The Stanford Epilepsy Training Program (ETP)
Stanford University School of Medicine and the Neurology Department sponsor a postdoctoral training program in epilepsy research. Epilepsy is a complex disease requiring an integrated multidisciplinary approach designed to effectively train future research leaders in the field. Accordingly faculty with a wide range of relevant expertise in the Departments of Biological Sciences, Molecular and Cellular Physiology, Comparative Medicine, Neurology and Neurological Sciences, Neurobiology, Neurosurgery, and Psychiatry at Stanford University have been assembled to create a training program that attracts fellows to careers in research areas especially relevant to the problems of epilepsy in man. The faculty employ modern neuroscience approaches including live imaging, cellular neurophysiology, optogenetics, biochemistry, genetics, neuroanatomical approaches, and the use of animal model systems for studies of normal and abnormal structure/function. Faculty research interests include cortical neuronal and glial development and function; physiological and morphological changes in nerve cells and circuits in animal models of chronic neocortical and hippocampal epileptogenesis; dissection and intervention of neuronal microcircuits implicated in seizures and epileptogenesis; development, organization, and synaptic physiology of the CNS, especially neocortex, thalamus, hippocampus; cellular and molecular aspects of long-term changes in neuronal excitability; and the roles of gene structure, expression and modulation on neuronal function, especially interneurons. Trainees may learn techniques of whole animal EEG, behavior, and intracranial recording; optogenetics; neurophysiology in reduced preparations such as slices or cultures; anatomic techniques for intracellular labeling and tract tracing, immunocytochemistry and in situ hybridization; cell culture; cell transplantation; experimental gene therapy; and use of transgenic animals. The training program consists of monthly integrative sessions, including seminars, didactic lectures, and clinical content, all focused on epilepsy. Participation of clinical department faculty fosters effective research interactions between trainees and a focus on the interface between basic neuroscience and clinical issues requiring investigation. The positions are advertised nationally and applicants solicited in accord with, and in the spirit of recruiting individuals from diverse backgrounds.
Stanford University School of Medicine has a particular emphasis on collaborative research in Epilepsy, and our training faculty make up the core this effort. A recent NCBI/Pubmed search (Appendix A) with the terms epilepsy and Stanford yielded 88 publications since 2010. Of these 66 were authored in part by ETP faculty and at least 40 of these broadly involved trainees. 12 of the publications were collaborative efforts among ETP faculty, 8 of these with recent appointees to the ETP. These publications appeared in such journals as J Neurosci, PNAS, and Neuron, among others. Note that this is not a comprehensive set of ETP fellow publications. These will be discussed later.
Ben Barres, M.D., PhD., Professor of Neurobiology, Neurology and Neurological Sciences and Developmental Biology: Dr. Barres is interested in the development and function of glial cells in the mammalian central nervous system. To understand the interactions between neurons and glial cells he has developed methods to highly purify and culture retinal ganglion cells (neurons) as well as the glial cell types they interact with, oligodendrocytes and astrocytes, from the rodent optic nerve and elsewhere. Barres and his fellows have used a large variety of methods to address these issues including cell purification by immunopanning, tissue culture, patch clamping, immunohistochemistry and molecular biology. Currently, they are focusing on several questions: (1) What are the cell-cell interactions that control myelination and node of Ranvier formation? (2) Do glial cells play a role in synapse formation and function? (3) What are the signals that promote the survival and growth of retinal ganglion cells; can this knowledge be used to promote their survival and regeneration after injury? (4) How do protoplasmic astrocytes, the main glial cell type in gray matter, develop and what is their function? Dr. Barres has found evidence for several novel glial signals that induce the onset of myelination, the clustering of axonal sodium channels, the survival and growth of retinal ganglion cells, and the formation of synapses. He is characterizing these processes and attempting to identify the glial-derived molecules. As neuron/glial interactions are an emerging topic in epilepsy research, Dr. Barres has been involved in many collaborative research projects, especially with Drs. Prince and Huguenard.
