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A Backbone for the Evolving Canadian Research Strategy

Judy Illes,1,* Samuel Weiss,2,* Jaideep Bains,3 Jennifer A. Chandler,4 Patricia Conrod,5 Yves De Koninck,6 Lesley K. Fellows,7 Deanna Groetzinger,8 Eric Racine,9 Julie M. Robillard,10 and Marla B. Sokolowski11 1Department of Medicine, Neuroethics Canada, University of British Columbia, Vancouver, BC, Canada 2Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, and CIHR Institute of , Mental Health and , Calgary, AB, Canada 3Department of Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada 4University of Ottawa, Centre for Health Law, Policy and Ethics, Ottawa, ON, Canada 5De´ p Psychiatrie, Universite´ de Montre´ al, Centre de Recherche, CHU Ste-Justine. Montreal, QC, Canada 6CERVO Brain Research Centre and Department of & , Universite´ Laval, Que´ bec, QC, Canada 7Department of & , McGill University, Montreal Neurological Institute, Montreal, QC, Canada 8Neurological Health Charities Canada, Toronto, ON, Canada 9Pragmatic Health Ethics Research Unit, Institut de recherches cliniques de Montre´ al (IRCM) and Department of Medicine, Universite´ de Montre´ al 10University of British Columbia, Scientist in Patient Experience, BC Children’s and Women’s Hospital Vancouver, BC, Canada 11Departments of Ecology and Evolutionary Biology & Cell and , University of Toronto, Toronto, ON, Canada *Correspondence: [email protected] (J.I.), [email protected] (S.W.) https://doi.org/10.1016/j.neuron.2018.12.021

Building on Canada’s strong traditions in neuroscience and ethics, neuroethics provides a backbone for the evolving Canadian Brain Research Strategy (CBRS) that, from the outset, incorporates ethically responsible discoveries in brain science into clinical, societal, educational, and commercial innovation.

A Grand Neuroethics Challenge carrying on today (Quirion, 2002). The standing the mechanisms underlying this One in three Canadians will be affected embedding of an already strong neuro- plasticity is at the root of any effort to treat by a brain or illness, dis- ethics platform into the new Canadian neurological and mental disorders. Neuro- order, or injury within their life. These con- Brain Research Strategy (CBRS; www. ethics is a necessary anchor into this ditions span the life cycle. Mental health canadianbrain.ca) is the latest and most question. It intersects with all pillars and conditions often affect young Canadians exciting step forward. The building of forms an explicit foundation for the Apply in the prime of life, with an estimated CBRS was initiated in 2015 and has pillar on which we focus in this paper. 75% of mental illnesses beginning before been nurtured under the leadership of The Apply pillar draws upon Canada’s the age of 24. Injuries to the nervous INMHA. Following a consensus meeting long tradition of pioneering work in neuro- system, such as concussion, occur of directors of neuroscience programs ethics, beginning with Canadian neuro- frequently in adult life and can lead to life- across Canada and other key stake- surgeon and Dr. Wilder long disability. Age-associated dementia holders in Halifax in September 2018, Penfield, who founded the Montreal Neuro- has surpassed other conditions as the the CBRS is moving forward as an orga- logical Institute. Penfield’s writings may be largest financial burden on the Canadian nizing entity independent of INMHA, with viewed as a precursor to neuroethical healthcare system today. A 2016 report an intersectoral steering committee that deliberation. Penfield was a student of Sir from the Evaluation Panel from the CIHR will work in continuous liaison with the William Osler, to whom Canada attributes Institute of Neurosciences, Mental Health conference leaders and participants and deep insights into science and the biomed- and Addiction (INMHA) placed the overall with a strategic eye on developing and ical sciences. Physician-bioethicist Joseph cost of neurological and mental health situating Canada as a neuroscience- J. Fins quotes a 1919 address by Osler, disorders to the Canadian economy at driven nation. ‘‘The Old Humanities and the New Sci- $61B CAD annually. In addition to a high Here we discuss the proposed key pil- ences,’’ to Oxford’s Classical Association, economic cost, brain disorders impose lars—Understand, Address, Apply, and in which he ‘‘admonished the divide be- staggering personal and societal tolls. Build—inspired by the distinguishing and tween the sciences and the humanities, Canadians firmly support the need for central question of the unfolding CBRS— observing that . the so-called Humanists ethical health research, innovation and how does the brain learn, remember, and have not enough Science, and Science economic advancement in neuroscience. adapt?—a question that seeks to under- sadly lacks the Humanities’’ (Fins, 2008). This commitment is underpinned by Can- stand the most fundamental aspects of We provide specific examples of neuro- ada’s multi-million-dollar investment in what defines the self (Figure 1). The ethics leadership in this country that bridge dedicated funding for neuroethics teams, powerful ability of the brain to change or the divide that Osler described, highlighting operating grants, and research chairs and rewire itself in response to experience is this country’s advances in neuroscience fellowships beginning in early 2000 and the foundation of human identity. Under- and law, mental health and addiction,

