Brandon Westover, MD, PhD
2014 Rappaport Research Scholar
Brandon Westover, MD, PhD, is a leader in the fields of critical care electroencephalography (EEG) and biomedical signal processing. The goal of Dr. Westover’s laboratory is to help intensive care unit (ICU) patients leave the hospital with better neurological outcomes. ICU patients are at risk for a host of neurological complications which could be prevented with better brain monitoring technology, including delirium, anoxic brain injury, over- and under-sedation, occult pain and seizures. With help from the Rappaport Family Fund, Dr. Westover’s research is pursuing its goal using two parallel strategies.
First, Dr. Westover’s group is developing computer algorithms for monitoring brain activity in patients at risk for neurological deterioration. One of the most exciting achievements to date is the development of a closed-loop anesthesia delivery (CLAD) system that is able to monitor and safely deliver anesthetic medications automatically to patients suffering from refractory seizures. In animal testing, the group’s CLAD system achieves tighter control than is possible with current clinical practices. They are applying for FDA approval to test this technology in humans suffering from refractory seizures. Another project in progress is the development of an EEG-based system for patients with ruptured brain aneurysms to warn physicians when brain activity “slows down,” indicating a high risk for developing a stroke. Dr. Westover’s laboratory is leading an international group to gather the EEG and clinical data needed to develop and rigorously validate this technology.
Second, Dr. Westover’s group is developing “Big Data” analytics to extract new medical knowledge from the rich and massive clinical data archives of the MGH ICU and Epilepsy Units. Efforts are underway to robustly capture, organize, and mine the medical data from the more than 5,000 patients cared for annually in MGH intensive care units and for the more than 10,000 patients with seizures and epilepsy evaluated at MGH. Early work is promising and suggests new ways of automatically identifying patients at the highest risk for delirium, seizures, and epilepsy. Dr. Westover and his group hope to rapidly expand on this work to develop new warning and decision-support systems for critical care medicine, and to accelerate discoveries in epilepsy.
Rakesh Karmacharya, MD, PhD, Psychiatry
2013 Rappaport Research Scholar
Originally from Nepal, Dr. Rakesh Karmacharya is an assistant professor in Psychiatry at Harvard Medical School and a member of the Psychiatric and Neurodevelopmental Genetics Unit of the MGH Center for Human Genetic Research. He is also a physician-scientist in the Chemical Biology Program at the Broad Institute of MIT and Harvard, and the medical director of the Schizophrenia and Bipolar Disorder Research Clinic at McLean Hospital.
Dr. Karmacharya received an A.B. in Biochemistry from Harvard University, an M.S. in Molecular Biophysics from Yale University and an MD and a PhD in Biophysics from the Albert Einstein College of Medicine in New York. His doctoral work focused on the quantum mechanics of proton tunneling in condensed phase. He completed an internship in Medicine at Massachusetts General Hospital (MGH), and a residency in psychiatry at MGH and McLean Hospital. He served as the chief resident of the Schizophrenia and Bipolar Disorder Program at McLean Hospital. After his residency, he undertook postdoctoral studies in chemical biology with Professor Stuart L. Schreiber at the Broad Institute of MIT and Harvard.
Dr. Karmacharya is generating induced pluripotent stem cells (iPSCs) in the laboratory by reprogramming skin cells obtained from patients with schizophrenia, bipolar disorder and matched controls. iPSCs are equivalent to human embryonic stem cells in that they have the capability of developing into any cell in the body.
Dr. Karmacharya’s team differentiates these patient iPSCs along the neuronal lineage to get live neuronal cells in the laboratory that carry the genetic makeup of the patients. They will profile these patient iPSC-derived neurons using high-content imaging as well as gene expression studies in the presence of different small molecule perturbations. Their goal is to identify robust cellular signatures that underlie the disease biology of schizophrenia and bipolar disorder. These disease signatures can then be used in high-throughput screens of small molecule libraries to discover compounds that can modulate and normalize the cellular disease signatures, with an eye towards identifying new diagnostic and therapeutic leads for schizophrenia and bipolar disorder.
