SINTN Op Plan Final4

8/9/2019 SINTN Op Plan Final4

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Stanford Institute for Neuro-Innovation and Translational Neurosciences

SINTN

Exploring and Promoting Innovation to Understand, Protect, and Repair the Brain and Spinal Cord

Institute for Neuro-Innovation

& Translational Neurosciences


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Executive Summary

The major goal of the Stanford Institute for Neuro-Innovation and Translational Neurosciences (SINTN) is torapidly advance our understanding of normal brain and spinal cord function at the molecular, cellular and neuralcircuit level, and to elucidate the pathological processes underlying malfunction of the nervous system followinginjury or neurologic and psychiatric diseases. SINTN will pioneer techniques to probe and manipulate nervoussystem function with the aim of accelerating the translation of these new discoveries into novel therapeuticapproaches that improve the quality of life for patients with disorders of the brain and spinal cord.

SINTN will pursue these goals by creating technological innovations and targeting research areas that offerthe opportunity for fundamental shifts in our understanding of normal brain function and in the treatment of

pathological brain function. Through the establishment and support of speci c initiatives, programs and cores, theinstitute will foster a culture of collaboration among leading basic, translational and clinical neuroscientists, whotogether will revolutionize the study and treatment of brain disorders.

Director: Gary Steinberg, MD, PhDCo-Director: Rob Malenka, MD, PhDProgram Director: Mehrdad Shamloo, PhDExecutive Committee:

Ben Barres, MD, PhD (Dept of Neurobiology)Karl Deisseroth, MD, PhD (Depts of Bioengineering and Psychiatry)Frank Longo, MD, PhD (Dept of Neurology)Robert Malenka, MD, PhD (Dept of Psychiatry)Susan McConnell, PhD (Dept of Biological Sciences)Mehrdad Shamloo, PhD (SINTN)Krishna Shenoy, PhD (Depts of Electrical Engineering and Bioengineering)Gary Steinberg, MD, PhD (Dept of Neurosurgery)


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Neural Plasticity and Repair

I. Neural Plasticity and Repair

Individual brain functions are mediated by complex interactions between many thousands of brain cells thatare organized into overlapping assemblies termed neural circuits. When functioning properly, these circuitsallow us to see, feel, learn, remember and create. When neural circuits do not function properly, brain disordersas symptomatically diverse as chronic pain, addiction, Parkinson’s disease, schizophrenia and Alzheimer’sdisease occur. The most remarkable feature of neural circuits is that they are not static but change in responseto experience—they are “plastic.” This plasticity occurs in large part because the communication processes thatoccur between nerve cells at synapses also are not static, but change in response to the brain activity generated byan experience. The electrical properties of nerve cells themselves are also plastic, as are the physical connections

between nerve cells. Understanding the detailed genetic and molecular mechanisms that underlie these variousforms of plasticity, and thus the plasticity of neural circuits, will provide key insights into how we learn andremember, and how these processes malfunction in psychiatric and neurologic disorders. This knowledge willalso allow us to develop novel strategies for taking therapeutic advantage of plasticity mechanisms to repairdamaged and malfunctioning neural circuits in brain diseases.

Overall Strategic Goals:

Achieve a detailed understanding of the molecular mechanisms underlying neural circuit plasticity• .

Track changes in the activity and structure of neural circuits in human brain disease.•

Develop methods to harness the power of brain plasticity to repair damaged and diseased neural circuits.••

Programs:

Parkinson’s Disease and Movement Disorders Program

Parkinson’s disease (PD) is a devastating, progressive disorder that affects an estimated 1.5 million Americans.Although we understand the basic cause of PD (the death of dopamine-producing brain cells in a small area of the

brainstem called the substantia nigra) we still have no cure. We also have only an imperfect understanding of thecircuit disruptions that cause symptoms such as tremor, hesitancy, and balance problems. The Parkinson’s Diseaseand Movement Disorders Program at Stanford brings together personnel from multiple departments includingneurology, neurosurgery, bioengineering and neuroscience in a tightly-knit collaborative structure to provide bothoutstanding clinical care and groundbreaking research in Parkinson’s disease and other movement disorders.

The team is involved in leading-edge investigation at multiple levels, from basic science in the laboratory, to


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translational research in the operating room, to clinical trials of new therapeutics. It will continue to pursuethe many ongoing projects aimed at unlocking the mysteries of PD and exploring state-of-the-art treatments.Laboratory studies exploring the basic mechanisms of deep brain stimulation (DBS) using sophisticated techniquesthat combine light-sensitive ion channels and beroptic light guides, have led to fundamental insights into theconnections and function of the neural circuits that malfunction to cause PD. In Stanford’s “OR as laboratory,” localelectrical recordings during DBS have revealed abnormal oscillations in the 20-30 Hz frequency band, which arehypothesized to play a major role in the genesis of Parkinsonian symptoms. With the seminal development of the“Parkinson’s in a Petri dish” model, cultures of skin cells derived from Parkinson patients can be made to exhibitParkinsonian characteristics, allowing experiments that would be impossible to perform in patients or animals. Inthe clinical arena, Stanford will soon begin trials of a gene therapy protocol for Parkinson’s treatment, introducinga speci c gene into subthalamic nucleus neurons with an adeno-associated viral vector, thus producing inhibitionin this area, which is usually overactive in Parkinson’s disease.