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Figure 1. Scientific Framework for the Proposed Canadian Brain Research Strategy (CBRS) as of September 2018 public outreach, and knowledge mobi- d Increase collaboration, data sharing, tively supported by six enabling principles: lization through patient engagement. We and technology development and collaboration, interdisciplinarity, open sci- conclude with a look to the future of inter- dissemination among Canadian re- ence, career development, education, and national collaboration with the International searchers and build on collective commercialization. These principles both Brain Initiative (IBI) and Neuroethics Global strengths. guide how research within the CBRS is Summit colleagues and partners. d Identify targets and milestones for conducted and set targets to advance a strategic and coordinated invest- sustainable mission and vision. The princi- ment in Canadian neuroscience and Co-creation of a CBRS ples are interwoven with five specifically mental health. The CBRS aims to be an integrated na- identified technology development areas d Train the next generation in interdis- tional research effort that builds on Cana- to probe, manipulate, decode how the ciplinary brain research, bridging da’s strengths and current investments in brain functions—imaging, stimulation, pho- diverse disciplines spanning the cutting-edge collaborative neuroscience tonics, genomics, and neuroinformatics— physical and computational sciences to drive transformative outcomes in neuro- that, together with embedded and rigorous to anthropology, sociology, and eco- logical and mental health for Canadians. experimental trial designs and outcome nomics. Its final design will enable Canada to: measurements, serve as platforms for d Develop meaningful collaborations a competitive Canadian neuroscience d Accelerate the understanding of with other Brain Initiatives on the research world today. the brain and translation to clinical international stage. The first pillar, Understand, focuses on treatments that address grand chal- normal braindevelopment and functioning, lenges in brain and mental health for To achieve these goals, the four pillars from synapses to circuits to behavior, Canadians. on which the CBRS is building are collec- and across the lifespan.

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Important insights by Canadian neurosci- that they are adapted to human capabil- novel neurodevelopmental and adult bio- entists have come from explorations of ities to support productive, socially cohe- markers for diseases for which diagnosis plasticity in a wide range of species, sive, and healthy lives on the one hand has historically relied largely on interview studies of human memory, discoveries and to mitigate triggers of distraction, data and patient reports. With this trans- in neural stem cells and regenerative alienation, and burnout on the other. formation comes the significant responsi- medicine, research, and inter- is possible because are bility both for deliberation and action, actions among genes and environments plastic and capable of change. Education, especially when applied to pediatric popu- during early childhood that guide human therefore, must be tailored to the mecha- lations, for which prediction is not 100% development. nisms that both enable and constrain accurate, and for cases where interven- From the outset, the Understand pillar underlying brain plasticity. Reciprocally, tions might modify outcomes. embraces the change in culture needed— techniques in The management of unexpected inter- from traditional siloed disciplines of ge- allow to study in ever ventional consequences or abnormal netics, , neurocomputing, greater depth how human factors, such findings in research and clinical medicine , ethics, and sociology to as education and culture, shape the struc- can pose unique human rights challenges cross-disciplinary collaboration—to reveal ture and function of the brain. As scien- for researchers, research participants, how the brain evolves over a lifetime. tists and scholars gain a more in-depth healthcare recipients, and third parties. This approach in turn allows funda- understanding of these mechanisms, Canadian neuroethicists and others have mental knowledge to be translated to targeted educational practice and pol- made pioneering contributions to this health challenges arising from dysfunction icies that optimize learning can be applied landscape (Illes et al., 2006) and continue of these basic brain processes (Address) in the classroom and other