John Pezaris, PhD, Neurosurgery
2012 Rappaport Research Scholar
As a graduate student at MIT, John Pezaris, PhD, pursued research in design for a supercomputer project. After his master’s degree, he switched fields to neuroscience, moving to Caltech for doctoral work in computation and neural systems. He noted that much of computer architecture was highly applicable to understanding the brain and developed state-of-the-art signal analysis to isolate activity from simultaneously recorded neurons. The methods developed have come into wide academic and commercial use.
As a research fellow at Harvard Medical School, he discovered that electrical stimulation in the thalamic lateral geniculate nucleus (LGN) can be used to transiently silence spiking activity in primary visual cortex. This led, in turn, to modulating on-going visual activity with electrical stimulation and to creating artificial visual percepts. While a number of prior investigators had attempted to put visual stimuli into the living brain, his results suggested the LGN is an advantageous target not previously utilized, and his papers on visual prosthetics described a novel approach that challenged prior scientific dogma. Recognition followed, with his being named a finalist for the Saatchi & Saatchi Award for World Changing Ideas, and a finalist for Scientist of the Year by Status Magazine (Greece) for his efforts in restoring sight to the blind.
Nicte Mejia-Gonzalez, MD, Neurology
2011 Rappaport Research Scholar
Nicte Mejia, MD, is an Assistant in Neurology at Massachusetts General Hospital and an Instructor in Neurology at Harvard Medical School. She was born in Guatemala of Mexican and Salvadorian parents, and she graduated medical school with honors from the Tecnologico de Monterrey in Monterrey, Mexico. Dr. Mejia obtained subspecialty training in Neurology and Movement Disorders at Mass General and Brigham and Women’s Hospital. Her clinical practice centers on caring for patients with Parkinson’s disease and other movement disorders.
Dr. Mejia’s research aims to improve neurologic care and outcomes for all patients, in particular addressing potential racial or socioeconomic inequalities in neurologic care. She actively collaborates with researchers across medical disciplines at MGH and other institutions on projects related to neurologic health equity. Her research has enormously benefited from the generous support of the Rappaport Family Foundation.
Dr. Mejia recently demonstrated significant nationwide racial and socioeconomic inequalities in access to Parkinson’s disease deep brain stimulation surgery. This work is critical for patients with Parkinson’s disease and their caregivers, as they often face years of progressive disability and poor quality of life. Her research was awarded funding to scientifically develop a Parkinson’s disease web portal for Latino patients and their caregivers to connect with a health coach. This much needed intervention will lay the foundation for many more clinical research projects aimed at improving care for underserved neurology patients.
Dr. Mejia has presented her findings pertaining to disparities in neurological care both regionally and nationally, including a Scientific Session platform presentation at the 2011 American Academy of Neurology annual meeting. Her most recent honors include selection as a 2012 Harvard Medical School Health Disparities Postgraduate Fellow and the recipient of an American Neurological Association Junior Academic Neurologist Scholarship Award. She has also successfully mentored two Harvard Medical School students who are underrepresented in medicine toward receiving scholarships. Moreover, she remains active at an institutional and national level in committees that pertain to clinical research training and diversity, and was recently appointed as director of diversity for the MGH Neurology Department and chair of the Neurology Department’s Diversity Committee.
Dr. Mejia actively participates in community outreach activities including speaking to underrepresented students on pursuing scientific and medical careers.
She will present her most recent research findings at the 2012 American Academy of Neurology annual meeting. Dr. Mejia plans to further develop her clinical research initiatives through local and national collaborative studies on access to neurologic care and clinical outcomes. She plans to obtain funding from the National Institutes for Health to solidify her neurologic health equity and clinical outcomes research activities.
Dr. Mejia’s ten year plan is to: 1) Become a well established, productive and innovative clinical researcher with neurologic clinical outcomes and health equity research collaborations globally; 2) Lead initiatives aimed to improve patients’ access to quality neurologic care; and 3) Be an active educator and mentor on neurologic outcomes and health equity research.
Mireya Nadal-Vicens, MD, PhD, Psychiatry
2010 Rappaport Research Scholar
Having trained in both basic molecular neuroscience and clinical adult and child psychiatry, Mireya Nadal-Vicens, MD, PhD, has begun to use basic research in a simple animal organism with the intent to drive drug discovery relevant to clinical applications in depression and other mood disorders. These disorders cause a tremendous social, personal and economic burden. Despite great treatment advances, the number of truly novel mechanisms for the basis of psychiatric medications has remained largely stagnant.
