Institute for Neuro-Innovation

& Translational Neurosciences

Stanford Institute for Neuro-Innovation and Translational

Neurosciences

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

Executive Summary
The major goal of the Stanford Institute for Neuro-Innovation and Translational Neurosciences (SINTN) is to
rapidly advance our understanding of normal brain and spinal cord function at the molecular, cellular and neural
circuit level, and to elucidate the pathological processes underlying malfunction of the nervous system following
injury or neurologic and psychiatric diseases. SINTN will pioneer techniques to probe and manipulate nervous
system function with the aim of accelerating the translation of these new discoveries into novel therapeutic
approaches 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 offer
the 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 specific initiatives, programs and cores, the
institute will foster a culture of collaboration among leading basic, translational and clinical neuroscientists, who
together will revolutionize the study and treatment of brain disorders.

Director: Gary Steinberg, MD, PhD

Co-Director: Rob Malenka, MD, PhD
Program Director: Mehrdad Shamloo, PhD
Executive 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)

Initiatives
The institute will pursue its goals in five specific areas of neuroscience:
Neural Plasticity and Repair (NPR)
Neurodegeneration and Regeneration (NDR)
Neurobiology of Cognitive and Developmental Disorders (NCDD)
Neuroengineering (NE)
Neuroscience and Society (NS)
SINTN will administer and facilitate these initiatives by: (1) establishing and supporting specific, interdisciplinary
research programs and centers; (2) providing key core facilities (Imaging Core, Behavioral Core, Gene Vector
Core); (3) providing seed funding for high-risk, innovative projects; (4) providing funding for graduate students
and postdoctoral fellows; and (5) supporting seminar series, symposia and retreats.

Neural Plasticity and Repair

I. Neural Plasticity and Repair

Individual brain functions are mediated by complex interactions between many thousands of brain cells that
are organized into overlapping assemblies termed neural circuits. When functioning properly, these circuits
allow us to see, feel, learn, remember and create. When neural circuits do not function properly, brain disorders
as symptomatically diverse as chronic pain, addiction, Parkinsons disease, schizophrenia and Alzheimers
disease occur. The most remarkable feature of neural circuits is that they are not static but change in response
to experiencethey are plastic. This plasticity occurs in large part because the communication processes that
occur between nerve cells at synapses also are not static, but change in response to the brain activity generated by
an 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 various
forms of plasticity, and thus the plasticity of neural circuits, will provide key insights into how we learn and
remember, and how these processes malfunction in psychiatric and neurologic disorders. This knowledge will
also allow us to develop novel strategies for taking therapeutic advantage of plasticity mechanisms to repair
damaged 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:

Parkinsons Disease and Movement Disorders Program

Parkinsons 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 the
circuit disruptions that cause symptoms such as tremor, hesitancy, and balance problems. The Parkinsons Disease
and Movement Disorders Program at Stanford brings together personnel from multiple departments including
neurology, neurosurgery, bioengineering and neuroscience in a tightly-knit collaborative structure to provide both
outstanding clinical care and groundbreaking research in Parkinsons disease and other movement disorders.
The team is involved in leading-edge investigation at multiple levels, from basic science in the laboratory, to

translational research in the operating room, to clinical trials of new therapeutics. It will continue to pursue
the 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 techniques
that combine light-sensitive ion channels and fiberoptic light guides, have led to fundamental insights into the
connections and function of the neural circuits that malfunction to cause PD. In Stanfords OR as laboratory, local
electrical recordings during DBS have revealed abnormal oscillations in the 20-30 Hz frequency band, which are
hypothesized to play a major role in the genesis of Parkinsonian symptoms. With the seminal development of the
Parkinsons in a Petri dish model, cultures of skin cells derived from Parkinson patients can be made to exhibit
Parkinsonian characteristics, allowing experiments that would be impossible to perform in patients or animals. In
the clinical arena, Stanford will soon begin trials of a gene therapy protocol for Parkinsons treatment, introducing
a specific gene into subthalamic nucleus neurons with an adeno-associated viral vector, thus producing inhibition
in this area, which is usually overactive in Parkinsons disease.
Objectives:
Investigate the basis of normal and abnormal movement, specifically focusing on Parkinsons disease,
emphasizing multiple levels of analyses: from molecules to cells in culture, to circuits composed of
networks 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 physician
visits and health care resource utilization, costing over $100 billion annually. Additionally, pain has a significant
impact on individuals and their families, affecting functionality and quality of life in ways that are difficult to
measure and value monetarily. Similarly, drug addiction is a chronic, relapsing medical illness with devastating
health 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 specific neural circuits that share specific components. This
explains why so many of the drugs that are abused have analgesic properties (e.g. nicotine, heroin, cocaine and
cannabinoids) 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 same
substances. The proximate causes of both disorders are also largely known. Trauma, infection or inflammation
cause adaptive changes in specific spinal cord and brain circuitry, known as plasticity. For reasons that remain
unclear, in certain individuals this plasticity becomes long-lasting, leading to chronic pain syndromes. In drug
addiction, drugs of abuse target specific 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 changes
also 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 epidemiologic
information that together will explain the neural basis of chronic pain syndromes and addiction. A multidisciplinary
cadre 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 be
to understand the changes in those circuits in which pain is perceived and processed and those that mediate the