Objectives:

Investigate the basis of normal and abnormal movement, speci cally focusing on Parkinson’s disease,•

emphasizing multiple levels of analyses: from molecules to cells in culture, to circuits composed ofnetworks of neurons, to patients in the operating room and in the clinics.

Develop novel therapeutic interventions using preclinical models, applied engineering techniques and•

methods of computational neuroscience.

Participate in pilot studies and multi-center trials of novel treatments, such as electrical and optical•

stimulation, gene therapy, and stem cell transplantation.

Pain and Addiction

Chronic pain affects hundreds of millions of people worldwide. It is a primary complaint resulting in physicianvisits and health care resource utilization, costing over $100 billion annually. Additionally, pain has a signi cant

impact on individuals and their families, affecting functionality and quality of life in ways that are dif cult tomeasure and value monetarily. Similarly, drug addiction is a chronic, relapsing medical illness with devastatinghealth and societal consequences. Extensive research at both the clinical and basic science levels has revealed that

both disorders are due to the aberrant functioning of speci c neural circuits that share speci c components. Thisexplains why so many of the drugs that are abused have analgesic properties (e.g. nicotine, heroin, cocaine andcannabinoids) and why many of the analgesics commonly used to treat pain have abuse potential (e.g. opioids).Additionally, both disorders involve the development of tolerance and dependence, often to the very samesubstances. The proximate causes of both disorders are also largely known. Trauma, infection or in ammationcause adaptive changes in speci c spinal cord and brain circuitry, known as “plasticity”. For reasons that remainunclear, in certain individuals this plasticity becomes long-lasting, leading to chronic pain syndromes. In drugaddiction, drugs of abuse target speci c molecular targets in the brain, leading to plasticity in most of the same

brain circuits that function pathologically in pain syndromes. In susceptible individuals, these plasticity changesalso become very long-lasting, leading to a chronic course of remission and relapse that characterizes addiction.

The goal of this program is to develop a comprehensive systems-neuroscience understanding of the central plasticity changes underlying the causes of, and potential therapies for, chronic pain syndromes and addiction.This approach will integrate detailed genetic, molecular, cellular, circuit-level, behavioral and epidemiologicinformation that together will explain the neural basis of chronic pain syndromes and addiction. A multidisciplinarycadre of Stanford investigators will work in both animal models and patients, using state-of-the-art molecular,electrophysiological, microscopic and human brain imaging techniques. A major focus of the research will beto understand the changes in those circuits in which pain is perceived and processed and those that mediate the


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rewarding properties of drugs of abuse. In addition, we will explore the circuits that mediate the craving that patients experience when they no longer have access to their favorite drug or medication.

A major strength of this program is that results from animal and human studies can be directly compared. As theneural circuit plasticity that mediates pain and addiction is being elucidated, Stanford investigators will also beexploring novel approaches to prevent or reverse these changes. The ultimate aim of this program is to translatethese research ndings into more effective and tailored treatments for pain and addiction, and into early therapeuticinterventions that will prevent their very occurrence.

Objectives:

Develop accurate rodent and human models of chronic pain syndromes and addiction.•

Use the animal and human models, along with studies in patients, to better understand the molecular•

events and neural circuit plasticity that lead to the development of chronic pain and addiction.

Apply new scienti c discoveries to develop innovative treatments for these disorders in animal and•

human models and translate those experimental treatments into therapy for patients.


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II. Neurodegeneration and Regeneration

Diseases such as spinal cord injury, macular degeneration, amyotrophic lateral sclerosis (ALS), stroke, Alzheimer’sdisease, and Huntington’s disease are caused by the degeneration of speci c cells in the brain and spinal cord.Advances in molecular genetics and cell biology have revealed some of the detailed pathophysiological processesunderlying the loss of neurons in these devastating brain disorders, thus opening the door for possible therapeuticinterventions. This initiative will support research on furthering our understanding of the molecular and cellularmechanisms that cause neurodegeneration, as well as efforts to develop approaches that will both preventdegeneration and promote regeneration.


Support basic research on understanding the acute and chronic mechanisms underlying•

neurodegenerative disorders.

Develop novel methods to prevent damage to the brain and spinal cord resulting from degenerative•

disease.Pioneer innovative strategies to regenerate and repair the central nervous system and restore neurologic•

function after injury and during neurodegenerative disorders, using human stem cell transplantation,small molecules and neuroprosthetics.

Programs:

Stanford Partnership for Spinal Cord Injury and Repair

Spinal cord injury (SCI) can cause catastrophic disability. But it also offers unique opportunities for research. SCIaffects over 2 million people worldwide, including at least 250,000 in the United States. The cost to our nation’seconomy from spinal cord injury is well over $9.7 billion, while the full human cost is beyond calculation:education, career, marriage, and independence are disrupted and sometimes never restored. In addition, manyother patients suffer spinal cord dysfunction related to degenerative spine disease, spinal cord demyelination(such as multiple sclerosis), spinal tumors and vascular malformations.

Through the establishment of the Stanford Partnership for Spinal Cord Injury and Repair, SINTN will providea broad base for collaboration in this area by promoting interactions between preclinical research and clinicaldevelopment of novel therapies. Its speci c tasks are to advance understanding of the mechanisms underlyingdamage to the spinal cord, to accelerate development of novel methods of repair, to explore innovative strategies

Neurodegeneration andRegeneration


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to restore function after injury, and to translatethese discoveries into enhanced quality-of-life for those with spinal cord injury anddysfunction.