Dr. Nadal-Vicens’ laboratory is focused on developing a simple new animal model of depression that would allow a large scale drug screen to identify new pharmacological agents capable of modifying mood disorders. By using a large screening assay in the fruit fly Drosophila melanogaster, the hope is to discover new medications able to reverse the brain changes brought on by stress and defeat.
Thanks to the generous support of the Rappaport Family Foundation, Dr. Nadal-Vicens has been able to further characterize the social defeat assay in the fruit fly Drosophila, wherein a single loss in a fighting arena leads to profound and long-lasting changes in the defeated fly’s behavior. In addition, she has been able to increase the volume of experiments in preparation for a larger screening. Through these steps, she has laid the foundations of two promising collaborations, both of which examine the role of different epigenetic modifications on this behavioral assay. Dr. Nadal-Vicens’ laboratory has also obtained some exciting results contrasting the role of valproic acid and lithium in this assay system, which may have important implications for how these commonly used drugs function in clinical mood disorders. This research is being submitted for publication, and would not have been possible without the philanthropic support of the Rappaport Family Foundation.
Hiroaki Wakimoto, MD, Neurosurgery
2009 Rappaport Research Scholar
With a background as an experienced neurosurgeon having fought glioblastoma for years in Japan, Hiroaki Wakimoto, MD has set an ultimate goal of developing a novel treatment strategy for this devastating disease. Despite efforts to improve outcomes, glioblastoma, a common brain cancer seen primarily in adults, remains one of the deadliest cancers, with median survival time of only 12-15 months. Recent research has shown that glioblastoma contains a subpopulation of cancer cells with a unique capability to initiate and drive cancer growth. These cells, therefore, need to be eliminated by therapies in order for the disease to be controlled.
Since joining the Brain Tumor Research Center at Massachusetts General Hospital in 2006, Dr. Wakimoto has successfully isolated these so-called glioblastoma stem cells (GSCs) from surgical specimens obtained at Mass General. When implanted into mice with immune deficiency, GSCs efficiently form intracranial tumors which closely resemble the pathology seen in original tumors in patients. This brain tumor model in mice gives greater value for testing novel therapeutics than conventional models. Dr. Wakimoto’s team also discovered that oncolytic herpes simplex viruses, which destroy cancer cells while sparing normal cells, are effective in killing GSCs, supporting the use of the agents in the clinics. To enhance anti-cancer activities of the viruses, the incorporation of therapeutic genes into viruses has been extensively tested using GSC models to determine whether this approach results in improved outcomes. In addition, GSCs from a series of patients have revealed one of two distinct “faces” of behavior in mouse brains: rich in blood vessels or highly infiltrative into the surrounding brain. As a result, research to elucidate the molecular characteristics that define the GSC features has started. If successful, the results may identify therapeutic targets for individual GSCs that can be explored to block exhibition of aggressive aspects of the cancer.
The generous support from the Rappaport Family Foundation has allowed Dr. Wakimoto to perform this innovative medical research that may lead to improvement in the lives of patients with brain cancer. Furthermore, the Rappaport award has been crucial in providing bridge funding that enables the research necessary for production of data to apply for federal funding. The findings made possible by the Rappaport award will be published in peer-reviewed scientific journals.
Mark W. Albers, MD, PhD, Neurology
2008 Rappaport Research Scholar
The focus of Dr. Albers’ laboratory is to gain a mechanistic understanding of early pathogenic processes of neurodegenerative diseases that are modifiable or reversible. Using mouse genetics, his lab has specifically tailored olfactory neurons to express disease genes associated with Alzheimer’s disease in a reversible manner, such that the disease gene can be turned off by feeding the mice a low-dose antibiotic. Patients with Alzheimer’s disease and Parkinson’s disease suffer olfactory deficits early in the course of their disease, pointing to a particular susceptibility of this neural circuit to the pathogenesis of these diseases, and making the olfactory system a logical starting point. Moreover, the olfactory neural circuit is one of the best-understood neural circuits in the mammalian brain. Characterization of this mouse model has uncovered a novel action of an Alzheimer’s disease gene – expression of this gene in less than 1% of the primary olfactory neurons is sufficient to cause olfactory deficits in behavioral assays. Reversal of the disease gene expression affects a complete recovery of the behavioral deficit in adult mice.