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 the
neural circuit plasticity that mediates pain and addiction is being elucidated, Stanford investigators will also be
exploring novel approaches to prevent or reverse these changes. The ultimate aim of this program is to translate
these research findings into more effective and tailored treatments for pain and addiction, and into early therapeutic
interventions 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 scientific discoveries to develop innovative treatments for these disorders in animal and
human models and translate those experimental treatments into therapy for patients.

Neurodegeneration and
Regeneration
II. Neurodegeneration and Regeneration
Diseases such as spinal cord injury, macular degeneration, amyotrophic lateral sclerosis (ALS), stroke, Alzheimers
disease, and Huntingtons disease are caused by the degeneration of specific cells in the brain and spinal cord.
Advances in molecular genetics and cell biology have revealed some of the detailed pathophysiological processes
underlying the loss of neurons in these devastating brain disorders, thus opening the door for possible therapeutic
interventions. This initiative will support research on furthering our understanding of the molecular and cellular
mechanisms that cause neurodegeneration, as well as efforts to develop approaches that will both prevent
degeneration and promote regeneration.
Overall Strategic Goals:
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. SCI
affects over 2 million people worldwide, including at least 250,000 in the United States. The cost to our nations
economy 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, many
other 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 provide
a broad base for collaboration in this area by promoting interactions between preclinical research and clinical
development of novel therapies. Its specific tasks are to advance understanding of the mechanisms underlying
damage to the spinal cord, to accelerate development of novel methods of repair, to explore innovative strategies

to restore function after injury, and to translate

these discoveries into enhanced quality-oflife for those with spinal cord injury and
dysfunction.
The partnership will encompass the efforts
of a community of basic neuroscientists,
translational neuroscientists, and clinicians.
Basic neuroscientists will work on multiple
topics including the molecular mechanisms
underlying axonal guidance and growth,
axonal myelination and re-myelination, and the
anatomy and physiology of spinal cord circuitry.
Translational neuroscientists will develop and
study animal models of SCI, which will be
invaluable not only for elucidating the detailed
pathophysiological mechanisms underlying
various types of SCI, but also for developing
and testing novel treatments. A core facility that
provides Stanford investigators with training in
the generation of these models will be critical
for the rapid translation of basic science findings
into advances in our understanding of the pathophysiology and treatment of SCI. Finally, the partnership will
benefit enormously from close interactions with SINTNs neuroengineering initiative, the Stanford Institute for
Stem Cell Biology and Regenerative Medicine and, most important, from the clinicians performing research
and providing treatment at the Spinal Injury Units of the VA Palo Alto Health Care System and the Santa Clara
Valley 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 on
the quality of life and livelihood. The annual total financial burden of major adult visual disorders in the United
States is an estimated $35.4 billion. The Stanford Center for Vision and Blindness Prevention is a leader in
vision 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 causes
of vision loss, including macular degeneration, glaucoma, infectious and degenerative corneal diseases, ischemic
and inflammatory optic neuropathies, diabetic retinopathy and retinopathy of prematurity. Central nervous system
diseases with significant visual involvement are also studied, including those with neurodegenerative, neoplastic,
ischemic, inflammatory and hereditary causes. An important focus of the center is understanding the development

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 and
translate 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 underlie
vision. Basic science research in vision at Stanford tackles issues such as developmental patterning of the eye and
visual circuitry, synaptic plasticity of the visual pathway, retinal and visual processing, visual object recognition
and reading, and visual-motor integration. Clinician scientists study mechanisms of disease including infection,
inflammation, ischemia, genetic abnormality and aging. They utilize state-of-the-art tools for both investigation
and therapeutic intervention of vision loss, including gene modification, stem cell implantation, imaging of ocular
and 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 into
devices, 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 new
technologies.