settings. For to review and refine related processes and informs technology development as example, one program has led para- through an open and democratic initiative well as methods such as artificial intelli- digm-shifting research in the areas of led by Canada’s Secretariat on Respon- gence and computational modeling that gene-environment interplay and critical sible Conduct of Research, of the Tri- may have transformative industrial appli- periods of brain development (Anreiter Agency (Canadian Institutes of Health cations and economic impact (Build). For et al., 2017). This effort is now focusing Research, the Natural Sciences and Engi- these three pillars, neuroethics is implicit, on the understanding of broad group dif- neering Research Council, and the Social encompassing both simple and complex ferences in outcomes toward a predictive Sciences and Humanities Research phenomena that include, for example, understanding of individual response to Council) Framework on Responsible the responsible conduct of research, experience. A number of large school- Conduct of Research. Systematic neuro- limiting the numbers and suffering of ani- based trials led by Canadian researchers ethical analyses have also yielded guid- mals in research, respecting persons and have shown that targeted neurodevelop- ance for disclosure of educational and protecting their autonomy and rights, mental interventions also promote mental health events that integrate practical and data and privacy protections, and antici- health and well-being, indirectly by pro- legal considerations with explicit appreci- pating both beneficial and consequential moting academic success and directly ation of human rights along the continuum outcomes. In Apply, the approach focuses by supporting important executive and of decisional capacity. Canadian neuro- on societal and cultural well-being, mak- other cognitive functions (e.g., Conrod ethics researchers have further created ing it the pillar for which neuroethics plays et al., 2013). innovative models for conveying critical the most explicit role. Canadian-led studies of brain plasticity brain health information that accounts have also revealed the interactive effects for age, individual values, cross-cultural At the Interface of Apply and of early experience, stress, nutrition, considerations, variation in ability, and Neuroethics , and exercise on learning outcomes, vulnerability. In an era of big data and The Apply pillar recognizes the impera- all of which have important implications for the growing implementation of open sci- tive of the CBRS to promote individual how educational environments are struc- ence approaches in Canadian neurosci- and societal well-being; evidence-based, tured. In adulthood, new doors are open ences (Canadian Open Neuroscience informed social and health policy; and ed- to optimizing education in the workplace Platform; www.conp.ca), new strategies ucation. The scope of the efforts supported and to ensuring an environment that sup- are continuously needed to ensure scien- by this pillar are broad: developing best ports peak human performance, whether tific standards and cultural sensitivity and practices in early childhood education, through social supports and technological to retain scientific, ethical, and legal rele- enabling the active participation of older innovations or general health measures vance and responsiveness. adults in society, helping teenagers make that promote resilience in the adult brain. To advance the goals of the CBRS, smart choices about drug and alcohol The transformation of the fields of psy- scholars and scientists working with the use, and supporting people as they navi- chiatry and neurology with the discovery Apply pillar have adopted a spiral model gate escalating demands in the workplace of biomarkers has led to opportunities for of translation to enable iterative, rapid, and at home. It includes consideration of detection and early intervention around and positive interactions between re- the critical role that new regulatory policies vulnerability before disease emerges, searchers and end-users: clinicians, pol- or technology play in how people interact, advanced diagnostics, and improved icy-makers, trainees, affected clinical learn, and contribute. It includes, as well, follow-up of response to treatment. Cana- populations and their advocacy, science the evolution of new tools and the way dians have been pioneers in developing writers, and news and social media. The

