The Journal of , December 12, 2018 • 38(50):10583–10585 • 10583

Commentary for the National Institutes of Health Initiative

X Diana W. Bianchi, Judith A. Cooper, XJoshua A. Gordon, Jill Heemskerk, XRichard Hodes, George F. Koob, X Walter J. Koroshetz, David Shurtleff, Paul A. Sieving, XNora D. Volkow, XJames D. Churchill, and XKhara M. Ramos National Institutes of Health, Bethesda, Maryland 20892

Background on the National Institutes from dysfunctional neural circuit activity. ance for the NIH BRAIN Initiative regard- of Health BRAIN Initiative Despite decades of progress, our rudimentary ing neuroethics is its strategic plan, BRAIN and neuroethics understanding of brain function impedes our 2025: A Scientific Vision, which was devel- The National Institutes of Health (NIH) ability to compensate for atypical circuit activ- oped with broad input from the scientific works tirelessly to support the best science ity in disorders such as depression, schizo- community and has four specific goals for and ensure that its funded research ad- phrenia, bipolar disorder, chronic pain, neuroethics: (1) establishing a shared vision heres to the highest ethical standards. addiction, autism, Alzheimer’s disease, and for the ethical conduct of human neurosci- From its inception, the NIH Brain Re- dystonia. The NIH BRAIN Initiative aims to ence research; (2) collecting and dissemi- search through Advancing Innovative deliver the tools and neurotechnologies that nating best practices in the conduct of Neurotechnologies (BRAIN) Initiative, will enable us to address this knowledge gap. ethical scientific research, particularly clini- an ambitious effort focused on under- As has occurred throughout the his- cal research; (3) supporting data-driven re- standing the , has made a tory of medicine, the emergence of new search to inform ethical issues arising concerted effort to integrate neuroethics technologies and capabilities may require from BRAIN Initiative research; and (4) into its science, motivated by the under- the evolution of ethical standards to guide developing outreach activities to engage standing that brain circuit activity is the how they should be first introduced into diverse stakeholders in discussion of the so- foundation of individual human experi- human subjects research and later applied cial and ethical implications of neuroscience ences and is uniquely entwined with our to the practice of medicine. NIH has sev- research (https://www.braininitiative.nih.gov/ sense of personal identity. In the 5 years eral valuable ethical frameworks in place strategic-planning//brain-2025-report). since the Initiative began, NIH has in- to guide the science, informed by policy Neuroethics strategy for the NIH vested over $950 million in BRAIN Initia- and laws regarding the protection of human tive research throughout the United States BRAIN Initiative research participants and animal research and around the world to develop novel The neuroethics strategy for the NIH BRAIN subjects. NIH is committed to ensuring it tools and neurotechnologies that will en- Initiative operationalizes these BRAIN 2025 considers and addresses the ethical implica- able unprecedented detailed maps of neu- goals, emphasizing proactive, ongoing as- tions of development and application of ral circuits, measures of the fluctuating sessment of the neuroethical implications BRAIN-funded tools and neurotechnolo- patterns of electrical and chemical activity of the development and application of gies and the increased knowledge that they flowing within those circuits, and under- BRAIN-funded tools and neurotechnolo- produce about the brain. In tandem with standing of how their interplay creates our gies. Early on, the Initiative established cognitive and behavioral capabilities. Un- the BRAIN Initiative’s launch in 2013, the an external Neuroethics Working Group derstanding neural circuit function is es- Presidential Commission for the Study of (NEWG) comprising both neuroethicists sential if we are to transform our ability to Bioethical Issues embarked on a 2-year and neuroscientists to provide expert diagnose and treat neurological, mental process of engaging with the scientific input on neuroethics (https://www. health, and substance use disorders, community, the public, and other stake- braininitiative.nih.gov/about/neuroethics- which are the leading cause of disability in holders to proactively identify a set of core working-group). The NEWG is part of the Ini- the United States. For this diverse group ethical standards both to guide neurosci- tiative’s Multi-Council Working Group, a of disorders, the burden of illness results ence research and to address some of the group of nongovernmental experts that pro- ethical dilemmas that may be raised by the vides scientific guidance for the Initiative. The application of neuroscience research find- synergistic efforts of these experts help to en- Received Aug. 13, 2018; revised Oct. 5, 2018; accepted Oct. 11, 2018. The authors are all federal employees of the National Institutes of ings. This process culminated in the pub- sure that neuroethical considerations are fully Health and declare no competing financial interests. lication of a two-volume report entitled integrated into the Initiative. The