The partnership will encompass the effortsof a community of basic neuroscientists,translational neuroscientists, and clinicians.Basic neuroscientists will work on multipletopics including the molecular mechanismsunderlying axonal guidance and growth,axonal myelination and re-myelination, and theanatomy and physiology of spinal cord circuitry.Translational neuroscientists will develop andstudy animal models of SCI, which will beinvaluable not only for elucidating the detailed

pathophysiological mechanisms underlyingvarious types of SCI, but also for developing

and testing novel treatments. A core facility that provides Stanford investigators with training inthe generation of these models will be criticalfor the rapid translation of basic science ndingsinto advances in our understanding of the pathophysiology and treatment of SCI. Finally, the partnership will

bene t enormously from close interactions with SINTN’s neuroengineering initiative, the Stanford Institute forStem Cell Biology and Regenerative Medicine and, most important, from the clinicians performing researchand providing treatment at the Spinal Injury Units of the VA Palo Alto Health Care System and the Santa ClaraValley Medical Center. We anticipate that the Stanford Partnership for Spinal Cord Injury and Repair will rapidly

become one of the world leaders in developing innovative approaches to the treatment of SCI.

Objectives:Explore fundamental pathophysiological mechanisms underlying acute and chronic spinal cord injury.•

Develop novel methods to repair the spinal cord after injury and to promote recovery of function.•

Lead the development of clinical trials for spinal cord injury treatments, including stem cell•

transplantation, spinal cord stimulation and neuroprosthetics.

Stanford Center for Vision and Blindness Prevention

Blindness and low vision affect more than 160 million people worldwide, frequently with devastating impact onthe quality of life and livelihood. The annual total nancial burden of major adult visual disorders in the UnitedStates is an estimated $35.4 billion. The Stanford Center for Vision and Blindness Prevention is a leader invision research and care, with key discoveries by members of the Departments of Biology, Engineering, Genetics,

Neurobiology, Ophthalmology and Psychology. In addition to investigating basic mechanisms of vision, visual pathways, and visual cognition, the Stanford Center for Vision and Blindness Prevention focuses on major causesof vision loss, including macular degeneration, glaucoma, infectious and degenerative corneal diseases, ischemicand in ammatory optic neuropathies, diabetic retinopathy and retinopathy of prematurity. Central nervous systemdiseases with signi cant visual involvement are also studied, including those with neurodegenerative, neoplastic,ischemic, in ammatory and hereditary causes. An important focus of the center is understanding the development


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of the visual system and the treatment and prevention of childhood visual disorders, including congenital cataract,strabismus, amblyopia and reading disorders. SINTN scientists and clinicians make fundamental discoveries andtranslate them rapidly toward diagnosis and treatment in order to ameliorate vision loss and prevent blindness.

The prevention of blindness starts with an appreciation for the neurons, circuits, and physiology that underlievision. Basic science research in vision at Stanford tackles issues such as developmental patterning of the eye andvisual circuitry, synaptic plasticity of the visual pathway, retinal and visual processing, visual object recognitionand reading, and visual-motor integration. Clinician scientists study mechanisms of disease including infection,in ammation, ischemia, genetic abnormality and aging. They utilize state-of-the-art tools for both investigationand therapeutic intervention of vision loss, including gene modi cation, stem cell implantation, imaging of ocularand brain visual structures with functional brain imaging, as well as modern tools of physics, chemical engineering,retinal prosthesis and nanotechnology. The goal is not only knowledge, but the translation of knowledge intodevices, diagnostic procedures and therapeutic approaches that will treat and prevent blindness.

Objectives:

Delineate the basic cellular mechanisms and brain systems underlying vision.•

Understand the genetics and etiology of visual dysfunctions using techniques ranging from genomics to•

imaging.Identify and develop effective treatment approaches to diseases that affect any components of the•visual system, utilizing pharmacology, microsurgery, prosthetics, regenerative medicine, and other newtechnologies.


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III. Neurobiology of Cognitive and Developmental Disorders

The development of the brain is one of nature’s most remarkable accomplishments, involving a complex arrayof genetic mechanisms that are modi ed by environmental in uences during infancy and childhood. Whenneurodevelopmental processes go awry, brain disorders ensue. These brain disorders routinely involve de cits

in many different cognitive functions, ranging from problems with learning and memory to de cits in socialcognition and the ability to recognize and interpret normal social cues. Among the most common of such cognitiveand developmental disorders are autism spectrum disorders (ASDs), which affect 1 in 150 children. Additionalrelated disorders include Down syndrome, Rett syndrome and Fragile X syndrome, all of which share clinicalfeatures with ASDs. Advances in human molecular genetics have identi ed mutations in individual neuronalgenes that predispose children to ASDs or, in the case of Fragile X and Rett syndromes, cause the disease. Themajor goal of this SINTN initiative is to take advantage of these genetic ndings and delve deeply into thedetailed mechanisms that underlie cognitive/developmental disorders with the goal of developing and testingnovel, more ef cacious treatments. The combination of Stanford’s outstanding basic neuroscience communitywith its outstanding clinical investigators, all of whom are focused on understanding the biological mechanismsthat lead to cognitive and developmental disorders, makes Stanford uniquely positioned to make rapid progressin this critical research area.