Neurobiology of Cognitive
and Developmental
Disorders
III. Neurobiology of Cognitive and Developmental Disorders
The development of the brain is one of natures most remarkable accomplishments, involving a complex array
of genetic mechanisms that are modified by environmental influences during infancy and childhood. When
neurodevelopmental processes go awry, brain disorders ensue. These brain disorders routinely involve deficits
in many different cognitive functions, ranging from problems with learning and memory to deficits in social
cognition and the ability to recognize and interpret normal social cues. Among the most common of such cognitive
and developmental disorders are autism spectrum disorders (ASDs), which affect 1 in 150 children. Additional
related disorders include Down syndrome, Rett syndrome and Fragile X syndrome, all of which share clinical
features with ASDs. Advances in human molecular genetics have identified mutations in individual neuronal
genes that predispose children to ASDs or, in the case of Fragile X and Rett syndromes, cause the disease. The
major goal of this SINTN initiative is to take advantage of these genetic findings and delve deeply into the
detailed mechanisms that underlie cognitive/developmental disorders with the goal of developing and testing
novel, more efficacious treatments. The combination of Stanfords outstanding basic neuroscience community
with its outstanding clinical investigators, all of whom are focused on understanding the biological mechanisms
that lead to cognitive and developmental disorders, makes Stanford uniquely positioned to make rapid progress
in this critical research area.
This initiative will bring together a diverse group of outstanding neuroscientists working on multiple levels of
investigation. Genetic analyses of patients have already led to the identification of mutant gene products that
are associated with various cognitive and developmental disorders. These genetic findings, in turn, lead to
the 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/genetic
manipulations and behavioral assays. A complementary and equally important on-going effort involves using
state-of-the-art techniques to obtain skin cells from patients, turn those cells into neurons, and study the problems
these neurons have in forming synapses and circuits. By comparing normal and diseased brains in both model
systems and humans, we will delineate disease pathophysiology and identify novel targets for the development
of better drug treatments.
Overall Strategic Goals:
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.

Programs:
Down Syndrome Research Center
The incidence of intellectual disability is about 1-2% in western countries. In about three-fourths of these
individuals, one of several hundred single gene disorders is the cause; the remainder is due to chromosomal
abnormalities, 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 finding potential
treatment strategies to improve the quality of life for individuals afflicted by these disorders, few if any treatments
have emerged. This is largely due to lack of a coherent understanding of basic cellular, molecular and systemic
changes 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 Research
Center will use its partnership with SINTN to build strong interdisciplinary collaborative research programs
aimed at advancing our understanding of the mechanisms causing intellectual disabilities in individuals with
Down syndrome, identifying commonalities with related neurodevelopmental and neurodegenerative disorders,
developing strategies to normalize behavioral and cognitive function, and translating these discoveries into viable
therapies that can improve the quality of life for individuals with intellectual disabilities.
The partnership with SINTN and the process of finding solutions to intellectual disabilities will engage and support
an 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 and
cognitive impairment associated with Down syndrome. This work will include the development of animal models
of Down syndrome, the analysis of the changes in neuronal circuits and synaptic plasticity mechanisms associated
with the emergence of cognitive impairment during early stages of brain development, as well as the age-related
loss 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 animal
facility will provide investigators with a reliable source of genetically defined mouse models of Down syndrome
to accelerate research programs and facilitate the generation of new animal models. Finally, working closely with
clinical faculty, the partnership will foster translational programs that will evaluate the effectiveness of treatment
strategies designed to normalize hypotonia, sleep disturbance, cognitive and psychiatric related disorders and agerelated 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 difficulty in acquiring language, repetitive movements, limited interests, and social and cognitive difficulties.
Autism costs billions of dollars to treat and exacts a large toll on patients, families and educational systems. Even
though autism is common, we know very little about its causes, and our behavioral and medical treatments are still
woefully inadequate. During the last two decades, autism research has focused mainly on the discovery of genes