Paul Buckmaster, D.V.M., Ph.D., Professor of Comparative Medicine: Dr. Buckmaster works on problems of hippocampal anatomy, physiology and experimental epilepsy. His major research goal is to understand the basic cellular mechanisms of epileptogenesis. His laboratory uses electrophysiological, molecular, and anatomical methods to examine the neuronal circuitry in rodent models of epilepsy. Current projects are focused on synaptic reorganization in the hippocampal dentate gyrus, changes in GABAergic circuitry in the dentate gyrus, and unit and EEG activity before and during spontaneous seizures, and neurotoxin induced epilepsy in California sea lions. Trainees in Dr. Buckmaster’s laboratory will learn a variety of electrophysiological and neuroanatomical techniques including in vivo intracellular recording and labeling, three-dimensional neuron reconstruction, whole-cell voltage-clamp recording, EEG and unit recording, in situ hybridization, immunocytochemistry, confocal microscopy, electron microscopy, and stereological methods.
Robert S. Fisher, MD PhD Dr. Fisher is Maslah Saul MD Professor of Neurology and Director of the Stanford Comprehensive Epilepsy Center. He received his Ph.D. in the Neurosciences in 1976 and an M.D. in 1977, from Stanford University. He then took specialty training in internal medicine at Stanford and in neurology at Johns Hopkins, where he was Co-Director of the Epilepsy Program for eleven years. He formerly was Chairman of the Department of Neurology, Chief of the Epilepsy Center at Barrow Neurological Institute in Phoenix, and Newsome Professor of Clinical Neurology at the University of Arizona. Dr. Fisher is author or co-author of over 120 peer-reviewed publications in medical journals, two books on epilepsy and two monographs. He frequently chairs symposia and meetings, speaks at national or international conferences on subjects related to seizure disorders, has been on review boards for national grant applications, and currently serves on the editorial board of several epilepsy and EEG-related journals. He has won research awards from the Klingenstein Foundation, the Epilepsy Foundation of America and the National Institutes of Health. His peers named him to be listed 1996-2003 in Best Doctors in America. Dr. Fisher has served in numerous positions in the epilepsy community, including as President of the American Epilepsy Society. He has been the main force behind laboratory and recent clinical studies of thalamic stimulation for epilepsy, and he is the pioneer in originating techniques for direct drug application to the seizure focus.
John Huguenard, Ph.D., Professor of Neurology and Neurological Sciences, and Program Director of the ETP.
His early biophysical studies with Doug Coulter of low threshold calcium currents and their modulation by selective petit mal anticonvulsants, and later experiments describing the effects of benzodiazepines and ethosuximide on thalamic neurons and networks, have instigated the development of novel epileptic therapies. Current research directions in Dr. Huguenard’s laboratory include regulation of excitability in thalamic and cortical neurons and the key role of synaptic integration in determining network state. Epilepsy is a network phenomenon and an emergent property of neural networks that stray from their normal function. Synaptic interactions among neurons can vary in a dynamic sense leading to distinct states during the initiation, propagation and termination of seizures. His laboratory studies the transitions between normal network function and these various epileptic states, efforts that have been aided through the use of genetic animal models of spontaneous seizures. He utilizes a number of modern approaches to this end, including live imaging, neurophysiology, and optogenetic circuit dissection and neuromodulation. Mouse knockouts are commonly used to define the roles of specific molecules (ion channels, neurotransmitter receptors, or transporters) in complex neuronal functions. Modeling is an important tool in the laboratory, useful in the integration of neurophysiological data and generation of hypotheses. Trainees in his laboratory will learn techniques for chronic EEG studies in animal models of epilepsy, biophysics of voltage-gated and synaptic currents in neurons with in vitro slice preparations, circuit mapping via laser scanning photostimulation (LSPS), multiphoton imaging of neural activity in fine structures (axons, dendrites) via Na+ and Ca2+ imaging, dynamic clamp, real time imaging of neurotransmitter output (esp. glutamate) and computer simulation tools (NEURON, MCell). There are currently 9 fellows in Dr. Huguenard laboratory.