NEWG or- We thank Dr. Amy Adams for helpful comments on this manuscript. Gray Matters, which strongly endorses ganizes topical workshops that explore neuro- Correspondence should be addressed to Dr. Khara M Ramos, National proactive integration of neuroethics into ethical implications of BRAIN Initiative Institutes of Health, 31 Center Drive, 8A31, Bethesda, MD 20892. E-mail: any neuroscience research endeavor (https:// [email protected]. research. Topics to date have included human https://doi.org/10.1523/JNEUROSCI.2091-18.2018 bioethicsarchive.georgetown.edu/pcsbi/ neuroscience research using invasive and non- Copyright © 2018 the authors 0270-6474/18/3810583-03$15.00/0 node/3543.html). Another source of guid- invasive neural devices and research with hu- 10584 • J. Neurosci., December 12, 2018 • 38(50):10583–10585 Bianchi et al. • Neuroethics for NIH BRAIN

Table 1. Neuroethics Guiding Principles manifest as behavioral, cognitive, or emo- the proposed research. For example, a re- 1. Make assessing safety paramount. tional perturbations and may not be imme- cent FOA supporting human neuroscience 2. Anticipate special issues related to capacity, autonomy, diately apparent. Although the Guiding research using invasive neural recording and agency. Principles were written for the NIH BRAIN and stimulating technologies required ap- 3. Protect the privacy and confidentiality of neural data. Initiative, they may prove useful to other plicants to address neuroethical consider- 4. Attend to possible malign uses of neuroscience tools and groups and organizations engaged in cutting- ations, including obtaining the informed neurotechnologies. edge technology development and research. consent from research participants who can 5. Use caution when moving neuroscience tools and To operationalize integration of neu- expect no direct therapeutic benefit from neurotechnologies into medical or non-medical uses. roethics throughout the NIH BRAIN Ini- engaging in the proposed research (https:// 6. Identify and address specific concerns of the public about tiative’s research portfolio, an internal grants.nih.gov/grants/guide/rfa-files/RFA- the brain. 7. Encourage public education and dialogue. neuroethics project team composed of NS-18-010.html). This neuroethics sec- 8. Behave justly and share the benefits of neuroscience NIH program staff ensures that neuroeth- tion was assessed as a nonscored, addi- research and resulting technologies. ics are considered throughout the grant tional review consideration facilitated by cycle, from developing funding plans for expert neuroethicists on the review panel. review and approval by NIH Institute and Like all NIH-funded research with human man neural tissue. These workshops provide Center Directors and throughout the participants, these studies were subject to important venues for stakeholders with vary- lifespan of managing funded projects. The review by institutional review boards, yet ing perspectives to discuss key neuroethical internal project team’s work is informed adding this additional review consider- considerations associated with BRAIN re- by the Guiding Principles and they inter- ation underscores the sensitivity of studies search and to facilitate building agreement on face with the external Neuroethics Work- involving monitoring and stimulating the how to advance research in the most ethical ing Group to share neuroethics questions human brain and supports ongoing over- manner. In the spirit of transparency, meeting elicited by BRAIN-funded research and sight of the work. This approach will in- videocasts and summaries are available online. receive expert input in return. form our efforts to establish a shared Concurrently, groups in the United States and The project team is also responsible for vision for the ethical conduct of human around the world are engaged in neuroethics a growing neuroethics research portfolio. neuroscience research. work focused on modern neuroscience ad- In 2016, NIH issued a Request for Infor- vancements (Rose, 2014; Goering and Yuste, mation (RFI) that solicited public input Looking ahead 2016; Greely et al., 2016; Farahany et al., 2018; on BRAIN-related neuroethics questions As the NIH BRAIN Initiative continues to Global Neuroethics Summit Delegates et al., amenable to research. Information from grow and increase our understanding of 2018; http://nationalacademies.org/HMD/ that RFI was used to develop a funding the human brain and how it functions, it Activities/Research/NeuroForum.aspx). opportunity announcement (FOA) to sup- should increasingly rely on a robust neu- Grounded in the scientific goals of the port research on ethical implications of ad- roethics infrastructure to identify and ad- NIH BRAIN Initiative, the NEWG devel- vancements in neurotechnology and brain dress neuroethical implications of the oped a set of Neuroethics Guiding Principles science supported by the NIH BRAIN Ini- research it funds. We envision an ongo- (Table 1) to frame and navigate the neu- tiative (https://grants.nih.gov/grants/guide/ ing, iterative process of neuroethics in- roethical questions that BRAIN-funded rfa-files/rfa-mh-17-260.html). Through 2 forming the trajectory of the neuroscience research will prompt. These Guiding Prin- years