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BRAIN 2025 A SCIENTIFIC VISION

Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Working Group Report to the Advisory Committee to the Director, NIH

June 5, 2014

ROSTER

Cornelia Bargmann, PhD (cochair) Eve Marder, PhD The Rockefeller University Brandeis University

William Newsome, PhD (cochair) Richard Normann, PhD Stanford University University of Utah

David Anderson, PhD Joshua Sanes, PhD California Institute of Technology Harvard University

Emery Brown, MD, PhD Mark Schnitzer, PhD Massachusetts Institute of Technology Stanford University and Massachusetts General Hospital

Terrence Sejnowski, PhD Karl Deisseroth, MD, PhD Salk Institute for Biological Studies Stanford University

David Tank, PhD John Donoghue, PhD Princeton University Brown University

Roger Tsien, PhD Peter MacLeish, PhD University of California, San Diego Morehouse School of Medicine

Kamil Ugurbil, PhD University of Minnesota

EX OFFICIO MEMBERS

Kathy Hudson, PhD John Wingfield, PhD National Institutes of Health National Science Foundation

Geoffrey Ling, MD, PhD Carlos Pea, PhD Defense Advanced Research Projects Food and Drug Administration Agency

EXECUTIVE SECRETARY

Lyric Jorgenson, PhD National Institutes of Health

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TABLE OF CONTE N TS

EXECUTIVE SUMMARY .... 5

PREAMBLE ...................................................................................................................... 9

SECTION I. THE BRAIN INITIATIVE: VISION AND PHILOSOPHY ......................................... 11

The Goal of the BRAIN Initiative ............................................................................. 12

Foundational Concepts: Neural Coding, Neural Circuit Dynamics, and Neuromodulation ......................................................................................... 13

Why Now? ............................................................................................................. 14

The Brain and Behavior .......................................................................................... 15

Strategies and Experimental Systems ..................................................................... 16

The Roads Not Taken ............................................................................................. 16

Studying the Healthy Brain Should Accelerate Understanding of Brain Disorders ............................................................................................................ 17

The Deliverables of the BRAIN Initiative ................................................................ 18

SECTION II. SCIENTIFIC REVIEW AND HIGH PRIORITY RESEARCH AREAS .......................... 20

1. Mapping the Structure and Components of Circuits ........................................... 20

2. Neuronal Dynamics: Recording Neuronal Activity Across Time and Space ...............................................................................................................26

3. Manipulating Circuit Activity .............................................................................. 34

4. The Importance of Behavior ............................................................................... 35

5. Theory, Modeling, and Statistics Will Be Essential to Understanding the Brain ......................................................................................................... 36

6. Human Neuroscience and Neurotechnology ....................................................... 40

7. Education ........................................................................................................... 48

8. Maximizing the Value of the BRAIN Initiative: Core Principles ............................49

9. Further Reading .......................... 56

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SECTION III. IMPLEMENTATION: GOALS, DELIVERABLES, TIMELINES, AND COSTS ...........59

1. Discovering Diversity .......................................................................................... 60

2. Maps at Multiple Scales ..................................................................................... 66

3. The Brain in Action ............................................................................................. 74

4. Demonstrating Causality .................................................................................... 83

5. Identifying Fundamental Principles .................................................................... 89

6. Advancing Human Neuroscience ........................................................................ 100

7. From BRAIN Initiative to the Brain ..................................................................... 107

8. Supporting the Core Principles of the BRAIN Initiative ........................................ 111

9. Cost Estimates ... 121

10. Concluding Remarks............................................................................... 124

11. References ....................................................................................................... 127

APPENDIX A HOW THE BRAIN INITIATIVE WILL ADVANCE CLINICAL RESEARCH...........136

APPENDIX B EXPERT CONSULTATIONS ............................ 142

APPENDIX C ACRONYM LIST ........................................................................................ 145

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EXECUTIVE SUMMARY EXECUTIVE SUMMARY

The human brain is the source of our thoughts, emotions, perceptions, actions, and memories; it confers on us the abilities that make us human, while simultaneously making each of us unique. Over recent years, neuroscience has advanced to the level that we can envision a comprehensive understanding of the brain in action, spanning molecules, cells, circuits, systems, and behavior. This vision, in turn, inspired the BRAIN Initiative. On April 2, 2013, President Obama launched the BRAIN Initiative to accelerate the development and application of new technologies that will enable researchers to produce dynamic pictures of the brain that show how individual brain cells and complex neural circuits interact at the speed of thought. In response to this Grand Challenge, the National Institutes of Health (NIH) convened a working group of the Advisory Committee to the Director, NIH, to develop a rigorous plan for achieving this scientific vision. This report presents the findings and recommendations of the working group, including the scientific background and rationale for the BRAIN Initiative as a whole and for each of seven major goals articulated in the report. In addition, we include specific deliverables, timelines, and cost estimates for these goals as requested by the NIH Director.

The charge from the President and from the NIH Director is bold and ambitious. The working group agreed that the best way to set this vision in motion is to accelerate technology development, as reflected in the name of the BRAIN Initiative: Brain Research through Advancing Innovative Neurotechnologies. The focus is not on technology per se, but on the development and use of tools for acquiring fundamental insight about how the nervous system functions in health and disease. The initiative is only one part of the NIHs investment in basic, translational, and clinical neuroscience, but neurotechnology should advance other areas as well. To achieve these goals, we recommend that the BRAIN Initiative develop over a tenyear period beginning in FY2016, with a primary focus on technology development in the first five years, shifting in the second five years to a primary focus on integrating technologies to make fundamental new discoveries about the brain. The distinction between these phases is not black and white, but rather is a matter of emphasis and opportunity. Discoverybased science will motivate technology development in the first phase, and further technology development will be needed as the focus shifts to discovery in later years.

In considering these goals and the current state of neuroscience, the working group identified the analysis of circuits of interacting neurons as being particularly rich in opportunity, with potential for revolutionary advances. Truly understanding a circuit requires identifying and characterizing the component cells, defining their synaptic connections with one another, observing their dynamic patterns of activity as the circuit functions in vivo during behavior, and perturbing these patterns to test their significance. It also requires an understanding of the algorithms that govern information processing within a circuit and between interacting circuits in the brain as a whole. The analysis of circuits is not the only area of neuroscience worthy of attention, but advances in technology are driving a qualitative shift in what is possible, and focused progress in this area will benefit many other areas of neuroscience.

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With these considerations in mind, the working group consulted extensively with the scientific community to evaluate challenges and opportunities in the field. The following areas were identified as high priorities for the BRAIN Initiative. These goals are intellectually and practically expanded in Sections II and III of this report.

#1. Discovering diversity: Identify and provide experimental access to the different brain cell types to determine their roles in health and disease. It is within reach to characterize all cell types in the nervous system, and to develop tools to record, mark, and manipulate these precisely defined neurons in the living brain. We envision an