This initiative will bring together a diverse group of outstanding neuroscientists working on multiple levels ofinvestigation. Genetic analyses of patients have already led to the identi cation of mutant gene products thatare associated with various cognitive and developmental disorders. These genetic ndings, in turn, lead tothe development of animal and cell-based models that are actively being studied at Stanford using innovative

basic science approaches, including electrophysiology, structural and functional imaging, molecular/geneticmanipulations and behavioral assays. A complementary and equally important on-going effort involves usingstate-of-the-art techniques to obtain skin cells from patients, turn those cells into neurons, and study the problemsthese neurons have in forming synapses and circuits. By comparing normal and diseased brains in both modelsystems and humans, we will delineate disease pathophysiology and identify novel targets for the developmentof better drug treatments.


Achieve a detailed understanding of the mechanisms underlying the neural circuit dysfunctions that are•

responsible for cognitive and developmental disorders using both animal models and human studies.

Identify potential novel drug targets for the treatment of these disorders.•

Develop and test new therapies.•

Neurobiology of Cognitiveand Developmental

Disorders


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Programs:

Down Syndrome Research Center

The incidence of intellectual disability is about 1-2% in western countries. In about three-fourths of theseindividuals, one of several hundred single gene disorders is the cause; the remainder is due to chromosomalabnormalities, malnutrition, fetal alcohol exposure or brain injury. One of the most common, Down syndrome,has been found in 1 of every 700 live births. Although there has been a profound interest in nding potentialtreatment strategies to improve the quality of life for individuals af icted by these disorders, few if any treatmentshave emerged. This is largely due to lack of a coherent understanding of basic cellular, molecular and systemicchanges in neuronal circuitry, and of the mechanisms of synaptic plasticity which underlie the acquisition,storage and processing of information in these disorders. The Stanford University Down Syndrome ResearchCenter will use its partnership with SINTN to build strong interdisciplinary collaborative research programsaimed at advancing our understanding of the mechanisms causing intellectual disabilities in individuals withDown syndrome, identifying commonalities with related neurodevelopmental and neurodegenerative disorders,developing strategies to normalize behavioral and cognitive function, and translating these discoveries into viabletherapies that can improve the quality of life for individuals with intellectual disabilities.

The partnership with SINTN and the process of nding solutions to intellectual disabilities will engage and supportan expanding community of neuroscientists and clinicians focused on issues of neurodevelopmental disorders.Consortiums of basic neuroscientists will work on a variety of topics relevant to the neurological, behavioral andcognitive impairment associated with Down syndrome. This work will include the development of animal modelsof Down syndrome, the analysis of the changes in neuronal circuits and synaptic plasticity mechanisms associatedwith the emergence of cognitive impairment during early stages of brain development, as well as the age-relatedloss of brain function in the third decade of life, which is linked to the appearance of early onset Alzheimer-like

pathologies. Similarly, groups of translational neuroscientists will work to develop relevant biometrics for rapid,reliable assessment of cognitive function and the evaluation of potential therapeutic strategies. A core animalfacility will provide investigators with a reliable source of genetically de ned mouse models of Down syndrometo accelerate research programs and facilitate the generation of new animal models. Finally, working closely withclinical faculty, the partnership will foster translational programs that will evaluate the effectiveness of treatmentstrategies designed to normalize hypotonia, sleep disturbance, cognitive and psychiatric related disorders and age-related dementia in individuals with Down syndrome.

Objectives:

Support basic research on reliable animal models to understand the mechanisms underlying reduced•

cognitive function.

Develop non-invasive biometrics for the assessment of cognitive function, and therapeutic strategies that•

can lead to a recovery of function.

Conduct clinical trials.•

Neurobiology of Autism Spectrum Disorders

Autism is a set of developmental disorders that affects more than a million children in the US. It is characterized by dif culty in acquiring language, repetitive movements, limited interests, and social and cognitive dif culties.Autism costs billions of dollars to treat and exacts a large toll on patients, families and educational systems. Eventhough autism is common, we know very little about its causes, and our behavioral and medical treatments are stillwoefully inadequate. During the last two decades, autism research has focused mainly on the discovery of genes


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that contribute to autism spectrum disorders (ASDs). Despite the identi cation of many susceptibility genes,little is known about possible neural mechanisms or pharmacological treatments. A coordinated effort is neededto explore the pathological links between mutations in identi ed autism susceptibility genes and alterations inneuronal physiology, neural circuits and behavior. A network of scientists and clinicians at Stanford are making acoordinated effort to elucidate the pathophysiological mechanisms of autism and to generate relevant preclinicalanimal models to facilitate the understanding and treatment of this devastating disorder.

Stanford scientists will take several approaches to understand the neural circuit dysfunctions that cause autism.Taking advantage of the discoveries involving the genetic causes of autism, the researchers will generate animalsexpressing the same genetic abnormalities and study them at the molecular, cellular, circuit and behavioral levels.Such animal models provide a unique way of connecting defects in genes with defects in neuronal circuits and

behavior, and will provide important clues as to how genetic abnormalities lead to faulty brain development andmaladaptive brain functions. Secondly, Stanford scientists have developed a new approach for acquiring skincells from children with autism and converting them into neurons. This method is allowing scientists, for the

rst time, to study neurons from patients with neurodevelopmental disorders in a controlled laboratory setting sothat aws in how those cells behave and wire together can be studied and corrected. Thirdly, Stanford scientistsare directly studying patients with autism spectrum disorders using state-of-the-art brain imaging techniquescombined with genetic analysis and treatment protocols. This will allow ndings from the preclinical studies using

animal models and neurons generated from patient’s skin cells to directly in uence studies of brain function in patients. Thus, Stanford is uniquely positioned to use comprehensive, multidisciplinary approaches to furtheringour understanding of the neurobiological basis of autism spectrum disorders. This will lead to the development ofnovel hypotheses and therapeutic approaches, which will also be tested in clinical trials at Stanford.

