THE 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® of Leading Categories MentalDALYs and Behavioral 2010Neurological Disorders Disorders 13.6 5.1 18.7 1. Neuropsychiatric Disorders

2. Cardiovascular and Circulatory 16,8 Diseases

3. Neoplasms 15,1

4. Musculoskeletal Disorders 11,8

5. Diabetes, Urogenital, Blood, and 8,0 Endocrine Diseases

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 2 US Burden of Disease Collaborators, JAMA, 2013 The Next Great American Project THE BRAIN INITIATIVE®

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 Focus on Circuit Structure THE BRAIN INITIATIVE® 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 Circuit Neuro/Mental Pathology Dysfunction 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 Press, Cambridge, MA THE BRAIN INITIATIVE® What is Next?

1974 2012

Original axial CT image form Siretom CT 6 scanner circa 1975. Physicians were fascinated by the ability to see the brain and ventricles for the first time. CLARITY: Neuroanatomy THE BRAIN INITIATIVE® for the 21st Century

Deisseroth et al, Stanford THE BRAIN INITIATIVE® Seven High Priority Research Areas

Brain Cell 1. Discovering diversity: Identify and provide experimental Types access to the different brain cell types to determine their roles in health and disease.

Tools for Circuit 2. Maps at multiple scales: Generate circuit diagrams that Diagrams vary in resolution from synapses to the whole brain.

Tech. to Monitor 3. The brain in action: Produce a dynamic picture of the Neural functioning brain by developing and applying improved Activity methods for large-scale monitoring of neural activity.

Precise Inter- 4. Demonstrating causality: Link brain activity to behavior ventional with precise interventional tools that change neural circuit Tools dynamics. THE BRAIN INITIATIVE® Seven High Priority Research Areas

Theory 5. Identifying fundamental principles: Produce conceptual and Data Analysis foundations for understanding the biological basis of Tools mental processes through development of new theoretical and data analysis tools.

Advance Develop innovative Human 6. Advancing human : Neuro- technologies to understand the and treat its science disorders; create and support integrated human brain research networks.

7. From BRAIN Initiative to the brain: Integrate new Integrate Approaches 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 SCAPE imaging of cortical neurons neurons >1mm deep in the colored by deconvolution – mouse brain – Cornell (Xu) 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 GFP Linked bacterial for bright protein mutated to bind signal serotonin Voltage imaging of single neuron New optogenetic serotonin sensor dynamics in mouse cortex in vivo – with high SNR in cultured cells – UC Stanford (Schnitzer/Lin) 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 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 167:882- 885 • 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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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)

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FY14 FY15 FY16 2015 & 2016 THE BRAIN INITIATIVE® 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 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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