The generous support from the Rappaport Family Fund afforded Dr. Albers’ team the opportunity to learn that olfactory neurons are dying at an accelerated rate when the disease gene is expressed. This is the first mouse neuron population shown to be susceptible to this disease gene. This advance has generated exciting studies that delve into the molecular mechanisms leading to accelerated neuronal death and to develop a system to screen for molecules that interfere with this neurodegenerative process. Insights gained from these studies may contribute to the development of an effective therapy for these devastating diseases. The funds provided by the Rappaport Family helped support investigator salaries and defrayed costs associated with laboratory work, ultimately facilitating this important research. Dr. Albers’ findings will be published as well as presented at two international meetings.
Giulia Fulci, PhD, Neurosurgery
2007 Rappaport Research Scholar
The Rappaport Award has been of immeasurable support in allowing Dr. Fulci’s research and career to move forward. Her research focuses on increasing efficacy of oncolytic virotherapy for brain tumors through transient suppression of the host’s innate antiviral defense responses. Oncolytic virotherapy is performed with viruses that selectively replicate in and kill tumor cells. Thus, these viruses can generate a progeny that spreads through the tumor while sparing the surrounding normal tissue. This is an excellent means to deliver an anti-tumor agent to isolated malignant cells that infiltrate the normal brain and that cause rapid re-occurrence of the cancer after standard treatments. Dr. Fulci is currently establishing a new magnetic resonance imaging (MRI) technique that allows monitoring in brain tumor patients the presence of antiviral immune responses, the intratumoral spread of the virus and the tumor response to the treatment throughout the therapy.
In summary, Dr. Fulci is establishing a state-of-the-art diagnostic tool that can evaluate in a quantitative and non-invasive fashion all three parameters and therefore provide fundamental information about the progress of the treatment. Through the Rappaport Family Fund, Dr. Fulci has received the support needed to obtain preliminary data for a National Institutes of Health R21 grant application that was recently awarded. This grant established her as an independent researcher and allows her to pursue her scientific interests. Moreover, her results were recently accepted for a presentation at an international meeting on gene therapy.
Mohammed R. Milad, PhD
2007 Rappaport Research Scholar
Dr. Milad’s research focuses on understanding the neurobiology of learning not to fear (fear extinction) in both the rat and human brains. Recently, the department of Psychiatry has built the behavioral neuroscience laboratory to allow Dr. Milad to continue his research. Particular emphasis of this new laboratory is to investigate the differences between males and females in their ability to inhibit fear and to understand the potential influence of gonadal hormones (i.e. estrogen and progesterone) on the neurobiology of fear extinction. The generous support of the Rappaport Family Fund has been instrumental in helping him to initiate this line of his research. The fund has allowed the purchase of animals and supplies for the laboratory. Moreover, the fund is contributing to the salary of a post-doctoral fellow to assist Dr. Milad in conducting his research. Dr. Milad is in the initial phase of gathering preliminary data that will permit him to apply for funding from the National Institutes of Health.
Thus, the support from the Rappaport Family Fund has allowed 1) the initiation of an important line of research to help understand differences between men and women in learning not to fear, 2) the scientific development of a post-doctoral fellow, and 3) the scientific development of a junior faculty member in the department of psychiatry.
Eric M. Morrow, MD, PhD, Psychiatry
2007 Rappaport Research Scholar
The Rappaport Award has provided important support for Dr. Morrow’s research. Dr. Morrow’s research has focused on neurodevelopmental and genetic mechanisms that are root causes of childhood neuropsychiatric illness such as autism and related disorders of cognitive development. During this year, Dr. Morrow has completed 3 projects which are now under review: 1) The first project involves using high-density SNP microarrays to identify loci in patients with autism from special founder populations. These patients were recruited as a part of the International Homozygosity Mapping Collaborative, an international genetics effort that Dr. Morrow co-directs. In this project, mutations in a gene were discovered in a subtype of autism involving comorbid seizure disorder. 2) In a second study, mutations in autism and mild mental retardation were discovered in a gene name alpha-neurexin-1. 3) In a third manuscript under review, Dr. Morrow conducted a mutational analysis of a gene involved in synapse remodeling in a patient cohort from the MGH Schizophrenia Research Program.