that contribute to autism spectrum disorders (ASDs). Despite the identification of many susceptibility genes,
little is known about possible neural mechanisms or pharmacological treatments. A coordinated effort is needed
to explore the pathological links between mutations in identified autism susceptibility genes and alterations in
neuronal physiology, neural circuits and behavior. A network of scientists and clinicians at Stanford are making a
coordinated effort to elucidate the pathophysiological mechanisms of autism and to generate relevant preclinical
animal 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 animals
expressing 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 and
maladaptive brain functions. Secondly, Stanford scientists have developed a new approach for acquiring skin
cells from children with autism and converting them into neurons. This method is allowing scientists, for the
first time, to study neurons from patients with neurodevelopmental disorders in a controlled laboratory setting so
that flaws in how those cells behave and wire together can be studied and corrected. Thirdly, Stanford scientists
are directly studying patients with autism spectrum disorders using state-of-the-art brain imaging techniques
combined with genetic analysis and treatment protocols. This will allow findings from the preclinical studies using
animal models and neurons generated from patients skin cells to directly influence studies of brain function in
patients. Thus, Stanford is uniquely positioned to use comprehensive, multidisciplinary approaches to furthering
our understanding of the neurobiological basis of autism spectrum disorders. This will lead to the development of
novel 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
specific 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 patientderived neurons, and use this information with that obtained from human studies to find new
pharmacological therapies.
Test novel therapies in animal models and use the results to initiate clinical trials.

Neuroengineering

IV. Neuroengineering
Major advances in molecular biology and bioengineering, combined with improved understanding of how neural
circuits mediate behavior, has made it possible to manipulate brain function in ways that were unimaginable as
recently as a decade ago. This initiative encompasses a range of programs with the common goal of developing
innovative techniques and strategies for manipulating brain circuits in the human brain therapeutically to alleviate
the symptoms and suffering caused by brain disorders. The methodologies used will vary across a broad spectrum
of approaches, ranging from the expression of genetically encoded ion channels activated by light to braincomputer interfaces, to the use of neural stem cells for replacing damaged tissue. While therapeutic intervention
will continue to be a mainstay of treatment for many brain disorders, SINTNs support of neuroengineering
programs promises to help revolutionize how we treat brain disorders while also providing tools with which we
can continue to improve our understanding of how neural circuits mediate brain functions.
Overall Strategic Goals:
Promote the development and application of novel methodologies for the manipulation of neural circuit
activity in the intact brain
Apply 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 prime
example, as he suffered an upper spinal cord injury and was never again able to walk, move his arms, or even
speak clearly. Despite substantial research focused on repairing damaged neural cells, there remains no meaningful
way to help these patients. Over the past few years an alternative approach that effectively bypasses the injury
has been developed and significantly advanced at Stanford. By reading out electrical activity from hundreds of
neurons 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 communication
and 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 these
exciting new medical systems into human clinical trials. The major objective is to provide a patient who is losing
the ability to communicate with a computer that can be controlled by thought alone. This system will convert the

neural impulses associated with the desire to move the arm into keyboard strokes and mouse movements, thereby
restoring the ability to communicate and interact with the world. In numerous laboratory experiments, Stanford
scientists have demonstrated innovations such as accurate decoding of movement intent and the ability to move a
computer cursor by thought control more quickly than an arm could move. We are in an ideal position to turn this
world-record performance in the laboratory into real-world gains for paralyzed patients.
Objectives:
Perform the first 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 specific technology to intervene in brain functioning. In this clinically-oriented collaborative effort,
Stanford engineers, neuroscientists, and physicians will develop, validate, and apply powerful and specific new
technologies for probing and tuning brain circuits, with outcomes that will reverberate through applied neuroscience
and throughout clinical fields ranging from depression to Parkinsons Disease. Recent advances, including many
at Stanford, have opened the door to fundamentally new strategies for tuning and modulating brain function,
including the use of light (optogenetics), ultrasound (HIFU),
magnetic fields (transcranial magnetic stimulation or TMS),
ionizing radiation (CyberKnife), and radiofrequency (RF)
modalities of energy delivery. The NINS team will capitalize
on these advances and the unique positioning of Stanford to
focus on technology development for both applied science
applications and for clinical translation.
Two examples (optogenetics and ultrasound) provide an
illustration 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 methodology
will be used to probe the neural circuit dynamics that
underlie adaptive brain functions as well as the neural
circuit dysfunctions that are responsible for brain disorders.
Ultrasound, in contrast, delivers mechanical and thermal
stimulation in a way that can excite or inhibit cells, and
can be depth-focused to provide a specificity that may be
further enhanced with novel receptors. An integrated team
of engineers, neuroscientists, and clinical neurologists, neurosurgeons, and psychiatrists will expand Stanfords
efforts in the use of these brain stimulation methods to treat brain disorders. These efforts will not only provide
novel treatments for patients whose symptoms are not responsive to medications, but will also allow unparalleled
opportunities to explore fundamental neurophysiologic questions about the diseases and circuits that are treated.