Liqun Luo, Ph.D. Professor of Biology and Investigator of the Howard Hughes Medical Institute. Dr. Luo uses molecular genetics to study the logic of neural circuit organization and assembly. The human brain is made of hundreds of billions of neurons. Most individual neurons have complex dendrites and axons that allow them to receive and send information to thousands of other neurons. Specific neurons participate in specialized neural circuits and perform dedicated functions. To comprehend this bewildering complexity, Dr. Luo’s group uses simpler brains of model organisms to uncover fundamental principles that are likely to be used in our own brain. Dr. Luo’s lab has developed genetic methods in fruit flies and mice that permit labeling and genetic manipulation of individual neurons in intact brains. They use these methods to study how neural circuits are organized in adult and how they are assembled during development. In particular, Dr. Luo’s lab has elucidated mechanisms by which exuberant axons and dendrites are pruned during the wiring of the nervous system. Defects in neuronal process pruning could contribute to epilepsy.
Susan McConnell, Ph.D., Susan B. Ford Professor of Biological Sciences: Dr. McConnell’s interests in developmental neurobiology involve studies of neurogenesis and neuronal migration in the developing cerebral cortex, the specification of discrete neuronal phenotypes through cell lineage and cell-cell interactions, the control of axonal growth between developing neocortex and targets, and factors that influence the formation of lamina-specific axonal connections within the neocortex. Trainees in her laboratory learn a variety of investigative approaches including transplantation of neuronal precursor cells, time-lapse imaging using laser scanning confocal microscopy, molecular biological aspects of cell-target identification and migration, cell and tissue culture, in situ hybridization, and intracellular electrophysiology and dye fills in brain slices together with axonal tracing techniques, and genetic manipulations of mouse development. Dr. McConnell has found that multipotent neuronal precursors in the embryonic cerebral cortex make an early commitment to generating young neurons that are destined for specific cortical layers just prior to the precursor cell’s final mitotic division. Dr. McConnell has collaborated with Dr. Huguenard on issues of Satb2-dependent specification of neuronal intrinsic cell fate.
Robert Malenka, M.D., PhD., Nancy Friend Pritzker Professor of Psychiatry and Behavioral Sciences: Dr. Malenka’s primary interest is in the detailed mechanisms by which activity, neurotransmitters and drugs modify synaptic transmission in a variety of brain regions including the hippocampus, somatosensory cortex, nucleus accumbens and ventral tegmental area. A major goal of his laboratory is to elucidate both the specific molecular events that are responsible for the triggering of various forms of synaptic plasticity and the exact modifications in synaptic proteins that are responsible for the observed, long-lasting changes in synaptic efficacy. His work on the mechanisms of long-term potentiation (LTP) and long-term depression (LTD) has led to the novel hypothesis that activity can rapidly and profoundly influence the synaptic distribution of glutamate receptors. Trainees in Dr. Malenka’s lab learn a range of cell biological, molecular and electrophysiological techniques that are applied to both brain slices and primary cultured neurons. These techniques include whole cell patch clamp recording, optogenetics, behavior, immunocytochemical localization of synaptic proteins, and transfection of cDNAs to express recombinant proteins. Dr. Malenka currently holds the Pritzker Chair of Psychiatry and has received a number of awards for his research including the Young Investigator Award from the Society for Neuroscience and several career development awards from NIH. His expertise on synaptic plasticity is highly valued by our trainees, as the process of epileptogenesis can be considered as a failure of proper circuit/synaptic homeostatic plasticity.
Brenda Porter M.D., Ph.D, Associate Professor of Neurology and Director of Pediatric Epilepsy at Stanford Children’s Health: Dr. Porter’s current research focuses on 1) The role of transcriptional regulation in the development of epilepsy following an episode of status epilepticus. Using mice and rats the lab is studying how cyclic-AMP response element (CRE) binding proteins promote epileptogenesis and how manipulating CRE transcription can be utilized to prevent epilepsy. 2) Understanding how microRNA expression is regulated following status epilepticus and its implication for the development of epilepsy. 3) The extracellular matrix that surrounds inhibitory interneurons, the perineuronal net has a unique structure that is degraded by proteases following an episode of status epilepticus. The lab is currently focused on how the loss of the net impacts epileptogenesis, the perineuronal net in human epilepsy tissue, and identifying protease inhibitors that will prevent net loss.