Dr. Morrow has applied the Rappaport Fellowship to salary support to provide protected time to complete studies, prepare manuscripts, and travel for international clinical research and national presentations.
Sydney S. Cash, MD, Neurology
2007 Rappaport Research Scholar
Dr. Cash’s laboratory focuses on trying to understand normal and abnormal oscillations in the human brain. Specifically, he and his team are interested in understanding the mechanisms which underlie rhythmic activity in sleep, cognition and epilepsy. They use both non-invasive and invasive methods to study these phenomena and hope to use these results to improve diagnostic and therapeutic efforts to cure neurological disease.
With help from the Rappaport Family Fund, one of their most exciting research programs focuses on using specialized microelectrodes (shown here) to record from the human cortex and understand how seizures start, spread and stop. About 50 million people worldwide suffer from epilepsy – as many as 1/3 of these patients have seizures which can not be controlled with medications alone. Using these microelectrodes, Dr. Cash and his colleagues have recorded seizure activity in patients undergoing surgery for poorly controlled epilepsy. These studies offer a unique view of the physiology of seizures at a level of detail which has never been achieved in humans before. Early results are promising and suggest new ways to understand how seizures start and spread. Dr. Cash and his team hope to quickly expand on this new understanding and build new systems for detecting, predicting and controlling seizures.
William T. Curry, Jr., MD, Neurosurgery
2006 Rappaport Research Scholar
The Rappaport Award provided immeasurable support in allowing Dr. Curry’s research to move forward. His team is combining herpes virus treatment of malignant brain tumors with immunotherapy approaches in an attempt to generate more effective and durable strategies for this intractable disease. G47D is a herpes simplex virus type I that has been engineered in the laboratory selectively to replicate in, and, thereby, kill, dividing cancer cells. Normal brain tissue is essentially unaffected. Furthermore, the virus is further mutated so that it does not inhibit the generation of an immune response, and inflammation in the infected tumor is promoted. In mice, they have combined intratumoral injection of this potent virus with intratumoral injection of immature dendritic cells, which are generated by culturing bone marrow cells with particular cytokines. These dendritic cells can then process components of dying tumor and travel to lymph nodes where an antitumor immune response is generated. Their work has demonstrated that this combination viral and dendritic cell therapy is very effective, and, in fact, can cure most established subcutaneous tumors in mice. The researchers are currently working on this model in the intracranial compartment and are also combining oncolytic HSV-1 treatment of tumors with other immune modifiers.
The Rappaport funds provided for animals and reagents for these studies. With these data, Dr. Curry has achieved additional funding from the American Brain Tumor Association to continue this work. Two abstracts have been accepted for presentation at national scientific meetings.
Jonathan Rosand, MD, Neurology
2005 Rappaport Research Scholar
Dr. Rosand is Assistant Professor of Neurology at Harvard Medical School and Director of Fellowship Training in Vascular and Critical Care Neurology at MGH. His research in the prevention and treatment of hemorrhagic stroke focuses on identifying the genes that underlie the disease. He was recently recruited to the newly formed MGH Center for Human Genetic Research. The Rappaport Family Fund provided support at this crucial time to hire staff to assist Dr. Rosand in the establishment of an infrastructure for research in genetics. With this structure now in place, Dr. Rosand is able to initiate genetic studies independently and is in a much stronger position to apply for federal funds for his research.
Daphne Holt, MD, PhD, Psychiatry
2004 Rappaport Research Scholar
The crucial support of the Rappaport Family Fund has allowed Dr. Holt to complete her studies in the field of schizophrenia functional neuroimaging. Completing and publishing the results of these studies will allow her to become an established investigator in this field, with state-of-the-art-training in the techniques of functional MRI, cognitive neuroscience, and clinical investigation in psychiatry.
