THE BRAIN INITIATIVE®
The NIH BRAIN Initiative
Walter Koroshetz, M.D.
Co-Chair, NIH BRAIN Multi-Council Working Group
Director, National Institute of Neurological Disorders and
Stroke, NIH
U.S. Burden of Diseases: 291 Diseases and Injuries
THE BRAIN INITIATIVE®
Leading Categories of DALYs 2010
Mental and Behavioral
Disorders
13.6
Neurological
Disorders
5.1
18.7
1. Neuropsychiatric Disorders
2. Cardiovascular and Circulatory
Diseases
16,8
3. Neoplasms
15,1
4. Musculoskeletal Disorders
11,8
5. Diabetes, Urogenital, Blood, and
Endocrine Diseases
8,0
6. Chronic Respiratory Diseases
6,5
7. Other Non-communicable Diseases
5,1
0,0
2,0
4,0
6,0
8,0 10,0 12,0 14,0 16,0 18,0 20,0
Percent of Total U.S. DALYs
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US Burden of Disease Collaborators, JAMA, 2013
THE BRAIN INITIATIVE®
The Next Great American Project
Three years ago, President
Obama announced a new
grand challenge: The Brain
Research through Advancing
Innovative Neurotechnologies
(BRAIN) Initiative
“So there is this enormous mystery waiting to be unlocked, and
the BRAIN Initiative will change that by giving scientists the tools
they need to get a dynamic picture of the brain in action and
better understand how we think and how we learn and how we
remember. And that knowledge could be – will be –
transformative.”
-- President Obama, April 2, 2013
THE BRAIN INITIATIVE®
Focus on Circuit Structure
and Function
We need to be able to see the circuits in action to:
• Understand how the brain moves, plans, executes
• Understand how to monitor and manipulate circuits for
improved function.
• The disability that patients with neuro/mental/substance abuse
disorders suffer is a direct result of disordered brain circuits.
Goal: Make circuit normalization/compensation the target
of intervention
Molecular/Structural
Pathology
Circuit
Dysfunction
Neuro/Mental
Functional Disability
Where Does Scientific Progress
THE BRAIN INITIATIVE®
Come From?
“New directions in science are launched by new tools
much more often than by new concepts. The effect of a
concept-driven revolution is to explain old things in new
ways. The effect of a tool-driven revolution is to discover
new things that have to be explained.”
Freeman Dyson (1997) Imagined Worlds
University Press, Cambridge, MA
Harvard
THE BRAIN INITIATIVE®
1974
Original axial CT image form Siretom CT
scanner circa 1975. Physicians were
fascinated by the ability to see the brain
and ventricles for the first time.
What is Next?
2012
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THE BRAIN INITIATIVE®
CLARITY: Neuroanatomy
for the 21st Century
Deisseroth et al, Stanford
THE BRAIN INITIATIVE®
Seven High Priority Research Areas
Brain
Cell
Types
Tools for
Circuit
Diagrams
Tech. to
Monitor
Neural
Activity
Precise
Interventional
Tools
1. Discovering diversity: Identify and provide experimental
access to the different brain cell types to determine their
roles in health and disease.
2. Maps at multiple scales: Generate circuit diagrams that
vary in resolution from synapses to the whole brain.
3. The brain in action: Produce a dynamic picture of the
functioning brain by developing and applying improved
methods for large-scale monitoring of neural activity.
4. Demonstrating causality: Link brain activity to behavior
with precise interventional tools that change neural circuit
dynamics.
THE BRAIN INITIATIVE®
Seven High Priority Research Areas
Theory
and Data
Analysis
Tools
5. Identifying fundamental principles: Produce conceptual
foundations for understanding the biological basis of
mental processes through development of new theoretical
and data analysis tools.
Advance
Human
Neuroscience
6. Advancing human neuroscience: Develop innovative
technologies to understand the human brain and treat its
disorders; create and support integrated human brain
research networks.
Integrate
Approaches
7. From BRAIN Initiative to the brain: Integrate new
technological and conceptual approaches produced in
goals #1-6 to discover how dynamic patterns of neural
activity are transformed into cognition, emotion,
perception, and action in health and disease.