David Prince, M.D., Edward F. and Irene Thiele Pimley Professor, and Former Chair, of Neurology and Neurological Sciences: Dr. Prince is the original director of the Epilepsy Training Program, and has remained active in the program through the current period of support. He continues to be an important part of the program, with a new role as Director of Integrative Training. Current research directions in Dr. Prince’s laboratory include 1) developmental studies of neuronal function in normal and epileptogenic rat neocortex, including experiments focused on cellular electrophysiology and anatomy of cortical developmental malformations and models of epilepsy in mice; 2) anatomic and physiologic properties of neurons in areas of chronic cortical injury and epileptogenesis in a model of post-traumatic epilepsy studied in vitro; alterations of membrane properties and reorganization of receptors and cortical circuits occurring after such injuries are being investigated; 3) prophylaxis of epileptogenesis. Trainees in his laboratory learn a variety of techniques including use of in vitro neocortical, hippocampal, and thalamic slices; combined physiologic-anatomic analysis of labeled neurons; immunocytochemistry; methods for drug application and assessment of physiological effects of agonists; models of acute epileptogenesis; production of chronic epileptogenic foci in mammalian brain and recordings from chronically implanted rats and mice. Dr. Prince and his fellows have employed patch-clamp techniques to study whole-cell currents and single channel activities from cortical and thalamic neurons. Collaborative interactions have been maintained with Drs. Huguenard, Barres and Buckmaster.
Richard Reimer MD, Associate Professor of Neurology and Neurological Sciences: Dr. Reimer joined the Stanford faculty after finishing a residency in neurology at UCSF and post-doctoral fellowship with Dr. Robert Edwards at UCSF. His post-doctoral work focused on identifying transporter proteins involved in neurotransmitter release and metabolism. His laboratory uses molecular, biochemical and cell biological approaches to understand how transporters are involved in the normal physiology of neurons and how their activity is modulated in pathological states including animal models of epilepsy. Trainees in his laboratory will learn techniques for studying expression and function of transporters, metabolism of neurotransmitters and trafficking of proteins. He is collaborating with Dr. Huguenard on studies of glutamate signaling and metabolism, especially in terms of mechanisms underlying sustained neurotransmitter release during seizure related activity.
Ivan Soltesz, PhD. James Doty Professor and Vice Chair of Neurosurgery, and Professor of Neurology & Neurological Sciences: Dr. Soltesz’s research program is focused on the principles of organization of GABAergic inhibition in the brain and the basis of circuit dysfunction in epilepsy. Current projects in the lab include the selective modulation of different cell types in various parts of the brain to block seizures and ameliorate epilepsy-related cognitive deficits, mechanisms of endocannabinoid control of circuit excitability, the role of interneurons in normal and abnormal network oscillations in the hippocampus, and the development of uniquely realistic, full-scale, 3D models of hippocampal circuits. Trainees in the lab are exposed to a variety of closely integrated experimental and theoretical techniques, including simultaneous patch clamp recordings from identified interneuron-principal cell pairs, rigorous identification of GABAergic interneuronal subtypes, in vivo recordings from different interneurons in awake behaving mice, in vivo imaging techniques, closed-loop in vivo optogenetics, behavioral approaches, and large-scale computational modeling methods using supercomputers.
