Neurosurgery Research Programs
Our laboratory investigates the pathophysiology and treatment of acute cerebral ischemia, as well as methods to restore neurologic function after stroke. Treatment strategies include mild brain hypothermia, gene transfer therapy and stem cell transplantation. Our clinical research develops innovative surgical, endovascular and radiosurgical approaches for treating patients with difficult intra cranial aneurysms, complex vascular malformations and occlusive disease, including Moyamoya disease.
Marion S. Buckwalter
Our lab focuses on how inflammatory responses after brain injury may affect neurological recovery. We utilize translational approaches to understand molecular mechanisms underlying functional recovery. Molecular events are modified in mice using either transgenic models or novel small molecule compounds, and then we evaluate the effects on functional recovery as well as on cellular and molecular responses.
Our primary research interest is to understand the molecular and cellular mechanisms of cell death in the CNS following acute injuries such as ischemia and trauma and chronic neurodegenerative diseases. We focus on the role of oxidative stress, mitochondrial dysfunction, DNA damage and repair, various gene expressions and various transcription factors in the pathogenesis of necrosis and/or apoptosis. The long-term goal of our research is to derive therapeutic strategies at the cellular and molecular level to ameliorate cell death in CNS injuries.
The long-term goal of our research is to understand the cellular and molecular mechanisms that underlie synapse function during behavior in the developing and mature brain, and how synapse function is altered during mental retardation. In this broad research area, we are specifically interested in the molecular underpinnings of activity-dependent regulation of synaptic strength, the role of postsynaptic protein translation in plastic changes of synaptic activity, and the impairment of synapses in autism spectrum disorders (e.g. Fragile X syndrome) that involves changes in postsynaptic protein translation and synaptic strength.
Our laboratory utilizes novel combinations of cell surface molecules to isolate pure populations of normal neural stem cells/progenitors and determines their relationships to purified malignant-brain tumor stem cells/progenitors; including the stage of development malignant transformation occurs, as well as, the genetic and epigenetic events that differentiate cancer progenitors from their normal cellular counterparts. Dr. Cheshier’s current research emphasis is on adult and pediatric high-grade brain malignancies including medulloblastoma and glioblastoma. The group has also recently developed lenti-viral reporter constructs capable of marking cell populations on the basis of biochemical pathway activation such as Wnt, Notch, and SHh. The laboratory has developed robust in vitro methods to study the developmental fates of neural and cancer cells including single-cell analysis. Cancer cell populations, including cancer stem cells, are regularly analyzed by orthotropic xenograft transplantation into immune-compromised mice. Their hope is to gain insights into the events that transform normal stem cells into cancer stem cells which will lead to targeted therapies against these highly malignant cancers.
Dr. Chichilnisky is a systems neurobiologist who explores how the retina of the eye processes and transmits visual information to the brain. The goal of the Chichilnisky lab is to understand signaling by the retina, its impact on vision, and the implications for treating vision loss. His laboratory focuses on the study of retinal ganglion cells, which are the output neurons of the retina that send visual information to the brain in their spatio-temporal patterns of electrical activity. The brain processes this incoming information to implement perception, visually guided movements, and other essential visual functions. Using unique techniques developed in collaboration with physicists, the lab records electrical activity of hundreds of neurons simultaneously, while stimulating them with patterns of light and/or injected current.
The Cho laboratory studies childhood brain tumors with a particular focus on medulloblastoma, the most common malignant brain tumor in children. They utilize a mix of computational/genomic and cell biological approaches to 1) understand the molecular and cellular basis of medulloblastoma, 2) generate new treatment strategies for patients diagnosed with this disease and 3) inform the current and next generation of medulloblastoma clinical trials.
My research interests revolve around novel techniques for the treatment of degenerative spinal conditions and neoplastic disease. Degenerative spine issues will unfortunately affect most of the adult population at some point in the life cycle, and often will become a chronic impediment to full performance of daily activities. Emerging techniques now allow certain conditions, such as stenosis, facet disease and scoliosis, to be treated using minimally invasive techniques, often as an outpatient and even to the point of avoidance of general anesthesia. In terms of anti-neoplastic therapies, local-regional strategies allow the delivery of very high concentrations of therapeutic agents directly into the tumor site, thereby limiting the collateral damage to surrounding normal tissues. Such approaches include catheter-based, or endovascular, techniques, as well as direct application of anti-tumoral agents at the time of surgery.