Objectives:

Develop novel approaches for understanding autism pathophysiology, such as studying the role of•

speci c mutations, generating novel animal models, and creating neurons from patients’ skin cells.

Elucidate the molecular, cellular and circuit defects in animal models of autism and in the patient-•

derived neurons, and use this information with that obtained from human studies to nd new

pharmacological therapies.Test novel therapies in animal models and use the results to initiate clinical trials.•


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IV. Neuroengineering

Major advances in molecular biology and bioengineering, combined with improved understanding of how neuralcircuits mediate behavior, has made it possible to manipulate brain function in ways that were unimaginable asrecently as a decade ago. This initiative encompasses a range of programs with the common goal of developinginnovative techniques and strategies for manipulating brain circuits in the human brain therapeutically to alleviatethe symptoms and suffering caused by brain disorders. The methodologies used will vary across a broad spectrumof approaches, ranging from the expression of genetically encoded ion channels activated by light to brain-computer interfaces, to the use of neural stem cells for replacing damaged tissue. While therapeutic interventionwill continue to be a mainstay of treatment for many brain disorders, SINTN’s support of neuroengineering

programs promises to help revolutionize how we treat brain disorders while also providing tools with which wecan continue to improve our understanding of how neural circuits mediate brain functions.


Promote the development and application of novel methodologies for the manipulation of neural circuit•

activity in the intact brainApply these methodologies therapeutically in patients•

Programs:

Brain-Computer Interfaces

Millions of people suffer from paralysis due to neurological injury and disease. Christopher Reeve was a primeexample, as he suffered an upper spinal cord injury and was never again able to walk, move his arms, or evenspeak clearly. Despite substantial research focused on repairing damaged neural cells, there remains no meaningfulway to help these patients. Over the past few years an alternative approach that effectively bypasses the injuryhas been developed and signi cantly advanced at Stanford. By reading out electrical activity from hundreds ofneurons in the brain, and using mathematical algorithms to convert this brain activity into control signals, it is

possible to guide prosthetic arms to help restore movement and computer cursors to help restore communicationand interaction with the world. These revolutionary new medical systems are termed Brain-Computer Interfaces(BCIs), Brain-Machine Interfaces (BMIs), or cortical neural prostheses.

To date, this research has been conducted primarily in animal models. We are currently poised to rapidly move theseexciting new medical systems into human clinical trials. The major objective is to provide a patient who is losingthe ability to communicate with a computer that can be controlled by thought alone. This system will convert the

Neuroengineering


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neural impulses associated with the desire to move the arm into keyboard strokes and mouse movements, therebyrestoring the ability to communicate and interact with the world . In numerous laboratory experiments, Stanfordscientists have demonstrated innovations such as accurate decoding of movement intent and the ability to move acomputer cursor by thought control more quickly than an arm could move. We are in an ideal position to turn thisworld-record performance in the laboratory into real-world gains for paralyzed patients.

Objectives:

Perform the rst long-term human brain-computer interface implant on the West Coast.•

Implement proven laboratory protocols to provide world-record performance for computer cursor•

movement and typing.

Develop next-generation systems for interfacing brain signals to computers.•

Neuromodulation and Interventional Neuroscience at Stanford (NINS)

Diseases of the human brain present major therapeutic and conceptual challenges due to the lack of appropriately powerful and speci c technology to intervene in brain functioning. In this clinically-oriented collaborative effort,Stanford engineers, neuroscientists, and physicians will develop, validate, and apply powerful and speci c newtechnologies for probing and tuning brain circuits, with outcomes that will reverberate through applied neuroscienceand throughout clinical elds ranging from depression to Parkinson’s Disease. Recent advances, including manyat Stanford, have opened the door to fundamentally new strategies for tuning and modulating brain function,

including the use of light (optogenetics), ultrasound (HIFU),magnetic elds (transcranial magnetic stimulation or TMS),ionizing radiation (CyberKnife), and radiofrequency (RF)modalities of energy delivery. The NINS team will capitalizeon these advances and the unique positioning of Stanford tofocus on technology development for both applied scienceapplications and for clinical translation.

Two examples (optogenetics and ultrasound) provide anillustration of the power of new neuromodulation techniques.Optogenetics employs genetically encoded proteins that can

be activated or inhibited by light, providing unprecedented power to turn on and off targeted sets of cells in the intact brain, and to do so remotely. This powerful methodologywill be used to probe the neural circuit dynamics thatunderlie adaptive brain functions as well as the neuralcircuit dysfunctions that are responsible for brain disorders.

Ultrasound, in contrast, delivers mechanical and thermalstimulation in a way that can excite or inhibit cells, andcan be depth-focused to provide a speci city that may befurther enhanced with novel receptors. An integrated team

of engineers, neuroscientists, and clinical neurologists, neurosurgeons, and psychiatrists will expand Stanford’sefforts in the use of these brain stimulation methods to treat brain disorders. These efforts will not only providenovel treatments for patients whose symptoms are not responsive to medications, but will also allow unparalleledopportunities to explore fundamental neurophysiologic questions about the diseases and circuits that are treated.


