate HL, Steinmetz P. In situ single unit recording of hypothalamic hamartoma under endoscopic direct visualization. Submitted for publication.
Neuropsychological Outcome Following HH Surgery
George Prigatano, Ph.D.
Jennifer Wethe, Ph.D.
This is a continuing project, investigating the neuropsychological profile of HH patients prior to any surgical therapy, and also to assess neuropsychological outcome following HH surgery.
Findings thus far confirm that there is a tremendous degree of variability of cognitive and behavioral strengths and weaknesses within the HH population of patients. However, most patients do have deficits that are apparent on testing, and the neuropsychology research group is attempting to relate these deficits to patient factors such as age and the severity of epilepsy.
Patients with HH, particularly those with refractory epilepsy, can often have very disabling cognitive and behavioral problems. HH is a human model for epileptic encephalopathy (deterioration of cognition and behavior in association with epileptic seizures), an important problem for all of the catastrophic epilepsies of childhood. Accordingly, findings on cognitive function, and the changes that take place over time, are of wide interest to pediatric epilepsy experts.
Another component of neuropsychology research at Barrow is to determine cognitive and behavioral outcome following surgery. While scattered reports in the medical literature suggest that HH patients benefit from successful surgery, we are seeking more detailed information about this. Much remains to be learned about the impact of treatment (either surgical resection or Gamma Knife) on the cognitive functioning of HH patients.
For more information > Barrow Neuropsychology Section
Reference
Prigatano GP, Wethe JV, Gray JA, Wang N, Chung S, Ng Y-t, Prenger E, Kerrigan JF. Intellectual functioning in presurgical patients with hypothalamic hamartoma and refractory epilepsy. Epilepsy Behav 2008;13:149-155.
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Barrow Neuroscience Research Center, Barrow Neurological Institute, Phoenix, Arizona