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spiral approach per se is novel for neuro- the landmark Harvard Committee report. dian studies on the representations of brain ethics, but it is well aligned with the prag- This concept is fundamental to high- health and in social matic orientation of Canadian neuroethics technology medicine that can now main- media (Robillard et al., 2015)havelaidthe that endeavors to: tain at least some physiological functions foundational work for opportunities in the artificially for long periods of time. Cana- CBRS to co-build resources with patient 1. Harness neuroscience insights to dian courts are presently wrestling with communities and apply them to ensure maximize the potential of every in- multiple challenges to brain death as a that the needs of end-users are met. dividual at every life stage. purely biomedical concept and in the 2. Identify and promote factors that ways that neuroscience and neurotech- Canada’s Next CBRS enhance individual and population nology may alter, but are unlikely to settle, Neuroethics Steps resilience, prevent brain insults and the social, cultural, philosophical, and reli- At the first meeting of the Global Neuro- health vulnerabilities, and promote gious questions at the heart of this issue. ethics Summit in Daegu, South Korea, recovery from brain disorders. Further providing deep roots for the the Working Group identified five ques- 3. Deliver innovative ethical and social CBRS Apply pillar, Canadian neuroethics tions for neuroethicists in the respective frameworks needed to catalyze scholarship has delved into the nature Brain Initiatives to take home, contem- and protect advances in all aspects and impact of public discourse about plate, and address (Global Neuroethics of neuroscience that pertain to neuroscience both in traditional and on- Summit Delegates et al., 2018). As we the CBRS. line media. This scholarship has applied have described in the framework for the 4. Encourage the sharing of data, new knowledge to a call for a cultural shift CBRS and through the three specific accelerated and systematized dis- in academic institutions to promote and themes of , public discourse, covery, and the implementation, reward public and policy engagement and patient engagement as examples, translation, and democratization of (Illes et al., 2010) and to pinpoint knowl- four questions are in direct sight of the technology within the nation and edge gaps and misunderstandings that CBRS and its focus on learning, remem- eventually outside. have the potential to thwart evidence- bering, and adapting: (1) What is the po- Overall, the model embraces an evi- informed ethics and rational debate. tential impact of a biological model or dence-informed approach to determine Research on the seductive allure of neu- neuroscientific account of disease on in- how research can be optimally synthe- roimages in the media, sometimes called dividuals, communities, and society? (2) sized and prioritized for the utmost ethical neuro-realism, has investigated the effect What are the ethical standards of data and social benefit of the citizens of our of visual information on people’s judg- collection, and how do local standards diverse country. ments, including in the context of addic- compare to those of global collaborators? tion (Racine et al., 2017). Much remains (3) How could brain interventions impact to be explored in this area, and it has spe- or reduce autonomy? (4) In which con- Applied Neurolaw, Public cial salience for the understanding and texts beyond the laboratory bench might Discourse, and Patient Engagement dissemination of knowledge about sub- an innovative technology be deployed? Since approximately 2010, Canadian neu- stance-use disorders, the far-reaching We emphasize the importance of cross- rolaw scholarship has taken a compre- impact of the opioid crisis across Canada, cultural considerations of privacy, con- hensive approach to issues related to and this country’s harm-reduction strate- sent, and responsibility as well as training the application of the law to neuroscience gies in the face of stigma, blame, and fluc- and outreach among many other princi- and to the incorporation of neurosci- tuating political views. ples and goals relevant to this neuroethics ence evidence in legal disputes. Key neu- Finally, a uniquely Canadian initiative, conversation. We defer the fifth question, rolaw questions relate, for example, to the Strategy for Patient-Oriented Research pertaining to capabilities that neural cells legal concepts of responsibility, privacy, (SPOR), emphasizes support, mutual in vitro might reflect or acquire, to later disability, mental health, human rights, in- respect, and a collaborative approach to phases of work and ongoing engagement tellectual property rights, and the regula- the generation of knowledge for health with the International Brain Initiative. tion of healthcare (Chandler et al., 2018). and illness. In developing social policy As the full implementation and gover- Evidence related to the brain is cited in that is responsive to recent advances in nance plan of the CBRS unfolds in 2019, the context of Canadian civil, criminal, sciences, SPOR fosters inclusiveness of it will align with the government of Cana- and human rights cases in support of legal patients and their families, caregivers, da’s priorities of knowledge mobilization arguments about a broad range of mat- and healthcare providers in research. and translation, innovation capacity build- ters. Neurolaw implications inform the Innovative