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Objectives:

Support theoretical work for design of novel strategies in energy deposition to neural tissue for•

therapeutic neuromodulation purposes (ultrasound, radiation, light, TMS, RF).

Develop and test new energy delivery reagents and hardware with intact-tissue systems (e.g. cultured•

neurons or tissue slices) in order to map stimulus space and re ne devices.

Support preclinical testing and validation of key new depth-targeted energy modalities, with suitable•

readouts (temperature, electrical activity, MRI BOLD, calcium, voltage, or behavior).Lead the development of clinical trials at Stanford to implement new neuromodulation technologies with•

rigorous scienti c justi cation, beginning with proof-of-principle studies (e.g. motor cortex activation orinhibition) and moving rapidly to disease circuit targeting.

Stem Cells, Tissue Engineering and Neurotransplantation

During development, stem cells orchestrate the formation of the entire human organism. As an individualmatures, stem cell function switches from tissue genesis to tissue maintenance and stem cells become increasingly

specialized within each organ system. Stem cells are abundant in the nervous system but, for reasons that are notwell understood, tissue repair signals do not instruct these cells to restore the complex neural circuitry that isformed during development. In experimental models, adult stem cells transplants reveal that these cells are capableof creating new neural networks in the developing brain. This suggests that the signals provided to the stem cellduring adult tissue repair are not instructing the stem cells to regenerate lost circuitry. Curiously, there are twosmall regions in the adult brain where stem cells are instructed to make new neurons, and this anomaly is beginningto provide insights into strategies for repairing the adult brain. A major goal of this program is to discover thesignals used in the developing brain as well as these unique “neurogenic” adult brain regions to understand howstem cells can be directed to generate new neurons for regeneration and repair. A second major goal is to studythe detailed properties of new neural stem cell lines as they become available, and to use these for the repair ofdamaged brain tissue. Preclinical investigations have suggested that transplanted neural stem cells restore functionafter brain injury or disease by enhancing endogenous mechanisms of plasticity and repair, including nativeneurogenesis, gliagenesis, vasculogenesis, synaptogenesis, axonal sprouting, dendritic branching and attenuationof the in ammatory response. These improved mechanisms of recovery may be secondary, in part, to release

of growth factors, trophic factors andneurotransmitters from the transplantedneural stem cells.

This cross-disciplinary research andtranslation program partners investigatorsin many disciplines including physics,engineering, materials sciences, biology,genetics neuroscience, and clinicalresearch. Many of the team investigatorshold joint appointments within bothSINTN and the Stanford Institute forStem Cell Biology and RegenerativeMedicine. The team will pursuefundamental investigations that identifythe precise signals that make stem cellsreplicate, migrate to sites of tissue repair,and differentiate into functional neurons


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or other regenerative cell types. The ultimate goal of this translational research is to apply new discoveries to patients. Indeed, Stanford scientists working in collaboration with industry partners have already demonstratedthat human neural progenitor cells can be produced in culture, cryopreserved, and safely implanted into the brainsof stroke patients. Although this past study was designed primarily to test safety and feasibility, ongoing studiesare examining the improvements observed in some patients to determine if stem cells can contribute to improvedmotor, sensory or cognitive function. Additional applications are being developed for patients with spinal cordinjuries, Parkinson’s disease, radiation-induced brain damage, fetal brain damage, and many other conditions.By combining sophisticated, state-of-the-art basic science approaches to understanding the basic biology of stemcells with strong translational and clinical research, this program will lead the way in the application of stem cell

biology to ef cacious therapeutic interventions.

Objectives:

Perform experimental neurotransplantation studies to determine the most effective cell type for•

transplantation in a given disease or injury, the optimal timing and location of transplantation, and themechanisms of neurologic recovery after transplantation.

Apply novel molecules, proteins, drugs, anti-in ammatory agents, growth factors and other agents•

to enhance the survival and bene cial effects of endogenous or transplanted neural stem cells in

experimental models of CNS disorders.Undertake bridging studies to translate these novel experimental concepts to clinical trials and ultimately•

to establish a new era in cell-based clinical therapies for disorders of the CNS.


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V. Neuroscience and Society

The initiatives and programs sponsored by SINTN promise to produce abundant new knowledge on brain functionand novel ways of manipulating brain function. Because the brain mediates all human behavior, the intellectualand technical output of SINTN has the potential to profoundly in uence many areas in society ranging from

the practice of medicine and the law to our understanding of the basis of social cooperativity and con ict. It istherefore imperative that SINTN sponsor an initiative that will attempt to place the latest advances in basic andclinical neuroscience into the broader context of society. Indeed, modern neuroscience research sponsored bySINTN has the potential to change our understanding of human nature itself, and the way human beings withincomplex societies interact.


Explore and de ne the potential societal impact of new ndings and methodologies in neuroscience.•

Provide constructive feedback to private and government agencies regarding how new ndings and•

methodologies in neuroscience should be viewed and used.