Thomas Südhof, M.D., Ph.D. Avram Goldstein Professor of Molecular & Cellular Physiology and Investigator of the Howard Hughes Medical Institute: The collective findings of Dr. Südhof’s research program have provided much of our current scientific understanding of behavior of the presynaptic neuron in neurotransmission and synapse formation. His work also has revealed the roles of presynaptic neurons in neuropsychiatric illnesses, such as autism or neurodegenerative disorders. Among the discoveries in his 20 years of research, Südhof revealed how synaptotagmin proteins sense calcium and mediate neurotransmitter release from presynaptic neurons. He also defined the molecules that organize release in space and time at a synapse, such as RIMs and Munc13’s, and identified central components of the presynaptic machinery that mediate the fusion of synaptic vesicles containing neurotransmitters with the presynaptic plasma membrane, the process that ultimately causes neurotransmitter release, and that is controlled by synaptotagmins. Südhof’s lab is currently focused on defining the relationship between specific synaptic proteins and information processing in the brain, with its concordant manifestations in behavior. This large-scale project attempts to provide insight both into the mechanisms underlying synaptic communication, and the processes causing human disease. A focus in the laboratory is synaptic dysfunction in neurodevelopmental disorders such as Autism along with the related cortical hyperexcitability that may be relevant to epilepsy.
Levels and numbers of trainees: Support is provided for 4 postdoctoral fellows, including 1-2 trainees with M.D. or M.D./Ph.D. degrees, and 2-3 trainees who have obtained their Ph.D. degrees, although the proportions of trainees will vary from year to year, depending on qualifications of the applicant pool. In general, four new trainees will be selected each year and each will be supported for one years, however, M.D. fellows without prior research experience often require a longer period of support. This period of support is coupled with the expectation the the trainee will apply for independent fellowship funding within the year. Fellows admitted to the program with M.D. degrees will usually have had residencies in adult or pediatric neurology or psychiatry and therefore be in their 5th or 6th postdoctoral years. An occasional qualified applicant might have had training in neurosurgery.
Selection of project, guidance and evaluation; course work, research opportunities: Most trainees will have selected a research laboratory for their postdoctoral training before applying to the ETP. This is appropriate, as the ETP usually only provides one year of support, and the typical period of postdoctoral training is 3-5 years. With targeted advertisements to the program, we will ask postdoctoral applicants to indicate one or more fields of interest and potential sponsors. A sponsor is selected who will evaluate the candidate’s suitability for training, and if appropriate help the fellow tailor his/her training program according to individual needs, and then act as research advisor. The amount and type of recommended course work varies in relation to the fellows’ academic background and research project(s), and is usually minimal, as postdoctoral fellows rarely take additional courses. However, there are significant opportunities for targeted training, and or tool development at Stanford, for example with quantitative or computational tools such as Python or MATLAB or training in microscopy or behavior in relevant research core facilities. Examples of potential didactic courses are given below. Most of the trainee’s time will be directly involved in research activities. Depending on each individual’s prior experience, this will involve a variable initial period when he/she will work together with the faculty sponsor and collaborators in a project of mutual interest. During this time, the fellow will be learning the basic techniques of the laboratory. For the remainder of the fellowship the trainee will work with increasing levels of independence. The possibility for collaborative research is one of the strengths of postdoctoral training within the program and postdoctoral fellows are encouraged to interact with more than one research group. A scheduled period of rotation through a second laboratory, a collaborative project carried out with the cooperation of two laboratories, or a less formal interaction might be planned. Faculty within the program have had an excellent record of collaboration and interaction which will be of benefit to trainees.
Individual faculty sponsors will have an opportunity to interact closely with trainees on a day-to-day basis and evaluate their progress, including capacities for critical assessment of literature, experimental design, originality, technical skills, data analysis, writing abilities, etc. Fellows will also participate in meetings of their own laboratory group. In addition, trainees will be required to present progress reports on their research once a year at meetings which will be attended by the faculty and trainees of the program, and other members of the Neurology and Neuroscience faculty. They will also be encouraged to present their work at Stanford Neurosciences Institute retreats, and at appropriate national meetings. The Training Program Steering Committee will meet yearly to review the progress of each trainee. Should fellowship performance be inadequate, the program director will explore with the sponsor, the fellow, or other faculty, ways in which improvements in performance or in the training opportunity can be made. Research projects will be selected to suit trainees’ goals through discussion with the sponsor, and other members of the neuroscience faculty at Stanford whose research and interests lie in a similar discipline. Faculty of the program have agreed to act as mentors for program trainees. Mentorship involves providing advice outside of the sponsor-trainee relationship regarding career development, experimental design and interpretation, publication strategies, etc. One mentor from each of the Basic Science and Epilepsy Research groups will be assigned to each trainee upon their appointment to the program, with one of these mentors normally the research advisor. Each mentor will meet twice annually with their mentees and provide a brief report to the Program Director and Steering Committee.