Our laboratory connects electronic systems to the nervous system to restore health and function after spinal cord injury. People whose bladder is paralyzed often have difficulty with bladder emptying and with continence. We are developing a second generation neural prosthesis, or implanted electrical stimulator, to restore these functions and reduce urinary tract infection, stone formation and kidney damage, and reduce the costs of their health care. People whose legs are paralyzed develop severe osteoporosis that can cause pathological fractures and other complications. We are studying whether osteoporosis can be prevented or reversed by vigorous exercise produced by electrical stimulation of leg muscles while on a rowing machine, in collaboration with the University of Oxford.
The interplay between motor cortex, sensory cortex, thalamus and basal ganglia is essential for neural computations involved in generating voluntary movements. Our laboratory’s goal is to dissect the functional organization of motor circuits, particularly cortico-thalamo-basal ganglia networks, using electrophysiology, 2-photon microscopy, optogenetics, and genetic tools. Our long-term scientific goal is to construct functional circuit diagrams and establish causal relationships between activity in specific groups of neurons, circuit function, animal motor behavior and motor learning, and thereby to decipher how the basal ganglia process information and guide motor behavior. We will achieve this by investigating the synaptic organization and function that involve the cortex, thalamus and basal ganglia at the molecular, cellular and circuit level. We aim to bridge the gap between molecular or cellular events and the circuit mechanisms that underlie motor behavior, with the objective of helping to construct the details of psychomotor disorder ‘circuit diagrams,’ such as the pathophysiological changes in Parkinson’s disease.
The Gephart lab focuses on translational neuro-oncology research, combining basic neuroscience, genetics, and tumor biology, with an unique insight into the pressing clinical questions facing patients with brain tumors. As a practicing neurosurgeon serving brain tumor patients in my clinic and operating room, our lab is uniquely positioned to be shaped by the clinical needs of patients. We focus on understanding the genetic and epigenetic mechanisms driving tumorigenesis in the central nervous system. Ultimately these insights will identify novel drug targets and improve diagnostic capacity. Our investigations into tumor cell biology, developmental neuroscience, cell signal transduction, and translational preliminary studies of novel therapeutics each feedback into and exponentially advance the field of neuro-oncology. Our discoveries in the lab develop hypotheses about novel treatments, and working with patients and primary samples forms projects for the lab regarding tumor cell biology and normal neurodevelopment.
The Lee Lab uses interdisciplinary approaches from biology and engineering to analyze, debug, and manipulate systems-level brain circuits. We seek to understand the connectivity and function of these large-scale networks in order to drive the development of new therapies for neurological diseases. This research finds its basic building blocks in areas ranging from medical imaging and signal processing to genetics and molecular biology.
My laboratory studies the biology of brain tumors with the goal of developing novel therapeutics for the treatment of malignant brain tumors and translating that research into clinical trials. Currently we are studying a variety of different protein pathways that we hypothesize to be important players in glioblastoma formation and growth. Using retrovirus to modulate gene expression in both primary and immortalized glial tumor cells we have identified a group of kinases that are important in glial tumorigenesis called casein kinase 2 (CK2). In particular we demonstrated that one isoform, CK2alpha, can enhance tumorigenic phenotypes as well as maintain glial cancer stem cells making it an important player in brain tumor biology. In addition, we are studying tumor suppressors that be used to help treat gliblastoma patients. One interesting candidate we have identified is Ikaros (IKZF1). IKZF1 was previously found to be involved in leukemia, but we demonstrate for the first time that it may be involved in other cancers including brain tumors. By understanding the biology behind how brain tumors occur we will help develop novel and more efficacious treatments for treating this deadly disease.
The Neural Prosthetics Translational Laboratory (NPTL) conducts research aimed at providing clinically useful neural prostheses for people with paralysis. Using tools and technologies developed in the Neural Prosthetics Systems Laboratory (NPSL), our eventual goal is to extract signals recorded from surgically implanted brain electrodes to provide accurate, high speed control of computer cursors and assistive technologies such as robotic arms. Our current projects are focused on improving neurally-directed computer cursor control and interface design; analyzing and utilizing possible control signals from electrocorticography (ECoG) in patients with epilepsy; evaluating stability of control signals from intracortical electrodes; and the development of wireless systems which will enable the next generation of neural prosthetic devices.
In adult human brain development, neurogenesis ceases at birth and the vast majority of areas in the adult mammalian brain no longer produce new neurons, even in the face of debilitating injury or disease. However, there are distinct exceptions to the rule. In rodents and humans, the hippocampus is one of the few areas where neurogenesis continues through adult life. Among other roles, the hippocampus is most well known as the area of the brain that mediates short-term learning and memory. Hippocampal function is affected in many diseases with grave human consequences. The two most common presentations of this dysfunction are memory deficits that accompany Alzheimer's disease and major depressive disorders. The fact that the addition/replacement of neurons uniquely occurs in the hippocampus suggests that neurogenesis itself plays a useful role within a pre-existing neural network. However, the mechanisms that regulate this process are not understood. Our research examines regions of adult brain where neurogenesis occurs to understand how the brain regulates and utilizes this ability to add or replace neurons.