research in ethics and the prac- ing, and a knowledge-based economy. It strategic trajectories of the CBRS Apply tice of brain science has harnessed novel will build on our existing and many planned pillar today as in, for example, a recent tools to support engagement, for example, global collaborations: for example, with medicolegal dispute over end-of-life deci- of participants with Alzheimer’s disease Australia for ; with the sion-making in a patient with a disorder of and uncovered critical tensions between U.S. for neurodegenerative diseases and . The intersection of law research ethics board requirements and disorders in neurodevelopment, including with neuroscience in Canada is also illus- the values and priorities of patient commu- pediatric epilepsy; and with the ERA-NET trated with the continued debate over the nities. Research on brain science and Neuron Consortium and concept of brain death, now 50 years after social discourse and, in particular, Cana- Project for psychiatric neurosurgery and

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, among others. Dynamic port from CIHR, NSERC, and McGill’s Healthy Global Neuroethics Summit Delegates, new initiatives such as the recent Tri- Brain for Healthy Lives Canada First Research Rommelfanger, K.S., Jeong, S.J., Ema, A., Excellence Fund. J.M.R. acknowledges support Fukushi, T., Kasai, K., Ramos, K.M., Salles, A., Agency initiative on artificial from the Canadian Consortium on Neurodegener- and Singh, I. (2018). Neuroethics questions to and society are on the horizon. The evolu- ation in Aging. J.A.C. is Bertram Loeb Research guide ethical research in the brain projects: A cross-cultural approach. Neuron 100, 19–36. tion and refinement of the CBRS will follow Chair and acknowledges support from CIHR, SSHRC, CBS, and the Bertram Loeb Institute. in the historical footsteps of Canadian Illes, J., Kirschen, M.P., Edwards, E., Stanford, neuroethics and be guided actively and L.R.,Bandettini,P.,Cho,M.K.,Ford,P.J., DECLARATION OF INTERESTS Glover, G.H., Kulynych, J., Macklin, R., et al.; collaboratively by the robust and dedi- Working Group on Incidental Findings in Brain cated efforts of contemporary Canadian The authors serve pro bono on many advisory Imaging Research (2006). Ethics. Incidental find- boards but declare no financial competing interests. ings in brain imaging research. Science 311, neuroethics leadership. 783–784. REFERENCES ACKNOWLEDGMENTS Illes,J.,Moser,M.A.,McCormick,J.B.,Racine, E., Blakeslee, S., Caplan, A., Hayden, E.C., Anreiter, I., Sokolowski, H.M., and Sokolowski, M.B. Ingram, J., Lohwater, T., McKnight, P., et al. The CBRS was initiated under the leadership of the (2017). Gene-environment interplay in behavior. (2010). Neurotalk: improving the Canadian Institutes of Health (CIHR), Institute for Brain Educ. Published online December 18, of neuroscience research. Nat. Rev. Neurosci. Neuroscience, Mental Health and Addiction 2017. https://doi.org/10.1111/mbe.12158. 11, 61–69. (INMHA; S.W., Scientific Director). Y.D.K. (Internal Advsory Board Chair), J.I. (Internal Advisory Board Chandler, J.A., Harrel, N., and Potkonjak, T. (2018). Quirion, R. (2002). A Canadian experiment: the Vice Chair), J.B., J.A.C., P.C., and D.G. are mem- Neurolaw today - A systematic review of the Institute of Neurosciences, Mental Health and bers of the Institute Advisory Board. J.I. is Canada recent law and neuroscience literature. Int. J. Law Addiction. How to link up the brain via a virtual insti- Research Chair in Neuroethics. Y.D.K. is sup- Psychiatry. . S0160-2527(18)30019-0. https://doi. tute. Trends Neurosci. 25, 268–270. ported by a Canada Research Chair in Chronic org/10.1016/j.ijlp.2018.04.00. Pain and Related Brain Disorders and a CIHR Racine, E., Sattler, S., and Escande, A. (2017). Free will and the brain disease model of addic- Foundation grant and is Scientific Director of Conrod, P.J., O’Leary-Barrett, M., Newton, N., Topper, L., Castellanos-Ryan, N., Mackie, C., and tion: The not so seductive allure of neuroscience Sentinel North (Canada First Research Excellence Girard, A. (2013). Effectiveness of a selective, per- and its modest impact on the attribution of free Fund). P.C. is Chercheur Boursier Senior, FRQ-S, sonality-targeted prevention program for adoles- will to people with an addiction. Front. Psychol. and the Fondation Julien/Marcelle et Jean Coutu cent alcohol use and misuse: a cluster randomized 8, 1850. Chair in Social and Community Pediatrics. E.R. is controlled trial. JAMA Psychiatry 70, 334–342. Chercheur Boursier Senior, FRQ-S. Weston Fellow Robillard, J.M., Cabral, E., Hennessey, C., M.B.S. acknowledges the Child and Brain Devel- Fins, J.J. (2008). A leg to stand on: Sir William Osler Kwon,B.K.,andIlles,J.(2015).Fuelinghope: opment Program at the Canadian Institute for and Wilder Penfield’s ‘‘neuroethics’’. Am. J. Bioeth. Stem cells in social media. Stem Cell Rev. 11, Advanced Research. L.K.F. acknowledges sup- 8, 37–46. 540–546.

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