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 refine 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 scientific justification, beginning with proof-of-principle studies (e.g. motor cortex activation or
inhibition) 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 individual
matures, 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 not
well understood, tissue repair signals do not instruct these cells to restore the complex neural circuitry that is
formed during development. In experimental models, adult stem cells transplants reveal that these cells are capable
of creating new neural networks in the developing brain. This suggests that the signals provided to the stem cell
during adult tissue repair are not instructing the stem cells to regenerate lost circuitry. Curiously, there are two
small regions in the adult brain where stem cells are instructed to make new neurons, and this anomaly is beginning
to provide insights into strategies for repairing the adult brain. A major goal of this program is to discover the
signals used in the developing brain as well as these unique neurogenic adult brain regions to understand how
stem cells can be directed to generate new neurons for regeneration and repair. A second major goal is to study
the detailed properties of new neural stem cell lines as they become available, and to use these for the repair of
damaged brain tissue. Preclinical investigations have suggested that transplanted neural stem cells restore function
after brain injury or disease by enhancing endogenous mechanisms of plasticity and repair, including native
neurogenesis, gliagenesis, vasculogenesis, synaptogenesis, axonal sprouting, dendritic branching and attenuation
of the inflammatory response. These improved mechanisms of recovery may be secondary, in part, to release
of growth factors, trophic factors and
neurotransmitters from the transplanted
neural stem cells.
This cross-disciplinary research and
translation program partners investigators
in many disciplines including physics,
engineering, materials sciences, biology,
genetics neuroscience, and clinical
research. Many of the team investigators
hold joint appointments within both
SINTN and the Stanford Institute for
Stem Cell Biology and Regenerative
Medicine. The team will pursue
fundamental investigations that identify
the precise signals that make stem cells
replicate, migrate to sites of tissue repair,
and differentiate into functional neurons

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 demonstrated
that human neural progenitor cells can be produced in culture, cryopreserved, and safely implanted into the brains
of stroke patients. Although this past study was designed primarily to test safety and feasibility, ongoing studies
are examining the improvements observed in some patients to determine if stem cells can contribute to improved
motor, sensory or cognitive function. Additional applications are being developed for patients with spinal cord
injuries, Parkinsons 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 stem
cells with strong translational and clinical research, this program will lead the way in the application of stem cell
biology to efficacious 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 the
mechanisms of neurologic recovery after transplantation.
Apply novel molecules, proteins, drugs, anti-inflammatory agents, growth factors and other agents
to enhance the survival and beneficial 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.

Neuroscience and
Society
V. Neuroscience and Society
The initiatives and programs sponsored by SINTN promise to produce abundant new knowledge on brain function
and novel ways of manipulating brain function. Because the brain mediates all human behavior, the intellectual
and technical output of SINTN has the potential to profoundly influence many areas in society ranging from
the practice of medicine and the law to our understanding of the basis of social cooperativity and conflict. It is
therefore imperative that SINTN sponsor an initiative that will attempt to place the latest advances in basic and
clinical neuroscience into the broader context of society. Indeed, modern neuroscience research sponsored by
SINTN has the potential to change our understanding of human nature itself, and the way human beings within
complex societies interact.
Overall Strategic Goals:
Explore and define the potential societal impact of new findings and methodologies in neuroscience.
Provide constructive feedback to private and government agencies regarding how new findings 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 pathologies
of the human mind and in developing treatments, until recently, neuroscientists have largely avoided dealing
with complex behaviors such as moral cognition and those linked to altruistic behavior and compassion. In part,
this has been due to the difficulty of objectively measuring and quantifying complex brain mechanisms. It has
been postulated that such behaviors involve the interconnection and integration of many neural circuits located
in diverse locations within the brain. For example, it is known that there is an integration of contextual social
knowledge within the prefrontal cortex, social semantic knowledge within the anterior and posterior temporal
cortex and basic emotional and motivational behavior within the cortico-limbic system.
To understand scientifically why it is that humans behave in a compassionate or altruistic manner, or in contrast
why they sometimes do not, requires a unique collaboration across a variety of disciplines, collaborations between
those who study the brain using objective measures and those who study the mind using first-person subjective
observation (such as Buddhism and other contemplative traditions, which have a long history of investigation
into the nature of mind). Only recently has it been possible to envision a robust interface between these two
investigative approaches. Building ever stronger bridges between these investigative traditions, CCARE will