THE BRAIN INITIATIVE®
The BRAIN
®
Initiative
2014 NIH BRAIN awards
• 58 awards, $46 million
2015 NIH BRAIN awards
• 67 awards, $38 million
• 130+ investigators, 8 countries
outside the US
2016 NIH BRAIN awards
• 100+ awards, $150+ million
• 170 investigators in the United
States and 8 other countries in FY16
• Since FY14, 13 countries total are
involved in US BRAIN projects
THE BRAIN INITIATIVE®
Optical Instrumentation
Deeper – anywhere in the brain
Faster – whole volumes rather than single image plane
More precise targeting
3-photon imaging of hippocampal
neurons >1mm deep in the
mouse brain – Cornell (Xu)
SCAPE imaging of cortical neurons
colored by deconvolution –
Columbia (Hillman, Paninski)
THE BRAIN INITIATIVE®
Probe Development
Sensors: voltage, transmitters/modulators, activity history,
activated synapses, MRI for calcium
Activators/inhibitors: chemical-genetic, photo-switchable
ligands, GPCR signaling, synaptic plasticity
Mutated Fast response to
Opsin
voltage changes
GFP-based
fluorophor
FRET donor
for bright
signal
Voltage imaging of single neuron
dynamics in mouse cortex in vivo –
Stanford (Schnitzer/Lin)
GFP Linked bacterial
protein mutated to bind
serotonin
New optogenetic serotonin sensor
with high SNR in cultured cells – UC
Davis (Tian)
THE BRAIN INITIATIVE®
Exciting New Discoveries
Dr. Arnold Kriegstein and colleagues identify candidate entry
receptor for Zika virus in neural stem cells
Single cell RNA-seq analysis of
different cell types during early
development (Cell Stem Cell)
• Examined expression of several
candidate entry receptors for Zika
virus
• Candidate AXL is highly expressed
in several cell types, including
human radial glial cells
• Loss of radial glia founder
populations leads to microcephaly
• AXL expression pattern is
conserved in mice, ferrets, and
human iPSCs – models for
infectivity and developmental
effects of Zika virus
THE BRAIN INITIATIVE®
Exciting Advances
Dr. Sarah Stanley and colleagues develop a system for using radio
waves outside the head to control neural activity in mice
Electromagnetic waves were used to manipulate specific ion
channels to modulate neural activity and feeding behavior (Nature)
• Iron nanoparticles were tethered to temperature-sensitive TRPV1
• Radio waves or magnetic fields activated glucose-sensing neurons in the
mouse hypothalamus, leading to increased plasma glucose levels, lowered
insulin levels, and stimulated feeding behaviors
• Genetically-manipulated TRPV1 selective to chloride ions were also created
• Electromagnetic waves
inhibited the same
class of neurons,
leading to decreased
plasma glucose,
higher insulin, and
suppressed feeding
Schematic of “Radiogenetics” System
THE BRAIN INITIATIVE®
BRAIN Neuroethics
BRAIN Neuroethics Working Group
• A consultative ethics group to work with BRAIN leadership
and BRAIN investigators
• Co-chaired by Dr. Christine Grady and Hank Greely
• First meeting was on Feb 9, 2016 with BRAIN PIs conducting
invasive human studies
• Second meeting was Aug 3• Workshop on privacy, ethics of research with invasive
neurotechnologies, data sharing; long-term obligations
to patients with invasive neural devices
• Yuste and Goering (2016) On the necessity of ethical
guidelines for novel neurotechnologies. Cell 167:882885
• Request for Information (RFI): Guidance for Opportunities in
Neuroethics closed July 29
• New funding opportunity planned for FY 2017, informed by
RFI input
THE BRAIN INITIATIVE®
BRAIN Initiative Alliance
Mission Statement: The aim of the BRAIN Initiative
Alliance is to coordinate and facilitate
communications from its members related to the
BRAIN Initiative.
Short Term Focus: Launched website that serves as a single point of
communication for all BRAIN Initiative-related announcements of
funding opportunities and accomplishments
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THE BRAIN INITIATIVE®
International Partnerships
Goals:
•
•
Develop a coordinated program to foster
collaborative research in areas of mutual
interest within the BRAIN Initiative
Jointly support research projects involving
Foreign and U.S. scientists; exchange of
scientific information
•
•
•
Funding for projects in Denmark provided by
Lundbeck Foundation
Funding for projects in Canada provided by
Brain Canada
Funding for projects in Australia provided by
the Australian National Health and Medical
Research Council
THE BRAIN INITIATIVE®
Performance Sites (Foreign)
Foreign Performance Sites
12
10
8
6
4
2
0
FY14
FY15
FY16
THE BRAIN INITIATIVE®
2015 & 2016
BRAIN Investigators Meeting
Meeting offers opportunity for BRAIN investigators to
interact across project areas, funding agencies
2nd Annual Meeting: December 11-12, 2015
• Almost 500 attendees
• Scientists and clinicians, federal staff,
non-government foundations, scientific press
• Over 190 scientific poster presentations
3rd Annual Meeting: December 12-14, 2016
• Expand 2016 meeting to include public/open session(s)
• Anticipate upwards of 1000 in attendance
• Includes sessions on the EU Human Brain Project and Global Efforts in
Neurotechnology Development
THE BRAIN INITIATIVE®
Exciting New Discoveries
3D Neural
Reconstruction
• PI: Jeff Lichtman, PhD
and colleagues, Cell
• Automated serial
sectioning of mouse
cortex
• Imaging with a scanning
electron microscope
• Virtual, 3D reconstruction
and analysis
• Nanometer scale
http://braininitiative.nih.gov/
THE BRAIN INITIATIVE®
Thank You!
Walter J. Koroshetz, M.D.
Director
National Institute of Neurological Disorders and Stroke
Email: [email protected]
Website: http://www.ninds.nih.gov/
Follow me @NINDSdirector
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