The Stanford University Medical Center (SUMC) Neurosurgery Spine Laboratory studies the clinical outcomes and biomechanical properties of various dynamic stabilization devices to improve upon the traditional rigid devices currently in use. We analyze the biomechanical properties of these devices using human cadavers and our Material Testing System (MTS, Eden Prairie, Minnesota) along with a pressure transducer/strain scanner. Using these instruments, we study the intradiscal pressures (IDPs) at the level of the semi-rigid fusions, as well as the effects of the fusions on adjacent segment IDPs; the results have been favorable when compared with traditional rigid devices.
In addition to studying the clinical and biomechanical evaluations of semi-rigid stabilization systems, we are investigating the biomechanical properties of various artificial discs placed into human cadaveric spines. The MTS system has also been used for these studies. We have also begun preliminary research with human disc cells. Human disc cells are grown in cell culture with the goal of creating replacement discs formulated from the patient's own disc material. This type of disc may be superior to the artificial discs currently being used.
Dr. Giles Plant is the Basic Science Director of The Stanford Partnership for Spinal Cord Injury and Repair and has specialized expertise in spinal cord injury (SCI) research with a focus on cell-based transplantation therapies. Our laboratory aims to elucidate new cellular and molecular repair strategies that will improve functional and anatomical outcomes following SCI. We are currently investigating the following projects:
- Efficacy of human neural stem cells and induced pluripotent stem cell (iPS) lines to improve functional outcomes in cervical SCI
- Capacity of intraspinal and intravenous mesenchymal stem cells to improve functional outcomes in cervical SCI models in rats and mice
- Assessment of adult and embryonic olfactory glia capacity to induce axonal regeneration and myelination in the injured and demyelinated central nervous system (CNS)
- Endogenous stem cell responses within defined models of SCI, and
- Biomaterials for spinal cord injury.
The long term goals are to develop neuroprotective and regenerative translational protocols for human clinical treatments. It is hoped that patients will have improved motor, sensory and autonomic functions, as well as experiencing fewer secondary complications such as bladder and bowel dysfunction, autonomic dysreflexia, pain and spasticity; the ultimate goal is in improving the quality of life for patients with SCI.
Our research group explores using administrative databases to improve patient outcomes in spine surgery procedures. Presently the group is working on a prospective measure to assess the risk of complications in spine surgery procedures. I am studying the impact of patient disease process, choice of operative approach, and patient pre-operative comorbidities on complication occurrence. Collaborating with the Biostatistics and Health Research and Policy departments at Stanford, we are developing statistical models that may be used to predict adverse event occurrence and to assist in relative risk modelling.
The goal of this effort will be to develop a clinical tool that may be used to assess pre-operatively the risk of peri-operative adverse events given patient-, condition- and approach-related variables. This will contribute to patient counseling and may inform post-operative care in at risk patients.
Presently, a prospectively developed measure of comorbidities is being modeled to ICD-9 nomencature for use in the Nationwide Inpatient Sample and Marketscan databases. Our longer term research goals are to develop clearer means of assessing outcomes in spine surgery procedures and developing patient-centered outcomes assessments that may be scalable for larger populations. We hope to expand these investigations and modelling activities into other aspects of neurosurgery and also to other common surgical procedures.
The ultimate goal of my laboratory and research is to rapidly advance our understanding of normal brain function at the molecular, cellular, circuit, behavioral and functional levels, and to elucidate the pathological process underlying malfunction of the nervous system following injury and neurologic disorders such as stroke, Alzheimer’s disease and autism. Our fundamental goal is to improve the quality of life for patients with brain disorders. We are aiming to probe and understand the process leading to the functional and behavioral malfunction in these disorders focusing on a set of target genes/proteins which we have discovered to be regulated in brain in the context of these disorders. We are using automated behavioral and functional methods and endpoints in the experimental and transgenic rodent models in conjunction with experimental therapeutic approaches such as small molecule therapeutics and stem cells delivery methods in order to manipulate the loss of function in these experimental models.