create a multi-disciplinary environment whereby compassion and altruism studies are supported and legitimized
within the broader scientific 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 the
neuroscientific study of the brain mechanisms, and from philosophical and contemplative perspectives to cognitive
and social psychology as well as neuroeconomics. Through such diverse research methods, CCARE will strive to
gain a deep understanding of compassion and its associated human behaviors in all its richness.
Objectives:
Use rigorous scientific methods to define 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 inindividuals.
Disseminate research findings 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 thus
of the human mind. This revolution will have implications far beyond basic science and medicine. Our societies
are built by our brains; deeper knowledge of those brains will affect education, law, business, government, and
many more parts of our social world. We are already beginning to see effects, from the commercial availability
of fMRI-based lie detection to neuro-marketing consulting firms. The Stanford Interdisciplinary Group on
Neuroscience and Society (SIGNS) is an effort by a broad range of Stanford faculty and students to explore how
advances in neuroscience will affect human societies. Currently coordinated by Stanford law faculty, fellows
and students, the group thus far includes participants from five of Stanfords 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 interested
in interdisciplinary research and education on the social consequences of neuroscience. It will immediately increase
communication among interested faculty and students throughout the University. SIGNS will encourage these
interdisciplinary efforts by supporting seminars, conferences, workshops, and courses. It will also disseminate
discussions 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.

Enabling Core Facilities

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 of
achieving this goal is to establish cores: staffed facilities providing services that individual investigators either
cannot provide themselves or that, when provided themselves, results in wasteful duplication of effort. SINTN
currently 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 those
that model disease processes. Scientists need to be able to probe complex behavioral and cognitive issues in these
mice, yet few laboratories (even those that generate mouse mutants in large numbers) are equipped to assess in
detail 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 expertise
and equipment to analyze mouse and rat behavior in ways that have great promise in identifying novel neural
substrates 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 profiling of CNS active compounds in efficacy models.

Neuroscience Imaging Core

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

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 and
analysis and 3D image rendering.
Identify new microscopy and image analysis technologies that are of interest to and will benefit 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 molecular
mechanisms underlying all brain functions, as well as for understanding how these mechanisms go awry in brain
disorders. A complementary and equally important strategy is delivery of inhibitory RNAs to eliminate or reduce
specific 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 specific proteins and replace
them with modified versions in specific 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 mediated
molecular manipulations allow unprecedented experimental control over synapses, cells and circuits in model
systems 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 and
cDNA plasmids. This will benefit SINTNs overall mission by preventing the duplication of efforts by Stanford
faculty and thus greatly increasing the efficiency of all of SINTNs 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 specific subsets
of brain cells with fine temporal control.
Provide training in the use of viruses and other vectors for manipulating brain cell functions

Institutional Elements

SINTN Institutional Elements

In addition to supporting specific research programs and cores, SINTN provides the Stanford community with
additional resources that serve to facilitate the efforts of faculty, fellows, staff and students. These include
individual 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 ($1million total), will cover the cost of all third-year Stanford neuroscience
graduate students who have not secured their own extramural grant support. This new source of funding will enable
the neuroscience faculty to extend the support of PhD students through the end of the third year of training. We
envision 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 every
year. The fellowship program is designed to foster innovative neuroscience and neuroengineering discoveries
that will revolutionize our understanding of brain function and/or the treatment of brain disorders, and ultimately
benefit 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 member
is awarded sufficient support to appoint a lead investigator for one year. Additional support will be provided to
cover modest materials, supplies and travel. We envision that the Neuro-Innovation and Translational Fellowship
will 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 anticipated
that discoveries from this fellowship program will lead to patents and commercialization of these neuroscience
innovations.

Neuro-Innovation Faculty Seed Grants

Through the Weston Havens Foundation, $300,000 annually will be available for faculty seed grants to allow
them to pursue high-risk, innovative studies on brain function and dysfunction. The foundations goal is to carry
on, finance or promote medical or other scientific research, or experimentation, having as the primary object the
benefit of humanity.

SINTN Seminar Series

SINTN sponsors a weekly seminar series each quarter. The aim of the series is to inform the neuroscience
community about basic and/or clinical research that is relevant to the future of neuroscience. On average, about
two-thirds of the audience will be from the basic sciences, while the remainder are scientists doing research in
clinical 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 composed
of lectures and labs in which students learn a host of modern neuroscience techniques, such as electrophysiology,
calcium imaging, membrane receptor trafficking 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 range
of neuroscience research at Stanford.

SINTN Annual Neuroscience Retreat

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