Integration of experiences within the program for an individual trainee will take place through attendance at recommended courses; a monthly student-faculty Journal Club or laboratory meeting; participation in seminars, especially the Stanford Neuroscience Institute weekly seminars and the Neurology Department Grand Rounds, and occasionally Neurosurgery Grand Rounds. Other opportunities are meetings of Stanford SCAN (Stroke Collaborative Action Network, Dr. Huguenard is a member), which meets monthly and focuses on experimental and clinical stroke and related neurological deficits including seizures, and the quarterly Epilepsy Program Conference (for which attendance is mandatory for program trainees), and inter-laboratory collaborative efforts arranged as part of an individual trainee’s program. There are 3-4 clinical epilepsy presentations each year developed specifically for, and attended by all, program trainees. Our Integrative Training Director, Dr. Prince will plan and oversee the Quarterly Conferences and Clinical Presentations, as well as develop other possibilities for trainee and/or faculty interaction. Dr. Prince was the originator of the quarterly conferences and obviously well qualified to assure cross-disciplinary synergy, as he has one foot in each of the basic and clinical research sides. Clinical presentations include visits to the epilepsy monitoring unit directed by Dr. Fisher, and lectures on current issues in clinical epilepsy by Drs. Graber, Fisher, Parvizi and Porter.
Research training of physicians: Postdoctoral fellows with M.D. degrees are given the opportunity to maintain their contacts with clinical neurology and patients with epilepsy by working in the General Neurology Outpatient Department 10% time (1 half day clinic per week) where they may gain experience teaching medical students and junior residents. As an alternative, they may elect to attend one of the weekly epilepsy clinics. In addition, they may attend a weekly clinical conference as mentioned above. Similar arrangements can be made for clinicians in other disciplines. Interactions with the basic neuroscience community are facilitated by attendance at seminars and the Neuroscience Journal Club where they have contacts with students in the pre- and postdoctoral Neuroscience Training Program. Clinicians training in basic neuroscience come into daily contact with other pre- and postdoctoral fellows in their laboratories. All trainees are encouraged to present posters at the annual School of Medicine Neuroscience Forum, and to attend the annual retreat of the Neuroscience Ph.D. Program where a variety of distinguished visiting neuroscientists review their fields. As part of a Professional Development and Ethics in Neuroscience course (Neurobiology 300), fellows are exposed to discussions of “survival skills” focused on grant writing, job opportunities and interviews, presentation of data at meetings, etc.
Qualifications, criteria, procedures: Research training is provided in areas relevant to basic science aspects of epilepsy for 1) candidates with M.D., M.D./Ph.D. or other medical degrees, and 2) individuals who have Ph.D degrees. From past experience, most M.D. or M.D./Ph.D. candidates interested in epilepsy research training will have completed a residency in clinical neurology, however, well-qualified candidates from other clinical neuroscience backgrounds (Neurosurgery, Psychiatry), or those who have chosen not to enter postdoctoral medical specialty training, will be considered. Candidates must have interests in developing academic careers that will be relevant to epilepsy-related research and must be U.S. citizens or permanent residents to be eligible for support. Candidates will be selected by a committee consisting of the Steering Committee. Evaluation will be based upon 1) past academic record including grade point average, GRE or MCAT scores; 2) letters of evaluation from predoctoral sponsor, head of the residency program, Department chairperson, etc. as appropriate; 4) previous research experience; 5) and career goals and interests in epilepsy. Although the committee will take into account previous research experience among M.D. applicants, it will endeavor also to identify those who, in the absence of such experience, have significant potential to become effective investigators and faculty members, on the basis of their academic and clinical records and career goals. The committee will make appropriate matches between the interests of a given applicant and the research activities of particular faculty members. Participation in research involving more than one neuroscience discipline, and collaborative research between laboratories will be encouraged.