Programs:

Center for Compassion and Altruism Research and Education (CCARE)

Although medical and cognitive sciences have been highly successful both in understanding the pathologiesof the human mind and in developing treatments, until recently, neuroscientists have largely avoided dealingwith complex behaviors such as moral cognition and those linked to altruistic behavior and compassion. In part,this has been due to the dif culty of objectively measuring and quantifying complex brain mechanisms. It has

been postulated that such behaviors involve the interconnection and integration of many neural circuits locatedin diverse locations within the brain. For example, it is known that there is an integration of contextual socialknowledge within the prefrontal cortex, social semantic knowledge within the anterior and posterior temporalcortex and basic emotional and motivational behavior within the cortico-limbic system.

To understand scienti cally why it is that humans behave in a compassionate or altruistic manner, or in contrastwhy they sometimes do not, requires a unique collaboration across a variety of disciplines, collaborations betweenthose who study the brain using objective measures and those who study the mind using rst-person subjectiveobservation (such as Buddhism and other contemplative traditions, which have a long history of investigationinto the nature of mind). Only recently has it been possible to envision a robust interface between these twoinvestigative approaches. Building ever stronger bridges between these investigative traditions, CCARE will

Neuroscience andSociety


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create a multi-disciplinary environment whereby compassion and altruism studies are supported and legitimizedwithin the broader scienti c community. CCARE participants will include neuroscientists performing human

brain imaging studies, cognitive psychologists, neuroeconomists, contemplative scholars and philosophers.Research will draw from varied disciplines – from etiological approaches that look at evolutionary roots to theneuroscienti c study of the brain mechanisms, and from philosophical and contemplative perspectives to cognitiveand social psychology as well as neuroeconomics. Through such diverse research methods, CCARE will strive togain a deep understanding of compassion and its associated human behaviors in all its richness.

Objectives:

Use rigorous scienti c methods to de ne the neural basis for compassion and altruistic behavior, and•

support collaborative research on compassion and altruistic behavior among a variety of disciplines, both nationally and internationally.

Create tools to potentiate feelings of compassion and altruism in individuals.•

Disseminate research ndings on an international scale using a number of media forums.•

Stanford Interdisciplinary Group on Neuroscience and Society (SIGNS)

Neuroscience is in the middle of a revolution that is transforming our understanding of the human brain, and thusof the human mind. This revolution will have implications far beyond basic science and medicine. Our societiesare built by our brains; deeper knowledge of those brains will affect education, law, business, government, andmany more parts of our social world. We are already beginning to see effects, from the commercial availabilityof fMRI-based “lie detection” to “neuro-marketing” consulting rms. The Stanford Interdisciplinary Group on

Neuroscience and Society (SIGNS) is an effort by a broad range of Stanford faculty and students to explore howadvances in neuroscience will affect human societies. Currently coordinated by Stanford law faculty, fellowsand students, the group thus far includes participants from ve of Stanford’s seven schools: Business, Education,Humanities and Sciences (particularly the Psychology Department), Law, and Medicine

Through workshops and discussions, SIGNS will build closer ties among Stanford scholars and students interestedin interdisciplinary research and education on the social consequences of neuroscience. It will immediately increasecommunication among interested faculty and students throughout the University. SIGNS will encourage theseinterdisciplinary efforts by supporting seminars, conferences, workshops, and courses. It will also disseminatediscussions and conclusions from these events via a variety of media outlets.

Objectives:

Promote communication and interdisciplinary work across the University among faculty and students•

interested in how neuroscience will affect society.

Support conferences, workshops, seminars, symposia, and courses on these subjects.•


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SINTN Enabling Core Facilities

A key function of SINTN is to provide facilities and services that will facilitate the efforts and productivity of a broad array of Stanford neuroscientists (faculty, postdoctoral fellows, students, and staff). One important way ofachieving this goal is to establish cores: staffed facilities providing services that individual investigators eithercannot provide themselves or that, when provided themselves, results in wasteful duplication of effort. SINTNcurrently has established two cores, with a third in the early planning stages.

Neuroscience Behavior Phenotyping and Pharmacology Core

Recent years have seen a vast increase in the generation of transgenic and knockout mouse lines, including thosethat model disease processes. Scientists need to be able to probe complex behavioral and cognitive issues in thesemice, yet few laboratories (even those that generate mouse mutants in large numbers) are equipped to assess indetail behavioral changes. Additionally, even well established rat models of neurologic disease or injury have not

always been well characterized in terms of reproducible behavioral outcomes. This facility provides expertiseand equipment to analyze mouse and rat behavior in ways that have great promise in identifying novel neuralsubstrates for the regulation of complex cognitive, emotional, perceptual, and sensory-motor behaviors.

Operational Goals:

Provide state-of-the-art behavioral and functional tools for studying cognitive and sensory/motor•

function in rodents.

Establish and perform behavioral and functional testing and expertise in an array of experimental rodent•

models of neurological and psychiatric disorders.

Enable neuropharmacological pro ling of CNS active compounds in ef cacy models.•

Neuroscience Imaging Core The Neuroscience Imaging Core provides access to high-end, capital-intensive microscopy equipment thatis generally not available in individual labs. As be ts a neuroscience microscopy facility, the majority of theequipment enables experiments that combine physiology and microscopy, enabling the collection of rich, spatially-and temporally-resolved data sets from living tissue. Particularly important is the fact that the facility will provideusers with initial training and on-site expertise in the proper use of the equipment to foster the collection ofmeaningful, high-quality data. The facility will also provide consulting services to assist in experimental design

Enabling Core Facilities


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so as to take best advantage of the available equipment

Operational Goals:

Provide training programs for users of the facility--both practical training on the instruments, and•

training seminars covering fundamentals of microscopy and image analysis.