of this FOA, nine research project research and neuroscience research in- ciples represent focused application of grants have been awarded (https://brain- forming neuroethics. As part of this pro- the ethical principles set forth in the initiative.nih.gov/funding/fundedAwards. cess, the Guiding Principles may evolve Belmont Report (https://www.hhs.gov/ htm). In addition to these projects, the neu- over time, perhaps as part of work to cre- ohrp/regulations-and-policy/belmont- roethics project team promotes neuroethics ate a set of shared norms that extends be- report/index.html). They provide an over- training through BRAIN-supported mech- yond NIH. arching framework that can help inform anisms (F32 and K99/R00), with two neuro- BRAIN 2025 notes that the NIH dialogues among stakeholders, including ethics postdoctoral fellowships awarded to BRAIN Initiative must adapt in response investigators, clinicians, institutional review date, and administrative supplements to to the evolving scientific landscape and boards, funders, research participants, pa- embed neuroethics in existing NIH BRAIN the Initiative is in the midst of an updated tients, and the public, both in the design Initiative grants. Our vision is that these planning process. A working group of the and conduct of research as they grapple neuroethics research efforts will add to the Advisory Committee to the NIH Director with ethical questions elicited by the Ini- neuroethics knowledge base that we draw (ACD), the highest-level advisory com- tiative that call for wider discussion and on to ensure that NIH BRAIN Initiative re- mittee at the NIH, is working to revisit the deeper understanding. For the NIH search holds to the highest ethical standards, priorities outlined in BRAIN 2025 through BRAIN Initiative, the purpose of applying for example, through development of new the lens of progress achieved to date, ris- the Guiding Principles and addressing neuroethics frameworks or tools that can ing scientific opportunities, and the new these neuroethical considerations is to be used in human neuroscience research set of tools and neurotechnologies emerg- help NIH BRAIN Initiative stakeholders laboratories. ing from the NIH BRAIN Initiative (https:// judiciously develop and deploy novel neu- Lastly, the Guiding Principles are also acd.od.nih.gov/working-groups/brain2. rotechnologies for biomedical research. considered during the grant review pro- 0.html). As part of this effort, NIH Director For example, in conducting human cess. Applicants and reviewers are familiar Dr. tasked a Neuroethics neuroscience research with novel neuro- with existing human subjects protections. Subgroup of the ACD working group to de- technologies, the Guiding Principles em- Some NIH BRAIN Initiative FOAs, how- velop a “Neuroethics Roadmap.” The group phasize the paramount importance of ever, have gone beyond these, with will characterize the neuroethical implica- assessing safety for research participants approaches to integrate additional consid- tions that may accompany both the devel- given that unexpected consequences may eration of the neuroethical implications of opment and use of new neurotechnologies Bianchi et al. • Neuroethics for NIH BRAIN J. Neurosci., December 12, 2018 • 38(50):10583–10585 • 10585 supported by the NIH BRAIN Initiative. tiative’s evolving research portfolio, con- Capestany BH, Church GM, Huang H, Song The Neuroethics Roadmap will enable NIH tinuing to host topical workshops on H (2018) The ethics of experimenting with leadership and program staff and the greater issues as they arise, and helping to shape human brain tissue. Nature 556:429–432. CrossRef Medline scientific community to have a shared un- the Initiative’s neuroethics research port- Global Neuroethics Summit Delegates, Rommel- derstanding of—and shared responsibility folio. These efforts underscore the critical fanger KS, Jeong SJ, Ema A, Fukushi T, Kasai for—the areas needing neuroethics-focused role that neuroethics will continue to have K, Ramos KM, Salles A, Singh I (2018) Neu- consideration when proposing or sup- within the NIH BRAIN Initiative going roethics questions to guide ethical research in porting research agendas. forward and its utility for helping advance the international brain initiatives. Neuron the tools and knowledge derived from the 100:19–36. CrossRef Medline It is anticipated that the ACD working Goering S, Yuste R (2016) On the necessity of group will deliver its final report, includ- Initiative into clinical applications that re- ethical guidelines for novel neurotechnolo- ing the Neuroethics Roadmap, to the full duce the burden of illness due to brain gies. Cell 167:882–885. CrossRef Medline ACD in June 2019. The Neuroethics diseases and disorders. Greely HT, Ramos KM, Grady C (2016) Neuro- Working Group will then inform the NIH ethics in the age of brain projects. Neuron 92: References 637–641. CrossRef Medline BRAIN Initiative’s implementation of the Farahany NA, Greely HT, Hyman S, Koch C, Rose N (2014) The : social Roadmap by providing ongoing input on Grady C, Pas᝺ca SP, Sestan N, Arlotta P, Bernat and ethical challenges. Neuron 82:1212–1215. the neuroethical implications of the Ini- JL, Ting J, Lunshof JE, Iyer EPR, Hyun I, CrossRef Medline