The Stanford Partnership for Spinal Cord Injury and Repair (SP-SCIR) is a consortium between members of the Department of Neurosurgery and the Spinal Cord Injury Units at the VA Palo Alto Health Care System and the Santa Clara Valley Medical Center. It aims to restore function after spinal cord injury by investigating the mechanisms underlying a traumatic spinal cord injury, developing novel methods of repair and regeneration, and maximizing quality of life with bioengineering and technology such as neural prostheses. Internal research collaborators include the Departments of Anesthesiology, Chemical and Systems Biology, Comparative Biology, Electrical Engineering, Materials Science and Engineering, Neurology and Neurological Sciences, and Orthopaedic Surgery. External research collaborators include the University of California San Francisco, Case Western Reserve University, the University and Federal Institute of Technology (ETH) Zurich, the Universities of Oxford and Cambridge, Harvard University, University of California Irvine and University of Western Australia.
My research focuses on screening strategies to identify and characterize cancer stem cells (CSCs) in human gliomas. We are pursuing this in several ways: 1) a novel colony-forming antibody live cell array to identify distinct CSC surface phenotypes, 2) RNAi screens to identify kinases critical for CSC tumorigenicity, 3) high throughput small molecule and chemical screens to identify compounds that selectively kill or target CSCs, and 4) identifying CSCs using the tumor specific EGFRvIII.
Stanford Neuromolecular Innovation Program (SNIP) is an interdisciplinary research initiative that brings together clinical experts in Neurosurgery and Neurology with leading basic scientists in the fields of Genetics, Biochemistry and Bioengineering. SNIP’s goal is to develop and implement new technologies to improve the diagnosis and treatment of patients affected by neurological conditions. Fundamentally, SNIP strives to provide better and more effective patient care.
The long-term goal of the research in my lab is to discover treatments to restore function following spinal cord injury, either by manipulation of transplanted stem cells or by activation of endogenous progenitors. Corticospinal motor neurons are the brain neurons that control the most precise aspects of voluntary movement. They send long axons down the spinal cord, and injury to these cells is central to paralysis in spinal cord injury. Future regeneration strategies are limited by the current understanding of the development of corticospinal motor neurons from stem cells, as well as of the response of these neurons to spinal cord injury. Understanding at the molecular level how corticospinal motor neurons normally develop, and how they respond to spinal cord injury, will enable enhancement of regeneration, either via transplantation of cells such as induced pluripotent stem (iPS) cells or by activation of endogenous stem or progenitor cells.
Our laboratory is particularly interested in microRNAs—small non-coding RNAs that simultaneously regulate the expression of multiple genes— and seeks to identify microRNA controls both over corticospinal motor neuron development and over these cells’ response to spinal cord injury. We have identified several microRNAs that appear to be differentially expressed during corticospinal motor neuron development, and may play a central role in this process. We are testing the ability of these microRNAs to alter the fate of progenitor or stem cells and turn them into corticospinal motor neurons. Building upon those developmentally regulated microRNAs, we are also investigating their specific roles in spinal cord injury, and their possible roles in recovery.
Mitochondria move and undergo fission and fusion in all eukaryotic cells. The accurate allocation of mitochondria in neurons is particularly critical due to the significance of mitochondria for ATP supply, Ca++ homeostasis and apoptosis and the importance of these functions to the distal extremities of neurons. In addition, defective mitochondria, which can be highly deleterious to a cell because of their output of reactive oxygen species, need to be repaired by fusing with healthy mitochondria or cleared from the cell. Thus mitochondrial cell biology poses critical questions for all cells, but especially for neurons: how the cell sets up an adequate distribution of the organelle; how it sustains mitochondria in the periphery; and how mitochondria are removed after damage. The goal of our research is to understand the regulatory mechanisms controlling mitochondrial dynamics and function and the mechanisms by which even subtle perturbations of these processes may contribute to neurodegenerative disorders.
The goal of this laboratory is to define targets for cancer therapeutics by identifying alterations in signal transduction proteins and then translate these findings into important clinical tools, including one of the first effective peptide vaccines against cancer. The major type of cancer that we study is glioblastoma multiforme, the most common and devastating of the human brain tumors, but this work has also had implications for lung, breast, ovarian and prostate cancers.
My lab mainly studies the protective effect of postconditioning against stroke. Reperfusion (the restoration of blood flow) is one of the first choices for ischemic stroke treatment. However, reperfusion can also cause overproduction of reactive oxygen species (ROS) or free radicals that lead to reperfusion injury. Limiting the damage caused by reperfusion is a key issue for stroke treatment. We were the first to demonstrate that interrupting the early hyperemic response after reperfusion reduces infarction after stroke, a novel phenomenon called postconditioning. Since postconditioning is performed after reperfusion, it has great potential for clinical application. In addition, we also study protective effect of preconditioning and mild hypothermia. The rationale for studying three means of neuroprotection is that we may discover mechanisms that these treatments have in common. Conversely, if they have differing mechanisms, we will be able to offer more than one treatment for stroke and increase a patient's chance for recovery.