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Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative 2.0

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Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative 2.0 The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative 2.0 From Cells to Circuits, Toward Cures 1 TABLE OF CONTENTS Executive Summary Introduction Priority Area 1: Discovering Diversity Priority Area 2: Maps at Multiple Scales Priority Area 3: Brain in Action Priority Area 4: Demonstrating Causality Priority Area 5: Identifying Fundamental Principles Priority Area 6: Human Neuroscience Priority Area 7: From BRAIN to Brain Priority Area 8: Organization of Science: BRAIN 2.0 I. Sharing Data II. Human Capital III. Sharing and Using BRAIN Initiative Technology IV. Public Engagement V. Bringing BRAIN Initiative Advances to Brain Disorders Transformative Projects Concluding Remarks Rosters 2 The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative 2.0 From Cells to Circuits, Toward Cures EXECUTIVE SUMMARY In 2019, we are at the midway point of The Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative. To date, this large-scale investment of resources and time has made significant progress in its quest to understand the brain. Given remarkable progress in technology development, the neuroscience community is poised to apply these new technologies, and accumulated knowledge, to further understand what many perceive to be one of the most complex entities known to humankind: the human brain. We should also be humbled about what studying ourselves reveals – and be prepared to tread carefully when we don’t know what we don’t know about possible consequences of newfound abilities to control the activity of brain cells and circuits. While this is not possible on a wide scale yet, it will be in time, and probably sooner than we think. In April 2013, recognizing the many scientific and ethical issues companion to The BRAIN Initiative®, NIH Director Dr. Francis Collins convened a high-level working group of the NIH Advisory Committee to the Director (ACD), the BRAIN Working Group (WG 1.0) and charged them with reviewing recent advances in neuroscience; articulating short-, medium-, and long-term goals for achieving a scientific and ethical vision of the BRAIN Initiative; and developing a scientific plan for achieving those goals. The BRAIN Initiative WG 1.0 established a strategic roadmap (BRAIN 2025: A Scientific Vision) structured into seven Priority Areas. BRAIN 2025 recognized that the fast pace and unpredictable path of neuroscience research would require that recommendations be re-examined as the BRAIN Initiative progressed. Dr. Collins convened a new working group (WG 2.0) to revisit the 2025 report’s priorities to assess progress to date and to identify new scientific opportunities. Beginning in April 2018, WG 2.0 members reviewed the existing BRAIN Initiative investment and progress and considered potential areas for growth and expansion. In so doing, WG 2.0 sought input from the broader neuroscience community and other BRAIN Initiative stakeholders through multiple modalities: a series of public workshops held between August 2018 and November 2018, three Town Hall events held between April 2018 and April 2019, and two requests for information (RFI). This report presents the findings and analyses of WG 2.0 regarding the NIH BRAIN Initiative investment to date and offers some specific suggestions regarding NIH activities in the BRAIN Initiative. WG 2.0 proposes that the ACD recommend to the NIH Director that the NIH BRAIN Initiative considers the findings, analyses, and suggestions in this report for incorporation into the ongoing research program. Some of our findings and suggestions may extend beyond the NIH mission or may require collaborative efforts with other federal agencies and organizations. In those cases, WG 2.0 proposes that the ACD recommend to the NIH Director that NIH engage with broader stakeholder communities as necessary and appropriate to achieve outcomes consistent with the content of this report. Priority Areas We have structured this report around the seven scientific Priority Areas identified by BRAIN 2025. Each of these constitutes a chapter that provides a brief description of how the Priority Area fits into the goal of understanding circuits; reviews accomplishments to date in context of the BRAIN 2025 short- and long-term goals; identifies gaps and opportunities; and presents revised short- and long-term goals. Next, we frame these scientific directions in a chapter entitled “Priority Area 8. Organization of Science,” that presents a 3 discussion of the overarching topics that affect all areas of science. These include data management and sharing; scientific workforce-related considerations; sharing and using BRAIN Initiative technologies; public engagement strategies; and connecting basic research to disease models under study. We conclude by offering ideas for transformative projects, which all involve complex and multiscale lines of inquiry. A brief accounting of progress and promise for each Priority Area appears below and is articulated in more detail in this report. Programming accomplished in the context of the NIH BRAIN Initiative from 2014 to the present is identified as “BRAIN 1.0,” while “BRAIN 2.0” represents upcoming programming from the present to 2026. NIH should be prepared to evaluate the outcome of these findings and suggestions and review the accomplishments of BRAIN 2.0 in 5 years. Priority Area 1. Discovering Diversity: Identify and provide experimental access to the different brain cell types to determine their roles in health and disease ● Progress in this Priority Area has been faster than anticipated, enabled by advances in high-throughput technologies and analytical methods. New opportunities for BRAIN 2.0 include expanding cell-type profiling and data analysis to integrate measurements of additional phenotypic features of brain cells; generating a protein-based understanding and access to cell types; enabling genetic and non-genetic access to cell types across multiple species; expanding human cell biology; and performing cell-type based models of circuit function. At the completion of the BRAIN Initiative, we expect that current and additional progress in this area will clarify, and perhaps even define, contributions of distinct cell types to circuit function and the physiological and pathological sequelae. Priority Area 2. Maps at Multiple Scales: Generate circuit diagrams that vary in resolution from synapses to the whole brain ● We have seen substantial progress in this Priority Area, reflected by impressive improvements in tissue processing and imaging that are bringing brain regions and circuitry into sharper relief for continued investigation. Opportunities for BRAIN 2.0 include increasing the speed and efficiency of these powerful new tools; expanding analyses to larger brains; increasing mapping of non-neuronal cell types and synapses; integrating structure and function mapping in the same brain; and acquiring and refining data- science advances to facilitate cross-species comparisons. At the completion of the BRAIN Initiative, we expect that continued progress in this area will allow us to understand the structure of the brain and its numerous functions more fully. This multidimensional view will be transformative for developing therapeutic approaches appreciative of this complex organ. Priority Area 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 ● We have seen good progress in this Priority Area, driven in part by improvements in hardware and integrated strategies that combine electrophysiology with optical imaging, optogenetics, and pharmacologic modulation. Opportunities for BRAIN 2.0 include expanding the ability to understand neuromodulatory function; tools to study larger (primate) brains; and sophisticated, computational tools to better assess behaviors (especially in natural settings). At the completion of the BRAIN Initiative, we expect that continued advances in this area will provide a clearer understanding of how dynamic activity in and across brain regions drives so many distinct behaviors in animals and in humans. 4 Priority Area 4. Demonstrating Causality: Link brain activity to behavior by developing and applying precise interventional tools that change neural circuit dynamics ● We have seen considerable progress in this Priority Area. All major short- and long-term goals are in the process of being completed. During BRAIN 2.0, we are poised to grasp new research opportunities in single-cell control, nanotechnologies, and machine learning. It may be time to consider applying methods developed in model systems to understanding neuropsychiatric disease states at the circuit level – as well as seeking to understand ancestral principles governing circuit operation shared across phylogeny and evolution. At the completion of the BRAIN Initiative, we envision widespread adoption of integrated neurotechnologies that enable scientists to modulate activity throughout the brain to drive desired and predictable outcomes. We expect that the fundamental understanding obtained as a culmination of the integration of theory, observation, and closed-loop experimentation described herein will allow the design of neurotechnologies that perform these perturbations safely and predictably. Priority Area 5. Identifying Fundamental Principles: Produce conceptual foundations for understanding the biological basis of mental processes through development of new theoretical and
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