Develop expertise to assist scientists with advanced microscopy and image analysis techniques such•

as, in vivo and in vitro 2-photon imaging, FRET techniques, array tomography image acquisition andanalysis and 3D image rendering.

Identify new microscopy and image analysis technologies that are of interest to and will bene t the•

Stanford research community.

Neuroscience Gene Vector and Virus Core

The delivery of recombinant genes into neurons is a critically important strategy for understanding the molecularmechanisms underlying all brain functions, as well as for understanding how these mechanisms go awry in braindisorders. A complementary and equally important strategy is delivery of inhibitory RNAs to eliminate or reducespeci c brain proteins. Genetically engineered viruses provide powerful tools for introducing these constructs into

brain cells. Indeed it is now possible, using a single virus particle, to both eliminate speci c proteins and replacethem with modi ed versions in speci c subsets of cells in the brain. It is also possible, using viruses, to express

proteins that will allow precise control over the electrical activity of individual nerve cells. These virally mediatedmolecular manipulations allow unprecedented experimental control over synapses, cells and circuits in modelsystems as well as in vivo in the mammalian brain. To facilitate the use of these state-of-the-art methodologies

by Stanford neuroscientists, this core will centralize the process of producing and distributing viral vectors andcDNA plasmids. This will bene t SINTN’s overall mission by preventing the duplication of efforts by Stanfordfaculty and thus greatly increasing the ef ciency of all of SINTN’s programs.

Operational Goals:Generate and maintain a cDNA and shRNA bank which Stanford faculty can access and contribute to.•

Produce state-of-the-art viral particles expressing cDNAs/shRNAs as requested by Stanford•

investigators.

Develop novel viral-based methods for delivery and expression of cDNAs/shRNAs into speci c subsets•

of brain cells with ne temporal control.

Provide training in the use of viruses and other vectors for manipulating brain cell functions•


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SINTN Institutional Elements

In addition to supporting speci c research programs and cores, SINTN provides the Stanford community withadditional resources that serve to facilitate the efforts of faculty, fellows, staff and students. These includeindividual fellowships, seed grants, seminar series, a student boot camp and an annual retreat.

SINTN Predoctoral Fellowships

SINTN will enhance the Neuroscience PhD program at Stanford by supporting all third year graduate students.SINTN has received a generous gift from Frances B. Nelson to support the Graduate Program in Neuroscience.This support, plus matching funds ($1 million total), will cover the cost of all third-year Stanford neurosciencegraduate students who have not secured their own extramural grant support. This new source of funding will enablethe neuroscience faculty to extend the support of PhD students through the end of the third year of training. Weenvision this will increase the total number of students admitted and provide a boost to the graduate neuroscience

program.

SINTN Neuro-Innovation and Translational Fellowships

SINTN seeks to accelerate technological innovation and the translation of basic science discoveries into clinical practice. In pursuit of those goals, SINTN will award one Neuro-Innovation and Translation Fellowship everyyear. The fellowship program is designed to foster innovative neuroscience and neuroengineering discoveriesthat will revolutionize our understanding of brain function and/or the treatment of brain disorders, and ultimately

bene t society by improving the quality of life for patients. The fellowship program will focus on building physician-scientist teams to better understand potential application areas for new discovery and to chart the practical implementation of these discoveries.

SINTN plans to conduct an annual request for applications, wherein the winning proposal and faculty memberis awarded suf cient support to appoint a lead investigator for one year. Additional support will be provided tocover modest materials, supplies and travel. We envision that the Neuro-Innovation and Translational Fellowshipwill not only accelerate the impact of our discoveries on society, but also will help train a new generation of

physicians and scientists who will innovate and change future preclinical-to-clinical translation. It is anticipatedthat discoveries from this fellowship program will lead to patents and commercialization of these neuroscienceinnovations.

Institutional Elements


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Neuro-Innovation Faculty Seed Grants

Through the Weston Havens Foundation, $300,000 annually will be available for faculty seed grants to allowthem to pursue high-risk, innovative studies on brain function and dysfunction. The foundation’s goal is “to carryon, nance or promote medical or other scienti c research, or experimentation, having as the primary object the

bene t of humanity.”

SINTN Seminar Series

SINTN sponsors a weekly seminar series each quarter. The aim of the series is to inform the neurosciencecommunity about basic and/or clinical research that is relevant to the future of neuroscience. On average, abouttwo-thirds of the audience will be from the basic sciences, while the remainder are scientists doing research inclinical departments.

SINTN Boot Camp

This intensive two-week course focuses on cellular and molecular aspects of neuroscience research and is held prior to the start of the Fall quarter for incoming Neuroscience Graduate Program students. The course is composedof lectures and labs in which students learn a host of modern neuroscience techniques, such as electrophysiology,calcium imaging, membrane receptor traf cking as monitored via time-lapse videography, synaptic physiology,

biochemical analysis of transporter function, and hair-cell function. The students are also exposed to a wide rangeof neuroscience research at Stanford.

SINTN Annual Neuroscience Retreat

SINTN sponsors an annual two day retreat typically attended by over 150 faculty, postdoctoral fellows, studentsand staff. Attendees engage in a series of research presentations, poster sessions and discussions. This is awonderful opportunity for the Stanford neuroscience community to learn about the research being done by bothclinical and basic science faculty.

Documents

SINTN Op Plan Final4