Dr. Holt is currently conducting what she hopes will be the definitive functional magnetic resonance imaging study of the neural basis of emotional perception abnormalities in psychosis. The purpose of this research is to identify early markers of illness to allow the development of methods to prevent the onset or slow the progression of schizophrenia. She has evidence that psychotic symptoms are associated with errors in the evaluation of the emotional significance of objects, social interactions and events in the environment. These errors result from a tendency to misattribute emotional significance to neutral or ambiguous information—an “affective misattribution bias.”
To understand the changes in brain function that give rise to this abnormality, Dr. Holt and her team have developed a novel experimental paradigm specifically designed to elicit this bias. Using this paradigm and the spatiotemporal imaging techniques developed at the MGH Martinos Center in Charlestown, her team is attempting to identify the timing and the functional neuroanatomy of this affective misattribution bias in psychotic patients with schizophrenia. After they have characterized the pattern of brain activity associated with this bias in psychosis, they will then determine whether they can detect the identical pattern in at-risk individuals who later go on to develop schizophrenia.
Robert Carter, MD, Neurosurgery
2003 Rappaport Research Scholar
Using funding provided by the Rappaport Family, Dr. Carter and his team have developed a new strategy for “starving” human brain tumors by decreasing their ability to grow new blood vessels. This was done by creating blocking proteins, which bind to the major molecule, VEGF, that is used by brain tumors to develop new blood vessel growth. With support from the Rappaport Foundation, three different adeno-associated viral vectors encoding these blocking proteins were produced. The team is now in a testing phase of pre-clinical mouse models. The group hopes to complete pre-clinical testing in 2004, and, if successful, apply to the FDA for approval for testing in human brain tumor patients.
H. Diana Rosas, MD, Neurology
2002 Rappaport Research Scholar
Since joining the Neurology faculty, Dr. Rosas has focused her research activities on brain imaging of patients with cognitive disorders, particularly Huntington’s disease. She has recently been promoted to assistant professor at Harvard Medical School and has been successful in getting independent funding from NIH. Much of the Rappaport funding was used to purchase key equipment needed to perform sophisticated data analyses required to develop and validate surrogate biomarkers for Huntington’s disease. A small portion was used to provide partial salary support for a laboratory research assistant, and the remaining funds were used for other related laboratory and office supplies.
Lee Goldstein, MD, PhD, Psychiatry
2001 Rappaport Research Scholar
Dr. Goldstein has developed a breakthrough optical imaging device that is able to identify a marker of early Alzheimer’s disease. Eventually, such a test might be used to measure the effectiveness of new strategies to treat or prevent Alzheimer’s symptoms and to diagnose the disease in its earliest stages, when new treatments are likely to be most effective. Dr. Goldstein is associate director for Basic Research at the Center for Ophthalmic Research of the BWH Department of Surgery, a member of the psychiatry departments at MGH and BWH and the MGH Laboratory for Oxidation Biology, and assistant professor of Psychiatry at Harvard Medical School.
The Rappaport funding provided salary and fringe benefit support to Dr. Goldstein during a time when he was pursuing continued funding for his important research.
Emad N. Eskandar, MD, Neurosurgery
2000 Rappaport Research Scholar
Dr. Eskandar is successfully progressing along an academic track with his own lab in the newly developed Center for Nervous System Repair. His research involves the exploration and use of microelectrode recordings to define the function of the basal ganglia and with translational studies to patients with movement disorders and Parkinson’s disease. As a Rappaport Scholar, Dr. Eskandar purchased equipment and software to construct a computer system that collected high-quality intraoperative physiologic data from patients undergoing surgery to treat Parkinson disease. With this system, Dr. Eskandar initiated an IRB approved protocol to study the activity of neurons in the subthalamic nucleus during visually guided movements. The computers and interface cards are used to run the visual experiment and to store and analyze the physiologic data. Dr. Eskandar’s group is currently the only one in the world conducting this kind of research. The preliminary results have been extremely interesting and are the subject of upcoming talks at the Congress of Neurologic Surgeons Meeting and American Association of Neurology meeting. In addition, Dr. Eskandar has submitted one paper and is preparing another at the present time.